Using PBPK modeling to supplement clinical data and support the safe and effective use of dolutegravir in pregnant and lactating women.

Optimal dosing in pregnant and lactating women requires an understanding of the pharmacokinetics in the mother, fetus, and breastfed infant. Physiologically-based pharmacokinetic (PBPK) modeling can be used to simulate untested scenarios and hence supplement clinical data to support dosing decisions. A PBPK model for the antiretroviral dolutegravir (mainly metabolized by UGT1A1) was verified using reported exposures in non-pregnant healthy volunteers, pregnant women, and the umbilical cord, lactating mothers, and breastfed neonates.

A tutorial on physiologically based pharmacokinetic approaches in lactation research.

In breastfeeding mothers, managing medical conditions presents unique challenges, particularly concerning medication use and breastfeeding practices. The transfer of drugs into breast milk and subsequent exposure to nursing infants raises important considerations for drug safety and efficacy. Modeling approaches are increasingly employed to predict infant exposure levels, crucial for assessing drug safety during breastfeeding.

Dose Optimization Informed by PBPK Modeling: State-of-the Art and Future.

Model-informed drug development (MIDD) is a powerful quantitative approach that plays an integral role in drug development and regulatory review. While applied throughout the life cycle of the development of new drugs, a key application of MIDD is to inform clinical trial design including dose selection and optimization. To date, physiologically-based pharmacokinetic (PBPK) modeling, an established component of the MIDD toolkit, has mainly been used for assessment of drug-drug interactions (DDIs) and consequential dose adjustments in regulatory submissions.

Advancing the utilization of real-world data and real-world evidence in clinical pharmacology and translational research-Proceedings from the ASCPT 2023 preconference workshop.

Real-world data (RWD) and real-world evidence (RWE) are now being routinely used in epidemiology, clinical practice, and post-approval regulatory decisions. Despite the increasing utility of the methodology and new regulatory guidelines in recent years, there remains a lack of awareness of how this approach can be applied in clinical pharmacology and translational research settings. Therefore, the American Society of Clinical Pharmacology & Therapeutics (ASCPT) held a workshop on March 21st, 2023 entitled "Advancing the Utilization of Real-World Data (RWD) and Real-World Evidence (RWE) in Clinical Pharmacology and Translational Research.

Evaluation of the drug-drug interaction potential of brigatinib using a physiologically-based pharmacokinetic modeling approach.

Brigatinib is an oral anaplastic lymphoma kinase (ALK) inhibitor approved for the treatment of ALK-positive metastatic non-small cell lung cancer. In vitro studies indicated that brigatinib is primarily metabolized by CYP2C8 and CYP3A4 and inhibits P-gp, BCRP, OCT1, MATE1, and MATE2K. Clinical drug-drug interaction (DDI) studies with the strong CYP3A inhibitor itraconazole or the strong CYP3A inducer rifampin demonstrated that CYP3A-mediated metabolism was the primary contributor to overall brigatinib clearance in humans.

Supplementing clinical lactation studies with PBPK modeling to inform drug therapy in lactating mothers: Prediction of primaquine exposure as a case example.

Evaluating the safety of primaquine (PQ) during breastfeeding requires an understanding of its pharmacokinetics (PKs) in breast milk and its exposure in the breastfed infant. Physiologically-based PK (PBPK) modeling is primed to assess the complex interplay of factors affecting the exposure of PQ in both the mother and the nursing infant. A published PBPK model for PQ describing the metabolism by monoamine oxidase A (MAO-A; 90% contribution) and cytochrome P450 2D6 (CYP2D6; 10%) in adults was applied to predict the exposure of PQ in mothers and their breastfeeding infants.

Creation of Novel Sensitive Probe Substrate and Moderate Inhibitor Models for a Comprehensive Prediction of CYP2C8 Interactions for Tucatinib.

A physiologically-based pharmacokinetic (PBPK) model was developed to simulate plasma concentrations of tucatinib (TUKYSA®) after single-dose or multiple-dose administration of 300 mg b.i.d.

Development and application of a PBPK modeling strategy to support antimalarial drug development.

As part of a collaboration between Medicines for Malaria Venture (MMV), Certara UK and Monash University, physiologically-based pharmacokinetic (PBPK) models were developed for 20 antimalarials, using data obtained from standardized in vitro assays and clinical studies within the literature. The models have been applied within antimalarial drug development at MMV for more than 5 years. During this time, a strategy for their impactful use has evolved.

Physiologically Based Pharmacokinetic Modelling to Predict Imatinib Exposures in Cancer Patients with Renal Dysfunction: A Case Study.

Imatinib is mainly metabolised by CYP3A4 and CYP2C8 and is extensively bound to α-acid glycoprotein (AAG). A physiologically based pharmacokinetic (PBPK) model for imatinib describing the CYP3A4-mediated autoinhibition during multiple dosing in gastrointestinal stromal tumor patients with normal renal function was previously reported. After performing additional verification, the PBPK model was applied to predict the exposure of imatinib after multiple dosing in cancer patients with varying degrees of renal impairment.

Use of Developmental Midazolam and 1-Hydroxymidazolam Data with Pediatric Physiologically Based Modeling to Assess Cytochrome P450 3A4 and Uridine Diphosphate Glucuronosyl Transferase 2B4 Ontogeny In Vivo.

Pediatric physiologically based pharmacokinetics modeling in drug development has grown in the past decade but uncertainty remains regarding ontogeny of some drug metabolizing enzymes. In this study, a midazolam and 1-hydroxymidazolam physiologically based pharmacokinetic model (PBPK) model was developed and used to define the ontogeny for hepatic cytochrome P450 (CYP) 3A4 and uridine diphosphate glucuronosyl transferase (UGT) 2B4. Data for model development and pharmacokinetic studies on intravenous midazolam in adults and pediatrics were collated from the literature.

Physiologically Based Pharmacokinetic Modeling to Determine the Impact of CYP2B6 Genotype on Efavirenz Exposure in Children, Mothers and Breastfeeding Infants.

The antiretroviral drug efavirenz remains widely used in children and mothers during breastfeeding in tuberculosis-endemic areas. Evaluating the safety of efavirenz during breastfeeding requires an understanding of its pharmacokinetics (PKs) in breast milk, its exposure in the breastfed infant, and the potential influence of polymorphisms in drug disposition genes. The interplay of these factors between the mother and the nursing infant is a complex scenario that can be readily investigated using physiologically-based PK (PBPK) modeling.

PBPK modeling of ivermectin-Considerations for the purpose of developing alternative routes to optimize its safety profile.

Although single-dose ivermectin has been widely used in mass-drug administration programs for onchocerciasis and lymphatic filariasis for many years, ivermectin may have utility as an endectocide with mosquito-lethal effects at dosages greater and longer than those used to treat helminths. The final physiologically-based pharmacokinetic (PBPK) model for ivermectin described here was able to capture, with reasonable accuracy, observed plasma drug concentration-time profiles and exposures of ivermectin after a single oral dose of the drug in healthy male (dose range 6-30 mg) and female subjects, in both fasted and fed states, in African patients with onchocerciasis (150 μg/kg) and in African children. The PBPK model can be used for further work on lactation, pediatric dosing (considering CYP3A4 and Pg-p ontogenies), and pregnancy, especially if nonstandard doses will be used.

Another Step Toward Qualification of Pediatric Physiologically Based Pharmacokinetic Models to Facilitate Inclusivity and Diversity in Pediatric Clinical Studies.

Robust prediction of pharmacokinetics (PKs) in pediatric subjects of diverse ages, ethnicities, and morbidities is critical. Qualification of pediatric physiologically-based pharmacokinetic (P-PBPK) models is an essential step toward enabling precision dosing of these vulnerable groups. Twenty-two manuscripts involving P-PBPK predictions and corresponding observed PK data (e.

Prediction of CYP-mediated DDIs involving inhibition: Approaches to address the requirements for system qualification of the Simcyp Simulator.

Physiologically-based pharmacokinetic (PBPK) modeling is being increasingly used in drug development to avoid unnecessary clinical drug-drug interaction (DDI) studies and inform drug labels. Thus, regulatory agencies are recommending, or indeed requesting, more rigorous demonstration of the prediction accuracy of PBPK platforms in the area of their intended use. We describe a framework for qualification of the Simcyp Simulator with respect to competitive and mechanism-based inhibition (MBI) of CYP1A2, CYP2D6, CYP2C8, CYP2C9, CYP2C19, and CYP3A4/5.

Effect of Early Treatment with Ivermectin among Patients with Covid-19.

Background: The efficacy of ivermectin in preventing hospitalization or extended observation in an emergency setting among outpatients with acutely symptomatic coronavirus disease 2019 (Covid-19), the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is unclear.

Methods: We conducted a double-blind, randomized, placebo-controlled, adaptive platform trial involving symptomatic SARS-CoV-2-positive adults recruited from 12 public health clinics in Brazil. Patients who had had symptoms of Covid-19 for up to 7 days and had at least one risk factor for disease progression were randomly assigned to receive ivermectin (400 μg per kilogram of body weight) once daily for 3 days or placebo.

Increasing application of pediatric physiologically based pharmacokinetic models across academic and industry organizations.

There has been a significant increase in the use of physiologically based pharmacokinetic (PBPK) models during the past 20 years, especially for pediatrics. The aim of this study was to give a detailed overview of the growth and areas of application of pediatric PBPK (P-PBPK) models. A total of 181 publications and publicly available regulatory reviews were identified and categorized according to year, author affiliation, platform, and primary application of the P-PBPK model (in clinical settings, drug development or to advance pediatric model development in general).

A best practice framework for applying physiologically-based pharmacokinetic modeling to pediatric drug development.

Pediatric physiologically-based pharmacokinetic (PBPK) models have broad application in the drug development process and are being used not only to project doses for clinical trials but increasingly to replace clinical studies. However, the approach has yet to become fully integrated in regulatory submissions. Emerging data support an expanded integration of the PBPK model informed approach in regulatory guidance on pediatrics.

Using physiologically-based pharmacokinetic modeling for predicting the effects of hepatic impairment on the pharmacokinetics of olanzapine and samidorphan given as a combination tablet.

A combination of olanzapine and samidorphan (OLZ/SAM) was recently approved by the US Food and Drug Administration for treatment of patients with schizophrenia or bipolar I disorder. The effects of moderate hepatic impairment on the pharmacokinetics (PKs) of olanzapine and samidorphan after a single dose of OLZ/SAM were characterized in a clinical study. Physiologically-based pharmacokinetic (PBPK) modeling was used to extend the clinical findings to predict the effects of varying degrees of hepatic impairment on the PKs of olanzapine and samidorphan.