Pharmacokinetics of Saquinavir With Atazanavir or Low‐Dose Ritonavir Administered Once Daily (ASPIRE I) or Twice Daily (ASPIRE II) in Seronegative Volunteers

Abstract

ASPIRE I and II were prospective, 3-way sequential crossover studies in healthy volunteers to compare the safety and pharmacokinetics of saquinavir/ritonavir (SQV/RTV) with saquinavir/atazanavir (SQV/ATV) administered either once daily (QD, ASPIRE I) or twice daily (BID, ASPIRE II). Treatments were separated by 10 days, and pharmacokinetic analyses were performed on days 11, 32, and 53. SQV pharmacokinetics were significantly higher when dosed with RTV compared to ATV (P < .05 for all comparisons). ATV pharmacokinetics were similar within treatment arms. ATV Cmin increased approximately 60%, and Cmax decreased approximately 35% with BID dosing compared with QD dosing. Women had higher exposure for all 3 protease inhibitors (PIs) compared with men after adjusting for weight. Adverse effects were primarily gastrointestinal-related with SQV/RTV and hyperbilirubinemia with SQV/ATV. Although SQV plasma concentrations were higher when coadministered with RTV, a combination of SQV/ATV administered BID may be a viable alternative in HIV-infected, PI-naive subjects intolerant to RTV.

Atazanavir pharmacokinetics in genetically determined CYP3A5 expressors versus non-expressors

“…Examples may include variability in the pregnane X receptor (PXR), which controls transcription of CYP3A and ABCB1, the CYP3A4 *1B genotype, and other influx or efflux transporters such as SLCO1B1, SLCO1A2, ABCC1 (MRP1), ABCC2 (MRP2) and ABCG2 (BCRP). 23 -27 The present study found higher atazanavir concentrations in women versus men, a finding described by others, 28 but women did not have lower weight-adjusted CL/F.…”

Atazanavir/Ritonavir-Based Combination Antiretroviral Therapy for Treatment of HIV-1 Infection in Adults

“…Although a 2.4-fold-higher atazanavir AUC was described in women versus men receiving atazanavir along with ritonavir-boosted saquinavir [27], when ritonavir-boosted or unboosted atazanavir is the only PI, no significant gender-related differences in atazanavir pharmacokinetic parameters have been identified [19–21,28]. …”

Variable adherence to prescribed dosing regimens for protease inhibitors: scope and outcomes

“…For the once-daily regimen, 73% patients will have at least one interval of more than 36 h and for the twice-daily regimen, 54% patients will have at least one interval of more than 36 h. Reproduced from [11 ]. ASPIRE I and II were prospective, three-way sequential crossover studies of healthy volunteers that compared the pharmacokinetics of SQV/r with SQV/ATV administered either once daily or twice daily [25]. The goal of these studies was to investigate a potential alternative to RTVboosted protease inhibitor therapy, a dual protease inhibitor regimen combining SQV and ATV.…”