Steady-State Pharmacokinetics of Twice-Daily Dosing of Saquinavir Plus Ritonavir in HIV-1-Infected Individuals

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Abstract

Objective:

To compare the steady state plasma pharmacokinetics of 1000 mg of saquinavir (SQV) in a soft-gel capsule (SGC) formulation in combination with 100 mg of ritonavir (RTV) (capsules) in a twice-daily dosing regimen in HIV-1infected 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 regimen 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 pharmacokinetic 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 second 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 (AUC0-12h), the maximum plasma concentration (Cmax), the plasma trough concentration (C12h), and the elimination half-life in plasma (t1/2). The obtained pharmacokinetic parameters were compared with those of 12 patients using 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 (1000 mg twice daily, normal breakfast) were: AUC0-12h, 18.84 h*mg/L; Cmax, 3.66 mg/L; C12h, 0.40 mg/L; and t1/2, 3.0 hours. The median values of the pharmacokinetic parameters for SQV HGC (400 mg twice daily, normal breakfast) were: AUC0-12h, 6.99 h*mg/L; Cmax, 1.28 mg/L; C12h, 0.23 mg/L; and t1/2, 3.9 hours. The exposure to SQV in the dosing regimen of 1000 mg twice daily in combination with 100 mg of RTV twice daily was significantly higher 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 with 100 mg of RTV twice daily were not significantly different after ingestion of a high-fat or normal breakfast (p > .35).

Conclusions:

The combination of 1000 mg of SQV SGC twice daily and 100 mg of RTV twice daily resulted in a higher exposure to SQV compared with the exposure to SQV obtained when SQV is used in the 400 mg/400 mg twice-daily combination with RTV. In this small number of patients, no significant differences in exposure were seen after ingestion of either a normal or high-fat breakfast. From a pharmacokinetic perspective, the combination of 1000 mg of SQV SGC twice daily and 100 mg of RTV twice daily seems to be a good option for further clinical evaluation.

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