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Adopted guidelines reflect a harmonised European approach to a specific scientific issue and should reflect the most recent scientific knowledge. However, whilst EU regulations are mandatory for all member states and EU directives must be followed by national laws in line with the directive, EMA guidelines do not have legal force and alternative approaches may be taken, but these obviously require more justification. This new series of the BJCP, developed in collaboration with the EMA, aims to address this issue by providing an annotated version of some relevant EMA guidelines and regulatory documents by experts. Hopefully, this will help in promoting their diffusion and in opening a forum for discussion with our readers. [ABSTRACT FROM AUTHOR]

Measurement of pre‐dose tacrolimus concentrations, also referred to as trough concentrations or C0 (in this paper the term C0 will be used), is the most frequently used parameter for therapeutic drug monitoring in patients after solid organ transplantation. C0 is relatively easy to obtain, and can be combined with other lab tests. C0 monitoring is convenient for patient and hospital staff. Adjusting the dose based on C0 assumes that the C0 has a good correlation with the overall exposure to the drug, as reflected in the area under concentration—time curve (AUC).However, C0 may not be the panacea it is suggested to be, and there are patients who may benefit from additional measurements to more precisely assess drug exposure. Especially in patients with a low C0/dose ratio, the peak tacrolimus concentrations after oral administration may be unexpectedly high, resulting in toxicity and (as has been shown already) in poor long‐term graft survival. At the other extreme, patients who only need a very low dose to reach target C0 may have a low peak and also a low AUC and may be underexposed.In this paper, the limitations of C0 will be discussed, and the type of studies needed to provide the evidence for implementation of more sophisticated therapeutic drug monitoring. The paper focuses on treatment of adult kidney transplant recipients. [ABSTRACT FROM AUTHOR]

Pharmacometric modelling plays a key role in both the design and analysis of regulatory trials in paediatric drug development. Studies in adults provide a rich source of data to inform the paediatric investigation plans, including knowledge on drug pharmacokinetics (PK), safety and efficacy. In children, drug disposition differs widely from birth to adolescence but extrapolating adult to paediatric PK, safety and efficacy either with pharmacometric or physiologically based approaches can help design or in some cases reduce the need for clinical studies. Aspects to consider when extrapolating PK include the maturation of drug metabolizing enzyme expression, glomerular filtration, drug excretory systems, and the expression and activity of specific transporters in conjunction with other drug properties such as fraction unbound. Knowledge of these can be used to develop extrapolation tools such as allometric scaling plus maturation functions or physiologically based PK. PK/pharmacodynamic approaches and well‐designed clinical trials in children are of key importance in paediatric drug development. In this white paper, state‐of‐the‐art of current methods used for paediatric extrapolation will be discussed. This paper is part of a conect4children implementation of innovative methodologies including pharmacometric and physiologically based PK modelling in clinical trial design/paediatric drug development through dissemination of expertise and expert advice. The suggestions arising from this white paper should define a minimum set of standards in paediatric modelling and contribute to the regulatory science. [ABSTRACT FROM AUTHOR]

Figures from the Editor's selected issue highlights will be displayed each month in the journal image carousel on the BJCP homepage http://bpspubs.onlinelibrary.wiley.com/hub/journal/10.1111/(ISSN)1365-2125/ You will really like this issue of the Br J Clin Pharmacology! In the third paper Gerd Mikus, from Heidelberg, Germany, describes a micro-dosed cocktail of three DOACs that can be used to identify drug-drug interactions. Stefan Weisshaar I et al i . from Vienna, Austria, are actively fighting this other epidemic and investigated the clinical effects of various dose ratios of morphine and naloxone in OUD patients. [Extracted from the article]

Aim: Pharmacokinetics have historically been assessed using drug concentration data obtained via blood draws and bench‐top analysis. The cumbersome nature of these typically constrains studies to at most a dozen concentration measurements per dosing event. This, in turn, limits our statistical power in the detection of hours‐scale, time‐varying physiological processes. Given the recent advent of in vivo electrochemical aptamer‐based (EAB) sensors, however, we can now obtain hundreds of concentration measurements per administration. Our aim in this paper was to assess the ability of these time‐dense datasets to describe time‐varying pharmacokinetic models with good statistical significance. Methods: We used seconds‐resolved measurements of plasma tobramycin concentrations in rats to statistically compare traditional one‐ and two‐compartmental pharmacokinetic models to new models in which the proportional relationship between a drug's plasma concentration and its elimination rate varies in response to changing kidney function. Results: We found that a modified one‐compartment model in which the proportionality between the plasma concentration of tobramycin and its elimination rate falls reciprocally with time either meets or is preferred over the standard two‐compartment pharmacokinetic model for half of the datasets characterized. When we reduced the impact of the drug's rapid distribution phase on the model, this one‐compartment, time‐varying model was statistically preferred over the standard one‐compartment model for 80% of our datasets. Conclusions: Our results highlight both the impact that simple physiological changes (such as varying kidney function) can have on drug pharmacokinetics and the ability of high‐time resolution EAB sensor measurements to identify such impacts. [ABSTRACT FROM AUTHOR]

Dihydroorotate dehydrogenase (DHODH) is a mitochondrial enzyme that is essential for pyrimidine de novo synthesis. Rapidly growing cancer cells and replicating viruses are dependent on host cell nucleotides, the precursors of which are provided by DHODH. Hence, DHODH becomes an ideal target for pharmacological intervention. RP7214 is a potent and selective inhibitor of human DHODH and has shown antiviral and antileukaemic activity in preclinical studies. This paper describes the phase I study that evaluated the safety and pharmacokinetics of single and multiple ascending doses (SAD and MAD) and the food effect of RP7214 in healthy volunteers (HVs). The study was a randomized, double‐blind, placebo‐controlled trial of single dose (100, 200 and 400 mg QD), multiple doses (200 and 400 mg BID for 7 days) and a food effect study at a single dose of 200 mg. A total of 18, 12 and 12 HVs were enrolled in the SAD, MAD and food effect parts of the study, respectively. RP7214 was well tolerated at all dose levels. There were 20 treatment‐emergent adverse events (TEAEs) reported, out of which most were mild to moderate in severity while three TEAEs were grade ≥3. RP7214 showed accumulation on multiple dosing. Steady‐state concentrations were reached within about 3‐6 days. The mean plasma half‐life at steady‐state was 12.8 hours (9.9‐15.3). Food did not impact the absorption of RP7214. Inhibition of DHODH, as evidenced by increased dihydroorotate levels, was observed, confirming target engagement. The high systemic exposure with a favourable safety profile shows potential for the development of RP7214 in SARS‐CoV‐2 and acute myeloid leukaemia (NCT04680429). [ABSTRACT FROM AUTHOR]

Drug transporters such as P-glycoprotein (P-gp) modulate intestinal drug absorption.[2] If P-gp expression is enhanced (e.g. after repetitive intake of rifampicin or rifabutin), absorption is lowered. Dolutegravir, drug-drug interactions, P-glycoprotein (P-gp), population pharmacokinetics, physiology-based pharmacokinetics, rifabutin Keywords: dolutegravir; drug-drug interactions; P-glycoprotein (P-gp); physiology-based pharmacokinetics; population pharmacokinetics; rifabutin EN dolutegravir drug-drug interactions P-glycoprotein (P-gp) physiology-based pharmacokinetics population pharmacokinetics rifabutin 2329 2331 3 06/20/23 20230701 NES 230701 We read with great interest the recent paper by Kawuma and co-workers[1] which we consider an excellent contribution to a topic of high clinical relevance. [Extracted from the article]

What is already known about this subject • The reviews already published on population pharmacokinetic/pharmacodynamic (PK/PD) analyses have focused on theory and have presented some clinical applications, evaluated validation practices in limited circumstances, defined the interest and sometimes the complexity of this approach in drug development or proposed a list of relevant articles. • None of them has exhaustively evaluated published analyses and more precisely the model-building steps. • In view of the statistical complexity of population PK/PD methodology, more attention is required to how models are built and how they are reported in the literature. What this study adds • With a strict methodology and by establishing a standardized tool, this survey provides an exhaustive, objective and up-to-date review of model-building practices. • It reveals deficiencies in information reporting in most articles and the genuine need for guidance in publishing. • An initial, minimal list of items is suggested, which can be used by authors and reviewers in pharmacology journals. • The value of published peer-reviewed papers could be greatly improved if authors were to address the suggested list of items systematically. Aims A descriptive survey of published population pharmacokinetic and/or pharmacodynamic (PK/PD) analyses from 2002 to 2004 was conducted and an evaluation made of how model building was performed and reported. Methods We selected 324 articles in Pubmed using defined keywords. A data abstraction form (DAF) was then built comprising two parts: general characteristics including article identification, context of the analysis, description of clinical studies from which the data arose, and model building, including description of the processes of modelling. The papers were examined by two readers, who extracted the relevant information and transmitted it directly to a MySQL database, from which descriptive statistical analysis was performed. Results Most published papers concerned patients with severe pathology and therapeutic classes suffering from narrow therapeutic index and/or high PK/PD variability. Most of the time, modelling was performed for descriptive purposes, with rich rather than sparse data and using NONMEM software. PK and PD models were rarely complex (one or two compartments for PK; Emax for PD models). Covariate testing was frequently performed and essentially based on the likelihood ratio test. Based on a minimal list of items that should systematically be found in a population PK–PD analysis, it was found that only 39% and 8.5% of the PK and PD analyses, respectively, published from 2002 to 2004 provided sufficient detail to support the model-building methodology. Conclusions This survey allowed an efficient description of recent published population analyses, but also revealed deficiencies in reporting information on model building. [ABSTRACT FROM AUTHOR]

Comments on several papers about developments in pediatrics, published in the June 2005 issue of "British Journal of Clinical Pharmacology." Administration of inaccurately measured doses to children of different ages; Monitoring of adverse drug reactions from pharmacies and primary care; Guidelines on pharmacodynamic and pharmacokinetic studies in children.

Aims: This paper describes the pharmacological findings from a study where otelixizumab, an anti‐CD3ɛ mAb, was dosed in new onset Type 1 diabetes mellitus (NOT1DM) patients. This is the first time that the full dose–response of an anti‐CD3ɛ mAb has been investigated in the clinic. The data have been validated using a previously developed pharmacokinetic/pharmacodynamic (PK/PD) model of otelixizumab to simulate the interplay between drug administration, CD3ɛ target engagement and downmodulation. Methods: Patients were randomized to control or active treatment with otelixizumab (1:4), administered via infusion over 6 days, in a dose‐ascending study consisted of three cohorts (n = 10 per cohort) at doses of 9, 18 or 27 mg respectively. The study allowed quantification of otelixizumab PK, CD3ɛ target engagement and its pharmacodynamic effect (CD3ε/TCR modulation on circulating T lymphocytes). Results: Otelixizumab concentrations increased and averaged to 364.09 (54.3), 1625.55 (72.5) and 2781.35 (28.0) ng ml−1 (Geom.mean, %CV) at the 9, 18 and 27 mg dose respectively. CD3ɛ target engagement was found to be rapid (within the first 30 min), leading to a receptor occupancy of ~60% within 6 h of dosing in all three doses. A dose–response relationship was observed with the two highest doses achieving a ~90% target engagement and consequential CD3ɛ/TCR downmodulation by Day 6. Conclusions: Data from this study revealed maximum target engagement and CD3ɛ/TCR modulation is achieved at doses of 18, 27 mg of otelixizumab. These findings can be useful in guiding dose selection in clinical trials with anti‐CD3ɛ mAbs. [ABSTRACT FROM AUTHOR]

Aims: Beta‐lactam dose optimization in critical care is a current priority. We aimed to review the pharmacokinetics (PK) of three commonly used beta‐lactams (amoxicillin ± clavulanate, piperacillin–tazobactam and meropenem) to compare PK parameters reported in critically and noncritically ill neonates, children and adults, and to investigate whether allometric and maturation scaling principles could be applied to describe changes in PK parameters through life. Methods: A systematic review of PK studies of the three drugs was undertaken using MEDLINE and EMBASE. PK parameters and summary statistics were extracted and scaled using allometric principles to 70 kg individual for comparison. Pooled data were used to model clearance maturation and decline using a sigmoidal (Hill) function. Results: A total of 130 papers were identified. Age ranged from 29 weeks to 82 years and weight from 0.9–200 kg. PK parameters from critically ill populations were reported with wider confidence intervals than those in healthy volunteers, indicating greater PK variability in critical illness. The standard allometric size and sigmoidal maturation model adequately described increasing clearance in neonates, and a sigmoidal model was also used to describe decline in older age. Adult weight‐adjusted clearance was achieved at approximately 2 years postmenstrual age. Changes in volume of distribution were well described by the standard allometric model, although amoxicillin data suggested a relatively higher volume of distribution in neonates. Conclusions: Critical illness is associated with greater PK variability than in healthy volunteers. The maturation models presented will be useful for optimizing beta‐lactam dosing, although a prospective, age‐inclusive study is warranted for external validation. [ABSTRACT FROM AUTHOR]

A biosimilar is a high quality biological medicine shown to be in essence the same as an original product. The European Medicines Agency (EMA) paved the way in the regulatory arena by creating a safeguarding framework for the development of biosimilars. Biosimilar is thus a regulatory term that alludes to the evidence-based studies required to demonstrate such very high similarity. They are therefore not innovative products but the pathway laid down by the EMA for their approval represented a new paradigm. This has brought some confusion and has cast doubts among healthcare professionals about the scientific evidence behind their authorization. Many papers have been published to clarify the concept, and to reassure those professionals, but misconceptions frequently still arise. Unfortunately, this prevents biosimilars from deploying their full therapeutic added value. This paper is intended to approach those misconceptions from a new angle, by explaining what a biosimilar is not...and why. A biosimilar is neither a generic, nor an original product. It is not a biobetter or a 'stand-alone'. Therefore, it should not be managed as such therapeutically, commercially or from a healthcare policy viewpoint. The EMA's criteria were acknowledged by other agencies, but a significant regulatory gap with a vast majority of regulatory bodies still remains. This leaves room for the so-called non-original biologics (NOB), i.e. non-biosimilar biologics, to be launched in many regions. Raising awareness of what a biosimilar is and what it is not, will generate trust in biosimilars among healthcare professionals and will ultimately benefit patients [ABSTRACT FROM AUTHOR]

In order to reduce the numbers of medication errors (MEs) that cause adverse reactions (ARs) many authors have tried to identify patient-related risk factors. However, the evidence remains controversial. The aim was to review systematically the evidence on the relationship between patient-related risk factors and the risk of serious ARs. A systematic search in Pubmed, Embase, Cochrane Systematic Reviews, Psychinfo and SweMed+ was performed. Included full text articles were hand searched for further references. Peer reviewed papers including adults from primary and secondary healthcare were included if they clearly defined seriousness of the ARs and described correlations to risk factors by statistical analysis. A total of 28 studies were identified including 85 212 patients with 3385 serious ARs, resulting in an overall frequency of serious ARs in 4% of patients. Age, gender and number of drugs were by far the most frequently investigated risk factors. The total number of drugs was the most consistent correlated risk factor found in both univariate and multivariate analyses. The number of drugs is the most frequently documented independent patient-related risk factor for serious ARs in both the general adult population as well as in the elderly. The existing evidence is however conflicting due to heterogeneity of populations and study methods. The knowledge of patient-related risk factors for experiencing ARs could be used for electronic risk stratification of patients and thereby allocation of healthcare resources to high risk patients. [ABSTRACT FROM AUTHOR]

Aims: The aim of this paper is to investigate the role of drug concentration samplings in the modelling of the dose-response relationship., Methods: Using an initial PK/PD model, a reference dataset was simulated. PK and PD samples were extracted to create reduced datasets. PK/PD and K-PD models were fitted to theses reduced datasets. Post hoc estimates from both types of models were compared to the initial PK/PD model and performance was assessed., Results: K-PD models were largely biased when the drug has a nonlinear elimination. PK/PD models with 1 PK and 2 PD samples were superior to K-PD models with 3 PD samples. PK/PD models with 1 or 2 PK samples and 3 PD samples proved to be superior to K-PD models with 4 PD samples., Conclusions: K-PD models should not be used when the drug has nonlinear elimination. K-PD models should not replace PK/PD modelling but are an alternative approach if the PD information is large enough., (© 2016 The British Pharmacological Society.)

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Seretide (GlaxoSmithKline, UK) is a combination inhaler which contains both fluticasone (FP) and salmeterol (SM). • A generic fluticasone/salmeterol (FP/SM) combination inhaler (Neolab, UK) has recently been developed. • Determination of therapeutic equivalence is essential in the development of generic products. WHAT THIS STUDY ADDS • This paper determines that in vitro fine particle dose may not predict pharmacokinetic and systemic pharmacodynamic outcomes. • This paper shows that the generic and reference products were equivalent in terms of FP, but not SM pharmacokinetics. • No significant differences were found between generic and reference products in terms of either adrenal suppression or hypokalaemia. AIM To compare a test version of HFA fluticasone/salmeterol (FP/SM) combination inhaler (Neolab, UK) with the reference product Seretide (GlaxoSmithKline, UK). METHODS An in vitro Anderson cascade impactor was used to compare the fine particle dose (<4.7 µm). Two separate randomized cross-over studies were performed to compare the systemic bioavailability of test vs. reference (T vs. R) formulations of FP/SM 250/25 µg pMDI in healthy volunteers. In study 1 blood pharmacokinetic analysis using oral charcoal block was performed over 24 h following a single dose of four puffs via pMDI alone. In study 2 systemic bioactivity was measured following single doses of four and eight puffs via a spacer device: serum potassium (K+) to reflect SM, and overnight urinary cortisol : creatinine (OUCC) for FP. An early pharmacokinetic profile was also assessed over 120 min. RESULTS The in vitro fine particle dose was similar for test vs. reference pMDI alone and via spacer. The results of both studies were consistent: No significant differences between formulations were seen in terms of FP kinetics. Analysis of SM kinetics revealed superiority of the test product. No significant dose–response or difference in T : R ratio was noted for OUCC. Fall in K+ revealed a significant dose–response with a non-significant T : R ratio. CONCLUSIONS The in vitro fine particle dose may not predict pharmacokinetic and systemic pharmacodynamic outcomes. Single dosing studies with fluticasone/salmeterol 250/25 µg via pMDI or with spacer showed pharmacokinetic equivalence with FP, but not SM. No significant difference between formulations was seen with either adrenal suppression or hypokalaemia. [ABSTRACT FROM AUTHOR]

What is already known about this subject • The pharmacokinetics of alemtuzumab have been incompletely described to date. • At most, presentations of half-life have been reported in clinical articles using data at the individual level. What this paper adds • This paper presents a comprehensive population pharmacokinetic–pharmacodynamic model for alemtuzumab in B-CLL patients using lymphocyte counts as the biomarker and links the model to clinical outcomes. Aims To characterize alemtuzumab pharmacokinetics and its exposure–response relationship with white blood cell (WBC) count in patients with B-cell chronic lymphocytic leukaemia (CLL). Methods Nonlinear mixed effects models were used to characterize plasma concentration–time data and WBC count-time data from 67 patients. Logistic regression was used to relate summary measures of drug exposure to tumour response. Results Alemtuzumab pharmacokinetics were best characterized by a two-compartment model with nonlinear elimination where Vmax (µg h−1) was [1020 × (WBC count/10 × 109 l−1)0.194], K m was 338 µg l−1, V1 was 11.3 l, Q was 1.05 l h−1 and V2 was 41.5 l. Intersubject variability (ISV) in Vmax, K m, V1 and V2 was 32%, 145%, 84% and 179%, respectively. The reduction in WBC over time was modelled by a stimulatory loss indirect response model with values of 18.2 for Emax, 306 µg l−1 for EC50, 1.56 × 109 cells l−1 h−1 for Kin and 0.029 per h for Kout. The probability of achieving a complete or partial response was ≥50% when the maximal trough concentration exceeded 13.2 µg ml−1 or when AUC0–τ exceeded 484 µg h−1 ml−1. Conclusions Alemtuzumab displayed time- and concentration-dependent pharmacokinetics with large interpatient variability, both in pharmacokinetics and pharmacodynamics, which was probably reflective of differences in tumour burden among patients. A direct relationship between maximal trough concentrations and clinical outcomes was observed, with increasing alemtuzumab exposure resulting in a greater probability of positive tumour response. [ABSTRACT FROM AUTHOR]

What is already known about this subject • In one of the largest studies in children to date, we have already published a paper that has described the pharmacokinetics of melphalan using a two-stage approach. What this study adds • The current paper is a follow-up study in which a population pharmacokinetic model for melphalan is developed and validated in children. • There have been no other population pharmacokinetic analyses published on melphalan given as a short infusion. • Additionally, a nomogram is produced to guide melphalan dosing. Aim To develop a population pharmacokinetic model for melphalan in children with malignant diseases and to evaluate limited sampling strategies for melphalan. Methods Melphalan concentration data following a single intravenous dose were collected from 59 children with malignant diseases aged between 0.3 and 18 years. The data were split into two sets: the model development dataset (39 children, 571 concentration observations) and the model validation dataset (20 children, 277 concentration observations). Population pharmacokinetic modelling was performed with the NONMEM software. Stepwise multiple linear regression was used to develop a limited sampling model for melphalan. Results A two-compartment model was fitted to the concentration- vs.-time data. The following covariate population pharmacokinetic models were obtained: (i) Clearance (l h−1) = 0.34.WT − 3.17.CPT + 0.0377.GFR, where WT = weight (kg), CPT = prior carboplatin therapy (0 = no, 1 = yes), and GFR = glomerular filtration rate (ml min−1 1.73 m−2); (ii) Volume of distribution (l) = 1.12 + 0.178.WT. Interpatient variability (coefficient of variation) was 27.3% for clearance and 33.8% for volume of distribution. There was insignificant bias and imprecision between observed and model-predicted melphalan concentrations in the validation dataset. A three-sample limited sampling model was developed which adequately predicted the area under the concentration–time curve (AUC) in the development and validation datasets. Conclusions A population pharmacokinetic model for melphalan has been developed and validated and may now be used in conjunction with pharmacodynamic data to develop safe and effective dosing guidelines in children with malignant diseases. [ABSTRACT FROM AUTHOR]

Understanding the dose-concentration-effect relationship is a fundamental component of clinical pharmacology. Interpreting data arising from observations of this relationship requires the use of mathematical models; i.e. pharmacokinetic (PK) models to describe the relationship between dose and concentration and pharmacodynamic (PD) models describing the relationship between concentration and effect. Drug development requires several iterations of pharmacometric model-informed learning and confirming. This includes modelling to understand the dose-response in preclinical studies, deriving a safe dose for first-in-man, and the overall analysis of Phase I/II data to optimise the dose for safety and efficacy in Phase III pivotal trials. However, drug development is not the boundary at which PKPD understanding and application stops. PKPD concepts will be useful to anyone involved in the prescribing and administration of medicines for purposes such as determining off-label dosing in special populations, individualising dosing based on a measured biomarker (personalised medicine) and in determining whether lack of efficacy or unexpected toxicity maybe solved by adjusting the dose rather than the drug. In clinical investigator-led study design, PKPD can be used to ensure the optimal dose is used, and crucially to define the expected effect size, thereby ensuring power calculations are based on sound prior information. In the clinical setting the most likely people to hold sufficient expertise to advise on PKPD matters will be the pharmacists and clinical pharmacologists. This paper reviews fundamental PKPD principles and provides some real-world examples of PKPD use in clinical practice and applied clinical research. [ABSTRACT FROM AUTHOR]

Fentanyl is a strong opioid that is available for various administration routes, and which is widely used to treat cancer-related pain. Many factors influence the fentanyl pharmacokinetics leading to a wide inter- and intrapatient variability. This systematic review summarizes multiple studied factors that potentially influence fentanyl pharmacokinetics with a focus on implications for cancer patients. The use of CYP3A4 inhibitors and inducers, impaired liver function, and heating of the patch potentially influence fentanyl pharmacokinetics in a clinically relevant way. In elderly patients, current data suggest that we should carefully dose fentanyl due to alterations in absorption and metabolism. The influence of BMI and gender on fentanyl pharmacokinetics is questionable, most probably due to a large heterogeneity in the published studies. Pharmacogenetics, e.g. the CYP3A5*3 gene polymorphism, may influence fentanyl pharmacokinetics as well, although further study is warranted. Several other factors have been studied but did not show significant and clinically relevant effects on fentanyl pharmacokinetics. Unfortunately, most of the published papers that studied factors influencing fentanyl pharmacokinetics describe healthy volunteers instead of cancer patients. Results from the studies in volunteers may not be simply extrapolated to cancer patients because of multiple confounding factors. To handle fentanyl treatment in a population of cancer patients, it is essential that physicians recognize factors that influence fentanyl pharmacokinetics, thereby preventing potential side-effects and increasing its efficacy. [ABSTRACT FROM AUTHOR]

Aim: Several studies have reported population pharmacokinetic models for phenobarbital (PB), but the predictive performance of these models has not been well documented. This study aims to do external evaluation of the predictive performance in published pharmacokinetic models. Methods: Therapeutic drug monitoring data collected in neonates and young infants treated with PB for seizure control was used for external evaluation. A literature review was conducted through PubMed to identify population pharmacokinetic models. Prediction‐ and simulation‐based diagnostics, and Bayesian forecasting were performed for external evaluation. The incorporation of allometric scaling for body size and maturation factors into the published models was also tested for prediction improvement. Results: A total of 79 serum concentrations from 28 subjects were included in the external dataset. Seven population pharmacokinetic studies of PB were identified as relevant in the literature search and included for our evaluation. The model by Voller et al showed the best performance concerning prediction‐based evaluation. In simulation‐based analyses, the normalized prediction distribution error of two models (those of Shellhaas et al and Marsot et al) obeyed a normal distribution. Bayesian forecasting with more than one observation improved predictive capability. Incorporation of both allometric size scaling and maturation function generally enhanced the predictive performance, with improvement as observed in the model of Vucicevic et al. Conclusions: The predictive performance of published pharmacokinetic models of PB was diverse. Bayesian forecasting and incorporation of both size and maturation factors could improve the predictability of the models for neonates. [ABSTRACT FROM AUTHOR]

The article introduces the papers in the present issue which focuses on drug therapy in kidney diseases. One paper deals with the palatability of the angiotensin receptor antagonists in children with kidney diseases. Another paper examines the effects of gastric emptying on the pharmacokinetics of oral mycophenolic acid in kidney transplant recipients.

Physiological changes during pregnancy may alter drug pharmacokinetics. Therefore, mechanistic understanding of these changes and, ultimately, clinical studies in pregnant women are necessary to determine if and how dosing regimens should be adjusted. Because of the typically limited number of patients who can be recruited in this patient group, efficient design and analysis of these studies is of special relevance. This paper is a summary of a conference session organized at the American Conference of Pharmacometrics in April 2011, around the topic of applying pharmacometric methodology to this important problem. The discussion included both design and analysis of clinical studies during pregnancy and in silico predictions. An overview of different pharmacometric methods relevant to this subject was given. The impact of pharmacometrics was illustrated using a range of case examples of studies around pregnancy., (© 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.)

The article presents the author's insights concerning the developments in clinical pharmacology from 1974-2014. It highlights the research articles published in the journal which focused on pharmacodynamics, pharmacokinetics, drug metabolism, therapeutics, and analytical methodology. It cites the changes which include changes in intellectual approach and theory and advances that have occurred in some areas of therapeutics.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • P2X7 receptors are involved in the production of pro-inflammatory cytokines, such as Il-1β, by central and peripheral immune cells. Il-1β has been implicated as an important mediator of inflammation. Therefore, the P2X7 receptor is an attractive therapeutic target for inflammatory diseases. WHAT THIS STUDY ADDS • Findings in pharmacokinetics, pharmacodynamics, safety and tolerability of a P2X7 receptor modulator, GSK1482160, from the first human study for the molecule are described. A pharmacokinetic/pharmacodynamic model for LPS-stimulated ATP-induced Il-1β production in blood allowed the integration of all relevant data and provided in vivo evidence of the nature of the drug-receptor interaction. The model has the potential to be used to simulate future trials. AIMS This paper describes findings from the first-in-human study for GSK1482160, an orally available allosteric P2X7 receptor modulator. The study aimed to assess the pharmacokinetics (PK), pharmacodynamics (PD), safety and tolerability of the compound in healthy subjects. METHODS Escalating single doses of up to 1 g were administered to healthy subjects in a single-blind and placebo-controlled fashion. Safety, tolerability, blood drug concentrations and ex vivo Il-1β production in blood were evaluated. RESULTS Drug concentration peaked within 3.5 h of dosing under fasting conditions and declined thereafter with a relatively short half-life of less than 4.5 h. Exposure was proportional to dose with between subject variability of less than 60%. A PK/PD model quantified Il-1β as a function of drug exposure. The model allowed simulation of in vivo pharmacology for various untested dose levels and regimens. Furthermore, the mechanistic model supported the hypothesis that the compound reduces the efficacy of ATP at the P2X7 receptor without affecting its affinity. No major safety or tolerability concerns were identified in this small study ( n= 29), except for one case of asymptomatic accelerated idioventricular rhythm at the top dose. CONCLUSION The model-based approach maximized analysis power by integrating all biomarker data and revealed mechanistic insight into the pharmacology of P2X7 modulation by GSK1482160. Simulations by this model ultimately led to the discontinuation of the development of this compound. The therapeutic relevance of the P2X7 receptor remains to be tested in patients. The mechanistic-model-based approach can be applied widely to drug development. [ABSTRACT FROM AUTHOR]

Physiological changes during pregnancy may alter drug pharmacokinetics. Therefore, mechanistic understanding of these changes and, ultimately, clinical studies in pregnant women are necessary to determine if and how dosing regimens should be adjusted. Because of the typically limited number of patients who can be recruited in this patient group, efficient design and analysis of these studies is of special relevance. This paper is a summary of a conference session organized at the American Conference of Pharmacometrics in April 2011, around the topic of applying pharmacometric methodology to this important problem. The discussion included both design and analysis of clinical studies during pregnancy and in silico predictions. An overview of different pharmacometric methods relevant to this subject was given. The impact of pharmacometrics was illustrated using a range of case examples of studies around pregnancy. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Before these trials were done, the effects of CYP3A4 inhibition and induction on the pharmacokinetics (PK) and pharmacodynamics (PD) of tolvaptan in healthy subjects were unknown. As tolvaptan is a CYP3A4 substrate, knowing the effects of inhibition and induction on CYP3A4-mediated metabolism was important for dosing recommendations. WHAT THIS STUDY ADDS • This paper describes the changes in tolvaptan PK and PD following inhibition or induction of CYP3A4 and explores the mechanisms behind the disparity seen between tolvaptan PK and effects on urine output. It also discusses the concentrations at which tolvaptan produces its maximal response on urine output and the timing of the onset and offset of this response. AIMS In vitro studies indicated CYP3A4 alone was responsible for tolvaptan metabolism. To determine the effect of a CYP3A4 inhibitor (ketoconazole) and a CYP3A4 inducer (rifampicin) on tolvaptan pharmacokinetics (PK) and pharmacodynamics (PD), two clinical trials were performed. METHODS For CYP3A4 inhibition, a double-blind, randomized (5:1), placebo-controlled trial was conducted in 24 healthy subjects given either a single 30 mg dose of tolvaptan ( n= 19) or matching placebo ( n= 5) on day 1 with a 72 h washout followed by a 3 day regimen of 200 mg ketoconazole, once daily with 30 mg tolvaptan or placebo also given on day 5. For CYP3A4 induction, 14 healthy subjects were given a single dose of 240 mg tolvaptan with 48 h washout followed by a 7 day regimen of 600 mg rifampicin, once daily, with 240 mg tolvaptan also given on the seventh day. RESULTS When co-administered with ketoconazole, mean Cmax and AUC(0,∞) of tolvaptan were increased 3.48- and 5.40-fold, respectively. Twenty-four hour urine volume increased from 5.9 to 7.7 l. Erythromycin breath testing showed no difference following a single dose of tolvaptan. With rifampicin, tolvaptan mean Cmax and AUC were reduced to 0.13- and 0.17-fold of tolvaptan administered alone. Twenty-four hour urine volume decreased from 12.3 to 8.8 l. CONCLUSIONS Tolvaptan is a sensitive CYP3A4 substrate with no inhibitory activity. Due to the saturable nature of tolvaptan's effect on urine excretion rate, changes in the pharmacokinetic profile of tolvaptan do not produce proportional changes in urine output. [ABSTRACT FROM AUTHOR]

• Chlorofluorocarbons (CFCs) have been implicated in damage to the ozone layer, and are due to be phased out in accordance with the Montreal Protocol. • Hydrofluoroalkane-134a (HFA) has been found to act as an adequate propellant for pressurized metered-dose inhaler delivery systems without the same deleterious environmental effects. • This paper presents data from both steady-state pharmacokinetic and pharmacodynamic assessments of HFA vs. CFC pressurized metered-dose inhaler formulations of budesonide. It demonstrates that they are therapeutically equivalent in terms of relative lung bioavailability, airway efficacy and systemic effects. A hydrofluoroalkane formulation of budesonide pressurized metered-dose inhaler has been developed to replace the existing chlorofluorocarbon one. The aim of this study was to evaluate the pharmacokinetic and pharmacodynamic characteristics of both formulations. Systemic bioavailability and bioactivity of both hydrofluoroalkane and chlorofluorocarbon pressurized metered-dose inhaler formulations at 800 µg twice daily was determined during a randomized crossover systemic pharmacokinetic/pharmacodynamic study at steady state in healthy volunteers. Measurements included the following: plasma cortisol AUC[area under the concentration-time curve (0-24 h)], budesonide AUC and C. Clinical efficacy was determined during a randomized crossover pharmacodynamic study in asthmatic patients receiving 200 µg followed by 800 µg budesonide via chlorofluorocarbon or hydrofluoroalkane pressurized metered-dose inhaler each for 4 weeks. Methacholine PC (primary outcome), exhaled nitric oxide, spirometry, peak expiratory flow and symptoms were evaluated. In the pharmacokinetic study, there were no differences in cortisol, AUC[area under the concentration-time curve (0-12 h)], T (time to maximum concentration) or C (peak serum concentration) between the hydrofluoroalkane and chlorofluorocarbon pressurized metered-dose inhaler. The ratio of budesonide hydrofluoroalkane vs. chlorofluorocarbon pressurized metered-dose inhaler for cortisol AUC was 1.02 (95% confidence interval 0.93-1.11) and budesonide AUC was 1.03 (90% confidence interval 0.9-1.18). In the asthma pharmacodynamic study, there was a significant dose response ( P < 0.0001) for methacholine PC (provocative concentration of methacholine needed to produce a 20% fall in FEV) with a relative potency ratio of 1.10 (95% confidence interval 0.49-2.66), and no difference at either dose. No significant differences between formulations were seen with the secondary outcome variables. Hydrofluoroalkane and chlorofluorocarbon formulations of budesonide were therapeutically equivalent in terms of relative lung bioavailability, airway efficacy and systemic effects. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THE SUBJECT • Ciclosporin's nephrotoxicity initially targets the proximal tubule and is, at least in part, driven by increased formation of oxygen radicals. • 1H-nuclear magnetic resonance spectroscopy (NMR)- and mass spectrometry (MS)-based biochemical profiling (metabolomics) allows for the sensitive detection of metabolite pattern changes in urine. • In systematic studies in rats we showed that ciclosporin caused urine metabolite pattern changes typical for proximal tubule damage and that these pattern changes seemed to be more sensitive than established clinical kidney function markers such as serum creatinine concentrations. WHAT THIS PAPER ADDS • This study showed that urine metabolite pattern changes as assessed by 1H-NMR and HPLC-MS are sensitive enough to detect the effect of ciclosporin as early as 4 h after a single oral dose. • In our previous rat studies, changes in urine metabolite pattern in response to ciclosporin translated into healthy humans, indicating the involvement of the same toxicodynamic mechanisms. • The results provide proof of concept for further development of this combination molecular marker strategy into diagnostic tools for the detection and monitoring of drug nephrotoxicity. AIMS The immunosuppressant ciclosporin is an efficient prophylaxis against transplant organ rejection but its clinical use is limited by its nephrotoxicity. Our previous systematic studies in the rat indicated urine metabolite pattern changes to be sensitive indicators of the negative effects of ciclosporin on the kidney. To translate these results, we conducted an open label, placebo-controlled, crossover study assessing the time-dependent toxicodynamic effects of a single oral ciclosporin dose (5 mg kg−1) on the kidney in 13 healthy individuals. METHODS In plasma and urine samples, ciclosporin and 15- F2t-isoprostane concentrations were assessed using HPLC-MS and metabolite profiles using 1H-NMR spectroscopy. RESULTS The maximum ciclosporin concentrations were 1489 ± 425 ng ml−1 (blood) and 2629 ± 1308 ng ml−1 (urine). The increase in urinary 15- F2t-isoprostane observed 4 h after administration of ciclosporin indicated an increase in oxidative stress. 15- F2t-isoprostane concentrations were on average 2.9-fold higher after ciclosporin than after placebo (59.8 ± 31.2 vs. 20.9 ± 19.9 pg mg−1 creatinine, P < 0.02). While there were no conclusive changes in plasma 15- F2t-isoprostane concentrations or metabolite patterns, non-targeted metabolome analysis using principal components analysis and partial least square fit analysis revealed significant changes in urine metabolites typically associated with negative effects on proximal tubule cells. The major metabolites that differed between the 4 h urine samples after ciclosporin and placebo were citrate, hippurate, lactate, TMAO, creatinine and phenylalanine. CONCLUSION Changes in urine metabolite patterns as a molecular marker are sufficiently sensitive for the detection of the negative effects of ciclosporin on the kidney after a single oral dose. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The clearance of many drugs is reduced in the elderly, but the data regarding phenytoin are conflicting. Most studies have estimated phenytoin metabolic clearance using total drug concentrations (bound plus unbound), which may be confounded by protein binding effects. Free phenytoin concentrations are independent of protein binding and should more accurately reflect true metabolic clearance changes in elderly patients. WHAT THIS STUDY ADDS • The two studies reported in this paper suggest a trend towards reduced free phenytoin ‘apparent clearance’ in the elderly, although statistically significant results were not found. Other published studies have largely found similar trends, suggesting an age effect. AIMS To test the hypothesis that the ‘apparent clearance’ of free phenytoin is reduced in elderly patients. METHODS Two separate studies were conducted comparing free phenytoin ‘apparent clearance’ in elderly vs. younger adults. The first study was a retrospective analysis of free phenytoin concentrations measured at Christchurch Hospital from 1997 to 2006. In the second study free phenytoin concentrations were measured prospectively in ambulatory subjects who were taking phenytoin regularly. RESULTS In the retrospective study ( n= 29), free phenytoin ‘apparent clearance’ was 0.27 ± 0.04 l kg−1 day−1 (95% CI 0.19, 0.34) in the elderly cohort vs. 0.37 ± 0.06 l kg−1 day−1 (95% CI 0.22, 0.52) in younger adults, but the difference was not statistically significant. In the prospective study, free phenytoin ‘apparent clearance’ showed a non-significant trend to being reduced in the elderly patients (0.12 ± 0.02 l kg−1 day−1, 95% CI 0.07, 0.17) compared with the younger cohort (0.18 ± 0.07 l kg−1 day−1, 95% CI 0.09, 0.26) in those not taking interacting drugs ( n= 21). CONCLUSIONS This research does not prove the hypothesis that the ‘apparent clearance’ of free phenytoin is reduced in the elderly. However, the trends found in these two studies are supported by trends in the same direction in other published studies, suggesting an age effect. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • While animal toxicology is routinely used for safety screening of compounds prior to their being tested in man, there is very little in the literature on the quantitative translation of cardiovascular drug effects from animal to man. WHAT THIS STUDY ADDS • This study compares pharmacokinetic–pharmacodynamic analysis of dog and human effects of PF-00821385 on heart rate. • This paper considers how quantitative translational knowledge of drug effects in dogs may be used to optimize future human studies. AIM To assess the translation of pharmacokinetic–pharmacodynamic (PK–PD) relationships for heart rate effects of PF-00821385 in dog and man. METHODS Cardiovascular telemetric parameters and concentration data were available for animals receiving active doses (0.5–120 mg kg−1, n= 4) or vehicle. PF-00821385 was administered to 24 volunteers and pharmacokinetic and vital signs data were collected. PK–PD models were fitted using nonlinear mixed effects. RESULTS Compartmental models with linear absorption and clearance were used to describe pharmacokinetic disposition in animal and man. Diurnal variation in heart and pulse rate was best described with a single cosine function in both dog and man. Canine and human heart rate change were described by a linear model with free drug slope 1.76 bpm µM−1[95% confidence interval (CI) 1.17, 2.35] in the dog and 0.76 bpm µM−1 (95% CI 0.54, 1.14) in man. CONCLUSIONS The preclinical translational of concentration–response has been described and the potential for further interspecies extrapolation and optimization of clinical trial design is addressed. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • MMF has been proposed as a treatment of steroid-dependent nephrotic syndrome and in the recent years, several studies have suggested its positive effect in preventing relapses. WHAT THIS PAPER ADDS • The population pharmacokinetics of MPA was first evaluated in children with idiopathic nephrotic syndrome and data fitted well with a two-compartment model with first-order absorption and lag time. • Body weight and serum albumin had a significant impact on oral clearance. • A three-point (T0, T1 and T4h) Bayesian estimator of AUC0–12 was developed. AIMS To develop a population pharmacokinetic model for mycophenolic acid (MPA) in children with idiopathic nephrotic syndrome (INS) treated with mycophenolate mofetil (MMF), identify covariates that explain variability and determine the Bayesian estimator of the area under the concentration–time curve over 12 h (AUC0–12). METHODS The pharmacokinetic model of MMF was described from 23 patients aged 7.4 ± 3.9 years (range 2.9–14.9) using nonlinear mixed-effects modelling (NONMEM) software. A two-compartment model with lag–time and first-order absorption and elimination was developed. The final model was validated using visual predictive check. Bayesian estimator was validated using circular permutation method. RESULTS The population pharmacokinetic parameters were apparent oral clearance 9.7 l h−1, apparent central volume of distribution 22.3 l, apparent peripheral volume of distribution 250 l, inter-compartment clearance 18.8 l h−1, absorption rate constant 5.16 h−1, lag time 0.215 h. The covariate analysis identified body weight and serum albumin as individual factors influencing the apparent oral clearance. Accurate Bayesian estimation of AUC0–12 was obtained using the combination of three MPA concentrations measured just before (T0), 1 and 4 h (T1 and T4) after drug intake with a small error of 0.298 µg h−1 ml−1 between estimated and reference AUC0–12. CONCLUSIONS The population pharmacokinetic model of MPA was developed in children with INS. A three-point (T0, T1 and T4h) Bayesian estimator of AUC0–12 was developed and might be used to investigate the relation between MPA pharmacokinetic and pharmacodynamics in children with INS and determine if there is any indication to monitor MPA exposure in order to improve patient outcome based on individual AUC-controlled MMF dosing. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The complexities of assessing the bioequivalence of endogenous drugs are recognised. • The FDA have published guidelines regarding the evaluation of levothyroxine and potassium chloride bioequivalence, whilst other authors have documented specific strategies to counter biases inherent in biostudies of endogenous drugs. • A consolidated consideration of valid methods to optimise the design of such studies is however lacking. WHAT THIS STUDY ADDS • This paper is to the author's knowledge the first summarising various key approaches used to assess the bioequivalence of endogenous drugs, and to propose a series of recommendations for studies in this field. BACKGROUND Assessment of the bioequivalence of generic versions of certain reference drugs is complicated by the presence of endogenous levels of said compounds which cannot be distinguished from externally derived compound levels following drug administration. If unaccounted for, the presence of endogenous compound biases towards equivalence in bioequivalence studies of these drugs. Bioequivalence assessments may be complicated further as disposition of the exogenous analogue can be subject to various endogenous processes resulting in nonlinear pharmacokinetics. To overcome these inherent biases a number of different strategies have been employed. AIMS To critically review methods used to overcome confounding biases in bioequivalence studies of ‘endogenous’ drugs. METHODS A literature search of the EMBASE and PubMed databases was performed. RESULTS The following strategies were identified: ablation/modulation of baseline endogenous substance levels; recruitment of ‘substance-deficient’ populations; restriction of dietary intake of the relevant substance; standardization of conditions with the potential to affect relevant homeostatic mechanisms; correction for baseline substance levels; and administration of supra-therapeutic drug doses. CONCLUSIONS On the basis of this review key study design concepts, intended to optimize the design of future bioequivalence studies of these so-called ‘endogenous drugs’, are described. The dual stable isotope method, which could be used in a specific context, is also discussed. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Smoking slows the metabolism of nicotine and accelerates the metabolism of chlorzoxazone. • Nicotine is a useful probe for phenotyping cytochrome P450 2A6 activity and chlorzoxazone is a frequently used probe for CYP2E1 activity. • The tobacco smoke constituents responsible for the reduced CYP2A6 and increased CYP2E1 activities are unknown. WHAT THIS PAPER ADDS • This study demonstrates that CYP2A6 and CYP2E1 activities are not affected by nicotine dosing. • High-dose nicotine treatment has a low potential of interaction with CYP2A6 and CYP2E1 substrates. • The mechanisms of tobacco smoke-elicited changes in CYP2A6 and CYP2E1 activities are yet to be determined. AIMS Smoking slows the metabolism of nicotine and accelerates the metabolism of chlorzoxazone, which are probe reactions for cytochrome P450 2A6 (CYP2A6) and CYP2E1 activities, respectively. We aimed to determine the role of nicotine in these metabolic effects of cigarette smoking. METHODS The study had a single-blind, randomized, crossover two-arm design. Twelve healthy smokers were given two transdermal patches with 42-mg nicotine a day or placebo patches, each for 10 days. The subjects abstained from smoking during the study arms. Oral chlorzoxazone was given on day 7 and deuterium-labelled nicotine-d2 and cotinine-d4 infusion on day 8. RESULTS There was no significant influence of transdermal nicotine administration on pharmacokinetic parameters of nicotine-d2 or on the formation of cotinine-d2. Nicotine decreased the volume of distribution (62.6 vs. 67.7 l, 95% confidence interval of the difference −9.7, −0.6, P= 0.047) of infused cotinine-d4. There were no significant differences in disposition kinetics of chlorzoxazone between the treatments. CONCLUSIONS CYP2A6 and CYP2E1 activities are not affected by nicotine. The tobacco smoke constituents responsible for the reduced CYP2A6 and increased CYP2E1 activities remain unknown. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Nicorandil injection is used for unstable angina and for acute heart failure in Japan. • The pharmacokinetics of nicorandil following oral administration have been described in healthy subjects. WHAT THIS STUDY ADDS • This paper describes the differences in nicorandil pharmacokinetics between healthy subjects and acute heart failure patients. • A population pharmacokinetic-pharmacodynamic model for nicorandil in acute heart failure patients is described using pulmonary artery wedge pressure as the biomarker. • A rational guide for initial dosing of nicorandil to achieve a target effect on pulmonary artery wedge pressure was based on pharmacokinetic and pharmacodynamic principles. AIMS The aims of the study were 1) to evaluate the pharmacokinetics of nicorandil in healthy subjects and acute heart failure (AHF) patients and 2) to evaluate the exposure-response relationship with pulmonary arterial wedge pressure (PAWP) in AHF patients and to predict an appropriate dosing regimen for nicorandil. METHODS Based on the data from two healthy volunteer and three AHF patient studies, models were developed to characterize the pharmacokinetics and pharmacodynamics of nicorandil. PAWP was used as the pharmacodynamic variable. An asymptotic exponential disease progression model was used to account for time dependent changes in PAWP that were not explained by nicorandil exposure. The modelling was performed using NONMEM version V. RESULTS The pharmacokinetics of nicorandil were characterized by a two-compartment model with linear elimination. CL, V1 and V2 in AHF patients were 1.96, 1.39 and 4.06 times greater than in healthy subjects. Predicted plasma concentrations were assumed to have an immediate concentration effect relationship on PAWP. An inhibitory Emax model with Emax of −11.7 mmHg and E C50 of 423 µg l−1 was considered the best relationship between nicorandil concentrations and PAWP. PAWP decreased independently of nicorandil exposure. This drug independent decline was described by an asymptotic decrease of 6.1 mmHg with a half-life of 5.3 h. CONCLUSIONS AHF patients have higher clearance and initial distribution volume of nicorandil compared with healthy subjects. The median target nicorandil concentration to decrease PAWP by 30% is predicted to be 748 µg l−1, indicating that a loading dose of 200 µg kg−1 and a maintenance dose of 400 µg kg−1 h−1 would be appropriate for the initial treatment of AHF. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Ketoconazole is a potent inhibitor of the cytochrome P450 3A4 enzyme system. • Co-administration of ketoconazole and drugs primarily metabolized by the cytochrome P450 3A4 enzyme system may result in increased plasma concentrations of the drugs, which could increase or prolong both therapeutic and adverse effects. • Therefore, unless otherwise specified, appropriate dosage adjustments may be necessary. WHAT THIS PAPER ADDS • The current study was conducted to determine the extent of interaction between the potent CYP3A inhibitor, ketoconazole, and the CYP 3A substrate, darunavir (given alone and with low-dose ritonavir). • This information provides data on the pharmacokinetic boosting ability of ketoconazole and serves as important guidance to HIV-infected patients and their treating physicians with regard to appropriate (co-)administration of darunavir/ritonavir and ketoconazole. Aims To investigate the interaction between ketoconazole and darunavir (alone and in combination with low-dose ritonavir), in HIV–healthy volunteers. Methods Volunteers received darunavir 400 mg bid and darunavir 400 mg bid plus ketoconazole 200 mg bid, in two sessions (Panel 1), or darunavir/ritonavir 400/100 mg bid, ketoconazole 200 mg bid and darunavir/ritonavir 400/100 mg bid plus ketoconazole 200 mg bid, over three sessions (Panel 2). Treatments were administered with food for 6 days. Steady-state pharmacokinetics following the morning dose on day 7 were compared between treatments. Short-term safety and tolerability were assessed. Results Based on least square means ratios (90% confidence intervals) , during darunavir and ketoconazole co-administration, darunavir area under the curve (AUC12h), maximum plasma concentration ( Cmax) and minimum plasma concentration ( Cmin) increased by 155% (80, 261), 78% (28, 147) and 179% (58, 393), respectively, compared with treatment with darunavir alone. Darunavir AUC12h, Cmax and Cmin increased by 42% (23, 65), 21% (4, 40) and 73% (39, 114), respectively, during darunavir/ritonavir and ketoconazole co-administration, relative to darunavir/ritonavir treatment. Ketoconazole pharmacokinetics was unchanged by co-administration with darunavir alone. Ketoconazole AUC12h, Cmax and Cmin increased by 212% (165, 268), 111% (81, 144) and 868% (544, 1355), respectively, during co-administration with darunavir/ritonavir compared with ketoconazole alone. Conclusions The increase in darunavir exposure by ketoconazole was lower than that observed previously with ritonavir. A maximum ketoconazole dose of 200 mg day−1 is recommended if used concomitantly with darunavir/ritonavir, with no dose adjustments for darunavir/ritonavir. [ABSTRACT FROM AUTHOR]

What is already known about this subject • Two recent papers have been published which have attempted to build a full population pharmacokinetic model for tobramycin in children with cystic fibrosis. • However, neither study was able to provide any information about between-subject variability (BSV) and between-occasion variability (BOV), which is necessary to justify and draw conclusions about the use of target concentration intervention (TCI). • In the publications no simulations were provided to show any new directions or evaluate current therapy. What this study adds • This study provides sound evidence that TCI must be undertaken in this patient group, as the BOV is significantly less than the BSV. • The simulations from this model clearly show that current dosing and monitoring methods will not achieve the necessary targets to maximize the pharmacokinetic–pharmacodynamic relationships of aminoglycosides in this patient group. • The model presented is able to be easily incorporated into Bayesian dose individualization software, e.g. Abbottbase or TCIworks, to achieve dosing targets more accurately. Aim The primary aim was to estimate the population pharmacokinetic parameters of once-daily intravenous (i.v.) tobramycin in paediatric cystic fibrosis (CF) patients and to investigate the influence of covariates. The second aim was to assess the need for target concentration intervention (TCI) for tobramycin in this patient group. Methods Retrospective demographic, dosing and concentration data were collected from 35 CF patients (21 female, 14 male) aged 0.5–17.8 years, from whom 318 tobramycin plasma concentrations were available. NONMEM was used to estimate the population pharmacokinetics of tobramycin. Simulations were performed using weight-based dosing with a weight from a covariate distribution model to evaluated current dosing schedules and monitoring practices. Results A two-compartment model best described the data with population parameter estimates for clearance of central compartment (CL) of 6.37 l h−1 per 70 kg; volume of central compartment ( Vc) of 18.7 l per 70 kg; intercompartmental clearance ( Q) of 0.393 l h−1; and volume of peripheral compartment ( Vper) of 1.32 l. The inclusion of total body weight as covariate reduced the random component of between-subject variability in CL from 50.1% to 11.7% and in Vc from 62.2% to 11.6%. The between-occasion variability on CL was estimated in the final model as 6.5%. Simulations show that one dose does not fit all and TCI and dose adjustment are required. Conclusions This study provides the first pharmacokinetic model of once-daily i.v. tobramycin for the use of target concentration intervention in paediatric CF patients. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Both chloroquine (CQ) and sulfadoxine/ pyrimethamine (SDx/PYR) remain important drugs in the control of malaria. • The available data on CQ, SDx and PYR are summary pharmacokinetic parameters based on classical/traditional methods, mostly in adults. • No study has described the population pharmacokinetics of a fixed-dose CQ + SDx/PYR combination in children with falciparum malaria. WHAT THIS STUDY ADDS • This study presents population pharmacokinetic data on CQ and SDx in children with uncomplicated falciparum malaria. • The study demonstrates that in age-based fixed-dose regimens with CQ and SDx, drug exposures and outcomes may be correctly predicted, although correlation with body weight is poor. • The study proposes dose modification to improve response with the CQ + SDx/PYR combination. AIMS To describe the pharmacokinetics of chloroquine (CQ) and sulfadoxine (SDx), and to identify predictors of treatment response in children with malaria given the CQ + SDx and pyrimethamine (PYR) combination. METHODS Eighty-six Ugandan children with uncomplicated falciparum malaria, 6 months to 5 years old, were randomly treated with prepacked fixed-dose CQ + SDx/PYR. The youngest children (<24 months) received half strength and the older (>24 months) full strength treatment. The reported day 14 failure rates were 48% and 18%, respectively. Capillary blood (100 μl) applied on to filter paper was collected on eight occasions during 28 days of follow up. Concentrations of CQ and SDx were determined. A population approach was used for the pharmacokinetic analysis. RESULTS A two-compartment model adequately described the data for both CQ and SDx. For CQ, the typical apparent clearance (CL/ F) and volume of distribution ( VC/ F) values were estimated to be 2.84 l h−1 and 230 l. The typical CL/ F for SDx was 0.023 l h−1, while the factor relating its VC/ F to normalized body weight was 1.6 l kg−1. Post hoc parameter estimates for both drugs showed lower maximum concentrations ( C max) and concentration-time curve areas (AUC(0,336 h)) in younger children. The AUC(0,336 h) for SDx and CQ were independently significant factors for prediction of cure. Simulations suggest that giving the higher dose to the youngest children would result in higher CQ and SDx concentrations and improved outcome. CONCLUSIONS The study results suggest that full-strength combination to all children would improve the cure rate. [ABSTRACT FROM AUTHOR]

What is already known about this subject • Exercise is known to affect absorption of other inhaled substances, but so far there are no reports on the effect of exercise on the absorption of inhaled insulin in humans. What this paper adds • This report is the first to investigate the effect of exercise on the absorption of inhaled insulin. • In this study in healthy volunteers we found that exercise early after dosing increased absorption (15–20%) of inhaled insulin over the first 2 h after start of exercise, with an approximately 30% increase in maximal insulin concentration, and unchanged overall absorption. Aims To investigate the effect of moderate exercise on the absorption of inhaled insulin. Methods A single-centre, randomized, open-label, three-period cross-over trial was carried out in 12 nonsmoking healthy subjects. A dose of 3.5 mg inhaled human insulin was administered via a nebulizer and followed in random order by either 1) no exercise (NOEX), 2) 30 min exercise starting immediately after dosing (EX0), or 3) 30 min exercise starting 30 min after dosing (EX30). The study was carried out as a 10 h euglycaemic glucose clamp (90 mg dl−1 (5.0 mmol l−1)). Results The absorption of insulin over the first 2 h after start of exercise was 16% increased for EX0 (ratio (95%CI) 1.16 (1.04, 1.30), P = 0.01) and 20% increased for EX30 (1.20 (1.05, 1.36), P < 0.01), both compared with NOEX; the overall insulin absorption during 6 h and 10 h after dosing was not influenced by exercise. The maximum insulin concentration ( C max) increased by 32% for EX0 and 35% for EX30 (both P < 0.01) compared with NOEX, while the time to C max was 31 min faster for EX0 ( P < 0.01), but not significantly different after EX30, compared with NOEX. Conclusions A significant and clinically relevant increase of insulin absorption over the first 2 h after the beginning of exercise was observed. Until data from studies using the specific insulin inhalers exists, patients using inhaled insulin should be made aware of a potential increased absorption and higher concentration of insulin in connection with exercise. [ABSTRACT FROM AUTHOR]

What is already known about this subject • Carnitine is essential for fatty acid metabolism, and is obtained from the diet and endogenous synthesis. • Patients with renal failure who are on chronic haemodialysis may require carnitine supplementation. • It is known that carnitine depletion in these patients may take years to develop, and that measurements of plasma carnitine may not be predictive of loss of carnitine from muscle, the main pool of carnitine in the body. What this study adds • This paper adds a quantitative understanding of the time-course of the relationship between haemodialysis and the plasma concentration of L-carnitine, with particular reference to how the carnitine pools in the body re-equilibrate after a dialysis session. • It also provides insight into the time-course of the depletion of L-carnitine in these patients. Aims Patients requiring chronic haemodialysis may develop a secondary carnitine deficiency through dialytic loss of L-carnitine. A previous report has described the plasma concentrations of L-carnitine in 12 such patients under baseline conditions and after L-carnitine administration (20 mg kg−1). A three-compartment pharmacokinetic model was developed to describe these data to make inferences about carnitine supplementation in these patients. Methods L-carnitine removal was mediated solely by intermittent haemodialysis, which was incorporated into the model as an experimentally derived dialysis clearance value that was linked to an on-off pulse function. Data were described by a model with a central compartment linked to ‘fast’- and ‘slow’-equilibrating peripheral compartments. Results The model adequately described the changing plasma concentrations of endogenous L-carnitine in individual haemodialysis patients. Based on pooled data (mean ± SD; n = 12), the volume of the central compartment was 10.09 ± 0.72 l and the transfer rate constants into and out of the slowly equilibrating pool were 0.100 ± 0.018 h−1 and 0.00014 ± 0.00016 h−1, respectively. The turnover time of L-carnitine in the slow pool (which was assumed to represent muscle) was approximately 300 days. The model was in general agreement with separate data on the measured loss of carnitine from muscle in dialysis patients. Conclusions Haemodialysis causes rapid reductions in plasma L-carnitine concentrations with each dialysis session. Plasma concentrations are restored between sessions by redistribution from peripheral compartments. However, during chronic haemodialysis, the ongoing dialytic loss of L-carnitine may lead to a slow depletion of the compound, contributing to a possible secondary deficiency. [ABSTRACT FROM AUTHOR]

What is already known about this subject • Levetiracetam has been evaluated for epilepsy since 1992. • Pharmacokinetic studies of levetiracetam have been conducted in healthy volunteers, in adults, children and elderly patients with epilepsy, and in patients with renal and hepatic impairment. • Although this antiepileptic has been well studied in Western countries, this paper describes the first such trial of the drug in a Chinese population. What this study adds • Information is given on the pharmacokinetics, dose proportionality, safety and tolerability profile of levetiracetam in healthy male Chinese volunteers, and the results are compared with published data obtained in White subjects. • The pharmacokinetics and the pattern of adverse events of levetiracetam in Chinese subjects are similar to the data reported in White subjects. Aims The main aims of this study were to evaluate the pharmacokinetics of levetiracetam in healthy male Chinese volunteers and to assess the dose proportionality between the 500-mg and 1500-mg single doses. Methods This was a randomized, single-centre, single-dose, two-way crossover study. Twenty-six healthy male Chinese subjects were enrolled. All subjects received a single dose of 500 mg or 1500 mg levetiracetam tablet(s) on the dosing day, and the wash-out period was 7 days. Blood was obtained for a 36-h pharmacokinetic evaluation. Results Following single-dose administration of 500 mg and 1500 mg of levetiracetam, the median tmax was 0.5 and 0.5 h; t1/2 was 7.3 ± 0.8 and 7.3 ± 0.7 h; Cmax was 13.6 ± 3.2 and 47.1 ± 12.1 µg ml−1; AUC0–∞ was 109.3 ± 14.1 and 340.4 ± 50.6 µg h−1 ml−1; and AUC0– t was 105.7 ± 13.3 and 329.0 ± 47.9 µg h−1 ml−1, respectively. Conclusions Both Cmax and AUCs were dose-proportional over the range of 500–1500 mg. The pharmacokinetic data obtained in these Chinese subjects were similar to the historical data from a matched group of White subjects. [ABSTRACT FROM AUTHOR]

Aim The aim of this systematic review was to assess the quality and outcomes of clinical trials investigating the effect of St John’s wort extracts on the metabolism of drugs by CYP3A. Methods Prospective clinical trials assessing the effect of St John’s wort (SJW) extracts on metabolism by CYP3A were identified through computer-based searches (from their inception to May 2005) of Medline, Cinahl, PsycINFO, AMED, Current Contents and Embase, hand-searches of bibliographies of relevant papers and consultation with manufacturers and researchers in the field. Two reviewers selected trials for inclusion, independently extracted data and recorded details on study design. Results Thirty-one studies met the eligibility criteria. More than two-thirds of the studies employed a before-and-after design, less than one-third of the studies used a crossover design, and only three studies were double-blind and placebo controlled. In 12 studies the SJW extract had been assayed, and 14 studies stated the specific SJW extract used. Results from 26 studies, including all of the 19 studies that used high-dose hyperforin extracts (>10 mg day−1), had outcomes consistent with CYP3A induction. The three studies using low-dose hyperforin extracts (<4 mg day−1) demonstrated no significant effect on CYP3A. Conclusion There is reasonable evidence to suggest that high-dose hyperforin SJW extracts induce CYP3A. More studies are required to determine whether decreased CYP3A induction occurs after low-dose hyperforin extracts. Future studies should adopt study designs with a control phase or control group, identify the specific SJW extract employed and provide quantitative analyses of key constituents. [ABSTRACT FROM AUTHOR]

Aims This paper describes the pharmacokinetics and effects of propofol in short-term sedated paediatric patients. Methods Six mechanically ventilated children aged 1–5 years received a 6 h continuous infusion of propofol 6% at the rate of 2 or 3 mg kg-1 h-1 for sedation following cardiac surgery. A total of seven arterial blood samples was collected at various time points during and after the infusion in each patient. Pharmacokinetic modelling was performed using NONMEM. Effects were assessed on the basis of the Ramsay sedation score as well as a subjective sedation scale. Results The data were best described by a two-compartment pharmacokinetic model. In the model, body weight was a significant covariate for clearance. Pharmacokinetic parameters in the weight-proportional model were clearance (CL) = 35 ml kg-1 min-1 , volume of central compartment (V 1 ) = 12 l, intercompartmental clearance (Q) = 0.35 l min-1 and volume of peripheral compartment (V 2 ) = 24 l. The interindividual variabilities for these parameters were 8%, < 1%, 11% and 35%, respectively. Compared with the population pharmacokinetics in adults following cardiac surgery and when normalized for body weight, statistically significant differences were observed for the parameters CL and V 1 (35 vs 29 ml kg-1 min-1 and 0.78 vs 0.26 l kg-1 P < 0.05), whereas the values for Q and V 2 were similar (23 vs 18 ml kg-1 min-1 and 1.6 vs 1.8 l kg-1 , P > 0.05). In children,... [ABSTRACT FROM AUTHOR]

Dapsone is employed for both non‐dermatological and dermatological indications but with non‐existent population pharmacokinetics (popPK) data in Nigerians. This study was therefore designed to develop a popPK model in Nigerians. Non‐compartmental analysis and nonlinear mixed effects modelling were utilized for data analysis. Eleven participants administered 50 mg dapsone tablet were included in the analysis. Derived pharmacokinetic parameters were: Cmax = 1.16 ± 0.32 μg/mL, Tmax = 3.77 ± 2.40 h, and t1/2z = 30.23 ± 11.76 h. PopPK model parameter estimates with inter‐individual variability were Tlag = 0.40 h (10.0%, fixed); ka = 1.78 h−1 (75.9%); V/F = 89.25 L (21.6%); and Cl/F = 1.32 Lh−1 (27.7%). Sex was significantly associated with Cl/F, and body weight with V/F. Best popPK model was one‐compartment with lag time, and first‐order absorption and elimination. Sex and body weight significantly influenced the clearance and distribution volume of dapsone respectively. [ABSTRACT FROM AUTHOR]

Aims: Pharmacokinetic/pharmacodynamic target attainment of ceftriaxone is compromised in intensive care unit (ICU) patients and non‐ICU hospitalized patients in Beira, Mozambique. Whether this also accounts for non‐ICU patients in a high‐income setting is unknown. We therefore assessed the probability of target attainment (PTA) of the currently recommended dosing regimen of 2 g every 24 h (q24h) in this patient group. Methods: We performed a multicentre population pharmacokinetic study in hospitalized non‐ICU adult patients empirically treated with intravenous ceftriaxone. During both the acute phase of infection (i.e. first 24 h of treatment) and convalescence, a maximum of 4 random blood samples were obtained per patient for ceftriaxone total and unbound concentration measurements. PTA was calculated using NONMEM and was defined as the percentage of patients of which the unbound ceftriaxone concentration exceeded the minimum inhibitory concentration (MIC) for >50% of the first dosing interval of 24 h. Monte Carlo simulations were performed to determine PTA for different estimated glomerular filtration rates (eGFR; CKD‐EPI) and MICs. PTA >90% was considered adequate. Results: Forty‐one patients provided 252 ceftriaxone total and 253 unbound concentrations. The median eGFR was 65 mL/min/1.73 m2 (5th to 95th percentile 36–122). With the recommended dose of 2 g q24h, PTA >90% was achieved for bacteria with an MIC ≤2 mg/L. Simulations showed that PTA was insufficient for an MIC of 4 mg/L in case the eGFR was 122 mL/min/1.73 m2 (PTA 56.9%) and for an MIC of 8 mg/L regardless of eGFR. Conclusion: The PTA of 2 g q24h ceftriaxone dosing is adequate for common pathogens during the acute phase of infection in non‐ICU patients. [ABSTRACT FROM AUTHOR]

Aims: Nalbuphine is a synthetic opioid with comparable analgesic activity to morphine but with a better safety profile. Nalbuphine is only available in injectable form due to low oral bioavailability. Nasal nalbuphine spray provides advantages in drug safety, avoids hepatic first‐pass metabolism, is non‐invasive and is convenient for patient‐controlled analgesia by self‐administration. This study aimed to evaluate the safety and pharmacokinetics (PK) of the newly developed nalbuphine nasal spray in comparison with a solution for injections. Methods: Twenty‐four healthy Caucasian volunteers were enrolled in this randomized, open‐label, cross‐over study. Subjects were administered one of the drugs: nasal spray 7.0 mg/dose, nalbuphine hydrochloride solution for injection 10 mg/dose intravenously (IV) or intramuscularly (IM). High‐performance liquid chromatography–tandem mass spectrometry was used to determine nalbuphine concentrations. Results: A comparison of PK profiles for IV, IM and intranasal (IN) routes of nalbuphine administration revealed a close similarity of absorption phases for nasal spray and IM injection. Differences between the mean Tmax and dose‐adjusted Cmax values for nasal spray and IM injection were statistically insignificant. The median values of the elimination rate constants and the terminal elimination half‐life following IV, IM and IN nalbuphine administration were similar. The mean absolute bioavailability of the nasal spray equalled 65.04%. Conclusions: The similarity of PK parameters of IM‐injected nalbuphine solution and the nasal spray allows us to assume the latter is a feasible alternative to intramuscular nalbuphine injections appropriate for self‐administration and field environments for managing moderate and severe pain of various aetiologies. [ABSTRACT FROM AUTHOR]

Tamoxifen is the most used hormonal therapy for oestrogen receptor‐positive breast cancer. CYP2D6 is the main enzyme in the metabolic pathway of tamoxifen to endoxifen. Variations in endoxifen plasma concentrations are associated with CYP2D6 polymorphisms. This study aimed to determine the association between the CYP2D6 polymorphisms and endoxifen plasma concentrations in a cohort of Zimbabwean breast cancer patients (n = 40). TaqMan genotyping and copy number assays were done to determine CYP2D6 genotypes. Tamoxifen and metabolites were quantitated using LC‐MS/MS. The population had high frequencies of the CYP2D6 reduced function alleles, *17 (15%) and *29 (18%). The median endoxifen concentration was 4.78 ng/mL, and in 55% of the patients, mostly intermediate metabolizers were below the endoxifen therapeutic threshold of 5.97 ng/mL. The CYP2D6 phenotypes and activity scores were significantly associated with endoxifen plasma concentrations (P = 0.0151) and with endoxifen to N‐desmethyl‐tamoxifen ratios (P = 0.0006). [ABSTRACT FROM AUTHOR]

Aims: The aim of this study was to quantify identifiable sources of variability, including key pharmacogenetic variants in oxypurinol pharmacokinetics and their pharmacodynamic effect on serum urate (SU). Methods: Hmong participants (n = 34) received 100 mg allopurinol twice daily for 7 days followed by 150 mg allopurinol twice daily for 7 days. A sequential population pharmacokinetic pharmacodynamics (PKPD) analysis with non‐linear mixed effects modelling was performed. Allopurinol maintenance dose to achieve target SU was simulated based on the final PKPD model. Results: A one‐compartment model with first‐order absorption and elimination best described the oxypurinol concentration–time data. Inhibition of SU by oxypurinol was described with a direct inhibitory Emax model using steady‐state oxypurinol concentrations. Fat‐free body mass, estimated creatinine clearance and SLC22A12 rs505802 genotype (0.32 per T allele, 95% CI 0.13, 0.55) were found to predict differences in oxypurinol clearance. Oxypurinol concentration required to inhibit 50% of xanthine dehydrogenase activity was affected by PDZK1 rs12129861 genotype (−0.27 per A allele, 95% CI −0.38, −0.13). Most individuals with both PDZK1 rs12129861 AA and SLC22A12 rs505802 CC genotypes achieve target SU (with at least 75% success rate) with allopurinol below the maximum dose, regardless of renal function and body mass. In contrast, individuals with both PDZK1 rs12129861 GG and SLC22A12 rs505802 TT genotypes would require more than the maximum dose, thus requiring selection of alternative medications. Conclusions: The proposed allopurinol dosing guide uses individuals' fat‐free mass, renal function and SLC22A12 rs505802 and PDZK1 rs12129861 genotypes to achieve target SU. [ABSTRACT FROM AUTHOR]

Aims: To investigate the drug‐drug interaction (DDI) of ciprofol injectable emulsion and mefenamic acid capsules in healthy subjects. Methods: Twenty healthy subjects were enrolled in this single‐centre, open‐label, two‐period DDI study. Ciprofol (0.4 mg kg−1) was administered as a single dose on days 1 and 5. A 500‐mg oral loading dose of mefenamic acid was given on day 4 followed by a 250‐mg maintenance dose every 6 h (a total of eight doses). Blood samples for pharmacokinetic analyses were collected. Depth of anaesthesia was monitored using the Modified Observer's Assessment of Alertness and Sedation (MOAA/S) scale and Bispectral Index scores (BISs). Results: Compared with administration of ciprofol alone, administration with mefenamic acid showed no significant difference in exposure. The geometric mean ratios (GMRs) and their 90% confidence intervals (CIs) for maximum plasma concentration (Cmax), area under the plasma concentration‐time curve calculated from 0 to the last measurement point (AUC0‐last) and AUC to infinity (AUC0‐inf) were 91.6% (86.5‐96.9%), 103.3% (100.3‐106.4%) and 107.0% (101.2‐113.2%), respectively. The MOAA/S and BIS curves for the two treatment periods essentially coincided, indicating that the anaesthesia effect of ciprofol was not affected by mefenamic acid. Seven subjects (35%) reported eight adverse events (AEs) when ciprorol was administered alone and 12 subjects (60%) reported 18 AEs when ciprofol was administered in combination with mefenamic acid. All AEs were mild. Conclusions: Mefenamic acid, a UGT1A9 inhibitor, had no significant effect on the pharmacokinetics and pharmacodynamics of ciprofol in healthy subjects. Ciprofol was safe and well tolerated when administered with mefenamic acid. [ABSTRACT FROM AUTHOR]

Aims: RO7049389 (linvencorvir) is a developmental oral treatment for chronic hepatitis B virus infection. The aim of this work was to conduct mass balance (MB) and absolute bioavailability (BA) analyses in healthy volunteers, alongside in vitro evaluations of the metabolism of RO7049389 and a major circulating active metabolite M5 in human hepatocytes, and physiologically based pharmacokinetic (PBPK) modelling to refine the underlying drug disposition paradigm. Methods: Participants in the clinical study (MB: Caucasian, male, n = 6; BA: Caucasian and Asian, male and female, n = 16, 8 in each ethnic groups) received oral [14C] or unlabelled RO7049389 (600/1000 mg) followed by 100 μg intravenous [13C]RO7049389. Metabolic pathways with fractions metabolized—obtained from the in vitro incubation results of 10 μM [14C]RO7049389 and 1 μM M5 with (long‐term cocultured) human hepatocytes in the absence and presence of the cytochrome P450 3A4 (CYP3A4) inhibitor itraconazole—were used to complement the PBPK models, alongside the clinical MB and BA data. Results: The model performance in predicting the pharmacokinetic profiles of RO7049389 and M5 aligned with clinical observations in Caucasians and was also successfully applied to Asians. Accordingly, the drug disposition pathways for RO7049389 were postulated with newly characterized estimates of the fractions: biliary excretion by P‐glycoprotein (~41%), direct glucuronidation via uridine 5′‐diphosphoglucuronosyltransferase 1A3 (~11%), hexose conjugation (~6%), oxidation by CYP3A4 (~28%) and other oxidation reactions (~9%). Conclusion: These results support the ongoing clinical development program for RO7049389 and highlight the broader value of PBPK and MB analyses in drug development. [ABSTRACT FROM AUTHOR]

Aims: The objective of this study was to evaluate the effects of a strong cytochrome P450 family (CYP) 3A4 inhibitor (itraconazole) and inducer (carbamazepine) on the pharmacokinetics and safety of nirmatrelvir/ritonavir. Methods: Pharmacokinetics were measured in two phase 1, open‐label, fixed‐sequence studies in healthy adults. During Period 1, oral nirmatrelvir/ritonavir 300 mg/100 mg twice daily was administered alone; during Period 2, it was administered with itraconazole or carbamazepine. Nirmatrelvir/ritonavir was administered as repeated doses or one dose in the itraconazole and carbamazepine studies, respectively. Nirmatrelvir and ritonavir plasma concentrations and adverse event (AE) rates in both periods were analysed. Results: Each study included 12 participants. Following administration of nirmatrelvir/ritonavir with itraconazole (Test) or alone (Reference), test/reference ratios of the adjusted geometric means (90% CIs) for nirmatrelvir AUCtau and Cmax were 138.82% (129.25%, 149.11%) and 118.57% (112.50%, 124.97%), respectively. After administration of nirmatrelvir/ritonavir with carbamazepine (Test) or alone (Reference), test/reference ratios (90% CIs) of the adjusted geometric means for nirmatrelvir AUCinf and Cmax were 44.50% (33.77%, 58.65%) and 56.82% (47.04%, 68.62%), respectively. Nirmatrelvir/ritonavir was generally safe when administered with or without itraconazole or carbamazepine. No serious or severe AEs were reported. Conclusions: Coadministration of a strong CYP3A4 inhibitor with a strong CYP3A inhibitor used for pharmacokinetic enhancement (i.e., ritonavir) resulted in small increases in plasma nirmatrelvir exposure, whereas coadministration of a strong inducer substantially decreased systemic nirmatrelvir and ritonavir exposures suggesting a contraindication in the label with CYP3A4 strong inducers. Administration of nirmatrelvir/ritonavir alone or with itraconazole or carbamazepine was generally safe. [ABSTRACT FROM AUTHOR]