Steady-state pharmacokinetics of twice-daily dosing of saquinavir plus ritonavir in HIV-1-infected individuals

Objective: To compare the steady state plasma pharmacokinetics of 1000 mg o f saquinavir (SQV) in a soft-get capsule (SGC) formulation in combination w ith 100 mg of ritonavir (RTV) (capsules) in a twice-daily dosing regimen in HIV-1-infected individuals with historical controls who used 400 mg of SQV in a hard-gel capsule (HGC) formulation in combination with 400 mg of RTV and to investigate the plasma pharmacokinetics of the 1000 mg/100 mg regime n after normal and high-fat breakfasts. Design: Open-label, crossover, steady-state pharmacokinetic study. Methods: Six HIV-1-infected individuals who used either 1200 mg of SQV (SGC or HGC) three times daily or 400 mg twice daily in combination with 400 mg of RTV twice daily were included. Each patient was switched to 1000 mg of SQV SGC twice daily in combination with 100 mg of RTV twice daily. After 14 days, the patients came to the hospital for assessment of a pharmacokineti c profile during 12 hours. Patients were randomized to receive a high-fat ( +/- 45 g of fat) or normal (+/- 20 g of fat) breakfast. After 7 days, a sec ond pharmacokinetic profile was assessed after ingestion of the drugs with the alternate breakfast. A noncompartmental pharmacokinetic method was used to calculate the area under the plasma concentration versus time curve (AU C(0-12h))the maximum plasma concentration (C-max), the plasma trough concen tration (C-12h), and the elimination half-life in plasma (t(1/2)). Tbe obta ined pharmacokinetic parameters were compared with those of 12 patients usi ng SQV HGC (400 mg twice daily) in combination with RTV (400 mg twice daily ). Results: The median values of the pharmacokinetic parameters for SQV SGC (1 000 mg twice daily, normal breakfast) were: AUC(0-12h), 18.84 h*mg/L; C-max , 3.66 mg/L; C-12h, 0.40 mg/L; and t(1/2), 3.0 hours. The median values of the pharmacokinetic parameters for SQV HGC (400 mg twice daily. normal brea kfast) were: AUC(0-12h), 6.99 h*mg/L C-max, 1.28 mg/L; C-12h, 0.23 mg/L; an d t(1/2) 3.9 hours. The exposure to SQV in the dosing regimen of 1000 mg tw ice daily in combination with 100 mg of RTV twice daily was significantly h igher than the exposure to SQV in a dosing regimen of 400 mg twice daily in combination with 400 mg of RTV twice daily. The pharmacokinetic parameters of SQV SGC in the dosing regimen of 1000 mg twice daily in combination wit h 100 mg of RTV twice daily were not significantly different after ingestio n of a high-fat or normal break-fast (p > .35). Conclusions: The combination of 1000 mg of SQV SGC twice daily and 100 mg o f RTV twice daily resulted in a higher exposure to SQV compared with the ex posure to SQV obtained when SQV is used in the 400 mg/400 mg twice-daily co mbination with RTV, In this small number of patients, no significant differ ences in exposure were seen after ingestion of either a normal or high-fat breakfast. From a pharmacokinetic perspective, the combination of 1000 mg o f SQV SGC twice daily and 100 mg of RTV twice daily seems to be a good opti on for further clinical evaluation.