Evaluation of the Effect of Loperamide on the Cardiac Repolarization Interval Using Exposure-Response Analysis.

This analysis assessed the relationship between the plasma concentrations of loperamide and its N-desmethyl loperamide meta- bolite (M1) and the potential QT interval prolongation at therapeutic and supratherapeutic doses. The exposure-response analysis was performed using the data from healthy adults participating in a randomized, double-blind, single-dose, four-way (placebo; loperamide 8 mg [therapeutic]; loperamide 48 mg [supratherapeutic]; moxifloxacin 400 mg [positive control]) crossover study. The electrocardiographic measurements extracted from 12-lead digital Holter recordings were time-matched to pharmacokinetic sampling of loperamide/M1.

Model-Informed Clinical Development of 6-Monthly Injection of Paliperidone Palmitate in Patients with Schizophrenia: Dosing Strategies Guided by Population Pharmacokinetic Modeling and Simulation (Part II).

Background And Objective: Paliperidone palmitate 6-month (PP6M) intramuscular (IM) injection is the longest-acting treatment available for patients with schizophrenia. A population pharmacokinetic (popPK) modeling and simulation approach was deployed to inform dosing strategies for PP6M.

Methods: The extensive analysis database included 15,932 paliperidone samples from 700 patients receiving gluteal paliperidone palmitate 3-month (PP3M) or PP6M injections in the double-blind phase of a phase-3 noninferiority study (NCT03345342).

Model-Informed Clinical Development of Once-Every-6-Month Injection of Paliperidone Palmitate in Patients with Schizophrenia: A Pharmacometric Bridging Approach (Part I).

Background And Objective: A model-informed drug development (MIDD) approach was implemented for paliperidone palmitate (PP) 6-month (PP6M) clinical development, using pharmacokinetics and pharmacokinetic/pharmacodynamic model-based simulations.

Methods: PP6M pharmacokinetics were simulated by extending the PP 3-month (PP3M) pharmacokinetic model to account for increased injection volume, and hence dose. Contribution of the MIDD approach to the design of the pivotal PP6M phase-3 study (PP6M/PP3M noninferiority study, NCT03345342) investigating schizophrenia relapse rates was twofold: (1) PP6M dose selection, and (2) hypothesis generation that lower trough concentrations (C) associated with PP6M, relative to PP3M, were not associated with lower efficacy, which was to be evaluated in the phase-3 study.

Model-based meta-analysis to quantify the effects of short interfering RNA therapeutics on hepatitis B surface antigen turnover in hepatitis B-infected mice.

The objective of this study was to compare the efficacy of short interfering RNA therapeutics (siRNAs) in reducing hepatitis B surface antigen (HBsAg) levels in hepatitis B-infected (HBV) mice across multiple siRNA therapeutic classes using model-based meta-analysis (MBMA) techniques. Literature data from 10 studies in HBV-infected mice were pooled, including 13 siRNAs, formulated as liposomal nanoparticles (LNPs) or conjugated to either cholesterol (chol) or N-acetylgalactosamine (GalNAc). Time course of the baseline- and placebo-corrected mean HBsAg profiles were modeled using kinetics of drug effect (KPD) model coupled to an indirect response model (IRM) within a longitudinal non-linear mixed-effects MBMA framework.

Mechanistic modeling projections of antibody persistence after homologous booster regimens of COVID-19 vaccine Ad26.COV2.S in humans.

Mechanistic model-based simulations can be deployed to project the persistence of humoral immune response following vaccination. We used this approach to project the antibody persistence through 24 months from the data pooled across five clinical trials in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-seronegative participants following vaccination with Ad26.COV2.

Mechanistic Model Describing the Time Course of Humoral Immunity Following Ad26.COV2.S Vaccination in Non-Human Primates.

Mechanistic modeling can be used to describe the time course of vaccine-induced humoral immunity and to identify key biologic drivers in antibody production. We used a six-compartment mechanistic model to describe a 20-week time course of humoral immune responses in 56 non-human primates (NHPs) elicited by vaccination with Ad26.COV2.

Pharmacodynamic-Mediated Drug Disposition (PDMDD) Model of Daratumumab Monotherapy in Patients with Multiple Myeloma.

Background And Objective: We aimed to quantify the daratumumab concentration- and CD38 dynamics-dependent pharmacokinetics using a pharmacodynamic mediated disposition model (PDMDD) in patients with multiple myeloma (MMY) following daratumumab IV or SC monotherapy. Daratumumab, a human IgG monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action, has been approved to treat patients with multiple myeloma (MM).

Methods: In total, 7788 daratumumab plasma samples from 850 patients with diagnosis of MMY were used.

Pharmacokinetic-Pharmacodynamic Modeling of the Ponesimod Effect on Heart Rate in Patients With Multiple Sclerosis.

The purpose of this study was to characterize the ponesimod effect on the heart rate (HR) in patients with multiple sclerosis (MS). A previous pharmacokinetic (PK) and pharmacodynamic model developed in healthy participants was updated using data from phase II and III trials conducted in patients with MS. Clinically relevant covariates were assessed.

Population pharmacokinetics and exposure-response analyses of daratumumab plus pomalidomide/dexamethasone in relapsed or refractory multiple myeloma.

Aim: A population pharmacokinetic (PPK) model was developed to characterize pharmacokinetics (PK) of subcutaneous or intravenous daratumumab administration in a new indication (i.e., combination with pomalidomide and dexamethasone [D-Pd] in patients with relapsed or refractory multiple myeloma [RRMM]).

An exposure-response analysis of ponesimod clinical efficacy in a randomized phase III study in patients with relapsing multiple sclerosis.

The efficacy of ponesimod and teriflunomide for the treatment of relapsing multiple sclerosis (MS) was compared in a randomized phase III trial. This study explores the exposure-response (E-R) relationships of efficacy end points (annualized relapse rate [ARR] and combined unique active lesions [CUALs]) of ponesimod observed in this trial. The E-R relationships were described using nonlinear mixed effects models for count data.

Plasma and Liver Pharmacokinetics of the N-Acetylgalactosamine Short Interfering RNA JNJ-73763989 in Recombinant Adeno-Associated-Hepatitis B Virus-Infected Mice.

JNJ-73763989 is an N-acetylgalactosamine conjugated short interfering RNA combination product consisting of two triggers in clinical development for chronic hepatitis B virus (HBV) infection treatment that induces a selective degradation of all HBV mRNA transcripts. Our aim is to characterize the plasma and liver pharmacokinetics (PK) of JNJ-73763989 after intravenous and subcutaneous administration in recombinant adeno-associated (rAAV) HBV infected mice. Forty-two male rAAV-HBV infected C57Bl/6 mice received JNJ-73763989 doses of 10 mg/kg i.

Exposure-response analyses of erdafitinib in patients with locally advanced or metastatic urothelial carcinoma.

Background: Exposure-response analyses were conducted to explore the relationship between selected efficacy and safety endpoints and serum phosphate (PO4) concentrations, a potential biomarker of efficacy and safety, in locally advanced or metastatic urothelial carcinoma patients with FGFR alterations treated with erdafitinib.

Methods: Data from two dosing regimens of erdafitinib in a phase 2 study (NCT02365597), 6 and 8-mg/day with provision for pharmacodynamically guided titration per serum PO4 levels, were analyzed using Cox proportional hazard or logistic regression models. Efficacy endpoints were overall survival (OS), progression-free survival (PFS), and objective response rate (ORR).

A translational model-based approach to inform the choice of the dose in phase 1 oncology trials: the case study of erdafitinib.

Purpose: Erdafitinib (JNJ-42756493, BALVERSA) is a tyrosine kinase inhibitor indicated for the treatment of advanced urothelial carcinoma. In this work, a translational model-based approach to inform the choice of the doses in phase 1 trials is illustrated.

Methods: A pharmacokinetic (PK) model was developed to describe the time course of erdafitinib plasma concentrations in mice and rats.

Erdafitinib's effect on serum phosphate justifies its pharmacodynamically guided dosing in patients with cancer.

A population pharmacokinetic (PK)-pharmacodynamic (PD) model was developed using data from 345 patients with cancer. The population PK-PD model evaluated the effect of erdafitinib total and free plasma concentrations on serum phosphate concentrations after once-daily oral continuous (0.5-12 mg) and intermittent (10-12 mg for 7 days on/7 days off) dosing, and investigated the potential covariates affecting erdafitinib-related changes in serum phosphate levels.

Bioequivalence and food effect of a fixed-dose combination of macitentan and tadalafil: Adaptive design in the COVID-19 pandemic.

The COVID-19 pandemic has forced clinical studies to accommodate imposed limitations. In this study, the bioequivalence part could not be conducted as planned. Thus, the aim was to demonstrate bioequivalence, using an adaptive study design, of tadalafil in fixed-dose combination (FDC) tablets of macitentan/tadalafil with single macitentan and tadalafil (Canadian-sourced) tablets and assess the effect of food on FDC tablets in healthy subjects.

SARS-CoV-2 binding and neutralizing antibody levels after Ad26.COV2.S vaccination predict durable protection in rhesus macaques.

Several COVID-19 vaccines have recently gained authorization for emergency use. Limited knowledge on duration of immunity and efficacy of these vaccines is currently available. Data on other coronaviruses after natural infection suggest that immunity to SARS-CoV-2 might be short-lived, and preliminary evidence indicates waning antibody titers following SARS-CoV-2 infection.

A quantitative systems pharmacology model for acute viral hepatitis B.

Hepatitis B liver infection is caused by hepatitis B virus (HBV) and represents a major global disease problem when it becomes chronic, as is the case for 80-90% of vertical or early life infections. However, in the vast majority (>95%) of adult exposures, the infected individuals are capable of mounting an effective immune response leading to infection resolution. A good understanding of HBV dynamics and the interaction between the virus and immune system during acute infection represents an essential step to characterize and understand the key biological processes involved in disease resolution, which may help to identify potential interventions to prevent chronic hepatitis B.

Population pharmacokinetics of the rilpivirine long-acting formulation after intramuscular dosing in healthy subjects and people living with HIV.

Objectives: To characterize the population pharmacokinetics of the rilpivirine long-acting (LA) formulation after intramuscular administration.

Methods: Rich and sparse rilpivirine plasma concentration data were obtained from seven clinical studies. In total, 18 261 rilpivirine samples were collected from 986 subjects (131 healthy subjects from Phase I studies and 855 people living with HIV from Phase IIb/III studies).

Delay differential equations based models in NONMEM.

Delay differential equations (DDEs) are commonly used in pharmacometric models to describe delays present in pharmacokinetic and pharmacodynamic data analysis. Several DDE solvers have been implemented in NONMEM 7.5 for the first time.

Multiscale model of hepatitis C virus dynamics in plasma and liver following combination therapy.

This work explores the application of a physiologically structured population (PSP) framework in modeling hepatitis C virus (HCV) kinetics. To do so, a model was developed for the viral RNA load in plasma and liver as observed in 15 patients treated with a combination therapy of pegylated interferon, ribavirin, and telaprevir. By including both intracellular and extracellular processes of the HCV lifecycle, the model provided a description of the treatment effect on the intracellular HCV lifecycle.

Population Pharmacokinetic Analysis of Darunavir and Tenofovir Alafenamide in HIV-1-Infected Patients on the Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Single-Tablet Regimen (AMBER and EMERALD Studies).

The single-tablet regimen darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg has undergone phase III studies AMBER (NCT02431247) and EMERALD (NCT02269917) in HIV-infected patients. An existing population pharmacokinetic (PopPK) model for cobicistat-boosted darunavir (DRV) was updated to describe DRV PK in AMBER and EMERALD. For TAF, a PopPK model was developed using richly sampled phase I/II data and updated with sparsely sampled AMBER data.

An Exposure-Response Analysis of the Clinical Efficacy of Ponesimod in a Randomized Phase II Study in Patients with Multiple Sclerosis.

Background And Objective: Ponesimod is a sphingosphine-1-phosphate receptor modulator being developed for the treatment of multiple sclerosis. The effects of disease-modifying treatments on magnetic resonance imaging (MRI) lesions in relapsing multiple sclerosis accurately predict effects on clinical relapses, therefore MRI lesion counts are generally accepted efficacy endpoints in phase II clinical studies of multiple sclerosis disease-modifying treatments. Here, we characterize the effect of ponesimod systemic exposure on the cumulative number of T1 gadolinium-enhancing (Gd+) lesions and the annualized relapse rate in a phase IIb study.