Saquinavir 500 mg Film-Coated Tablets Demonstrate Bioequivalence to Saquinavir 200 mg Hard Capsules When Boosted with Twice-Daily Ritonavir in Healthy Volunteers

Abstract

Objective

To establish the bioequivalence of a 500 mg film-coated tablet of saquinavir mesylate (FCT SQV) to the 200 mg hard-capsule saquinavir mesylate (HC SQV), both boosted with ritonavir and administered under fed conditions.

Methods

We carried out a multi-centre, open-label, randomized, two-sequence, four-period, two-treatment, replicated crossover study in 93 healthy men and 7 healthy women. Individuals were randomly assigned to receive sequential single doses of saquinavir in one of two treatment sequences: ABAB or BABA. Individuals received 100mg ritonavir twice daily for 24 days. On days 14, 17, 20 and 23, study participants took 1000mg of HC SQV (five 200 mg capsules, treatment A) or FCT SQV (two 500 mg tablets, treatment B) with a high-fat, high-calorie breakfast, and pharmacokinetic analyses were carried out over the next 24 hours. Area under the saquinavir concentration–time curve (AUC_0–∞), maximum saquinavir plasma concentration (C_max), time to C_max and terminal half-life were calculated. The relative bioavailability of FCT SQV versus HC SQV was calculated as the ratio of the respective estimated mean saquinavir AUC_0-∞ and C_max. The calculation was based on an ANOVA including the factors site, sex, sequence, period, treatment and study participant to the log-transformed parameters log(AUC_0-∞) and log(C_max); the relative bioavailability and the 90% confidence intervals (CIs) were estimated using the treatment contrasts of the ANOVA. Bioequivalence was concluded as for both parameters, AUC_0-∞ and C_max, the 90% CIs for the relative bioavailability were entirely included in the reference region [0.80–1.25].

Results

Saquinavir plasma concentration–time profiles for the two formulations were similar. Geometric mean AUC_0-∞ and C_max values were clearly increased for FCT SQV (26 826 versus 24 430 h*ng/ml; and 3644 versus 3064 ng/ml, respectively); ratios of mean exposures were estimated to be 1.10 for AUC_0-∞ and 1.19 for C_max of saquinavir. However, the corresponding two-sided 90% CIs (1.04–1.16 and 1.14–1.25, respectively) all fell within the limits set for equivalence (0.80, 1.25). The adverse event profile for FCT SQV was similar to that for HC SQV.

Conclusion

The new 500 mg FCT SQV formulation is bioequivalent to the 200 mg HC SQV formulation, at the dose of 1000 mg, in combination with 100 mg ritonavir under fed conditions. The 500 mg FCT SQV formulation reduces pill count for boosted saquinavir (SQV/r) from six capsules to three tablets twice daily. This may increase patient acceptability of SQV/r, particularly in less treatment-experienced patients.