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Registration of innovative biologics in Emerging Markets (EMs) poses many opportunities and challenges. The BRIC-MT countries (Brazil, Russia, India, China, Mexico, and Turkey) that are the fastest growing markets and regulators in these countries have imposed certain requirements, including the need for local clinical studies, for registration of biologics. The regulatory landscape in these countries is rapidly evolving, which necessitates an up-to-date understanding of such requirements. There is growing evidence which suggests that race, after accounting for body weight differences, may not influence the pharmacokinetics of biologics to the same extent that it does for small molecules. Thus, the requirements for clinical pharmacology trials in EMs are driven mainly by regulatory needs set forth by local Ministry of Health. In addition to the clinical Phase I to III studies done in the global program that supports registration in large geographies, countries such as China require local single and multiple dose Phase I studies. Participating in global studies with clinical sites within their country may be sufficient for some markets, while other regulators may be satisfied with a Certificate of Pharmaceutical Product. This paper discusses the current requirements for registration of innovative biologics in key EMs. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) has been shown to alter the pharmacokinetics of drugs that are eliminated not only via the renal pathway but also by nonrenal clearance and transport. Dosing recommendations in subjects with CKD have historically come from small pharmacokinetic (PK) studies, which have been insulated from the broader clinical development strategy. Opportunities for prospective strategic integration of both preclinical and clinical data on drug clearance mechanisms, model-based approaches, and clinical knowledge of therapeutic index are therefore often missed in designing and analyzing the results of PK studies in subjects with CKD, and eventually providing dosing recommendations. These considerations are valuable in designing informative PK studies in subjects with CKD, as well as for guiding kidney function-related inclusion/ exclusion criteria in the broader clinical program and ultimately defining dosing guidelines that optimize benefit-risk balance for these special patient populations based on all available data. This paper offers points to consider for drug developers to increase adoption of a contemporary multidisciplinary approach, which includes key considerations on study design and conduct, methodologies for analysis (population PK and physiologically based PK modeling), and a roadmap to interpret the effect of kidney function on the overall benefit-risk profile of drugs in development. [ABSTRACT FROM AUTHOR]

Use of the immunomodulators thiopurines and methotrexate (MTX) in the treatment of inflammatory bowel disease (IBD), i.e., Crohn's disease and ulcerative colitis (UC), is considered to be good clinical practice. However, despite being administered to a considerable number of IBD patients over the years, questions remain about the most rational treatment regimens of azathioprine (AZA), 6-mercaptopurine (6-MP), and MTX, and results from a range of recent studies necessitate increased attention to how to optimize the use of these immunomodulators. First and foremost, it is of utmost importance to define the subgroup of IBD patients in need of immunomodulators, including those in need of combination therapy with biologic agents, especially because some side effects may be rather severe. Second, colorectal cancer is observed more often in IBD patients than in the background population. However, a recent nationwide Dutch study pointed to a preventive effect of thiopurines. Finally, the need for an appropriate approach to the discontinuation of immunomodulators is emphasized. Since controversy continues regarding the most appropriate use of immunomodulators, this paper is focusing on pharmacokinetics, pharmacogenetics, and therapeutic blood testing, as well as the occurrence of adverse events, when using AZA, 6-MP, and MTX in an attempt to determine a more up-to-date and rational treatment regimen in IBD. [ABSTRACT FROM AUTHOR]

Obesity remains a US national health crisis and a growing concern worldwide. Concerningly, individuals who are obese are at an increased risk for comorbid diseases that include, but are not limited to, hypertension, diabetes, cardiovascular disease, and cancer. Beyond the risk for developing these conditions, obesity may also impact the pharmacological activity of the therapies being used to treat them and other disease states. The pharmacokinetics (PK), pharmacodynamics (PD), safety, and efficacy of therapies, both currently marketed and under clinical development, may be directly impacted by the physiological alterations that occur secondary to the occurrence of chronic excess body weight. The increased prevalence of this disease should not be ignored. Both private and federal institutions involved in drug research and development should consider, as appropriate, a greater inclusion of individuals who are obese in clinical trials throughout the entirety of drug development, and leverage the available PK, PD, safety, and efficacy data to make more informed dosing recommendations. [ABSTRACT FROM AUTHOR]

An objective of the Precision Medicine Initiative, launched in 2015 by the US Food and Drug Administration and National Institutes of Health, is to optimize and individualize dosing of drugs, especially anticancer agents, with high pharmacokinetic and pharmacodynamic variability. The American Society of Clinical Oncology recently reported that 40% of obese patients receive insufficient chemotherapy doses and exposures, which may lead to reduced efficacy, and recommended pharmacokinetic studies to guide appropriate dosing in these patients. These issues will only increase in importance as the incidence of obesity in the population increases. This publication reviews the effects of obesity on (1) tumor biology, development of cancer, and antitumor response; (2) pharmacokinetics and pharmacodynamics of small‐molecule anticancer drugs; and (3) pharmacokinetics and pharmacodynamics of complex anticancer drugs, such as carrier‐mediated agents and biologics. These topics are not only important from a scientific research perspective but also from a drug development and regulator perspective. Thus, it is important to evaluate the effects of obesity on the pharmacokinetics and pharmacodynamics of anticancer agents in all categories of body habitus and especially in patients who are obese and morbidly obese. As the effects of obesity on the pharmacokinetics and pharmacodynamics of anticancer agents may be highly variable across drug types, the optimal dosing metric and algorithm for difference classes of drugs may be widely different. Thus, studies are needed to evaluate current and novel metrics and methods for measuring body habitus as related to optimizing the dose and reducing pharmacokinetic and pharmacodynamic variability of anticancer agents in patients who are obese and morbidly obese. [ABSTRACT FROM AUTHOR]

This study aimed to optimize the dosing regimens of voriconazole (VRC) for pediatric patients after hematopoietic cell transplantation with different cytochrome P450 (CYP) 2C19 phenotypes and body weights, based on pharmacokinetic (PK)/pharmacodynamic (PD) analysis. The PK parameters of VRC were derived from previous literature. Combined with key factors affecting VRC, patients were categorized into 9 subgroups based on different CYP2C19 phenotypes (poor metabolizer/intermediate metabolizer, normal metabolizer, and rapid metabolizer/ultrarapid metabolizer) and typical body weights (15, 40, and 65 kg). Monte Carlo simulation was used to investigate dosing regimens for different groups. The area under the 24‐hour free drug concentration–time curve to the minimum inhibitory concentration (MIC) > 25 was used as the target value for effective treatment. The probability of target achievement and the cumulative fraction of response were determined on the basis of the assumed MICs and MICs distribution frequency of Aspergillus species and Candida species. When the MIC was ≤1 mg/L, 4 mg/kg every 12 hours was sufficient for optimal effects in groups 1‐3 and groups 5 and 6; however, 6 mg/kg every 12 hours was required for group 4, and 8 mg/kg every 12 hours was required for groups 7‐9. In empirical treatment, lower (2‐6 mg/kg every 12 hours) and higher (6‐12 mg/kg every 12 hours) dosing regimens were recommended for Candida spp. and Aspergillus spp., respectively. Our findings will assist in selecting appropriate dosing regimens of VRC for pediatric patients after hematopoietic cell transplantation with different CYP2C19 phenotypes and body weights. Clinically, it is better to continuously adjust the dosing on the basis of the therapeutic drug monitoring. [ABSTRACT FROM AUTHOR]

The article presents the discussion on correction "Ofoegbu A, Ettienne EB. Pharmacogenomics and Morphine. J Clin Pharmacol."

This article presents the population pharmacokinetic (PopPK) analysis and exposure‐response analyses for the primary efficacy end point—acute graft‐versus‐host disease (aGVHD) day 28 response—and select safety measures (incidence of thrombocytopenia, hypertriglyceridemia, and cytomegalovirus infection) from a phase 3 randomized, double‐blind study comparing itacitinib plus corticosteroids versus placebo plus corticosteroids for the treatment of aGVHD. The PopPK data set contained sparse data from patients with aGVHD and select enriched data from healthy volunteers. The structural model was a 2‐compartment model with first‐order elimination and dose‐dependent nonlinear absorption with dual first‐order absorption pathways with lag times. Strong cytochrome P450 (CYP) 3A inhibitor coadministration, moderate renal impairment, and participant population (healthy volunteers vs patients with aGVHD) were covariates on apparent clearance. Participant population was also a covariate on apparent intercompartmental clearance and lag time of the secondary absorption compartment. Apparent clearance decreased 42% with coadministration of strong CYP3A inhibitors. Simulations supported the following dose reductions with concomitant use of a strong CYP3A inhibitor: 300 mg once daily to 200 mg once daily, 400 mg once daily to 300 mg once daily, and 600 mg once daily to 400 mg once daily. No dose adjustment is recommended for any other covariate based on the magnitude of impact when they were retained in the model. The exposure‐response relationship was characterized between itacitinib exposure and probability of aGVHD day 28 response using a linear logistic regression model. Both itacitinib exposure and aGVHD risk status were significant predictors of response. There was no relationship between itacitinib exposure and thrombocytopenia, hypertriglyceridemia, or cytomegalovirus infection. [ABSTRACT FROM AUTHOR]

Direct oral anticoagulants have been an increasingly used class of drugs in the setting of nonvalvular atrial fibrillation, defying vitamin K antagonists' monopoly when it comes to anticoagulation due to its several limitations. Direct oral anticoagulants (DOACs) have entered the market as a noninferior and safer option in comparison with vitamin K antagonists, as their respective phase III clinical trials proved. The aim of this article was to update and summarize data on their clinical pharmacology and to review real‐world data to know their comparative effectiveness and safety. We performed a systematic review using PubMed, Google Scholar, Embase, and Web of Science as search engines. Regarding pharmacodynamics, there were no substantial changes reported from their original profile. There were many advances in the knowledge about clinical pharmacokinetics of DOACs that have had a direct impact on their clinical use, mainly related to drug‐drug interactions. In a real‐world setting, DOACs have shown to be noninferior in preventing thromboembolic events compared to vitamin K antagonists. In regards to safety, DOACs have shown a lower bleeding risk relative to warfarin. Comparison between DOACs has demonstrated rivaroxaban to have the highest bleeding risk. Overall, the evidence gathered showed few changes from the original data presented in phase III clinical trials, concluding that their real‐world use coincides greatly with them. [ABSTRACT FROM AUTHOR]

Through examining the incidence of cardiovascular diseases (CVDs) among nonsteroidal anti‐inflammatory drug (NSAID) users and nonusers, this study aims to compare the risks contributed by different NSAIDs in a Chinese population. The retrospective cohort including 4 298 368 adults without CVD from electronic health records between 2008 and 2017 in Hong Kong was adopted. A total of 4.5% of individuals received NSAIDs including celecoxib, etoricoxib, diclofenac, ibuprofen, indomethacin, mefenamic acid, or naproxen for ≥4 consecutive weeks at baseline. Cox regression, including NSAID use as a time‐dependent covariate and adjusted with patient's characteristics, was conducted to examine the association between NSAID exposure and incident CVD. After a median follow‐up of 6.9 years (30 million person‐years), a total of 258 601 cases of incident CVD was recorded. NSAID use was shown to be associated with a significantly higher risk of CVD (hazard ratio [HR], 1.32 [95%CI, 1.28–1.37]) compared to non‐NSAID use. Similar results in coronary heart disease (HR, 1.37 [95%CI, 1.31–1.43]), stroke (HR, 1.27 [95%CI, 1.21–1.33]), and heart failure (HR, 1.25 [95%CI, 1.16–1.34]) were obtained. Overall, similar CVD risk was observed across users of NSAIDs except for etoricoxib, which showed a higher risk (HR, 2.01 [95%CI, 1.63–2.48]). Considering that a higher CVD risk was consistently displayed among NSAID users, NSAIDs should be used cautiously, and the usage of etoricoxib in the Chinese population should be reviewed. [ABSTRACT FROM AUTHOR]

To streamline drug development, the United States Food and Drug Administration (FDA) can consider the extrapolation of adult efficacy data to children when the disease and drug effects are sufficiently similar. This study explored whether the relationship between drug exposure and response for selected drugs in systemic lupus erythematosus (SLE) was sufficiently similar to support a consideration of the extrapolation of adult efficacy data to children of ≥5 years of age. An exposure–response analysis of drugs used to treat SLE was conducted using published exposure versus response and efficacy versus time data. Statistical analyses included noncompartmental analysis of a drug's area under the effect curve and direct Imax pharmacodynamic (PD) modeling. Six drugs were included: azathioprine, belimumab, cyclophosphamide, hydroxychloroquine, mycophenolate/mycophenolic acid, and rituximab. For belimumab, the net change in responders at week 52 (the primary end point) was nearly identical between 1 adult trial and the pediatric trial. For mycophenolate, PD modeling suggested no significant differences in exposure and SLE disease activity between adults and children. For azathioprine, cyclophosphamide, hydroxychloroquine, and rituximab the data were not sufficient to quantitatively characterize the exposure–response relationship, but the clinical or pharmacologic response between children and adults was similar overall. Adult SLE data should be leveraged to guide pediatric drug development programs and identify areas with residual uncertainty regarding the effectiveness or safety of a drug in children. The degree to which efficacy extrapolation can reduce clinical trial requirements in pediatric SLE should be individualized for each new drug product, depending in part on the mechanism of action of the drug and the similarity of disease manifestations in children and adults. [ABSTRACT FROM AUTHOR]

Lamotrigine is the most widely used anti‐epileptic drug in pregnancy because of its low teratogenicity. However, there is an increased metabolism and clearance of lamotrigine in pregnancy contributing to suboptimal drug therapy and poor disease control, prompting the need for proactive dosage adjustments. The present study aimed to develop a pharmacometric model‐based framework for recommending an optimal dosage regimen for lamotrigine in pregnancy. A systematic review was performed to obtain aggregate data from the literature on the clearance of lamotrigine in pregnancy. The data were incorporated into simulations using PUMAS software to estimate the plasma concentrations at the preconception stage and during the 3 trimesters of pregnancy. Simulated drug exposures for different doses were investigated to ascertain plasma concentrations similar to the preconception value and above the minimum effective concentration. The simulated mean steady‐state trough plasma concentrations of lamotrigine were significantly decreased in pregnant women over the course of the 3 trimesters (3.17 ± 0.93 mg/L, 2.14 ± 0.86 mg/L, and 1.51 ± 0.65 mg/L, respectively), compared with non‐pregnant women (4.31 ± 1.14 mg/L) (P <.001). The simulation studies revealed that doses of 150 mg, 175 mg, 225 mg, and 250 mg twice daily in the preconception stage and the 3 trimesters, respectively, achieve the target concentrations. Thus, the model‐informed dosage regimen of lamotrigine proposed in this study shall be used to initiate appropriate dosing in pregnant women; however, the safety and efficacy of the drug must be assured through therapeutic drug monitoring in order to avoid therapeutic failure of lamotrigine in pregnancy. [ABSTRACT FROM AUTHOR]

Artemisinin is an antimalarial compound derived from the plant Artemisia annua L., also known as sweet wormwood. According to the World Health Organization, artemisinin‐based combination therapy (ACT) is an essential treatment for malaria, specifically Plasmodium falciparum, which accounts for most malaria‐related mortality. ACTs used to treat uncomplicated malaria include artemether‐lumefantrine, artesunate‐amodiaquine, artesunate‐mefloquine, artesunate‐sulphadoxine‐pyrimethamine, and dihydroartemisinin‐piperaquine. Although the mechanism of action and clinical capabilities of artemisinin in malaria treatment are widely known, more information on the potential for drug interactions needs to be further investigated. Some studies show pharmacokinetic and pharmacodynamic drug interactions with HIV antiviral treatment but few studies have been conducted on most other drug classes. Based on known genotypes of cytochrome P450 (CYP) enzymes, CYP2B6 and CYP3A are primarily involved in the metabolism of artemisinin and its derivatives. Reduced functions in these enzymes can lead to subtherapeutic concentrations of the active metabolite, dihydroartemisinin, that may cause treatment failure, which has been shown in some studies with cardiovascular, antibiotic, and antiparasitic drugs. Although the clinical importance remains unclear to date, clinicians should be aware of potential drug‐drug interactions and monitor patients on ACT closely. [ABSTRACT FROM AUTHOR]

Dipeptidyl peptidase-4 (DPP-4) inhibition is a well- characterized treatment for type 2 diabetes mellitus (T2DM). The objective of this model-based meta-analysis was to describe the time course of HbA1c response after dosing with alogliptin (ALOG), saxagliptin (SAXA), sitagliptin (SITA), or vildagliptin (VILD). Publicly available data involving late-stage or marketed DPP-4 inhibitors were leveraged for the analysis. Nonlinear mixed-effects modeling was performed to describe the relationship between DPP-4 inhibition and mean response over time. Plots of the relationship between metrics of DPP-4 inhibition (ie, weighted average inhibition [WAI], time above 80% inhibition, and trough inhibition) and response after 12 weeks of daily dosing were evaluated. The WAI was most closely related to outcome, although other metrics performed well. A model was constructed that included fixed effects for placebo and drug and random effects for intertrial variability and residual error. The relationship between WAI and outcome was nonlinear, with an increasing response up to 98% WAI. Response to DPP-4 inhibitors could be described with a single drug effect. The WAI appears to be a useful index of DPP-4 inhibition related to HbA1c. Biomarker to response relationships informed by model-based meta-analysis can be leveraged to support study designs including optimization of dose, duration of therapy, and patient population. [ABSTRACT FROM PUBLISHER]

The author reflects on the importance of information and communication technology (ICT) application in an innovative medical curriculum of clinical pharmacology. Problem-based learning (PBL) approach is used to determine the pharmacokinetics and pharmacodynamics of drugs to treat patients with chronic diseases. Information regarding the topics presented during the 2006 International Union of Physiological Sciences (IUPS) conference held in Beijing, China is also presented.

Anti–vascular endothelial growth factor (VEGF) therapy is used to slow the disease progression of neovascular age‐related macular degeneration. Due to the treatment burden of frequent intravitreal injections, anti‐VEGFs are often used on treat and extend protocols rather than the labeled frequency. The current goal of anti‐VEGF drug development is to minimize treatment burden by reducing the number of intravitreal injections. The purpose of this systemic review and model‐based meta‐analysis (MBMA) was to (1) perform modeling to describe the disease progression of neovascular age‐related macular degeneration in the absence of treatment, as well as in the presence of abicipar, aflibercept, brolucizumab, or ranibizumab intervention; (2) and to simulate virtual head‐to‐head comparisons among the drugs with an extended dose schedule of once every 12 weeks (Q12). Data sources were PubMed, internal Allergan data, www.clinicaltrials.gov, and www.clinicaltrialsregister.eu. Eligibility assessment was performed by 2 independent review authors. Randomized, controlled trials that had at least 1 arm with an anti‐VEGF (aflibercept, abicipar, bevacizumab, brolucizumab, pegaptanib, or ranibizumab), a control arm of placebo or anti‐VEGF, a treatment duration of at least 4 months, reported best‐corrected visual acuity data, and at least 20 patients were included. A total of 22 trials, consisting of 55 arms, from across 9500+ subjects and 500+ best‐corrected visual acuity observations were used to develop the model. Consistent with reported data, results from the model showed that abicipar Q12 underperformed ranibizumab (every 4 weeks), aflibercept (every 4 weeks), and brolucizumab (every 8 weeks/Q12) labeled dosing schedules. However, when all drugs were virtually tested using the extended schedule, abicipar outperformed ranibizumab and aflibercept and produced a similar week 52 change from baseline as brolucizumab. Predicted week 52 changes from baseline were 5.92 ± 1.02, 3.04 ± 1.61, 6.61 ± 0.284, and 3.02 ± 2.35 best‐corrected visual acuity letters for abicipar, aflibercept, brolucizumab, and ranibizumab, respectively, using the Q12 schedule. Results demonstrate the feasibility of Q12 dosing with clinically meaningful letter gains for abicipar and brolucizumab. The model developed under this MBMA has utility for exploring different regimens for existing or novel anti‐VEGF agents. [ABSTRACT FROM AUTHOR]

As a first‐in‐class, selective, potent inhibitor of the isocitrate dehydrogenase‐2 (IDH2) mutant protein, enasidenib was approved by the US Food and Drug Administration in 2017 for the treatment of adult patients with relapsed or refractory acute myeloid leukemia with an isocitrate dehydrogenase‐2 mutation. An in vitro study showed that enasidenib at clinically relevant concentrations has effects on multiple drug metabolic enzymes and transporters, including inhibition of P‐glycoprotein, breast cancer resistance protein, organic anion transporter (OAT) P1B1, and OATP1B3 transporters. Therefore, a drug‐drug interaction study was conducted to assess the impact of enasidenib at steady state on the pharmacokinetics of several probe compounds in patients with relapsed or refractory acute myeloid leukemia or myelodysplastic syndrome, including the probes herein described in this article, digoxin and rosuvastatin. Results from 8 patients (all Asian) with a mean age of 67.1 years showed that following coadministration of enasidenib (100 mg, 28‐day once‐daily schedule) for 28 days (at steady state), digoxin's (0.25 mg) area under the plasma concentration–time curve from time 0 to 30 days was 1.2‐fold (90% confidence interval, 0.9‐1.6), compared with digoxin alone. Following coadministration of enasidenib (100 mg, 28‐day once‐daily schedule) for 28 days (at steady state), rosuvastatin's (10 mg) area under the plasma concentration–time curve from time 0 to infinity was 3.4‐fold (90% confidence interval, 2.6‐4.5) compared with rosuvastatin alone. These results should serve as the basis for dose recommendations for drugs that are substrates of P‐glycoprotein, breast cancer resistance protein, OATP1B1, and OATP1B3 transporters, when used concomitantly with enasidenib. [ABSTRACT FROM AUTHOR]

Cilostazol, a phosphodiesterase III inhibitor, has vasodilating and antiplatelet properties with a low rate of bleeding complications. It has been used over the past 25 years for improving intermittent claudication in patients with peripheral artery disease (PAD). Cilostazol also has demonstrated efficacy in patients undergoing percutaneous revascularization procedures for both PAD and coronary artery disease. In addition to its antithrombotic and vasodilating actions, cilostazol also inhibits vascular smooth muscle cell proliferation via phosphodiesterase III inhibition, thus mitigating restenosis. Accumulated evidence has shown that cilostazol, due to its "pleiotropic" effects, is a useful, albeit underutilized, agent for both coronary artery disease and PAD. It is also potentially useful after ischemic stroke and is an alternative in those who are allergic or intolerant to classical antithrombotic agents (eg, aspirin or clopidogrel). These issues are herein reviewed together with the pharmacology and pharmacodynamics of cilostazol. Large studies and meta-analyses are presented and evaluated. Current guidelines are also discussed, and the spectrum of cilostazol's actions and therapeutic applications are illustrated. [ABSTRACT FROM AUTHOR]

Population pharmacokinetics consists of analyzing pharmacokinetic (PK) data collected in groups of individuals. Population PK is widely used to guide drug development and to inform dose adjustment via therapeutic drug monitoring and model‐informed precision dosing. There are 2 main types of population PK methods: parametric (P) and nonparametric (NP). The characteristics of P and NP population methods have been previously reviewed. The aim of this article is to answer some frequently asked questions that are often raised by scholars, clinicians, and researchers about P and NP population PK methods. The strengths and limitations of both approaches are explained, and the characteristics of the main software programs are presented. We also review the results of studies that compared the results of both approaches in the analysis of real data. This opinion article may be informative for potential users of population methods in PK and guide them in the selection and use of those tools. It also provides insights on future research in this area. [ABSTRACT FROM AUTHOR]

Baricitinib is a JAK1/2 inhibitor that was first approved for treating moderate to severe rheumatoid arthritis (RA) but that later showed considerable efficacy in the control of exaggerated inflammatory responses that occur in a wide range of diseases. There is a growing body of evidence, obtained from clinical trials and case reports, demonstrating clinical and paraclinical improvement in patients following administration of baricitinib including RA, systemic lupus erythematosus, psoriasis, atopic dermatitis, alopecia areata, interferon‐mediated autoinflammatory diseases, graft‐versus‐host disease, diabetic kidney disease, and, recently, coronavirus disease‐19. However, despite overall encouraging results, many adverse effects have been observed in baricitinib‐treated patients, ranging from simple infections to increased risk of malignancies, particularly in long‐term use. The significant efficacy of baricitinib, versus the probable adverse effects, urge further investigation before establishing it as a part of standard therapeutic protocols. Here, we have provided a review of the studies that have used baricitinib for treating various inflammatory disorders and summarized the advantages and disadvantages of its administration. [ABSTRACT FROM AUTHOR]

Hospitalized pediatric patients and those with complex or chronic conditions treated on an outpatient basis are commonly prescribed multiple drugs, resulting in increased risk for drug‐drug interactions (DDIs). Although dedicated DDI evaluations are routinely performed in healthy adult volunteers during drug development, they are rarely performed in pediatric patients because of ethical, logistical, and methodological challenges. In the absence of pediatric DDI evaluations, adult DDI data are often extrapolated to pediatric patients. However, the magnitude of a DDI in pediatric patients may differ from adults because of age‐dependent physiological changes that can impact drug disposition or response and because of other factors related to the drug (eg, dose, formulation) and the patient population (eg, disease state, obesity). Therefore, the DDI magnitude needs to be assessed in children separately from adults, although a lack of clinical DDI data in pediatric populations makes this evaluation challenging. As a result, pediatric DDI assessment relies on the predictive performance of the pharmacometric approaches used, such as population and physiologically based pharmacokinetic modeling. Therefore, careful consideration needs to be given to adequately account for the age‐dependent physiological changes in these models to build high confidence for such untested DDI scenarios. This review article summarizes the key considerations related to the drug, patient population, and methodology, and how they can impact DDI evaluation in the pediatric population. [ABSTRACT FROM AUTHOR]

Half‐life is a standard result reported with analysis of pharmacokinetic data. Different definitions such as noncompartmental half‐life, terminal half‐life, effective half‐life, and context‐sensitive half‐life can yield substantially different estimates of the quantity "half‐life." Time to attainment of steady‐state conditions is generally derived from (terminal) half‐life and therefore sensitive toward the definition of half‐life. Thus, estimates of the time to attain steady state must be provided with a precise definition of steady state and the method used for estimation, particularly for drugs with long (terminal) half‐life. For clinical purposes, terminal half‐life can have limited relevance if drug concentrations in the terminal elimination phase are low. A general rule for which half‐life to use is infeasible. While limited accumulation can be negligible if a plateau in pharmacokinetics/pharmacodynamics is reached or with a wide therapeutic window (ie, exposure range), small additional drug accumulation can be highly relevant for drugs with a narrow therapeutic window. Beyond the average, estimation of individual time to attainment of steady state can add highly relevant information about the variability between subjects. Simulations from population models and the use of different definitions of steady state provide an assessment of robustness of the results. The relevance of accurate estimation of time to attainment of steady state is illustrated with cenerimod, an sphingosine‐1‐phosphate 1 receptor modulator with long half‐life currently in clinical development for which estimates of time to steady state ranged from 35 to 110 days with different calculations. [ABSTRACT FROM AUTHOR]

Pregnancy is associated with several physiological changes that can alter the pharmacokinetics (PK) and pharmacodynamics of drugs. These may require dosing changes in pregnant women to achieve drug exposures comparable to the nonpregnant population. There is, however, limited information available on the PK and pharmacodynamics of drugs used during pregnancy. Practical difficulties in performing PK studies and potential liability issues are often the reasons for the availability of limited information. Over the past several years, there has been a rapid development in the application of various modeling strategies such as population PK and physiologically based PK modeling to provide guidance on drug dosing in this special patient population. Population PK models rely on measured PK data, whereas physiologically based PK models integrate physiological, preclinical, and clinical data to quantify changes in PK of drugs in various patient populations. These modeling strategies offer a promising approach to identify the drugs with PK changes during pregnancy and guide dose adjustment in pregnant women. This review focuses on PBPK modeling to guide drug therpay in pregnancy. [ABSTRACT FROM AUTHOR]

The incidence of migraine is higher among women than men and peaks during the reproductive years, when contraceptive medication use is common. Atogepant, a potent, selective antagonist of the calcitonin gene‒related peptide receptor—in development for migraine prevention—is thus likely to be used by women taking oral contraceptives. This phase 1, open‐label, single‐center, 2‐period, fixed‐sequence study examined the effect of multiple‐dose atogepant 60 mg once daily on the single‐dose pharmacokinetics of a combination oral contraceptive, ethinyl estradiol 0.03 mg and levonorgestrel 0.15 mg (EE/LNG), in healthy postmenopausal or oophorectomized women. For participants in period 1, a single dose of EE/LNG was followed by a 7‐day washout. In period 2, atogepant was given once daily on days 1‐17; an oral dose of EE/LNG was coadministered with atogepant on day 14. Plasma pharmacokinetic parameters for EE and LNG were assessed following administration with and without atogepant. Twenty‐six participants aged 45‐64 years enrolled; 22 completed the study in accordance with the protocol. The area under the concentration‐time curve extrapolated to infinity (AUC0‐∞) of LNG was increased by 19% when administered with atogepant. Coadministration of atogepant and a single dose of EE/LNG did not substantially alter the pharmacokinetics of EE; the ∼19% increase in plasma AUC0‐∞ of LNG is not anticipated to be clinically significant. Overall, atogepant alone and in combination with EE/LNG was generally well tolerated, with no new safety signals identified. [ABSTRACT FROM AUTHOR]

This pilot study examined how exemestane (an aromatase inhibitor [AI]) affected osteoprotegerin (OPG) urine concentrations in postmenopausal women. Exemestane (25 mg, single dose) was given to 14 disease‐free women past menopause in this nonrandomized, open‐label study. Before dosing, urine specimens were gathered. Three days later, these women returned to provide urine specimens for pharmacokinetic (measurement of major parent drug and enzymatic product) and pharmacodynamic (profiling of OPG) analysis. Urine concentrations of the major parent drug (exemestane) and enzymatic product (17‐hydroexemestane) were quantified using liquid chromatography‐tandem mass spectrometry. An analyst software package was used for data processing. Following the manufacturer's guidelines, OPG urine concentrations were quantified using a human osteoprotegerin TNFRSF11b ELISA kit from Sigma‐Aldrich. A microplate reader helped to carry out OPG data analysis and processing. Our results highlight that OPG urine concentrations were decreased 3 days after drug dosage (mean predosage OPG concentration, 61.4 ± 24.1 pg/mL; vs mean postdosage OPG concentration, 45.7 ± 22.1 pg/mL; P =.02, Wilcoxon rank test). Among the 14 volunteers enrolled in the study, 4 subjects had an increase of less than 1‐fold, and the rest showed an average of a 2‐fold decrease in OPG concentration (range, 1.1‐5.4; standard deviation, 1.3) after exemestane administration. There was no association between fold decrease in OPG urine concentration and the pharmacokinetics of the major parent drug (exemestane) and its enzymatic product (17‐hydroexemestane). We concluded that one of the off‐target pharmacological effects of AIs (eg ,exemestane) may result in the reduction of osteoprotegerin. [ABSTRACT FROM AUTHOR]

Upadacitinib is a selective Janus kinase (JAK) 1 inhibitor being developed for treatment of rheumatoid arthritis. This study characterizes the relationships between upadacitinib exposure and interleukin (IL)‐6–induced signal transducer and activator of transcription proteins 3 (STAT3) phosphorylation (pSTAT3) and IL‐7–induced STAT5 phosphorylation (pSTAT5) in the ex vivo setting as measures for JAK1 and JAK1/JAK3 inhibition, respectively, with comparison to tofacitinib. Drug plasma concentrations and ex vivo IL‐6–induced pSTAT3 and IL‐7–induced pSTAT5 in blood from subjects evaluated in 2 phase 1 studies who received immediate‐release 1 mg to 48 mg upadacitinib, 5 mg twice daily (BID) tofacitinib, or placebo were determined. Exposure‐response models were developed, and the effects of different upadacitinib doses on ex vivo biomarker responses were simulated and compared to tofacitinib. Upadacitinib (and tofacitinib) reversibly inhibited IL‐6–induced pSTAT3 and IL‐7–induced pSTAT5 in a concentration‐dependent manner. Model‐estimated values of 50% of the maximum effect were 60.7 nM for upadacitinib and 119 nM for tofacitinib for IL‐6–induced pSTAT3 inhibition, and 125 nM for upadacitinib and 79.1 nM for tofacitinib for IL‐7–induced pSTAT5 inhibition. Tofacitinib 5 mg BID is estimated to have a similar magnitude of effect on IL‐6–induced pSTAT3 to ∼3 mg BID of upadacitinib (immediate‐release formulation), whereas a 4‐fold higher dose of upadacitinib (∼12 mg BID), is estimated to show a similar magnitude of inhibition on IL‐7–induced pSTAT5 as tofacitinb 5 mg BID. This study confirms that in humans, upadacitinib has greater selectivity for JAK1 vs JAK3 relative to the rheumatoid arthritis approved dose of tofacitinib, and results from these analyses informed the selection of upadacitinib IR doses evaluated in phase 2. [ABSTRACT FROM AUTHOR]

Itacitinib is a potent, selective JAK‐1 inhibitor currently in phase 3 development for the treatment of acute and chronic graft‐versus‐host disease (GVHD) in combination with corticosteroids. Itacitinib is primarily eliminated via metabolism by cytochrome P‐450 (CYP)3A4 with minimal renal elimination. A drug‐drug interaction study was conducted to evaluate the impact of the strong CYP3A inhibitor itraconazole or the strong CYP3A4 inducer rifampin on the pharmacokinetics of itacitinib in healthy volunteers. In cohort 1, subjects received 200 mg sustained release (SR) tablets of itacitinib on days 1 and 6 and 200 mg itraconazole on days 2‐7. In cohort 2, subjects received 200 mg SR itacitinib on days 1 and 9 and 600 mg rifampin on days 2‐9. Thirty‐six subjects were enrolled, 18 in each cohort with 17 completing itacitinib dosing in cohort 1 and 15 completing itacitinib dosing in cohort 2. Coadministration of itraconazole with itacitinib resulted in a nearly 5‐fold increase in area under the concentration‐time curve (AUC0‐∞) (geometric mean ratio [GMR] 4.88, 90%Cl 4.17‐5.72) and an ∼3‐fold increase in peak concentration (Cmax) (GMR 3.15, 90%Cl 2.58‐3.54). Coadministration of rifampin with itacitinib resulted in a nearly 80% decrease in AUC0‐∞ (GMR 0.208, 90%Cl 0.173, 0.249) and Cmax (GMR 0.231, 90%Cl 0.195, 0.274). Results of this study informed the study design of the phase 3 GVHD protocols with regard to coadministration of strong CYP3A inhibitors and CYP3A4 inducers. These data combined with phase 3 data will inform final dosing recommendations. [ABSTRACT FROM AUTHOR]

Joining the Food and Drug Administration/University of Maryland Center of Excellence in Regulatory Science and Innovation Workshop to discuss and identify solutions to optimize pediatric drug development and, in particular, to address the question as to whether we are ready to incorporate pediatric ontogeny into modeling was the opportunity to share learnings, confront ideas, and present examples of studies performed in industry and academia. This was not only the opportunity to reflect on the experience and the knowledge so far within the current regulatory framework but also to look at the future and explore new and future approaches as well as best practices with the use of modeling and simulation and extrapolation as part of pediatric development. [ABSTRACT FROM AUTHOR]

Challenges in pediatric drug development include small patient numbers, limited outcomes research, ethical barriers, and sparse biosamples. Increasingly, pediatric drug development is focusing on extrapolation: leveraging knowledge about adult disease and drug responses to inform projections of drug and clinical trial performance in pediatric subpopulations. Pharmacokinetic‐pharmacodynamic (PK‐PD) modeling and extrapolation aim to reduce the numbers of patients and data points needed to establish efficacy. Planning for PK‐PD and biomarker studies should begin early in the adult drug development program. Extrapolation relies on the assumption that both the underlying disease and the mechanism of action of the drug used to treat that disease are similar in adults and pediatric subpopulations. Clearly, developmental changes in PK and PD need to be considered to enhance the quality of PK‐PD modeling and, therefore, increase the success of extrapolation. This article focuses on the influence of differences in PD between adults and pediatric subpopulations that are highly relevant for the use of extrapolation. [ABSTRACT FROM AUTHOR]

Comparative analyses of the efficacies of dopaminergic agonists (pramipexole, ropinirole, and rotigotine patch) and α‐2‐δ ligands (gabapentin enacarbil and pregabalin) for treatment of primary restless leg syndrome (RLS) are lacking because of the few head‐to‐head clinical trials. A model‐based meta‐analysis approach was employed to quantitatively compare the efficacies of these 5 first‐line RLS drugs. Longitudinal efficacy data of RLS drugs were collected from published eligible literature. Mean changes in both the International Restless Leg Syndrome Study Group (IRLS) rating scale and Clinical Global Impression Improvement (CGI‐I) scale response rate were analyzed. A study‐level population pharmacodynamic model was used to fit the dose‐effect relationship and to describe the therapeutic effect over time for RLS drugs and placebo, and the typical efficacies of these drugs were compared. The onset of action was rapid for RLS drugs. In the placebo group, typical maximum IRLS reduction (Emax,IRLS) and CGI‐I response rate (Emax,CGI‐I) were –9.34 points and 48.2%, respectively. After deducting placebo effects, we found that the baseline IRLS score was significantly correlated with the Emax,IRLS of dopaminergic agonists. Typical Emax,IRLS of dopaminergic agonists was expressed as −7.7−0.682×(baseline IRLS score −24) points. Typical Emax,IRLS values of pregabalin and gabapentin enacarbil were –5.95 points and –4.00 points, respectively. The therapeutic effect of dopaminergic agonists was found to be associated with baseline symptom severity. In RLS patients with more severe symptoms, the therapeutic effect of dopaminergic agonists tended to be better than that of α‐2‐δ ligands. [ABSTRACT FROM AUTHOR]

The evaluation of potential of a new molecular entity (NME) to inhibit P‐glycoprotein (P‐gp) in vivo is an integral part of drug development and is recommended by regulatory agencies. In this study, we compared the performance of 5 prediction methods and their associated criteria (including those from the European Medicines Agency, the US Food and Drug Administration, and the Pharmaceuticals and Medical Devices Agency of Japan) for assessing the potential of an NME to inhibit P‐gp in vivo based on in vitro assessment. We collected in vitro (eg, half‐maximal inhibitory concentration [IC50], fraction unbound to plasma protein) and in vivo (eg, dose, maximum concentration, change in maximum concentration or area under the plasma concentration–time curve of the substrate digoxin) data for 50 Food and Drug Administration–approved, orally administered drug products containing 53 NMEs, from the University of Washington Metabolism and Transport Drug Interaction Database, Drugs@FDA, and PubMed. All methods yielded similar accuracy with small differences in false‐negative (FN) and false‐positive (FP) predictions. In addition, use of ratio of the theoretical maximum gastrointestinal concentration to IC50 is sufficient for a reasonable prediction for these orally administered drugs as potential P‐gp inhibitors based on our dataset. The FN and FP rates varied depending on the cut‐off value for the ratio of the theoretical maximum gastrointestinal concentration/IC50. Possible reasons underlying FP and FN results from different methods should be taken into consideration to predict in vivo P‐gp inhibition. [ABSTRACT FROM AUTHOR]

The safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity of JNJ‑61178104, a novel anti–tumor necrosis factor‐alpha (TNFα) and anti–interleukin‐17A (IL‑17A) bispecific antibody, were investigated in a placebo‐controlled, first‐in‐human study. Healthy subjects (n = 54) received a single dose of JNJ‐61178104 by either intravenous infusion (0.1, 0.3, 1, 3, and 10 mg/kg) or subcutaneous injection (1 mg/kg). Blood samples for measurement of serum JNJ‐61178104 concentrations, total IL‐17A, total TNFα, and detection of antidrug antibodies were collected for up to 16 weeks after dosing and assessed using electrochemiluminescence immunoassays. PK parameters were calculated by noncompartmental analysis and estimated by nonlinear mixed‐effects modeling. JNJ‐61178104 was generally well tolerated in healthy subjects. For the intravenous cohorts, mean maximum concentration, and area under the concentration‐time curve values increased in a dose‐proportional manner. Mean clearance ranged from 6.73 to 9.99 mL/day/kg, mean volume of distribution at terminal phase after intravenous administration ranged from 51.0 to 91.9 mL/kg, and mean half‐life ranged from 4.3 to 9.7 days following intravenous administration. After a single subcutaneous dose of 1 mg/kg, median time to maximum concentration was 4.0 days, mean bioavailability was 52.0% and mean half‐life was 5.3 days. A linear 2‐compartment population model with first‐order elimination adequately characterized the pharmacokinetics with parameters consistent with noncompartmental analysis estimates. Body weight and antidrug antibodies were significant covariates on JNJ‐61178104 clearance. The time to reach mean maximum serum total TNFα and total IL‐17A concentrations appeared to be dose dependent across the 0.1 mg/kg to 10 mg/kg IV dose groups. All subjects who received active treatment were antidrug antibody positive after dosing with JNJ‐61178104. [ABSTRACT FROM AUTHOR]

The pharmacokinetics, safety, and tolerability of a single dose of moxifloxacin were characterized in 31 pediatric patients already receiving antibiotics for a suspected or proven infection in an open‐label phase 1 study. A dosing strategy for each age cohort (Cohort 1: ≥6 years to ≤14 years; Cohort 2: ≥2 years to <6 years; Cohort 3: >3 month to <2 years) was developed using physiology‐based pharmacokinetic modeling combined with a stepwise dosing scheme to obtain a similar exposure to adults receiving 400 mg of moxifloxacin. Doses, adjusted to body weight and age, were gradually escalated from 5 mg/kg in Cohort 1 to 10 mg/kg in Cohort 3 based on interim analysis of the pharmacokinetic and safety data. Plasma and urine samples before and after the 60‐minute infusion were collected for the analysis of moxifloxacin and its metabolites using a validated high‐pressure liquid chromatography assay with tandem mass spectrometry. Moxifloxacin and metabolite concentrations in plasma were within the ranges observed in adults; however, clearance of all analytes was lower in pediatric patients compared with adults. Population pharmacokinetic analyses using the achieved exposure levels in the 3 age cohorts (with known body weight and clearance) predicted similar efficacy and safety profiles to adults. Moxifloxacin was well tolerated in all pediatric age cohorts. Adverse events related to moxifloxacin were mild or moderate in intensity and showed no correlation with increased weight‐adjusted doses. Our findings guided the selection of age‐appropriate clinical doses for a subsequent phase 3 clinical trial in pediatric patients with complicated intra‐abdominal infections. [ABSTRACT FROM AUTHOR]

Clobazam (CLB) is a 1,5‐benzodiazepine that has been widely used as an anxiolytic and antiseizure drug (ASD) since it was first synthesized over 50 years ago. CLB was approved in the United States in 2011 as adjunctive therapy for seizures in patients ≥2 years old with Lennox‐Gastaut syndrome. CLB pharmacokinetics (PK) have been studied in single‐ and multiple‐dose administrations in healthy subjects. Salient features include high bioavailability, linear PK, and negligible effects from coadministration of other ASDs. CLB is highly and extensively absorbed, with little effect from food; time to maximum plasma concentration is 0.5 to 4 hours following the dose. After CLB doses of 20 to 40 mg/day, the volume of distribution is 99 to 120 L, with oral clearance ranging from 1.9 to 2.3 L/h. CLB is lipophilic and distributes throughout the body after oral administration. It is metabolized in the liver by cytochrome P450 (CYP) isoenzymes CYP3A, CYP2C19, and CYP2B6, and its main active metabolite is N‐desmethylclobazam. The half‐life of CLB after a single oral dose ranges from 36 to 42 hours; the half‐life of N‐desmethylclobazam ranges from 59 to 74 hours. The metabolites of CLB are primarily excreted renally. Population PK modeling using data from healthy subjects and patients with Lennox‐Gastaut syndrome indicates that race, sex, age, weight, and renal function do not influence CLB PK. As CLB has been extensively studied since the 1970s, this review is meant to provide a consolidated and comprehensive resource on CLB PK for both prescribers and scientists alike. [ABSTRACT FROM AUTHOR]

Understanding the physiological fluctuations in the corrected QT (QTc) interval is important to accurately interpret the variations in drug‐induced prolongation. The present study aimed to define the time course of the effect of moxifloxacin on the QT interval to understand the duration of the responses to moxifloxacin. This retrospective analysis was performed on data taken from a thorough QT 4‐way crossover study with 40 subjects. Each period consisted of a baseline electrocardiogram (ECG) day (day –1) and a treatment day (day 1). On both days, ECGs were recorded simultaneously using 2 different systems operating in parallel: a bedside ECG and a continuous Holter recording. The subjects were randomized to 1 of 4 treatments: 5 mg and 40 mg of intravenous amisulpride, a single oral dose of moxifloxacin (400 mg), or placebo. Standardized meals, identical in all 4 periods, with similar nutritional value were served. Bedside ECG results confirmed that the moxifloxacin peak effect was delayed in the fed state and showed that the Fridericia corrected QT prolongation induced by moxifloxacin persisted until the end of the 24‐hour measurement period. The use of continuous Holter monitoring provided further insight, as it revealed that the moxifloxacin effect on QTc was influenced by diurnal and nocturnal environmental factors, and hysteresis effects were noticeable. The findings suggested that moxifloxacin prolongs QTc beyond its elimination from the blood circulation. This is of relevance to current concentration‐effect modeling approaches, which presume the absence of hysteresis effects. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the safety and tolerability of intravenous (IV) levetiracetam (LEV) as a monotherapy in children aged 1 month‐16 years and to explore the pharmacokinetics (PK) of IV LEV and the time to seizure after IV then oral administration of LEV in pediatric children with epilepsy. Children diagnosed with acute unprovoked seizures requiring in‐hospital IV LEV administration were included. After administration, the clinical seizure outcomes, side effects, and the Korean‐Child Behavior Checklist were monitored and the PK and repeated time to seizure were analyzed via modeling using NONMEM software. Overall, 37 children with epilepsy were enrolled and underwent a PK analysis (median age, 4.6 years; median weight, 18.0 kg). Nine children (24.3%) had seizure recurrence during the follow‐up period (median, 3.8 months) and 5 children (13.5%) experienced LEV‐associated adverse events such as irritability (n = 2; 5.4%) and somnolence (n = 3; 8.1%). The plasma LEV concentrations after IV LEV were best described by a one‐compartment linear PK model. Only body weight was associated with both the clearance and volume of distribution of LEV. The Weibull distribution model described the time to seizure recurrence well; no statistically significant predictor for the time to seizure was identified. Therefore, IV LEV was a well‐tolerated and effective alternative in children with acute unprovoked seizures, and models for the PK and time to repeated seizure recurrence after LEV were successfully developed. In particular, the current use of a weight‐based IV LEV dosing regimen in pediatric children is practical. [ABSTRACT FROM AUTHOR]

Abstract: Effective drug therapy to optimally influence disease requires an understanding of a drug's pharmacokinetic, pharmacodynamic, and pharmacogenomic interrelationships. In pediatrics, age is a continuum that can and does add variability in drug disposition and effect. This article addresses the many important factors that influence drug disposition and effect relative to age. What is known about the influence of maturation on the processes of drug absorption, distribution, metabolism, excretion, and drug receptor dynamics are outlined. Our state of understanding of many of these factors remains in flux, however, and only with additional study will we be able to better anticipate and model drug‐response relationships across the age continuum. Being able to continuously improve our care of the ill pediatric patient while simultaneously being able to accurately determine the utility of new drugs and chemical entities in this population requires our enhanced understanding of these disposition characteristics. [ABSTRACT FROM AUTHOR]

Abstract: Aspirin remains the standard for stroke prophylaxis. However, as many as 20%‐25% of patients may fail to show a full response to aspirin. Ideally, patients who are resistant to aspirin could be identified, then receive an increased dose of aspirin or be changed to an alternative therapy more efficiently. We have developed an in vitro assay that may make this possible. Healthy volunteers (n = 13) between 18 and 50 years of age were tested for both ex vivo and in vivo responses to aspirin. Dimethyl sulfoxide (DMSO) was selected as the solvent for aspirin in the assay. DMSO can exhibit antiplatelet effects, necessitating the use of a concentration low enough to avoid such antiplatelet effects. Blood samples were tested against DMSO 0%, 0.05%, 0.5%, and 1% w/v with and without aspirin 0, 50, and 100 μM. The effects of both agents were measured via whole‐blood aggregometry. A 3‐dimensional response model described the data well, quantifying the combinatorial effect of DMSO and aspirin on platelet aggregation. Across all participants, baseline aggregation stimulated with collagen 1 μM or arachidonate 0.5 mM was approximately 18 and 13 Ω, respectively. The response model showed that 0.05% DMSO with 100 μM aspirin would provide platelet aggregation of 3.4 Ω. A DMSO concentration of 0.05% in the absence of aspirin would result in no discernable effects on platelet aggregation (17.7 Ω). Overall, the use of 100 μM of aspirin in 0.05% DMSO provides a robust method to test for ex vivo inhibition of platelet aggregation. [ABSTRACT FROM AUTHOR]

Abstract: This study tested the capability of an assay to predict aspirin response and reduce ischemic events, and healthcare costs, and delays to optimal treatment. Patients who needed aspirin in the course of normal medical care were included. Patients were excluded if they had disorders affecting platelet function, alcohol use within 24 hours of a test, or NSAID use. Dose escalation of chewable aspirin from 81 mg, to 162 mg, to 325 mg daily occurred based on the results of whole blood impedance aggregation testing to the agonists, collagen (1ug/mL, 5 ug/mL) and arachidonate (0.5 mM) after 10–14 days of treatment. The experimental in vitro test was conducted in triplicate by performing aggregometry on samples spiked to a concentration of 10 uM of aspirin in 0.05% dimethyl sulfoxide. Of the 36 patients who were compliant 16 were found to be resistant to the antiplatelet effects of 81 mg daily aspirin. Nine of these patients were predicted to stay resistant despite dose increase. Once tested at higher doses, ten remained resistant. Seven of the 16 patients were predicted to become sensitive to a higher dose while six actually did. Predicted response to increased doses of aspirin was in good agreement with actual response. Sensitivity of the assay was 83% and specificity was 80%. Results are promising and indicate that it is possible to predict, with reasonable accuracy, if a patient will have an adequate platelet response to aspirin or if the patient will never respond to aspirin necessitating an alternative antiplatelet regimen. Larger, multisite studies are inevitably needed. [ABSTRACT FROM AUTHOR]

Abstract: Individualization of patient drug dosing to maximize efficacy and minimize toxicity is the goal of clinical pharmacology. Here we review the history of drug dosing individualization from early predictions for renally eliminated drugs based on kidney function through the introduction of clearance concepts for metabolic processes, the differentiation of volume of distribution between pharmacokinetics and chemistry, the role of transporters, the unique pharmacokinetic aspects of oral dosing, and the relevance of protein binding to the emergence of pharmacogenomics. The Food and Drug Administration listing of pharmacogenomic markers in approved drug labeling is analyzed with respect to the promise of genomics in terms of picking the right drug for the patient based on genetic information vs selecting or adjusting the dosage regimen based on genetic information: the former resulting in a great advance, whereas the latter has shown less convincing evidence of clinical relevance. Finally, new information on individualized predictive methodologies based on marker drugs for enzymes and transporters is reviewed. We conclude that although individualization of drug dosing will work for most drugs primarily excreted unchanged in the urine, individualization of dosing regimens is not critical for wide‐therapeutic‐index drugs, whereas for narrow‐therapeutic‐index drugs predictions are most often more hype than reality, with therapeutic drug monitoring required. However, continuing advances in discovering and validating biomarkers will lead to predictions of pharmacokinetics/pharmacodynamics in the individualized patient that should result in shifting the hype to reality with time. [ABSTRACT FROM AUTHOR]

Abstract: Delafloxacin, a fluoroquinolone, has activity against gram‐positive organisms including methicillin‐resistant Staphylococcus aureus and fluoroquinolone‐susceptible and –resistant gram‐negative organisms. This study was conducted to determine delafloxacin pharmacokinetics after a single intravenous infusion or oral dose administration in subjects with varying degrees of renal function. The study was an open‐label, parallel‐group crossover study in subjects with normal renal function or with mild, moderate, or severe renal impairment. Subjects received 300 mg delafloxacin intravenously, placebo intravenously, and 400 mg delafloxacin orally in 3 periods separated by ≥14‐day washouts. Blood and urine pharmacokinetic parameters were calculated using noncompartmental methods. Delafloxacin total clearance decreased with decreasing renal function, with a corresponding increase in AUC0–∞. After intravenous administration, mean total clearance was 13.7 and 7.07 L/h, and mean AUC0–∞ was 22.6 and 45.0 μg·h/mL in normal and severe renal subjects, respectively. Mean renal clearance as determined by urinary excretion was 6.03 and 0.44 L/h in normal and severe renal impairment subjects, respectively. Total clearance exhibited linear relationships to eGFR and CLCR. Similar observations were found after oral administration of delafloxacin. Single doses of delafloxacin 300 mg intravenously and 400 mg orally were well tolerated in all groups. In conclusion, renal insufficiency has an effect on delafloxacin clearance; a dosing adjustment for intravenous dosing is warranted for patients with severe renal impairment (eGFR < 30 mL/min). [ABSTRACT FROM AUTHOR]

A study was performed to investigate the effect of an intravaginally administered antimycotic, an antibiotic, and a spermicide plus the co-usage of tampons on the pharmacokinetics (PK) of levonorgestrel (LNG) and anastrozole (ATZ) administered as an intravaginal ring (IVR) releasing 1050 μg ATZ per day and 40 μg LNG per day. In this parallel-group, randomized, open-label study, healthy premenopausal women received an IVR as the main treatment. Comedications were administered on 3 consecutive evenings during treatment with IVR on days 9-11 (group A, 400 mg miconazole; group B, 100 mg clindamycin; group C, 75 mg nonoxynol-9); tampon co-usage (group D) was performed on days 20-23. The primary PK parameter was the average plasma concentration (Cav,ss) of ATZ and LNG at defined intervals, mainly prior to, during, and up to 7 days after the start of comedication. Fifty-two subjects were included, and at least 11 subjects per group completed the treatments. Overall, the medications and comedications were safe and well tolerated. Very similar ATZ and LNG plasma levels were observed across all groups. The calculated ratios of Cav,ss confirmed the absence of PK interactions because all relevant point estimates and 90% confidence intervals were within the range of 0.800-1.250, which is typically used in bioequivalence studies. These results demonstrate the absence of PK interactions between ATZ/LNG released from IVR and the tested antibiotic, antimycotic, spermicide, and tampons. Therefore, no restrictions for the use of the IVR are needed to continue the clinical program intended to treat endometriosis symptoms. [ABSTRACT FROM AUTHOR]

Investigation of the cardiovascular proarrhythmic potential of a new chemical entity is now an integral part of drug development. Studies suggest that meals and glycemic changes can influence QT intervals, and a semimechanistic model has been developed that incorporates the effects of changes in glucose concentrations on heart rate (HR) and QT intervals. This analysis aimed to adapt the glucose-HR-QT model to incorporate the effects of exenatide, a drug that reduces postprandial increases in glucose concentrations. The final model includes stimulatory drug effects on glucose elimination and HR perturbations. The targeted and constant exenatide plasma concentrations (>200 pg/mL), via intravenous infusions at multiple dose levels, resulted in significant inhibition of glucose concentrations. The exenatide concentration associated with 50% of the stimulation of HR production was 584 pg/mL. After accounting for exenatide effects on glucose and HR, no additional drug effects were required to explain observed changes in the QT interval. Resulting glucose, HR, and QT profiles at all exenatide concentrations were adequately described. For therapeutic agents that alter glycemic conditions, particularly those that alter postprandial glucose, the QT interval cannot be directly compared to that with placebo without first accounting for confounding factors (eg, glucose) either through mathematical modeling or careful consideration of mealtime placement in the study design. [ABSTRACT FROM AUTHOR]

The characterization of the pharmacokinetic (PK) and pharmacodynamic (PD) properties in pediatric patients is essential in supporting the recommended dosage of canakinumab in the relevant population. Here the PK and PD properties of canakinumab-a monoclonal antibody-in pediatric patients with systemic juvenile idiopathic arthritis (SJIA) are presented. Blood samples were obtained from 4 phase 2/3 clinical studies in patients with SJIA. Canakinumab PK properties and total interleukin (IL)-1β kinetic properties were characterized by a population-based PK-binding model. On administration, canakinumab increased total IL-1β complex in SJIA patients. Canakinumab clearance and volume of distribution were not impacted by age in pediatric patients after correction for the patient's body weight. The estimated serum clearance of canakinumab was 0.106 ± 0.00689 L/day, with a corresponding volume of distribution at steady state of 3.2 L and an estimated half-life of 22 days, based on a model typical body weight of 33 kg. Body-weight-based dosing provided comparable canakinumab exposure across the age groups in patients 2 to <20 years with SJIA. In younger children, a modest increase in the turnover rate of IL-1β was observed. Compared to other indications, IL-1β production rate was higher and clearance was slower in patients with SJIA. Low immunogenicity incidence of 3.1% was observed, and none of the patients had neutralizing antibodies. In conclusion, the PK/PD findings further support dose selection of canakinumab in patients with SJIA. [ABSTRACT FROM AUTHOR]

The pharmacokinetics (PK) and pharmacodynamics (PD) of omarigliptin, a novel once-weekly DPP-4 inhibitor, were assessed following single and multiple doses in healthy subjects. Absorption was rapid, and food did not influence single-dose PK. Accumulation was minimal, and steady state was reached after 2 to 3 weeks. Weekly (area under the curve) AUC and Cmax displayed dose proportionality within the dose range studied at steady state. The average renal clearance of omarigliptin was ∼2 L/h. DPP-4 inhibition ranged from ∼77% to 89% at 168 hours following the last of 3 once-weekly doses over the dose range studied. Omarigliptin resulted in ∼2-fold increases in weighted average postprandial active GLP-1. Omarigliptin acts by stabilizing active GLP-1, which is consistent with its mechanism of action as a DPP-4 inhibitor. Administration of omarigliptin was generally well tolerated in healthy subjects, and both the PK and PD profiles support once-weekly dosing. A model-based assessment of QTc interval risk from the single ascending dose study predicted a low risk of QTc prolongation within the likely clinical dose range, a finding later confirmed in a thorough QT trial. [ABSTRACT FROM AUTHOR]

Drug-drug interaction (DDI) studies involving warfarin are typically conducted with subtherapeutic doses of warfarin to ensure the safety of volunteers. However, this approach may potentially have a systemic bias of underestimating pharmacodynamic (PD) DDI effect on warfarin at therapeutic levels of anticoagulation. We demonstrate here the utility of model-based DDI prediction for a clinically relevant warfarin regimen, using the example of epacadostat (INCB024360), the first-in-class indoleamine 2,3-dioxygenase 1 inhibitor in clinical development as a novel orally active immuno-oncological therapy. Observed data from a dedicated clinical DDI study using subtherapeutic warfarin suggested warfarin pharmacokinetics (PK), but not PD (anticoagulation), was significantly affected by concomitant epacadostat. However, subsequent PK/PD modeling and simulations indicated a clinically important DDI effect on warfarin PD at a higher baseline of the international normalization ratio (INR) and enabled recommendation of warfarin dose adjustment that is dependent on epacadostat dosing regimen and target INR. [ABSTRACT FROM AUTHOR]

The study's primary objective was to compare the pharmacokinetics (PK) and pharmacodynamics (PD) of single subcutaneous (SC) or intramuscular (IM) 300-mg doses of natalizumab with IV 300-mg doses of natalizumab in patients with multiple sclerosis (MS). Secondary objectives included investigation of the safety, tolerability, and immunogenicity of repeated SC and IM natalizumab doses. DELIVER was a 32-week, open-label, multicenter study of natalizumab-naive patients with relapsing-remitting MS (RRMS) or secondary progressive MS (SPMS) randomized to receive 300 mg natalizumab by SC injection, IM injection, or IV infusion. PK and PD were evaluated over 8 weeks after the first natalizumab treatment (Part 1) and over 24 weeks with repeated dosing every 4 weeks, beginning at week 8 (Part 2). Seventy-six patients (24 with RRMS and 52 with SPMS) were enrolled in DELIVER. Following SC or IM administration of natalizumab, peak serum concentrations were approximately 40% of those observed with IV administration and showed no major differences in elimination characteristics. Mean bioavailability relative to IV administration was 57.1% to 71.3% with SC administration and 48.7% with IM administration; mean trough serum concentrations were similar with SC or IV administration and lower with IM administration. Following single or multiple doses of natalizumab, PD response was comparable across administration routes and disease stages. No meaningful differences were observed across administration groups in the incidence or nature of overall adverse events, serious adverse events, administration site reactions, hypersensitivity reactions, or antinatalizumab antibodies. These findings support the comparability of PD measures of natalizumab administered IV, SC, or IM. [ABSTRACT FROM AUTHOR]

We present a race-specific model of propofol-induced loss of consciousness that is based on pharmacodynamic data collected and adapted from the peer-reviewed literature. In the proposed race-specific model that includes EC05 and EC95 concentrations, the median (EC50) (and where available 95%CI) propofol concentrations at the effect site compartment for propofol-induced loss of consciousness for whites, Chinese, blacks, and Indians are 2.8 (2.7-2.9), 2.2 (2.2-2.3), 2.0, and 1.9 μg/mL, respectively. [ABSTRACT FROM AUTHOR]

Sepsis remains a major cause of mortality and morbidity in neonates, and, as a consequence, antibiotics are the most frequently prescribed drugs in this vulnerable patient population. Growth and dynamic maturation processes during the first weeks of life result in large inter- and intrasubject variability in the pharmacokinetics (PK) and pharmacodynamics (PD) of antibiotics. In this review we (1) summarize the available population PK data and models for primarily renally eliminated antibiotics, (2) discuss quantitative approaches to account for effects of growth and maturation processes on drug exposure and response, (3) evaluate current dose recommendations, and (4) identify opportunities to further optimize and personalize dosing strategies of these antibiotics in preterm and term neonates. Although population PK models have been developed for several of these drugs, exposure-response relationships of primarily renally eliminated antibiotics in these fragile infants are not well understood, monitoring strategies remain inconsistent, and consensus on optimal, personalized dosing of these drugs in these patients is absent. Tailored PK/PD studies and models are useful to better understand relationships between drug exposures and microbiological or clinical outcomes. Pharmacometric modeling and simulation approaches facilitate quantitative evaluation and optimization of treatment strategies. National and international collaborations and platforms are essential to standardize and harmonize not only studies and models but also monitoring and dosing strategies. Simple bedside decision tools assist clinical pharmacologists and neonatologists in their efforts to fine-tune and personalize the use of primarily renally eliminated antibiotics in term and preterm neonates. [ABSTRACT FROM AUTHOR]