Applications of pharmacometrics in drug development.

The last two decades have witnessed profound changes in how advanced computational tools can help leverage tons of data to improve our knowledge, and ultimately reduce cost and increase productivity in drug development. Pharmacometrics has demonstrated its impact through model-informed drug development (MIDD) approaches. It is now an indispensable component throughout the whole continuum of drug discovery, development, regulatory review, and approval.

Evaluating drug interaction potential from cytokine release syndrome using a physiologically based pharmacokinetic model: A case study of teclistamab.

Cytokine release syndrome (CRS) was associated with teclistamab treatment in the phase I/II MajesTEC-1 study. Cytokines, especially interleukin (IL)-6, are known suppressors of cytochrome P450 (CYP) enzymes' activity. A physiologically based pharmacokinetic model evaluated the impact of IL-6 serum levels on exposure of substrates of various CYP enzymes (1A2, 2C9, 2C19, 3A4, 3A5).

Demonstrating Bioequivalence for Two Dose Strengths of Niraparib and Abiraterone Acetate Dual-Action Tablets Versus Single Agents: Utility of Clinical Study Data Supplemented with Modeling and Simulation.

Background And Objective: The combination of niraparib and abiraterone acetate (AA) plus prednisone is under investigation for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) and metastatic castration-sensitive prostate cancer (mCSPC). Regular-strength (RS) and lower-strength (LS) dual-action tablets (DATs), comprising niraparib 100 mg/AA 500 mg and niraparib 50 mg/AA 500 mg, respectively, were developed to reduce pill burden and improve patient experience. A bioequivalence (BE)/bioavailability (BA) study was conducted under modified fasting conditions in patients with mCRPC to support approval of the DATs.

Teclistamab: Mechanism of action, clinical, and translational science.

Multiple myeloma (MM) remains incurable despite improvements in treatment options. B-cell maturation antigen (BCMA) is predominantly expressed in B-lineage cells and represents a promising new target for MM. Teclistamab (TECVAYLI ) is the first T-cell redirecting bispecific antibody approved for patients with MM.

Challenging the Norm: A Multidisciplinary Perspective on Intravenous to Subcutaneous Bridging Strategies for Biologics.

The transition from intravenous (i.v.) to subcutaneous (s.

Artificial Intelligence: From Buzzword to Useful Tool in Clinical Pharmacology.

The advent of artificial intelligence (AI) in clinical pharmacology and drug development is akin to the dawning of a new era. Previously dismissed as merely technological hype, these approaches have emerged as promising tools in different domains, including health care, demonstrating their potential to empower clinical pharmacology decision making, revolutionize the drug development landscape, and advance patient care. Although challenges remain, the remarkable progress already made signals that the leap from hype to reality is well underway, and AI promises to offer clinical pharmacology new tools and possibilities for optimizing patient care is gradually coming to fruition.

Mechanism-based pharmacokinetic and pharmacodynamic modeling for bispecific antibodies: challenges and opportunities.

Introduction: Unlike conventional antibodies, bispecific antibodies (bsAbs) are engineered antibody- or antibody fragment-based molecules that can simultaneously recognize two different epitopes or antigens. Over the past decade, there has been an explosion of bsAbs being developed across therapeutic areas. Development of bsAbs presents unique challenges and mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) modeling has served as a powerful tool to optimize their development and realize their clinical utility.

Training the next generation of pharmacometric modelers: a multisector perspective.

The current demand for pharmacometricians outmatches the supply provided by academic institutions and considerable investments are made to develop the competencies of these scientists on-the-job. Even with the observed increase in academic programs related to pharmacometrics, this need is unlikely to change in the foreseeable future, as the demand and scope of pharmacometrics applications keep expanding. Further, the field of pharmacometrics is changing.

Latent variable indirect response modeling of clinical efficacy endpoints with combination therapy: application to guselkumab and golimumab in patients with ulcerative colitis.

Accurate characterization of longitudinal exposure-response of clinical trial endpoints is important in optimizing dose and dosing regimens in drug development. Clinical endpoints are often categorical, for which much progress has been made recently in latent variable indirect response (IDR) modeling with single drugs. However, such applications have not yet been used for trials employing multiple drugs administered concurrently.

Development of Therapeutic Proteins for a New Subcutaneous Route of Administration After the Establishment of Intravenous Dosages: A Systematic Review.

Therapeutic proteins may first be developed as intravenous (i.v.) therapies with new subcutaneous (s.

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).

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.

Ibrutinib does not have clinically relevant interactions with oral contraceptives or substrates of CYP3A and CYP2B6.

Ibrutinib may inhibit intestinal CYP3A4 and induce CYP2B6 and/or CYP3A. Secondary to potential induction, ibrutinib may reduce the exposure and effectiveness of oral contraceptives (OCs). This phase I study evaluated the effect of ibrutinib on the pharmacokinetics of the CYP2B6 substrate bupropion, CYP3A substrate midazolam, and OCs ethinylestradiol (EE) and levonorgestrel (LN).

Efficacy and Safety Exposure-Response Relationships of Apalutamide in Patients with Nonmetastatic Castration-Resistant Prostate Cancer.

Purpose: To evaluate the relationship between exposure of apalutamide and its active metabolite, N-desmethyl-apalutamide, and selected clinical efficacy and safety parameters in men with high-risk nonmetastatic castration-resistant prostate cancer.

Patients And Methods: An exploratory exposure-response analysis was undertaken using data from the 1,207 patients (806 apalutamide and 401 placebo) enrolled in the SPARTAN study, including those who had undergone dose reductions and dose interruptions. Univariate and multivariate Cox regression models evaluated the relationships between apalutamide and N-desmethyl-apalutamide exposure, expressed as area under the concentration-time curve at steady state, and metastasis-free survival (MFS).

Predictions of Systemic, Intracellular, and Lung Concentrations of Azithromycin With Different Dosing Regimens Used in COVID-19 Clinical Trials.

Azithromycin (AZ), a broad-spectrum macrolide antibiotic, is being investigated in patients with coronavirus disease 2019 (COVID-19). A population pharmacokinetic model was implemented to predict lung, intracellular poly/mononuclear cell (peripheral blood monocyte (PBM)/polymorphonuclear leukocyte (PML)), and alveolar macrophage (AM) concentrations using published data and compared against preclinical effective concentration 90% (EC ) for severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). The final model described the data reported in eight publications adequately.

Pharmacokinetic Drug-Drug Interaction of Apalutamide, Part 2: Investigating Interaction Potential Using a Physiologically Based Pharmacokinetic Model.

Background: Apalutamide is predominantly metabolized via cytochrome P450 (CYP) 2C8 and CYP3A4, whose contributions change due to autoinduction with repeated dosing.

Objectives: We aimed to predict CYP3A4 and CYP2C8 inhibitor/inducer effects on the steady-state pharmacokinetics of apalutamide and total potency-adjusted pharmacologically active moieties, and simulated drug-drug interaction (DDI) between single-dose and repeated-dose apalutamide coadministered with known inhibitors/inducers.

Methods: We applied physiologically based pharmacokinetic modeling for our predictions, and simulated DDI between single-dose and repeated-dose apalutamide 240 mg coadministered with ketoconazole, gemfibrozil, or rifampicin.

Optimization of clinical dosing schedule to manage neutropenia: learnings from semi-mechanistic modeling simulation approach.

Neutropenia is a common side-effect of oncology drugs. We aimed to study the impact of exposure and dosing schedule on neutropenia to guide selection of dosing schedules that minimize neutropenia potential while maintaining the desired minimum concentration (C) required for target engagement. Dose, frequency and PK parameters were chosen for five hypothetical drugs of various half-lives to (1) achieve same exposure with continuous dosing and evaluate impact of 4 intermittent dosing schedules; and (2) achieve same nadir for continuous and intermittent dosing and evaluate impact on % time above C, a surrogate assumed to indicate target engagement.

Population Pharmacokinetics of Total and Free Erdafitinib in Adult Healthy Volunteers and Cancer Patients: Analysis of Phase 1 and Phase 2 Studies.

A population pharmacokinetic (PK) model was developed using data pooled from 6 clinical studies (3 in healthy volunteers and 3 in cancer patients) to characterize total and free plasma concentrations of erdafitinib following single- and multiple-dose administration, to understand clinically relevant covariates, and to quantify the inter- and intraindividual variability in erdafitinib PK. An open, linear, 3-compartment disposition model with first-order absorption and a lag time was used to describe the PK profile of total and free erdafitinib plasma concentrations. The PK of erdafitinib were linear and time independent.

Effect of Fluconazole and Itraconazole on the Pharmacokinetics of Erdafitinib in Healthy Adults: A Randomized, Open-Label, Drug-Drug Interaction Study.

Background And Objectives: Erdafitinib, an oral selective pan-fibroblast growth factor receptor (FGFR) kinase inhibitor, is primarily metabolized by cytochrome P450 (CYP) 2C9 and 3A4. The aim of this phase 1 study was to assess the pharmacokinetics and safety of erdafitinib in healthy participants when coadministered with fluconazole (moderate CYP2C9 and CYP3A inhibitor), and itraconazole (a strong CYP3A4 and P-glycoprotein inhibitor). The effect of CYP2C9 genotype variants (*1/*1, *1/*2, *1/*3) on the pharmacokinetics of erdafitinib was also investigated.

Effect of Plasma Protein Binding on the Pharmacokinetics of Erdafitinib: Results of an Integrated Cross-Study Analysis.

Erdafitinib, a potent oral fibroblast growth factor receptor inhibitor, is a low extraction ratio drug highly bound to alpha-1-acid glycoprotein (AGP) with free fraction (f ) varying across populations. This analysis aimed to characterize the impact of plasma protein binding on erdafitinib pharmacokinetics (PK). Plasma protein-binding data (f , AGP, albumin) and PK parameters were pooled from 6 phase 1 studies in healthy participants and 1 first-in-human study in patients with cancer.

Population Pharmacokinetics of Apalutamide and its Active Metabolite N-Desmethyl-Apalutamide in Healthy and Castration-Resistant Prostate Cancer Subjects.

Background: Apalutamide is a next-generation androgen receptor inhibitor approved for treatment of subjects with high-risk, non-metastatic, castration-resistant prostate cancer (NM-CRPC).

Objective: The objective of this study was to characterize the population pharmacokinetics of apalutamide and its metabolite N-desmethyl-apalutamide in healthy male and castration-resistant prostate cancer subjects.

Methods: Plasma concentration data for apalutamide and N-desmethyl-apalutamide from 1092 subjects (seven clinical studies) receiving oral apalutamide (30-480 mg) once daily were pooled for a population pharmacokinetic analysis using a non-linear mixed-effect modelling approach.