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Plasma population pharmacokinetics and penetration into cerebrospinal fluid of indinavir in combination with zidovudine and lamivudine in HIV-1-infected patients

Zhou, Xiao-Jiana; Havlir, Diane V.b; Richman, Douglas D.b; Acosta, Edward P.a; Hirsch, Martinc; Collier, Ann C.d; Tebas, Pabloe; Sommadossi, Jean-Pierrea; the AIDS Clinical Trials Group Study 343 Investigators

Clinical Science

Objectives: To evaluate plasma population pharmacokinetics and penetration into cerebrospinal fluid (CSF) by indinavir (IDV) in HIV-infected individuals receiving IDV, zidovudine and lamivudine.

Methods: Plasma population pharmacokinetic analysis was performed on 805 IDV plasma values from 171 patients, using a non-linear mixed-effects modeling approach. CSF data from 19 patients were analyzed using an individual approach.

Results: Mean individual Bayesian estimates for oral clearance (CL) and volume of distribution (V) by the final model that incorporated interoccasion variability were 0.75 l/h per kg [coefficient of variation (CV) 54.8%] and 1.74 l/kg (CV 82.7%), respectively. Mean model-predicted plasma IDV level at 8 h, maximal level, area under the plasma level–time curve up to 8 h and plasma half-life were 0.42 μmol/l (CV 57.5%), 9.51 μmol/l (CV 47.3%), 29.56 μmol/l⋅h (CV 46.9%) and 1.50 h (CV 20.9%), respectively. The mean IDV CSF level was 0.11 μmol/l (CV 49.7%) and the mean CSF:plasma concentration ratio was 0.017.

Conclusions: Population estimates of pharmacokinetic parameters of IDV and its CSF penetration were in excellent agreement with previously reported data from individual analyses. Intraindividual interoccasion variability of IDV pharmacokinetics was estimated to be of similar order of magnitude to its interindividual variability, which may affect response to long-term antiretroviral therapy involving IDV. CSF levels of IDV exceeded its in vitro 95% inhibitory concentration of HIV replication. Given that CSF is virtually free of protein, viral suppression in the central nervous system should be achievable with an IDV-containing regimen.

From the aDepartments of Clinical Pharmacology and Medicine, Birmingham Veteran Affairs Medical Center, Center for AIDS Research, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, the bUniversity of California at San Diego and San Diego Veterans Affairs Medical Center, San Diego, California, the cInfectious Disease Unit and AIDS Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, the dUniversity of Washington School of Medicine, Seattle, Washington and eWashington University, St Louis, Missouri, USA.

Requests for reprints to Dr J.-P. Sommadossi, Department of Clinical Pharmacology, University of Alabama at Birmingham, 1670 University Boulevard, VH G019, Birmingham, Alabama, USA.

Received: 8 June 2000;

revised: 22 August 2000; accepted: 4 September 2000.

Sponsorship: This work was supported by the AIDS Clinical Trials Group of NIAID. Indinavir was provided by Merck; zidovudine and lamivudine were provided by Glaxo Wellcome.

© 2000 Lippincott Williams & Wilkins, Inc.