Background: Combination therapy including 3 protease inhibitors may be an option for drug-experienced patients. However, drug interactions can lead to toxicities or sub-therapeutic drug concentrations. We hypothesised that adding indinavir (IDV) 400 mg BD to lopinavir/ritonavir (LPV/RTV) would result in therapeutic concentrations of both drugs in the blood plasma (BP) and therapeutic levels of IDV in CSF and semen.

Methods: 10 HIV-1⁺ men on LPV/RTV (+ at least one NRTI, + 3 with NVP) participated in a pharmacokinetic (PK) study. Sampling was performed prior to and 2 weeks after adding IDV to stable regimens. Blood was drawn at 0h and then 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 10, 12 hrs post-observed drug intake. CSF and semen was obtained 12 hrs post-drug intake. BP, CSF, and seminal plasma (SP) drug concentrations were determined by validated HPLC-MS/MS.

Results: Ten (10) men provided BP for 0–12 hrs PK determination. Six (6) patients provided CSF and 5 proved SP samples. BP LPV PK parameters were within previously described ranges. All patients had undetectable (e.g., < 10ng/ml) LPV concentrations in CSF. Median SP LPV concentrations were 248 ng/ml (range 96–2,777). Eight (8) men provided blood samples for the 2^nd 0–12 hrs study; 4 patients provided CSF and semen. When co-dosed with IDV, the median PK parameters for LPV were Cmax 14,387 ng/ml (8,668–19,552), Cmin 5612 ng/ml (1,168–10,945), Tmax 2.75 hrs (1.5–4), AUC_0-12 114,845 ng/ml hrs (58,163–203,960), t½ 11.55 hrs (3.1–21.5). Two (2) of 4 had LPV concentrations in CSF detectable at 27 and 29 ng/ml, respectively. Median SP LPV concentrations were 655 ng/ml (20–2,734). Post IDV the median increase from baseline for LPV Cmax, Cmin and AUC_0-12 was +9% (range -23%– +78%), +46% (-68%– +130%) and +20% (-36%– +102%), respectively. None of these were statistically significant p = 0.32, 0.32 and 0.2. (Wilcoxen signed rank) due to wide inter-patient variability. At visit 2, median IDV PK parameters were Cmax 3,365 ng/ml (range 2,130–5,194), Cmin 293 ng/ml (14–766), Tmax 2.25 hrs (1–3), AUC_0-12 22,452 ng/ml·hrs (11,243–33,661), t½ 2.8hrs (1.4–3.7). Median CSF IDV concentrations were 39 ng/ml (21–86). Median SP IDV concentrations were 592 ng/ml (96–983).

Conclusions: Adding IDV 400 mg BD to LPV/RTV containing regimens did not significantly alter median LPV PK parameters. However, wide inter-patient variability existed. IDV concentrations in BP (Cmin), CSF, and SP were above target concentrations in 5/8, 4/4, and 3/4 samples, respectively.