Saquinavir soft gelatin capsule - A comparative safety review

The HIV-1 protease inhibitor (PI) saquinavir is available as a soft gelatin capsule (SGC) formulation. At the recommended dosage of saquinavir SGC (12 00mg 3 times daily), this formulation provides around 8-fold greater exposu re than the established hard gelatin capsule (HGC) formulation at the recom mended dosage of 600mg 3 times daily. As with the HGC formulation, the most common adverse events seen with saqui navir SGC are gastrointestinal symptoms (e.g. diarrhoea, abdominal discomfo rt and nausea). Some of these may occur with a slightly higher frequency wi th the SGC than with the HGC formulation. Saquinavir SGC has only a minimal effect on nonfasting serum lipid and cholesterol levels. Like other PIs, saquinavir is metabolised by the cytochrome P450 (CYP) 3A4 isoenzyme and is susceptible to interactions with inducers (e.g. rifabutin and rifampicin) and inhibitors (e.g. clarithromycin and ketoconazole) of th is enzyme. Ritonavir, nelfinavir, indinavir and delavirdine, all CYP3A4 inh ibitors, greatly increase saquinavir plasma concentrations and the therapeu tic implications of these interactions continue to he evaluated. While saqu inavir is the least potent CYP 3A inhibitor among the PIs, several drugs (n otably terfenadine, astemizole and cisapride) should not be given in combin ation with saquinavir. Therefore, although the SGC formulation enhances saquinavir exposure, it ha s a similar safety profile to the HGC formulation. Saquinavir, formulated as the hard gelatin capsule (HGC) formulation. was t he first HIV protease inhibitor (PI) to be approved for the treatment of HI V infection. When used in combination with other antiretrovirals, saquinavi r HGC has been demonstrated to provide a survival advantage,([1-4]) althoug h the poor bioavailability of this formulation means that it is less effect ive than the other currently licensed PIs. Subsequently, saquinavir has bee n reformulated as an enhanced soft gelatin capsule (SGC), resulting in incr eased drug exposure and enhanced antiretroviral activity compared with the HGC formulation.([5,6]) The currently recommended dosage of saquinavir SGC, 1200mg 3 times daily, provides around 8-fold greater exposure than the rec ommended dosage of the HGC formulation (600mg 3 times daily), as quantified by the area under the curve to 24 hours(AUC(0-24h)).([6]) This review focuses on the safety profile of saquinavir SGC and compares it with the safety profiles of other PIs. Pertinent data concerning the non-n ucleoside reverse transcriptase inhibitors (NNRTIs) delavirdine, nevirapine and efavirenz, and the reverse transcriptase inhibitors (NRTIs), including abacavir, are also considered. The review incorporates data from published literature sources (e.g. MEDLINE), case reports, conference abstracts and prescribing information. Information was selected on the basis of relevancy to the subject and the most pertinent and recent data was cited as far as practicable.