Exposure-Response Analyses for Belzutifan to Inform Dosing Considerations and Labeling.

Belzutifan (Welireg, Merck & Co., Inc., Rahway, NJ, USA) is an oral, potent hypoxia-inducible factor-2α inhibitor, recently approved in the United States for the treatment of von Hippel-Lindau (VHL) disease-associated renal cell carcinoma (RCC) and other VHL disease-associated neoplasms.

Model-Informed Selection of the Recommended Phase III Dose of the Inhibitor of Apoptosis Protein Inhibitor, Xevinapant, in Combination with Cisplatin and Concurrent Radiotherapy in Patients with Locally Advanced Squamous Cell Carcinoma of the Head and Neck.

Xevinapant, an oral inhibitor of apoptosis protein (IAP) inhibitor, demonstrated efficacy in combination with chemoradiotherapy in a randomized phase II study (NCT02022098) in patients with locally advanced squamous cell carcinoma of the head and neck at 200 mg/day on days 1-14 of a 3-week cycle. To confirm 200 mg/day as the recommended phase III dose (RP3D), we integrated preclinical, clinical, pharmacokinetic/pharmacodynamic (PK/PD), and exposure-response modeling results. Population PK/PD modeling of IAP inhibition in peripheral blood mononuclear cells in 21 patients suggested the pharmacologically active dose range was 100-200 mg/day, with a trend for more robust inhibition at the end of the dosing interval at 200 mg/day based on an indirect response model.

Population pharmacokinetic analyses for belzutifan to inform dosing considerations and labeling.

Belzutifan (Welireg, Merck & Co., Inc., Rahway, NJ, USA) is an oral, potent inhibitor of hypoxia-inducible factor 2α, approved for the treatment of certain patients with von Hippel-Lindau (VHL) disease-associated renal cell carcinoma (RCC), central nervous system hemangioblastomas, and pancreatic neuroendocrine tumors.

Predicted Bezlotoxumab Exposure in Patients Who Have Received a Hematopoietic Stem Cell Transplant.

Purpose: Bezlotoxumab is approved for prevention of recurrent Clostridioides (Clostridium) difficile infection (CDI) in adults receiving antibacterial treatment for CDI who are at high risk for recurrent CDI. Previous studies have shown that although serum albumin levels are an important predictor for bezlotoxumab exposure, this has no clinically meaningful impact on efficacy. This pharmacokinetic modeling study assessed whether hematopoietic stem cell transplant (HSCT) recipients, at increased risk of CDI and exhibiting decreased albumin levels within the first month posttransplant, are at risk of clinically relevant reductions in bezlotoxumab exposure.

Eculizumab Pharmacokinetics and Pharmacodynamics in Patients With Neuromyelitis Optica Spectrum Disorder.

To investigate the pharmacokinetics and pharmacodynamics of the approved 900/1,200 mg dosing regimen for the terminal complement component 5 (C5) inhibitor eculizumab in patients with neuromyelitis optica spectrum disorder (NMOSD). Data were analyzed from 95 patients with aquaporin-4-IgG-positive NMOSD who received eculizumab during the PREVENT study (ClinicalTrials.gov: NCT01892345).

Eculizumab Pharmacokinetics and Pharmacodynamics in Patients With Generalized Myasthenia Gravis.

To investigate the pharmacokinetics, pharmacodynamics, and exposure-response of the approved 900/1,200 mg dosing regimen for the terminal complement component 5 (C5) inhibitor eculizumab in patients with generalized myasthenia gravis (gMG). The analysis used data from 62 patients aged ≥ 18 years with anti-acetylcholine receptor (AChR) antibody-positive refractory gMG who received eculizumab during the REGAIN study (ClinicalTrials.gov: NCT01997229).

Design and rationale of two phase 3 randomised controlled trials (COUGH-1 and COUGH-2) of gefapixant, a P2X3 receptor antagonist, in refractory or unexplained chronic cough.

Background: We present study designs, dose selection and preliminary patient characteristics from two phase 3 clinical trials of gefapixant, a P2X3 receptor antagonist, in refractory chronic cough (RCC) or unexplained chronic cough (UCC).

Methods: COUGH-1 (NCT03449134) and COUGH-2 (NCT03449147) are randomised, placebo-controlled, double-blind, parallel-group trials in subjects with RCC or UCC (age ≥18 years; cough duration ≥1 year; Cough Severity Visual Analogue Scale score ≥40 mm). The primary efficacy study periods are 12 weeks (40-week extension; COUGH-1) and 24 weeks (28-week extension; COUGH-2).

A time-to-event analysis of the exposure-response relationship for bezlotoxumab concentrations and CDI recurrence.

Bezlotoxumab is a monoclonal antibody approved for the prevention of recurrent Clostridium difficile infection (rCDI). In a previous exposure-response (E-R) analysis of bezlotoxumab exposure and rCDI, based on data from two phase 3 trials in participants who received placebo or bezlotoxumab 10 mg/kg, rCDI was treated as a binary endpoint and discontinued subjects were imputed as not having rCDI, resulting in an apparent positive E-R trend between rCDI rates and bezlotoxumab exposure. Therefore, a time-to-event (TTE) analysis was applied to investigate the E-R relationship, accounting for the time to rCDI occurrence and participant discontinuation.

Making Better Dose Decisions: Using Exposure-Response Modeling to Integrate Efficacy Outcome of Two Phase IIb Clinical Trials of Ubrogepant for Migraine Treatment.

Ubrogepant (MK-1602) is a novel, oral, calcitonin gene-related peptide receptor antagonist in clinical development with positive phase III outcomes for acute treatment of migraine. This paper describes the population exposure-response (E-R) modeling and simulations, which were used to inform the phase III dose-selection rationale, based on ~ 800 participants pooled across two phase IIb randomized dose-finding clinical trials. The E-R model describes the placebo and ubrogepant treatment effects based on migraine pain end points (2-hour pain relief and 2-hour pain freedom) at various dose levels.

Population Pharmacokinetics and Pharmacodynamics of Bezlotoxumab in Adults with Primary and Recurrent Infection.

The fully human monoclonal antibody bezlotoxumab is indicated for preventing the recurrence of (formerly ) infection (CDI) in adults who receive antibacterial treatment for CDI and who are at high risk for a CDI recurrence. The efficacy and safety of 10-mg/kg of body weight bezlotoxumab were demonstrated in two phase 3 trials: the MODIFY I (ClinicalTrials.gov registration number NCT01241552) and MODIFY II (ClinicalTrials.

Extending a Systems Model of the APP Pathway: Separation of - and -Secretase Sequential Cleavage Steps of APP.

The abnormal accumulation of amyloid- (A) in the brain parenchyma has been posited as a central event in the pathophysiology of Alzheimer's disease. Recently, we have proposed a systems pharmacology model of the amyloid precursor protein (APP) pathway, describing the A APP metabolite responses (A40, A42, sAPP, and sAPP) to -secretase 1 (BACE1) inhibition. In this investigation this model was challenged to describe A dynamics following -secretase (GS) inhibition.

Population PK Analyses of Ubrogepant (MK-1602), a CGRP Receptor Antagonist: Enriching In-Clinic Plasma PK Sampling With Outpatient Dried Blood Spot Sampling.

Merck & Co., Inc. (Kenilworth, New Jersey) has recently published an integrated strategy for implementation of dried blood spots (DBS) in late-stage trials for population pharmacokinetic (PK) modeling.

Systems Pharmacology Analysis of the Amyloid Cascade after β-Secretase Inhibition Enables the Identification of an Aβ42 Oligomer Pool.

The deposition of amyloid-β (Aβ) oligomers in brain parenchyma has been implicated in the pathophysiology of Alzheimer's disease. Here we present a systems pharmacology model describing the changes in the amyloid precursor protein (APP) pathway after administration of three different doses (10, 30, and 125 mg/kg) of the β-secretase 1 (BACE1) inhibitor MBi-5 in cisterna magna ported rhesus monkeys. The time course of the MBi-5 concentration in plasma and cerebrospinal fluid (CSF) was analyzed in conjunction with the effect on the concentrations of the APP metabolites Aβ42, Aβ40, soluble β-amyloid precursor protein (sAPP) α, and sAPPβ in CSF.

A PK-PD model-based assessment of sugammadex effects on coagulation parameters.

Exposure-response analyses of sugammadex on activated partial thromboplastin time (APTT) and prothrombin time international normalized ratio (PT(INR)) were performed using data from two clinical trials in which subjects were co-treated with anti-coagulants, providing a framework to predict these responses in surgical patients on thromboprophylactic doses of low molecular weight or unfractionated heparin. Sugammadex-mediated increases in APTT and PT(INR) were described with a direct effect model, and this relationship was similar in the presence or absence of anti-coagulant therapy in either healthy volunteers or surgical patients. In surgical patients on thromboprophylactic therapy, model-based predictions showed 13.

Early stage development of the glycine-1 re-uptake inhibitor SCH 900435: central nervous system effects compared with placebo in healthy men.

Aims: To report the first three studies with SCH 900435, a selective glycine-1 re-uptake inhibitor in development for treating schizophrenia, using systematic evaluations of pharmacodynamics to understand the observed effects.

Methods: Three double-blind, placebo-controlled studies (single, visual effect and multiple dose) were performed. In the single and multiple dose study SCH 900435 (0.