Covariate Model Selection Approaches for Population Pharmacokinetics: A Systematic Review of Existing Methods, From SCM to AI.

A growing number of covariate modeling methods have been proposed in the field of popPK modeling, but limited information exists on how they all compare. The objective of this study was to perform a systematic review of all popPK covariate modeling methods, focusing on assessing the existing knowledge on their performances. For each method of each article included in this review, evaluation setting, performance metrics along with their associated values, and relative computational times were reported when available.

Pharmacokinetic Modeling and Simulation with Pharmacogenetic Insights Support the Relevance of Therapeutic Drug Monitoring for Myeloablative Busulfan Dosing in Adult HSCT.

Therapeutic drug monitoring (TDM) of busulfan (Bu) is well-established in pediatric hematopoietic stem cell transplantation (HSCT), but its use in adults is limited due to a lack of clear recommendations and scarcity of evidence regarding its utility. GSTA1 promoter variants are reported to affect Bu clearance in both adults and pediatric patients. This study aimed to evaluate the value of preemptive genotyping GSTA1 and body composition (obesity) in individualizing Bu dosing in adults, through pharmacokinetic (PK) modeling and simulations.

Clinical Pharmacokinetics of Radiopharmaceuticals from SPECT/CT Image Acquisition by Contouring in Patients with Gastroenteropancreatic Neuroendocrine Tumors: Lu-177 DOTATATE (Lutathera) Case.

Background And Objective: Lu-177 DOTATATE (Lutathera) is a radiolabeled analog of somatostatin administered intravenously in patients with somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors. Biodistribution of Lu-177 DOTATATE in tumor and healthy tissues can be monitored by serial post-injection scintigraphy imaging. Patient exposure to the drug is variable with the recommended fixed dosage, and hence there is a variable response to treatment.

Combined Semi-mechanistic Target-Mediated Drug Disposition and Pharmacokinetic-Pharmacodynamic Models of Alirocumab, PCSK9, and Low-Density Lipoprotein Cholesterol in a Pooled Analysis of Randomized Phase I/II/III Studies.

Background And Objectives: Alirocumab is a cholesterol-lowering monoclonal antibody targeting proprotein convertase subtilisin kexin type 9 (PCSK9) indicated in the prevention of cardiovascular risk and exhibiting target-mediated drug disposition (TMDD). The aim of this work was to develop an integrated pharmacokinetic-pharmacodynamic model to describe the interaction of alirocumab with PCSK9 and its impact on the evolution of low-density lipoprotein cholesterol (LDL-C) levels and explore labeling specification for subpopulations.

Methods: Using data collected from nine phase I/II/III clinical studies (n = 527, subcutaneous or intravenous administration), a TMDD model considering the quasi-steady-state approximation was developed to characterize the interaction dynamics of alirocumab and PCSK9, combined with an indirect pharmacodynamic model describing the inhibition of LDL-C by PCSK9 in a one-step approach using nonlinear-mixed effects modeling.