Guiding Dyslipidemia Treatment: A Population Pharmacokinetic–Pharmacodynamic Framework for Obicetrapib

• Published in: Journal of clinical pharmacology Vol. 64; no. 9; pp. 1150 - 1164
• Main Authors: Dunn, Allison, Ditmarsch, Marc, Kastelein, John J. P., Kling, Douglas, Neild, Annie, Davidson, Michael H., Gobburu, Joga
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01-09-2024
• Subjects: Adult; Aged; Anticholesteremic Agents - pharmacokinetics; Anticholesteremic Agents - pharmacology; Body weight; cardiovascular; Cholesterol; Cholesterol Ester Transfer Proteins - antagonists & inhibitors; Cholesterol, HDL - blood; Cholesterol, LDL - blood; Cholesteryl ester transfer protein; Clinical trials; Decision making; Dyslipidemia; Dyslipidemias - drug therapy; Female; High density lipoprotein; Humans; Low density lipoprotein; Male; Metabolic disorders; Middle Aged; model informed drug development; modeling and simulation; Models, Biological; Pharmacodynamics; Pharmacokinetics; pharmacometrics; population pharmacokinetics; Population studies; Young Adult; modeling and simulation; cardiovascular; model informed drug development; pharmacometrics; pharmacodynamics; population pharmacokinetics
• ISSN: 0091-2700; 1552-4604; 1552-4604
• DOI: 10.1002/jcph.2448

Obicetrapib is a selective inhibitor of cholesteryl ester transfer protein that is currently in phase 3 of development for the treatment of dyslipidemia as adjunct therapy. The purpose of this study was to comprehensively characterize the pharmacokinetic (PK) and pharmacodynamic (PD) disposition of obicetrapib. Data from 7 clinical trials conducted in healthy adults and those with varying degrees of dyslipidemia were included for model development. The structural model that best described obicetrapib PK was a 3‐compartment model with 4‐compartment transit absorption and first‐order elimination. Body weight was the only covariate found to significantly explain observed variability and was therefore included using allometric scaling on all disposition parameters. For a typical patient weighing 75 kg, the estimated apparent total body clearance and apparent volume of distribution of the central compartment was 0.81 L/h and 36.1 L, respectively. The final PK model parameters were estimated with good precision and were ultimately leveraged to sequentially inform 2 turnover models that describe obicetrapib's effect on low‐density lipoprotein cholesterol (LDL‐C) and high‐density lipoprotein cholesterol (HDL‐C) concentrations. The maximum stimulatory effect of obicetrapib on LDL‐C loss was estimated to be 1.046, while the maximum inhibitory effect of obicetrapib on HDL‐C loss was 0.691. This corresponds to a predicted typical maximum percent change from baseline LDL‐C and HDL‐C of 51.1% and 224%, respectively. The final sequential model described obicetrapib PKPD well and was ultimately able to both demonstrate evidence of internal consistency and support decision‐making throughout the development lifecycle.