¹Division of Clinical Pharmacology and Toxicology, University Hospital of Lausanne, and Institute of Microbiology, University Hospital of Lausanne, Lausanne; Division of Infectious Disease, University Hospital of Bern, Bern; and Unit of Biochemistry and Clinical Psychopharmacology, Centre for Psychiatric Neuroscience, Cery Hospital, Prilly-Lausanne.

Correspondence: Chin B. Eap, PhD, Unit of Biochemistry and Clinical Psychopharmacology, Centre for Psychiatric Neuroscience, Cery Hospital, Prilly-Lausanne, Switzerland. E-mail: Chin.Eap@chuv.ch

^*A complete list of members of the Swiss HIV Cohort Study appears at the end of the article.

^*Support for this work was provided by the Swiss National Science Foundation (grant 3345C0-100935/1 and grant 3347-069366) and by the Swiss HIV Cohort Study. The funding sources had no role in the design, conduct, and reporting of the study or in the decision to submit the manuscript for publication.

Received 31 May 2006; Accepted 13 June 2006.

Abstract

Background and Objective: Protease inhibitors are highly bound to orosomucoid (ORM) (₁-acid glycoprotein), an acute-phase plasma protein encoded by 2 polymorphic genes, which may modulate their disposition. Our objective was to determine the influence of ORM concentration and phenotype on indinavir, lopinavir, and nelfinavir apparent clearance (CL_app) and cellular accumulation. Efavirenz, mainly bound to albumin, was included as a control drug.

Methods: Plasma and cells samples were collected from 434 human immunodeficiency virus–infected patients. Total plasma and cellular drug concentrations and ORM concentrations and phenotypes were determined.

Results: Indinavir CL_app was strongly influenced by ORM concentration (n = 36) (r² = 0.47 [P = .00004]), particularly in the presence of ritonavir (r² = 0.54 [P = .004]). Lopinavir CL_app was weakly influenced by ORM concentration (n = 81) (r² = 0.18 [P = .0001]). For both drugs, the ORM1 S variant concentration mainly explained this influence (r² = 0.55 [P = .00004] and r² = 0.23 [P = .0002], respectively). Indinavir CL_app was significantly higher in F1F1 individuals than in F1S and SS patients (41.3, 23.4, and 10.3 L/h [P = .0004] without ritonavir and 21.1, 13.2, and 10.1 L/h [P = .05] with ritonavir, respectively). Lopinavir cellular exposure was not influenced by ORM abundance and phenotype. Finally, ORM concentration or phenotype did not influence nelfinavir (n = 153) or efavirenz (n = 198) pharmacokinetics.

Conclusion: ORM concentration and phenotype modulate indinavir pharmacokinetics and, to a lesser extent, lopinavir pharmacokinetics but without influencing their cellular exposure. This confounding influence of ORM should be taken into account for appropriate interpretation of therapeutic drug monitoring results. Further studies are needed to investigate whether the measure of unbound drug plasma concentration gives more meaningful information than total drug concentration for indinavir and lopinavir.