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Islatravir (MK-8591) is a highly potent type 1 human immunodeficiency virus (HIV-1) nucleoside reverse transcriptase translocation inhibitor with a long intracellular half-life that is in development for the prevention and treatment of HIV-1. We conducted a randomized, double-blind, placebo-controlled, phase 1 trial in adults without HIV-1 infection. Participants received islatravir or placebo subdermal implants for 12 weeks and were monitored throughout this period and after implant removal. The co-primary end points were safety and tolerability of the islatravir implant and pharmacokinetics, including concentration at day 85, of islatravir triphosphate in peripheral blood mononuclear cells (PBMCs). Secondary end points included additional pharmacokinetic parameters for islatravir triphosphate in PBMCs and the plasma pharmacokinetic profile of islatravir. Based on preclinical data, two doses were assessed: 54 mg ( n  = 8, two placebo) and 62 mg ( n  = 8, two placebo). The most frequently reported adverse events were mild-to-moderate implant-site reactions (induration, hematoma, pain). Throughout the 12-week trial, geometric mean islatravir triphosphate concentrations were above a pharmacokinetic threshold of 0.05 pmol per 10 6 PBMCs, which was estimated to provide therapeutic reverse transcriptase inhibition (concentration at day 85 (percentage of geometric coefficient of variation): 54 mg, 0.135 pmol per 10 6 cells (27.3); 62 mg, 0.272 pmol per 10 6 cells (45.2)). Islatravir implants at both doses were safe and resulted in mean concentrations above the pharmacokinetic threshold through 12 weeks, warranting further investigation of islatravir implants as a potential HIV prevention strategy. A subdermal implant of the HIV-1 antiretroviral islatravir delivers sustained drug release over 12 weeks in humans.

Background Infants with acute lymphoblastic leukemia (ALL) treated with high-dose methotrexate may have reduced methotrexate clearance (CL) due to renal immaturity, which may predispose them to toxicity. Objective The aim of this study was to develop a population pharmacokinetic (PK) model of methotrexate in infants with ALL. Methods A total of 672 methotrexate plasma concentrations were obtained from 71 infants enrolled in the Children’s Oncology Group (COG) Clinical Trial P9407. Infants received methotrexate 4 g/m 2 intravenously for four cycles during weeks 4–12 of intensification. A population PK analysis was performed using NONMEM ® version 7.4. The final model was evaluated using a non-parametric bootstrap and a visual predictive check. Simulations were performed to evaluate methotrexate dose and the utility of a bedside algorithm for dose individualization. Results Methotrexate was best characterized by a two-compartment model with allometric scaling. Weight was the only covariate included in the final model. The coefficient of variation for interoccasion variability (IOV) on CL was relatively high at 25.4%, compared with the interindividual variability for CL and central volume of distribution (10.7% and 13.2%, respectively). Simulations identified that 21.1% of simulated infants benefitted from bedside dose adjustment, and adjustment of methotrexate doses during infusions can avoid supratherapeutic concentrations. Conclusion Infants treated with high-dose methotrexate demonstrated a relatively high degree of IOV in methotrexate CL. The magnitude of IOV in the CL of methotrexate suggests that use of a bedside algorithm may avoid supratherapeutic methotrexate concentrations resulting from high IOV in methotrexate CL.

Cardiovascular disease remains a significant global health burden, and development of cardiovascular drugs in the current regulatory environment often demands large and expensive cardiovascular outcome trials. Thus, the use of quantitative pharmacometric approaches which can help enable early Go/No Go decision making, ensure appropriate dose selection, and increase the likelihood of successful clinical trials, have become increasingly important to help reduce the risk of failed cardiovascular outcomes studies. In addition, cardiovascular safety is an important consideration for many drug development programs, whether or not the drug is designed to treat cardiovascular disease; modeling and simulation approaches also have utility in assessing risk in this area. Herein, examples of modeling and simulation applied at various stages of drug development, spanning from the discovery stage through late-stage clinical development, for cardiovascular programs are presented. Examples of how modeling approaches have been utilized in early development programs across various therapeutic areas to help inform strategies to mitigate the risk of cardiovascular-related adverse events, such as QTc prolongation and changes in blood pressure, are also presented. These examples demonstrate how more informed drug development decisions can be enabled by modeling and simulation approaches in the cardiovascular area.