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

Objectives: To evaluate plasma population pharmacokinetics and penetration into cerebrospinal fluid (CSF) by indinavir (IDV) in HIV-infected individua ls receiving IDV, zidovudine and lamivudine. Methods: Plasma population pharmacokinetic analysis was performed on 805 ID V plasma Values from 171 patients, using a non-linear mixed-effects modelin g approach. CSF data from 19 patients were analyzed using an individual app roach. Results: Mean individual Bayesian estimates for oral clearance (CL) and vol ume of distribution (V) by the final model that incorporated interoccasion variability were 0.75 I/h per kg [coefficient of variation (CV) 54.8%]: and 1.74 I/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 mu mol/l (CV 57.5%), 9.51 mu mol/l (CV 47.3%), 29.56 mu mol/l.h (CV 46.9%) and 1.50 h (CV 20.9%), respectively. The mean I DV CSF level was 0.11 mu mol/l (CV 49.7%) and the mean CSF plasma concentra tion ratio was 0.017. Conclusions: Population estimates of pharmacokinetic parameters of IDV and its CSF penetration were in excellent agreement with previously reported da ta from individual analyses. Intraindividual interoccasion variability of I DV pharmacokinetics was estimated to be of similar order of magnitude to it s interindividual variability, which may affect response to long-term antir etroviral therapy involving IDV. CSF levers 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. (C) 2000 Lippincott Williams & W ilkins.