Lopinavir/ritonavir combined with twice-daily 400 mg indinavir: pharmacokinetics and pharmacodynamics in blood, CSF and semen

J Antimicrob Chemother. 2004 Aug;54(2):498-502. doi: 10.1093/jac/dkh357. Epub 2004 Jul 14.

Abstract

Objectives: To evaluate the steady-state blood plasma (BP), CSF and seminal plasma (SP) pharmacokinetics (PK) of twice-daily indinavir 400 mg and lopinavir/ritonavir.

Methods: Ten HIV-1-positive men on lopinavir/ritonavir participated in a PK study. PK sampling was performed before and 2 weeks after adding indinavir to lopinavir/ritonavir-containing regimens. BP, CSF and SP RNA levels, CD4 counts and blood chemistry were checked at baseline and 2 weeks after indinavir.

Results: At baseline: lopinavir parameters (n=10) in BP were within expected levels. Median lopinavir trough concentrations (n=5) in CSF and SP were below the limit of detection (BLD) (i.e. <10 ng/mL) and 248 ng/mL (range 96-2777), respectively. After indinavir: lopinavir C(max), C(min) and AUC(0-12) increased by 9%, 46% and 20%, respectively (P<0.32, P<0.32 and P<0.20). In two of four men lopinavir concentrations in CSF were detectable at 27 and 29 ng/mL. Median SP lopinavir concentration was 655 ng/mL (20-2734). Median indinavir PK parameters were C(max) 3365 ng/mL (range 2130-5194), C(min) 293 ng/mL (14-766), T(max) 2.25 h (1-3), AUC(0-12) 22452 ng/mL.h (11243-33661), and t(1/2) 2.8 h (1.4-3.7). Median indinavir concentrations in CSF and SP were 39 ng/mL (21-86) and 592 ng/mL (96-983). Two of eight men who initially had detectable BP viral load (VL) became BLD (<50 copies/mL) after the addition of indinavir, and in 2/4 men with low-level viraemia in SP (BPVL BLD) their SPVL became BLD after addition of indinavir.

Conclusions: Adding indinavir 400 mg twice daily to lopinavir/ritonavir-containing regimens did not significantly alter the median lopinavir PK parameters. However, wide interpatient variability in lopinavir concentrations was seen. In contrast plasma indinavir levels were >80 ng/mL in seven of eight plasma samples, and all CSF and semen samples collected.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Area Under Curve
  • CD4 Lymphocyte Count
  • Chromatography, High Pressure Liquid
  • Drug Combinations
  • HIV Infections / metabolism*
  • HIV Protease Inhibitors / blood
  • HIV Protease Inhibitors / cerebrospinal fluid
  • HIV Protease Inhibitors / pharmacokinetics*
  • HIV-1 / metabolism
  • Humans
  • Indinavir / blood
  • Indinavir / cerebrospinal fluid
  • Indinavir / pharmacokinetics*
  • Lopinavir
  • Male
  • Mass Spectrometry
  • Middle Aged
  • Pyrimidinones / blood
  • Pyrimidinones / cerebrospinal fluid
  • Pyrimidinones / pharmacokinetics*
  • RNA, Viral / biosynthesis
  • Semen / metabolism*
  • Viral Load

Substances

  • Drug Combinations
  • HIV Protease Inhibitors
  • Pyrimidinones
  • RNA, Viral
  • Lopinavir
  • Indinavir