Comparison of Galenic Formulations of Orlistat (Tetrahydrolipstatin)
- 8 Downloads
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.
Unable to display preview. Download preview PDF.
- Flatt JP. The biochemistry of energy expenditure. In Bray (Ed.) Recent advances in obesity research II, pp. 211–228, Newman Publishing, London, 1978Google Scholar
- Güzelhan C, Crijns HJMJ, Peeters PAM, Jonkman JHG, Hartmann D. Pharmacological activity (inhibition of fat absorption) and tolerability in healthy volunteers of tetrahydrolipstatin (THL) -A specific lipase inhibitor. International Journal of Obesity 15 (Suppl. 1): 29, 1991Google Scholar
- Hauptman J, Jeunet F, Hartmann D. Initial studies in humans with the novel gastrointestinal lipase inhibitor Ro 18-0647 (tetrahydrolipstatin). American Journal of Nutrition 55: 309S–313S, 1992Google Scholar
- Jones B, Kenward MG (Eds). Design and analysis of cross-over trials. Chapman and Hall, London/New York, 1989Google Scholar
- McNamara DJ. Relationship between blood and dietary cholesterol. In Pearson & Dutson (Eds) Meat and health. Advances in meat research, Vol. 6, pp. 63–87, Elsevier, London, 1990Google Scholar
- Meier MK, Blum-Kaelin D, Bremer K, Isler D, Joly R, et al. Preclinical profile of the lipase inhibitor tetrahydrolipstatin (Ro 18-0647, THL), a potential drug for the treatment of obesity. International Journal of Obesity 15 (Suppl. 1): 31, 1991Google Scholar
- Mills PR, Horton PW, Watkinson G. The value of the 14C breath test in the assessment of fat absorption. Scandinavian Journal of Gastroenterology 14: 913–921, 1979Google Scholar
- Newcomer AD, Holman AF, DiMagno EP, Thomas PJ, Carlson GL. Triolein breath test. A sensitive and specific test for fat malabsorption. Gastroenterology 76: 6–13, 1979Google Scholar
- SAS/STAT® User’s Guide, Version 6, Vol. 2, 4th ed., p. 893, Cary, NC, USAGoogle Scholar
- van de Kamer JH, ten Bokkel Huinink H, Weyers HA. Rapid method for the determination of fat in feces. Journal of Biological Chemistry 177: 347–355, 1949Google Scholar