Background:  Antiretroviral regimens based on dual protease inhibitors have shown promising results in the complex management of HIV⁺ patients in salvage therapy settings. This strategy, however, may also be associated with the potential for undesirable drug interactions. The aim of this study was to investigate the pharmacokinetics of saquinavir hard gell (SQV)/fosamprenavir (fAPV) 1000/700 mg twice dialy when administered with ritonavir (r) 100 or 200 mg twice daily.

Methods:  We studied the pharmacokinetics of 18 HIV⁺ patients (1 female; mean age 42 years) on SQV/r 1000/100 mg twice daily. Patients were given SQV/r 1000/100 mg with a 20-g fat meal on day 1; on day 2 they were switched to SQV/fAPV/r 1000/700/100 mg twice daily, and on day 12 to 1000/700/200 mg twice daily. Safety analysis was performed at screening, on day 1, 11, and 22 and at follow-up. On pharmacokinetic study days (1, 11, 22), blood was drawn pre-dose and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours post-dose. Geometric mean ratios and 95%CI were used to compare SQV pharmacokinetic parameters measured on the 3 study phases. SQV/fAPV/ r concentrations were measured by HPLC-MS/MS.

Results:  At screening, mean ±SD CD4 cell count was 442±233/mm³ and plasma HIV-RNA <200 copies/mL in all patients. No significant changes in ALT, AST, glucose, or total cholesterol triglycerides were observed. SQV pharmacokinetic data on 17 patients are summarized in the table below. On day 11, SQV AUC_0-12 (GMR, 95%CI:  0.86, 0.73 to 1.19), C_trough (0.76, 0.62 to 1.19), and C_max (0.91, 0.79 to 1.23) showed a not statistically significant decrease. On day 22, SQV AUC_0-12 (GMR, 95%CI:  1.12, 0.88 to 1.73), C_trough (1.03, 0.80 to 1.79), and C_max (1.20, 0.97 to 1.74) showed a not statistically significant increase. fAPV concentrations were not affected by SQV co-administration: all patients had an APV C_trough >HIV_WT-MEC (Geometric mean 1252 ng/mL day 11 and 1120 ng/mL day 22).

SQV Pharmacokinetic data

C_trough=trough concentration; C_max=maximum concentration; AUC=area under concentration-time curve

Conclusions:  SQV/fAPV/r was well tolerated. SQV AUC_0-12, C_trough and C_max decreased by 14%, 24%, and 9% on D11 and increased by 12%, 3%, and 20% on D22. Although the changes were not statistically significant, SQV therapeutic drug monitoring is recommended to ensure adequate concentrations when 100 mg r twice daily are administered.

Keywords: pharmacokinetics; saquinavir; fosamprenavir