Conflicting results on how T-20 affects tipranavir

Two small cohort studies reached opposite conclusions on whether the fusion inhibitor enfuvirtide raises levels of the protease inhibitor tipranavir, and 7th HIV Pharmacology Workshop attendees could not sort out the discrepancy in an open discussion.

Daniel Gonzalez de Requena (University of Turin) measured tipranavir levels in 55 people beginning 500/200 mg of tipranavir/ritonavir twice daily with or without enfuvirtide. Defining troughs as levels measured 11 to 13 hours after dosing, he found a significantly higher mean trough in people taking enfuvirtide (41,069 ng/mL + 20,174 ng/mL) than in those not taking the fusion inhibitor (27,261 ng/mL + 17,516 ng/mL) (P = 0.011). Ritonavir troughs were also significantly higher with than without enfuvirtide.

Tipranavir elimination half-life averaged 9.69 hours in the enfuvirtide group and 5.36 hours in the no-enfuvirtide group. Volume of distribution of tipranavir also proved higher with enfuvirtide than without it (9.85 versus 6.5 L). Tipranavir area under the concentration-time curve (AUC) and peak concentration did not differ significantly between groups. Because of these findings, Gonzalez speculated that higher tipranavir volume of distribution and longer half-life with enfuvirtide could explain the higher tipranavir concentrations. He did not report any between-group differences in antiviral efficacy or tipranavir/ritonavir tolerability.

Adrian Curran (University Hospital Vall dHebron, Barcelona) recorded nonsignificantly lower tipranavir troughs in 11 people taking the boosted protease inhibitor with enfuvirtide than in 4 not injecting enfuvirtide. Analyzing 44 tipranavir trough samples, he recorded a median reading of 35.30 mg/mL (interquartile range 28.00 to 43.30 mg/mL) with enfuvirtide and 39.45 (27.00 to 44.50) mg/mL without enfuvirtide (P = 0.7). Ritonavir troughs were moderately lower with enfuvirtide than without it (0.13 versus 0.20 mg/mL, P = 0.08). Men had significantly lower tipranavir troughs than women (34.42 versus 43.69 mg/mL, P = 0.005), but weight did not correlate with tipranavir trough. Gonzalez saw no weight difference in his enfuvirtide and no-enfuvirtide groups, and both groups were predominantly male. As in the Turin study, Curran recorded no differences in tipranavir peaks or AUC with versus without enfuvirtide.

Moderating a discussion of the two studies, Michael Kurowski (Therapia, Berlin) noted that the interaction Gonzalez reported comes as a surprise since tipranavir and enfuvirtide have entirely different chemical structures and metabolism mechanisms. He stressed the small numbers in both analyses and agreed that a formal pharmacokinetic studynot additional case reportsare needed to resolve the conflict.