Integrated Population Pharmacokinetic/Viral Dynamic Modelling of Lopinavir/Ritonavir in HIV-1 Treatment-Naive Patients

• Type of Material: Article
• Authors: Kun Wang, Shanghai University of Traditional Chinese Medicine; David Z. D'Argenio, University of Southern California; Edward P. Acosta, University of Alabama Birmingham; Anandi Sheth, Emory University; Cecile Delille Lahiri, Emory University; Jeffrey Lennox, Emory University; Corenna Kerstner-Wood, University of Alabama Birmingham; Ighovwerha Ofotokun, Emory University
• Language: English
• Date: 2014-04-01
• Publisher: Springer (part of Springer Nature): Springer Open Choice Hybrid Journals - CC-BY-NC
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2013 Springer International Publishing Switzerland.
• Final Published Version (URL): http://dx.doi.org/10.1007/s40262-013-0122-1
• Title of Journal or Parent Work: Clinical Pharmacokinetics
• ISSN: 0312-5963
• Volume: 53
• Issue: 4
• Start Page: 361
• End Page: 371
• Grant/Funding Information: Supported by National Institutes of Health grants 1K23 A1073119 (IO), 5K12 RR017643 (IO), 1U01AI103408-01 (IO), P41-EB001978 (DZD), KL2TR000455 (ANS), UL1TR000454(ANS), Emory University CFAR (NIH P30 A1050409), and the Atlanta Clinical and Translational Science Institute (NIH MO1 RR00039).
• Keywords: RITONAVIR; IN-VIVO; VIRUS TYPE-1 INFECTION; Pharmacology & Pharmacy; HIV-1-INFECTED PATIENTS; ALPHA-1-ACID GLYCOPROTEIN; EXPOSURE; LOPINAVIR PHARMACOKINETICS; Science & Technology; RAPID TURNOVER; PROTEIN-BINDING; Life Sciences & Biomedicine; THERAPY
• Research Categories: Health Sciences, Public Health; Health Sciences, Pharmacology

Abstract

Background: Lopinavir (LPV)/ritonavir (RTV) co-formulation (LPV/RTV) is a widely used protease inhibitor (PI)-based regimen to treat HIV-infection. As with all PIs, the trough concentration (C trough) is a primary determinant of response, but the optimum exposure remains poorly defined. The primary objective was to develop an integrated LPV population pharmacokinetic model to investigate the influence of α-1-acid glycoprotein and link total and free LPV exposure to pharmacodynamic changes in HIV-1 RNA and assess viral dynamic and drug efficacy parameters. Methods: Data from 35 treatment-naïve HIV-infected patients initiating therapy with LPV/RTV 400/100 mg orally twice daily across two studies were used for model development and simulations using ADAPT. Total LPV (LPVt) and RTV concentrations were measured by high-performance liquid chromatography with ultraviolet (UV) detection. Free LPV (LPVf) concentrations were measured using equilibrium dialysis and mass spectrometry. Results: The LPVt typical value of clearance ( CLLPVt/F) was 4.73 L/h and the distribution volume (V LPVt) was 55.7 L. The clearance ( CL LPVt/F) and distribution volume (V fF) for LPVf were 596 L/h and 6,370 L, respectively. The virion clearance rate was 0.0350 h-1. The simulated LPVLPVttrough values at 90 % (EC90) and 95 % (EC95) of the maximum response were 316 and 726 ng/mL, respectively. Conclusions: The pharmacokinetic-pharmacodynamic model provides a useful tool to quantitatively describe the relationship between LPV/RTV exposure and viral response. This comprehensive modelling and simulation approach could be used as a surrogate assessment of antiretroviral (ARV) activity where adequate early-phase dose-ranging studies are lacking in order to define target trough concentrations and possibly refine dosing recommendations.