Background:  Pharmacokinetic data in HIV⁺ adults show that co-administration of standard doses of tipranavir (TPV) and lopinavir/rotinavir (LPV/RTV) reduces the C_min, C_max, and AUC of LPV by 40 to 60%, while TPV and RTV levels are unchanged. We studied the effects of LPV and RTV dose adjustments in an attempt to overcome this interaction.

Methods:  This is an open-label trial including HIV⁺ adults on stable LPV 400 mg/RTV 100 mg twice daily with no other protease inhibitor (PI) or non-nucleoside reverse transcriptase inhibitor (NNRTI). To this, 7 patients added TPV 500 mg and RTV 200 mg (total LPV 400 mg/ RTV 300 mg:  Group A) and 6 patients added TPV 500 mg, LPV 133 mg/ RTV 33 mg plus RTV 100 mg (total LPV 533mg/RTV 233mg: Group B), all twice daily starting on day 1. Pre-dose trough (Ctr) PI levels were done on day 1 and full 12-hour pharmacokinetics on day 14. Plasma PI concentrations were determined by HPLC-MS/MS. Paired pharmacokinetic data were compared using Wilcoxon signed rank sum tests.

Results:  Of the 13 HIV⁺ men who entered the study, 1 in group A stopped because of grade 3 nausea and vomiting. For the 12 patients who completed the study, median age was 50 years, weight 77 kg, viral load <50 copies/mL, time on LPV/RTV ≥11 months. The table summarizes LPV and RTV Ctr. LPV Ctr was <4.0 mg/mL on days 1 and 14 in 3 of 6 and 2 of 6 patients for group A, and 1 of 6 and 2 of 6, respectively, for group B. Differences in LPV Ctr between days 1 and 14 were not statistically significant (p = 0.44 for group A, p = 1.0 for group B). RTV Ctr was below the limit of quantitation (<0.025 mg/mL) on days 1 and 14 in 2 of 6 and 1 of 6 patients for group A, and 1 of 6 and 0 of 6, respectively, for group B. RTV Ctr tended to be higher on day 14 than day 1 for group A (p = 0.06) but not for group B (p = 0.16). Median (range) TPV Ctr on day 14 was 36.5 mg/mL (14.4 to 53.4) for group A and 43.2 mg/mL (17.4 to 64.1) for group B, as compared with 21.6 mg/mL (95%CI 19.5, 23.4) from historical data for TPV 500 mg/RTV 200 mg (n = 106 HIV⁺ males). Overall (n = 12), LPV Ctr was linearly correlated with RTV Ctr within LPV’s therapeutic range.

Conclusions:  Increased RTV plasma concentrations were generally associated with increased LPV levels when TPV was co-administered with LPV/RTV. However, therapeutic drug monitoring should be encouraged in view of the substantial inter-patient variability in LPV Ctr seen on day 14.