Comparison of Galenic Formulations of Orlistat (Tetrahydrolipstatin)

Summary

Orlistat (tetrahydrolipstatin) reduces absorption of dietary fat by inhibiting lipases in the gastrointestinal tract. Since conventional bioavailability testing by pharmacokinetic methods is meaningless, 2 capsule formulations [containing orlistat as micronised powder (A) or granules (B)] were compared using the following pharmacological end-points: faecal fat excretion after multiple 3-times-daily doses, and ¹⁴C-recovery in breath (breath test) and in faeces after single doses administered with ¹⁴C-triolein. The study was conducted in 12 hospitalised healthy male subjects at dose levels of 50 and 150mg according to a balanced 4-way crossover scheme. The diet was standardised with an intake of 76g fat per day.

Orlistat was generally well tolerated. The few adverse events of moderate intensity were limited to the gastrointestinal tract and were consequences of the pharmacological action of the drug. At the 50 and 150mg doses, respectively, mean faecal fat excretion (% of dietary fat intake) was 29.6 and 35.4% for capsule A, and 30.4 and 37.4% for capsule B. Mean ¹⁴C-recovery in faeces (% of ¹⁴C-dose) was 52.5 and 56.2% for A, and 50.5 and 62.9% for B. Mean cumulative ¹⁴C-excretion in breath after 24 hours (% of ¹⁴C-dose) was 17.6 and 13.6% for A and 16.7 and 11.2% for B. At the 50mg dose both capsules were pharmacologically equivalent. At the 150mg dose B showed a trend towards superior efficacy compared with A (p = 0.09). The 150mg doses were significantly more effective (p < 0.05) than the 50mg doses. There were no significant carry-over effects.

All investigated end-points yielded consistent results. The ¹⁴C-breath test proved to be a reliable and convenient method to assess fat absorption in relative terms and thus to compare galenic formulations of orlistat.