Lopinavir/ritonavir combined with twice-daily 400 mg indinavir: Pharmacokinetcs and pharmacodynamics in blood, CSF and semen
Isaac A., Taylor S., Cane P., Smit E., Gibbons SE., White DJ., Drake SM., Khoo S., Back DJ.
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. <10ng/mL) and 248 ng/mL (range 96-2777), respectively. After indinavir: lopinavir Cmax, Cmin and AUC0-12 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 Cmax 3365 ng/mL (range 2130-5194), Cmin 293 ng/mL (14-766), Tmax 2.25 h (1-3), AUC0-12 22452 ng/mL·h (11243-33661), and t1/2 2.8h (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 >80ng/mL in seven of eight plasma samples, and all CSF and semen samples collected. © The British Society for Antimicrobial Chemotherapy 2004; all rights reserved.