The unbound percentage of saquinavir and indinavir remains constant throughout the dosing interval in HIV positive subjects

Abstract

Aims To measure the unbound plasma concentrations of saquinavir (SQV) and indinavir (IDV) and to relate them to the total plasma concentrations in order to establish the unbound percentage of protease inhibitors in vivo during a full dosage interval profile. Methods HIV‐infected subjects (n = 35; median CD4 cell count = 340 × 10⁶ cells l⁻¹, range: 120–825; viral load < 50 copies ml⁻¹ in 22/35) treated with SQV or IDV containing regimens were studied. Plasma drug samples were collected at 0, 2, 4, 8 and 12 h postdose for the twice daily regimens and 0, 1, 2, 4 and 8 h for the three times daily regimens. Ultra‐filtration was used to separate unbound IDV and SQV in plasma and their respective concentrations were measured by a fully validated method using high performance liquid chromatography‐mass spectometry (h.p.l.c.‐MS/MS). Results Based on the ratio AUC_unbound/AUC_total, the median unbound percentage (95% CI for differences) of SQV and IDV from all the samples studied was 1.19% (0.99, 1.58%) and 36.3% (35.1, 44.2%), respectively. No significant difference was seen in the percentage binding of SQV between patients receiving SQV alone (median = 1.49%) or with ritonavir (median = 1.09%; P = 0.141; 95% CI for difference between medians = −0.145, 0.937) over the pharmacokinetic profile. Similarly, no significant difference was seen in the percentage binding of IDV in patients receiving IDV alone (median 35.2%) or with ritonavir (median = 41.3%; P = 0.069; 95% CI for difference between medians = −0.09, 15.4). The unbound concentrations of SQV (P < 0.0001; 95% CI for r  ² = 0.634, 0.815) and IDV (P < 0.0001; 95% CI for r² = 0.830, 0.925) remained constant as a proportion of total concentration over the full dosing profile. Conclusions These in vivo data confirm previously published in vitro measurements of SQV and IDV protein binding. The unbound percentage of both protease inhibitors remained constant over the dosing interval.