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Recently, an optimal dosing algorithm (OptiDose) was developed to compute the optimal drug doses for any pharmacometrics model for a given dosing scenario. In the present work, we enhance the OptiDose concept to compute optimal drug dosing with respect to both efficacy and safety targets. Usually, these are not of equal importance, but one is a top priority, that needs to be satisfied, whereas the other is a secondary target and should be achieved as good as possible without failing the top priority target. Mathematically, this leads to state-constrained optimal control problems. In this paper, we elaborate how to set up such problems and transform them into classical unconstrained optimal control problems which can be solved in NONMEM. Three different optimal dosing tasks illustrate the impact of the proposed enhanced OptiDose method. [ABSTRACT FROM AUTHOR]

Background and Objective: Trichuriasis caused by the human whipworm Trichuris trichiura poses a significant public health concern. Albendazole-ivermectin co-medication is currently the most effective treatment. Studies conducted in Tanzania and Côte d'Ivoire unveiled differences in efficacy for albendazole-ivermectin combination therapy in both countries. A pharmacometrics approach was used to assess co-medication and study population effects on the pharmacokinetics of the two main metabolites of albendazole. An exploratory exposure-efficacy analysis was also carried out to investigate relationships between exposure measures and the egg reduction rate. Methods: Pharmacokinetic data from studies in Tanzania and Côte d'Ivoire in adolescents (aged 12–19 years) were included in the pharmacometric analysis. Participants received a single dose of either albendazole 400 mg alone or in combination with ivermectin 200 µg/kg. A pharmacometric analysis was performed to investigate the potential effects of the study population and co-administered ivermectin on the apparent clearance of the metabolites of albendazole. Non-linear mixed-effects modeling was conducted with MonolixSuite 2023R1. The pharmacokinetic exposure measures derived from simulations with individual model parameters were used in the exploratory-exposure response analysis. Results: Pharmacokinetic profiles were best described by a two-compartment model for albendazole sulfoxide and a one-compartment model for albendazole sulfone, with a transit compartment and linear elimination. While no co-medication effect was found, apparent clearance of albendazole sulfoxide (albendazole sulfone) in the Tanzanian study population was 75% (46%) higher than that in the Côte d'Ivoire study population. Exposure-efficacy response analyses indicated that peak concentration and the time-above-exposure threshold were associated with the egg reduction rate. Conclusions: Study population but not co-administered ivermectin showed an effect on apparent clearance of albendazole sulfoxide and albendazole sulfone. Polymorphisms in drug-metabolizing enzymes and host-parasite interaction may explain this result. Difference in drug exposure did not explain the disparate efficacy responses in Tanzania and Côte d'Ivoire. Peak concentration and time-above-threshold were exposure measures associated with the egg reduction rate. Further studies evaluating genetic and resistance patterns in various regions in Africa are warranted. [ABSTRACT FROM AUTHOR]

Machine Learning (ML) is a fast-evolving field, integrated in many of today's scientific disciplines. With the recent development of neural ordinary differential equations (NODEs), ML provides a new tool to model dynamical systems in the field of pharmacology and pharmacometrics, such as pharmacokinetics (PK) or pharmacodynamics. The novel and conceptionally different approach of NODEs compared to classical PK modeling creates challenges but also provides opportunities for its application. In this manuscript, we introduce the functionality of NODEs and develop specific low-dimensional NODE structures based on PK principles. We discuss two challenges of NODEs, overfitting and extrapolation to unseen data, and provide practical solutions to these problems. We illustrate concept and application of our proposed low-dimensional NODE approach with several PK modeling examples, including multi-compartmental, target-mediated drug disposition, and delayed absorption behavior. In all investigated scenarios, the NODEs were able to describe the data well and simulate data for new subjects within the observed dosing range. Finally, we briefly demonstrate how NODEs can be combined with mechanistic models. This research work enhances understanding of how NODEs can be applied in PK analyses and illustrates the potential for NODEs in the field of pharmacology and pharmacometrics. [ABSTRACT FROM AUTHOR]

Purpose: Spironolactone is a potassium sparing diuretic used for decades. Until now, pharmacokinetic (PK) studies of spironolactone have not been conducted in infants and therefore pediatric dosing is based on expert opinion. We aimed to describe the PK profiles of spironolactone and its main metabolites (7alpha-thiomethylspironolactone (TMS) and canrenone (CAN)) in infants up to two years of age. Methods: The PK of spironolactone and its main metabolites were evaluated following an oral administration of spironolactone (1 mg/kg/dose) to pediatric patients with chronic heart failure, ascites, and/or oedema. The plasma concentration of spironolactone and metabolites (TMS and CAN) was determined using an ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS). Based on rich sampling PK data, the estimation of population PK parameters was performed using nonlinear mixed‐effects modelling software Monolix 2018R2. Results: A total of 150 spironolactone, 158 TMS, and 158 CAN concentrations from 23 patients (ages: 3 days–21 months; median weight 4.3 kg (2.2–12.6)) were available for PK analysis. A one-compartment model for spironolactone, TMS, and CAN best fitted the data. The median (range) of individual estimated apparent clearance values were 47.7 (11.9–138.1) L/h for spironolactone, 9.7 (1.5–66.9) L/h for TMS, and 1.0 (0.2–5.9) L/h for CAN. The disposition of spironolactone and metabolites was mainly affected by size of the patient: body weight explained 22% of inter-individual variability of spironolactone clearance. None of the undesirable effects of spironolactone was documented during the study period. Conclusion: The pharmacokinetics of spironolactone and its metabolites was highly variable between patients below 2 years of age. Body weight explained a significant part of this variability; this highlights the need to take it into account for dosing prescription in this population. (Clinical trial Registration Number 2013–001189-40). [ABSTRACT FROM AUTHOR]

Determining a drug dosing recommendation with a PKPD model can be a laborious and complex task. Recently, an optimal dosing algorithm (OptiDose) was developed to compute the optimal doses for any pharmacometrics/PKPD model for a given dosing scenario. In the present work, we reformulate the underlying optimal control problem and elaborate how to solve it with standard commands in the software NONMEM. To demonstrate the potential of the OptiDose implementation in NONMEM, four relevant but substantially different optimal dosing tasks are solved. In addition, the impact of different dosing scenarios as well as the choice of the therapeutic goal on the computed optimal doses are discussed. [ABSTRACT FROM AUTHOR]

Background and Objective: Infliximab, an anti-tumour necrosis factor (TNF)-α monoclonal antibody, has been approved in chronic inflammatory disease, including rheumatoid arthritis, Crohn's disease and ankylosing spondylitis. This study aimed to investigate and characterise target-mediated drug disposition of infliximab and antigen mass turnover during infliximab treatment. Methods: In this retrospective cohort of 186 patients treated with infliximab for rheumatoid arthritis, Crohn's disease or ankylosing spondylitis, trough infliximab concentrations were determined from samples collected between weeks 0 and 22 after treatment initiation. Target-mediated pharmacokinetics of infliximab was described using target-mediated drug disposition modelling. Target-mediated elimination parameters were determined for rheumatoid arthritis and Crohn's disease, assuming ankylosing spondylitis with no target-mediated elimination. Results: The quasi-equilibrium approximation of a target-mediated drug disposition model allowed a satisfactory description of infliximab concentration–time data. Estimated baseline TNF-α amounts were similar in Crohn's disease and rheumatoid arthritis (R0 = 0.39 vs 0.46 nM, respectively), but infliximab-TNF complex elimination was slower in Crohn's disease than in rheumatoid arthritis (kint = 0.024 vs 0.061 day−1, respectively). Terminal elimination half-lives were 13.5, 21.5 and 16.5 days for rheumatoid arthritis, Crohn's disease and ankylosing spondylitis, respectively. Estimated amounts of free target were close to baseline values before the next infusion suggesting that TNF-α inhibition may not be sustained over the entire dose interval. Conclusions: The present study is the first to quantify the influence of target antigen dynamics on infliximab pharmacokinetics. Target-mediated elimination of infliximab may be complex, involving a multi-scale turnover of TNF-α, especially in patients with Crohn's disease. Additional clinical studies are warranted to further evaluate and fine-tune dosing approaches to ensure sustained TNF-α inhibition. [ABSTRACT FROM AUTHOR]

Background: Moxidectin has recently attracted attention as a novel candidate for the treatment of helminth infections, including Strongyloides stercoralis. This study aims to characterize the population pharmacokinetics (PPK) of moxidectin in S. stercoralis-infected adults using a pharmacometric approach, and to perform model-based simulations to explore different drug dosing strategies. Methods: A PPK study embedded in a dose-escalation phase IIa trial was conducted in NamBak, Laos. Eight micro blood samples were collected from each of 96 S. stercoralis-infected adults following a moxidectin dose-ranging study, from 2 to 12 mg. A PPK model was developed using nonlinear mixed-effects modeling, and dosing strategies were explored using simulations in S. stercoralis-infected subjects with varying age and body weight (n = 5000 per dosing strategy). Results: A two-compartment model including delayed absorption with lag-time best described the available PK data. Allometric scaling was applied to account for the influence of body weight. High clearance was found in the infected adults (4.47 L/h [95% confidence interval 3.63–5.39] for a 70 kg individual) compared with that previously reported for healthy adults. Model-based simulations indicated similar variability in mean ± standard deviation area under the curve from time zero to infinity of 1907 ± 1552 and 2175 ± 1670 ng × h/mL in the 60–70 kg weight group, after 8 mg fixed- or weight-based dosing, respectively. Conclusion: We describe the first PPK model for moxidectin in adults with S. stercoralis infection. Equivalent exposures after fixed-dose and weight-dependent dosing strategies support the use of a simple fixed-dose approach, particularly in large-scale treatment programs. Trial Registration: Registered at ClinicalTrials.gov (NCT04056325). [ABSTRACT FROM AUTHOR]

Modeling of retrospectively collected multi-center data of a rare disease in pediatrics is challenging because laboratory data can stem from several decades measured with different assays. Here we present a retrospective pharmacometrics (PMX) based data analysis of the rare disease congenital hypothyroidism (CH) in newborns and infants. Our overall aim is to develop a model that can be applied to optimize dosing in this pediatric patient population since suboptimal treatment of CH during the first 2 years of life is associated with a reduced intelligence quotient between 10 and 14 years. The first goal is to describe a retrospectively collected dataset consisting of 61 newborns and infants with CH up to 2 years of age. Overall, 505 measurements of free thyroxine (FT4) and 510 measurements of thyrotropin or thyroid-stimulating hormone were available from patients receiving substitution treatment with levothyroxine (LT4). The second goal is to introduce a scale/location-scale normalization method to merge available FT4 measurements since 34 different postnatal age- and assay-specific laboratory reference ranges were applied. This method takes into account the change of the distribution of FT4 values over time, i.e. a transformation from right-skewed towards normality during LT4 treatment. The third goal is to develop a practical and useful PMX model for LT4 treatment to characterize FT4 measurements, which is applicable within a clinical setting. In summary, a time-dependent normalization method and a practical PMX model are presented. Since there is no on-going or planned development of new pharmacological approaches for CH, PMX based modeling and simulation can be leveraged to personalize dosing with the goal to enhance longer-term neurological outcome in children with the rare disease CH. [ABSTRACT FROM AUTHOR]

Background: Hemodialysis (HD) dose targets and ultrafiltration rate (UFR) limits for pediatric patients on chronic HD are not known and are derived from adults (spKt/V>1.4 and <13 ml/kg/h). We aimed to characterize how delivered HD dose and UFR are associated with survival in a large cohort of patients who started HD in childhood. Methods: Retrospective analysis on a cohort of patients <30 years, on chronic HD since childhood (<19 years), having received thrice-weekly HD 2004–2016 in outpatient DaVita centers. Outcome: Survival while remaining on HD. Predictors: (I) primary analysis: mean delivered dialysis dose stratified as spKt/V ≤1.4/1.4–1.6/>1.6 (Kaplan–Meier analysis), (II) secondary analyses: UFR and alternative dialysis adequacy measures [eKt/V, body-surface normalized Kt/BSA] on continuous scale (Weibull regression model). Results: A total of 1780 patients were included (age at the start of HD: 0–12y: n=321, >12–18y: n=1459; median spKt/V=1.55, eKt/V=1.31, Kt/BSA=31.2 L/m2, UFR=10.6 mL/kg/h). (I) spKt/V<1.4 was associated with lower survival compared to spKt/V>1.4–1.6 (P<0.001, log-rank test), and spKt/V>1.6 (P<0.001), with 10-year survival of 69.3% (59.4–80.9%) versus 83.0% (76.8–89.8%) and 84.0% (79.6–88.5%), respectively. (II) Kt/BSA was a better predictor of survival than spKt/V or eKt/V. UFR was additionally associated with survival (P<0.001), with increased mortality <10/>18 mL/kg/h. Associations did not alter significantly following adjustment for demographic characteristics (age, etiology of kidney disease, and ethnicity). Conclusions: Our results suggest usefulness of targeting Kt/BSA>30 L/m2 for best long-term outcomes, corresponding to spKt/V>1.4 (>12 years) and >1.6 (<12 years). In contrast to adults, higher UFR of 10–18 ml/kg/h was not associated with greater mortality in this population. [ABSTRACT FROM AUTHOR]

The objectives are to characterize oscillations of physiological functions such as heart rate and body temperature, as well as the sleep cycle from behavioral states in generally stable preterm neonates during the first 5 days of life. Heart rate, body temperature as well as behavioral states were collected during a daily 3-h observation interval in 65 preterm neonates within the first 5 days of life. Participants were born before 32 weeks of gestational age or had a birth weight below 1500 g; neonates with asphyxia, proven sepsis or malformation were excluded. In total 263 observation intervals were available. Heart rate and body temperature were analyzed with mathematical models in the context of non-linear mixed effects modeling, and the sleep cycles were characterized with signal processing methods. The average period length of an oscillation in this preterm neonate population was 159 min for heart rate, 290 min for body temperature, and the average sleep cycle duration was 19 min. Oscillation of physiological functions as well as sleep cycles can be characterized in very preterm neonates within the first few days of life. The observed parameters heart rate, body temperature and sleep are running in a seemingly uncorrelated pace at that stage of development. Knowledge about such oscillations may help to guide nursing and medical care in these neonates as they do not yet follow a circadian rhythm. [ABSTRACT FROM AUTHOR]

Providing the optimal dosing strategy of a drug for an individual patient is an important task in pharmaceutical sciences and daily clinical application. We developed and validated an optimal dosing algorithm (OptiDose) that computes the optimal individualized dosing regimen for pharmacokinetic–pharmacodynamic models in substantially different scenarios with various routes of administration by solving an optimal control problem. The aim is to compute a control that brings the underlying system as closely as possible to a desired reference function by minimizing a cost functional. In pharmacokinetic–pharmacodynamic modeling, the controls are the administered doses and the reference function can be the disease progression. Drug administration at certain time points provides a finite number of discrete controls, the drug doses, determining the drug concentration and its effect on the disease progression. Consequently, rewriting the cost functional gives a finite-dimensional optimal control problem depending only on the doses. Adjoint techniques allow to compute the gradient of the cost functional efficiently. This admits to solve the optimal control problem with robust algorithms such as quasi-Newton methods from finite-dimensional optimization. OptiDose is applied to three relevant but substantially different pharmacokinetic–pharmacodynamic examples. [ABSTRACT FROM AUTHOR]

Background: Characterizing the dynamics of serum creatinine concentrations (Scr) and associated creatinine clearance (CLcr) as a measure of kidney function in extremely low birth weight (≤ 1000 g; ELBW) neonates remains challenging. Methods: We performed a retrospective study that included longitudinal Scr (enzymatic assay) data from 148 ELBW neonates up to 6 weeks after birth. Change of Scr and inter-individual variability was characterized with nonlinear mixed-effect modeling. Key covariates such as gestational age (GA), mode of delivery (MOD), and treatment with ibuprofen or inotropic agents were investigated. Results: A total of 2814 Scr concentrations were analyzed. GA was associated with Scr at birth (higher with advancing GA), and GA and MOD showed an association with postnatal maturation of CLcr (faster clearance increase with advancing GA and after C-section). Small CLcr decrease (≤ 5%) was quantified during ibuprofen treatment. For a GA of 27 weeks, mean Scr (estimated CLcr) at birth was 0.61 mg/dl (0.23 ml/min), increasing to 0.87 mg/dl (0.27 ml/min) at day three, and decreasing to 0.36 mg/dl (0.67 ml/min) at day 42 after birth. Conclusions: We report the first mathematical model able to characterize Scr and CLcr in ELBW neonates during the first 6 weeks of life in a quantitative manner as a function of GA, MOD, and ibuprofen treatment. This model allows the derivation of GA-adjusted reference ranges for ELBW neonates and provides a rationale for normative Scr concentrations, and as such will help clinicians to further optimize monitoring and treatment decisions in this vulnerable patient population. [ABSTRACT FROM AUTHOR]

Background and Objective: Although acetaminophen is frequently used during pregnancy, little is known about fetal acetaminophen pharmacokinetics. Acetaminophen safety evaluation has typically focused on hepatotoxicity, while other events (fetal ductal closure/constriction) are also relevant. We aimed to develop a fetal–maternal physiologically based pharmacokinetic (PBPK) model (f-m PBPK) to quantitatively predict placental acetaminophen transfer, characterize fetal acetaminophen exposure, and quantify the contributions of specific clearance pathways in the term fetus. Methods: An acetaminophen pregnancy PBPK model was extended with a compartment representing the fetal liver, which included maturation of relevant enzymes. Different approaches to describe placental transfer were evaluated (ex vivo cotyledon perfusion experiments, placental transfer prediction based on Caco-2 cell permeability or physicochemical properties [MoBi®]). Predicted maternal and fetal acetaminophen profiles were compared with in vivo observations. Results: Tested approaches to predict placental transfer showed comparable performance, although the ex vivo approach showed highest prediction accuracy. Acetaminophen exposure in maternal venous blood was similar to fetal venous umbilical cord blood. Prediction of fetal acetaminophen clearance indicated that the median molar dose fraction converted to acetaminophen-sulphate and N-acetyl-p-benzoquinone imine was 0.8% and 0.06%, respectively. The predicted mean acetaminophen concentration in the arterial umbilical cord blood was 3.6 mg/L. Conclusion: The median dose fraction of acetaminophen converted to its metabolites in the term fetus was predicted. The various placental transfer approaches supported the development of a generic f-m PBPK model incorporating in vivo placental drug transfer. The predicted arterial umbilical cord acetaminophen concentration was far below the suggested postnatal threshold (24.47 mg/L) for ductal closure. [ABSTRACT FROM AUTHOR]

Background and Objective: Little is known about acetaminophen (paracetamol) pharmacokinetics during pregnancy. The aim of this study was to develop a physiologically based pharmacokinetic (PBPK) model to predict acetaminophen pharmacokinetics throughout pregnancy.Methods: PBPK models for acetaminophen and its metabolites were developed in non-pregnant and pregnant women. Physiological and enzymatic changes in pregnant women expected to impact acetaminophen pharmacokinetics were considered. Models were evaluated using goodness-of-fit plots and by comparing predicted pharmacokinetic profiles with in vivo pharmacokinetic data. Predictions were performed to illustrate the average concentration at steady state (Css,avg) values, used as an indicator for efficacy, of acetaminophen achieved following administration of 1000 mg every 6 h. Furthermore, as a measurement of potential hepatotoxicity, the molar dose fraction of acetaminophen converted to N-acetyl-p-benzoquinone imine (NAPQI) was estimated.Results: PBPK models successfully predicted the pharmacokinetics of acetaminophen and its metabolites in non-pregnant and pregnant women. Predictions resulted in the lowest Css,avg in the third trimester (median [interquartile range]: 4.5 [3.8-5.1] mg/L), while Css,avg was 6.7 [5.9-7.4], 5.6 [4.7-6.3], and 4.9 [4.1-5.5] mg/L in non-pregnant, first trimester, and second trimester populations, respectively. Assuming a constant raised cytochrome P450 2E1 activity throughout pregnancy, the molar dose fraction of acetaminophen converted to NAPQI was highest during the first trimester (median [interquartile range]: 11.0% [9.1-13.4%]), followed by the second (9.0% [7.5-11.0%]) and third trimester (8.2% [6.8-10.1%]), compared with non-pregnant women (7.7% [6.4-9.4%]).Conclusion: Acetaminophen exposure is lower in pregnant than in non-pregnant women, and is related to pregnancy duration. Despite these findings, higher dose adjustments cannot be advised yet as it is unknown whether pregnancy affects the toxicodynamics of NAPQI. Information on glutathione abundance during pregnancy and NAPQI in vivo data are required to further refine the presented model. [ABSTRACT FROM AUTHOR]

Purpose: The prodrug metamizole is prescribed intravenously for postoperative pain in children, including off-label use in infants < 1 year. We aimed to assess the pharmacokinetics of the main metabolites of metamizole in children aged 3–72 months. Methods: A single dose of 10 mg/kg metamizole was administered intravenously for postoperative analgesia. Pharmacokinetic samples were drawn at predefined time points. Pharmacokinetics of the main active metabolite 4-methylaminoantipyrine and three other metabolites was characterized by both non-compartmental and population pharmacokinetic analysis. AUC0–inf of 4-methylaminoantipyrine was calculated by non-compartmental analysis for two age cohorts (3–23 months, 2–6 years) and compared with the 80–125% range of adult dose–adjusted reference exposure (AUCref). Population pharmacokinetic analysis investigated age and weight dependency of the pharmacokinetics and optimal dosing strategies to achieve equivalent adult exposure. Results: A total of 25 children aged 5 months–5.8 years (7.8–24.8 kg) with at least one concentration sample were included; 19 children had ≥ 5 predefined samples up to 10 h after metamizole dose administration. AUC0–inf of 4-methylaminoantipyrine in children 2–6 years was 29.9 mg/L/h (95% CI 23.4–38.2), significantly lower than AUCref (80–125% range 39.2–61.2 mg/L/h). AUC0–inf of 4-methylaminoantipyrine in infants < 2 years was 43.6 mg/L/h (95% CI 15.8–119.0), comparable with AUCref, while infants < 12 months showed increased exposure. Observed variability could be partially explained by covariates weight and age. Conclusions: Age-related changes in pharmacokinetics of 4-methylaminoantipyrine requires reduced weight–based IV dosing in infants < 1 year compared with infants and children up to 6 years (5 versus 10–20 mg/kg) to achieve equivalent adult exposure. Trial registration: ClinicalTrials.gov identifier: NCT02660177. [ABSTRACT FROM AUTHOR]

Neonates, infants, and children differ from adults in many aspects, not just in age, weight, and body composition. Growth, maturation and environmental factors affect drug kinetics, response and dosing in pediatric patients. Almost 80% of drugs have not been studied in children, and dosing of these drugs is derived from adult doses by adjusting for body weight/size. As developmental and maturational changes are complex processes, such simplified methods may result in subtherapeutic effects or adverse events. Kidney function is impaired during the first 2 years of life as a result of normal growth and development. Reduced kidney function during childhood has an impact not only on renal clearance but also on absorption, distribution, metabolism and nonrenal clearance of drugs. 'Omics'-based technologies, such as proteomics and metabolomics, can be leveraged to uncover novel markers for kidney function during normal development, acute kidney injury, and chronic diseases. Pharmacometric modeling and simulation can be applied to simplify the design of pediatric investigations, characterize the effects of kidney function on drug exposure and response, and fine-tune dosing in pediatric patients, especially in those with impaired kidney function. One case study of amikacin dosing in neonates with reduced kidney function is presented. Collaborative efforts between clinicians and scientists in academia, industry, and regulatory agencies are required to evaluate new renal biomarkers, collect and share prospective pharmacokinetic, genetic and clinical data, build integrated pharmacometric models for key drugs, optimize and standardize dosing strategies, develop bedside decision tools, and enhance labels of drugs utilized in neonates, infants, and children. [ABSTRACT FROM AUTHOR]

Model-based drug development (MBDD) has been recognized as a concept to improve the efficiency of drug development. The acceptance of MBDD from regulatory agencies, industry, and academia has been growing, yet today’s drug development practice is still distinctly distant from MBDD. This manuscript is aimed at clarifying the concept of MBDD and proposing practical approaches for implementing MBDD in the pharmaceutical industry. The following concepts are defined and distinguished: PK–PD modeling, exposure–response modeling, pharmacometrics, quantitative pharmacology, and MBDD. MBDD is viewed as a paradigm and a mindset in which models constitute the instruments and aims of drug development efforts. MBDD covers the whole spectrum of the drug development process instead of being limited to a certain type of modeling technique or application area. The implementation of MBDD requires pharmaceutical companies to foster innovation and make changes at three levels: (1) to establish mindsets that are willing to get acquainted with MBDD, (2) to align processes that are adaptive to the requirements of MBDD, and (3) to create a closely collaborating organization in which all members play a role in MBDD. Pharmaceutical companies that are able to embrace the changes MBDD poses will likely be able to improve their success rate in drug development, and the beneficiaries will ultimately be the patients in need. [ABSTRACT FROM AUTHOR]

Partial adherence with a prescribed or randomly assigned dose gives rise to unintended variability in actual drug exposure in clinical practice and during clinical trials. There are tremendous costs associated with incomplete and/or improper drug intake—to both individual patients and society as a whole. Methodology for quantifying the relation between adherence, exposure and drug response is an area of active research. Modeling and statistical approaches have been useful in evaluating the impact of adherence on therapeutics and in addressing the challenges of confounding and measurement error which arise in this context. This paper reviews quantitative approaches to using adherence information in improving therapeutics. It draws heavily on applications in the area of HIV pharmacology. [ABSTRACT FROM AUTHOR]

Population pharmacokinetics has been an important technique used to explore and define relevant sources of variation in drug exposure and response in patient populations. This has been especially true in the area of antiretroviral therapy where the assurance of adequate and sustained drug exposure of multiple agents is highly correlated with therapeutic success. Population pharmacokinetic analyses across the four drug classes and 20 US FDA-approved products used to treat HIV have been published to date. The published reports were predominantly based on actual clinical trials conducted in HIV-infected patients with one or more agents administered. Modelling and simulation approaches have been used in the evaluation of antiretroviral agent outcomes incorporating problematic design and analysis factors such as sparse plasma sampling, data imbalance and censored data. Additional benefits of population modelling approaches applied to the investigation of antiretroviral agents include the ability to assess dosing compliance, understanding and quantifying drug-drug interactions in order to select dosing regimens and the screening of new drug candidates. Pharmacokinetic/pharmacodynamic models have been used to characterise the relationship between drug exposure and virological and immunological response, and to predict clinical outcome. These models offer the best opportunity for individualising and optimising patient therapy, particularly when adjusted for adherence/compliance. The impact of population pharmacokinetics in the area of antiretroviral therapy can be directly assessed by its role in the validation of surrogate markers such as viral RNA load, therapeutic drug monitoring and the management of individual patient outcomes via exposure-toxicity relationships. Each of these population pharmacokinetic outcomes has contributed to the current regulatory environment, specifically in the area of accelerated approval of new antiretroviral agents. [ABSTRACT FROM AUTHOR]

Background and objective: Telithromycin, a ketolide antibacterial, demonstrates concentration-dependent bactericidal activity against the major pathogens causing community-acquired respiratory tract infections. The objective of this study was to explore the relationships between pharmacokinetic/pharmacodynamic predictor variables, such as area under the plasma concentration-time curve (AUC) over minimum inhibitory concentration (MIC) [AUC/MIC], maximum plasma concentration (Cmax) over MIC (Cmax/MIC) and microbiological outcome from telithromycin therapy for community-acquired pneumonia (CAP). Patients and methods: Data were pooled from five phase III studies of oral telithromycin (800mg once daily for 7–10 days) for the outpatient treatment of adults with CAP. Only subjects with a single pathogen isolated at baseline, a telithromycin MIC determination and at least one plasma pharmacokinetic sample were included. Bacteriologically modified intent-to-treat (bmITT) and bacteriologically evaluable per protocol (PPb) populations were analysed. Individual AUC and Cmax Bayesian estimates were obtained with a population pharmacokinetic model. Logistic regression, nonparametric smoothing, and classification analysis and regression tree (CART) were used to assess the relationship between AUC/MIC and Cmax/MIC and microbiological outcome by pathogen. Results: The bmITT population included 224 patients (Streptococcus pneumoniae in 113, Haemophilus influenzae in 89 and Staphylococcus aureus in 22). Median telithromycin MIC was 0.015 µg/mL for S. pneumoniae, 2.0 µg/mL for H. influenzae and 0.12 µg/mL for S. aureus, with median AUC/MIC of 907.1, 6.9 and 98.4, and median Cmax/MIC of 172.0, 1.3 and 20.4 for the three pathogens, respectively. Both logistic regression and nonparametric smoothing showed the probability of microbiological cure to be consistently greater than 90% over the observed range of predictor variables. No reliable AUC/MIC or Cmax/MIC breakpoints were identified by CART. Conclusion: Telithromycin exhibits near-maximal efficacy against three major pathogens causing CAP at a dose of 800mg once daily. [ABSTRACT FROM AUTHOR]

Objective: To describe the relationship between plasma magnesium (Mg(2+)) concentration and blood pressure response in pregnant women with preeclampsia.Methods: Fifty-one preeclamptic women were studied after receiving two consecutive magnesium sulfate infusions (120 mg/kg for 1 hour and 24 mg/kg for 5 hours). Mg(2+) concentration and systolic/diastolic blood pressure were measured at 0, 0.5, 1, 2, 4, 6, 7, 9, 11, 13 and 15 hours after the beginning of the first infusion. A population pharmacokinetic-pharmacodynamic model was fitted to the data with the computer program NONMEM.Results: Pharmacokinetics were described by a two-compartment model. Population parameter estimates were 5.0 L/h for body clearance (CL), 24L for central volume (V(c), 25L for peripheral volume ((V)(p)) and 5.6 L/h for intercompartment clearance (Q). The interindividual variability in CL, V(c), V(p) and Q was 39, 26, 38, and 59%, respectively. The mean population estimates for systolic (diastolic) blood pressure were 36.8 (27.8) mm Hg for the maximum decrease (E(max)), 0.75 (0.88) mmol/L for the Mg2+ concentration (above baseline) eliciting half-maximum effect (EC(50)) and 0.76 (0.5) h(-1) for the equilibrium rate (k(eo)) of the effect compartment model.Conclusion: Mg(2+ )concentrations within the range (2-4 mmol/L) proposed for treatment of preeclampsia produce greater than half-maximal lowering of systolic and diastolic blood pressure. [ABSTRACT FROM AUTHOR]

The article offers information on the International Society of Pharmacometrics (ISoP) which evolved from the American Society of Pharmacometrics (AsoP). The change from ASoP to ISoP was due to the increasing number of its international members all over the world. Its vision and mission remain the same which is the promotion of the role of pharmacometrics in advancing the discovery, development and utilization of new medicines for treating diseases to improve human health and well being.

The article provides information on the 2013 American Conference on Pharmaceutics (ACoP) to be held in Fort Lauderdale, Texas.

The authors comment on the affiliation between the American Society of Pharmacometrics (ASoP) and the "Journal of Pharmacokinetics and Pharmacodynamics," under which the journal is designated as an official publication of ASoP. They relate that the strategic partnership is in line with the mission of ASoP to promote the role of pharmacometrics in drug development. They announce the selection of Peter Bonate as designated associate editor of ASoP to the journal.