Angela T. Melia

Retrospective population‐based analysis of the dose‐response (fecal fat excretion) relationship of orlistat in normal and obese volunteers

Orlistat, an inhibitor of gastrointestinal lipases, limits the absorption of ingested fat and could become a potential treatment for obesity. This analysis was performed to elucidate the relationship between orlistat dose and intensity of inhibition of dietary fat absorption (assessed by measuring fecal fat excretion). In 11 phase I double‐blind, placebo‐controlled, parallel‐group randomized studies, a total of 171 subjects received oral daily doses that ranged from 30 to 1200 mg orlistat or matching placebo three times a day for 9 to 10 days. The results of the daily mean fecal fat excretion percentage (relative to ingested fat) were correlated to the orlistat daily dose. A simple maximum‐effect model that included a basal value was used to fit the dose‐response relationship for all evaluable subjects. The mean maximum percentage of ingested fat excreted in the feces was approximately 32% during orlistat administration compared with 5% during placebo administration. The orlistat daily dose that produced 50% of the maximum effect was 98 mg/day. The model‐fitting suggests the existence of a steep portion of the dose‐response curve up to approximately 400 mg/day, with a subsequent tendency to plateau at higher doses. Such an analysis was instrumental in identifying appropriate doses to be used in therapeutic trials for weight loss in obese patients.

Review of Limited Systemic Absorption of Orlistat, a Lipase Inhibitor, in Healthy Human Volunteers

Orlistat, a lipase inhibitor, acts locally in the gastrointestinal tract. Systemic absorption is not required for its efficacy, but knowledge of the extent of its systemic absorption is important for its safe use in obese patients, the intended target population. Pharmacokinetic screening was carried out by monitoring plasma concentrations of unchanged orlistat in 25 phase 1 studies (including two mass balance studies) in normal and obese healthy volunteers. The results of these studies indicate an extremely low degree of systemic absorption for orlistat when administered with a hypocaloric, well‐balanced diet with 20% to 30% of calories derived from fat (50–80 gm). To further characterize the pharmacokinetics and excretion pathways of orlistat, two mass balance studies using 14C‐labeled orlistat were conducted. After oral dosing of radiolabeled orlistat with a fatty meal (28–30 gm fat), almost the entire dose was recovered from fecal samples; little was found in plasma and urine. It is concluded that systemic absorption of orlistat is negligible; at a clinically efficacious dose level, orlistat is unlikely to produce systemic lipase inhibition.

The Effect of Orlistat, an Inhibitor of Dietary Fat Absorption, on the Absorption of Vitamins A and E in Healthy Volunteers

An open‐label, placebo‐controlled, randomized, two‐way crossover study was performed in 12 healthy volunteers (between 20 and 44 years of age) to assess the effect of orlistat, a gastrointestinal lipase inhibitor that reduces dietary fat absorption and is being developed for weight control in obesity, on the absorption of vitamins A and E. Each participant received a single oral dose of 25,000 IU vitamin A followed 24 hours later by a single oral dose of 400 IU vitamin E on two separate occasions: during oral administration of 120 mg orlistat or placebo three times daily for 9 days. The two treatments were separated by a washout period of at least 2 weeks. Serial blood samples for pharmacokinetic analysis were collected at specified times over 24 hours after each dose of vitamin A for determination of serum concentrations of retinol, and over a period of 5 days after each dose of vitamin E for determination of serum concentrations of α‐tocopherol, total cholesterol, and triglycerides. Orlistat significantly reduced the absorption of vitamin E (∼43% according to maximum concentration and ∼60% according to area under the concentration‐time curve), but not that of vitamin A, at the dose levels studied. The results of this study will aid in the implementation of a vitamin supplementation strategy, should vitamin deficiency occur in patients undergoing orlistat therapy.

Metabolic Profiles of Minimally Absorbed Orlistat in Obese/Overweight Volunteers

To determine the metabolic profile of minimally absorbed orlistat in obese/overweight patients, an open‐label, single‐dose study was performed in eight obese/overweight volunteers between 23 and 68 years of age. Each subject received a single oral dose of 360 mg orlistat containing approximately 400 μCi of 14C‐labeled orlistat. Serial blood samples were collected at specified times over 10 hours after administration of orlistat for determination of total radioactivity, unchanged orlistat, and major metabolites in the plasma. Urine samples were collected over 24 hours and analyzed to evaluate the urinary recovery of total radioactivity and the profile of orlistat metabolites in the urine. In addition, all fecal samples were collected and analyzed for total radioactivity. Urinary and fecal recovery of the administered dose of total radioactivity were 1.13 ± 0.50% (24‐hour data only) and 96.4 ± 18.1% (n = 7), respectively. Maximum observed concentration (Cmax) and time to Cmax (tmax) values of plasma total radioactivity were 150 ± 51 ng·eq/mL and 6.8 ± 1.5 hrs, respectively. All these parameters obtained in obese/overweight subjects were similar to those reported previously in healthy subjects. On the basis of the area under the concentration‐time curve from 0 to 10 hours (AUC0–10), two major metabolites comprise a total of ∼42% of the total radioactivity in plasma. The primary metabolite (M1) has a short half‐life (∼2 hours), whereas the secondary metabolite (M3) disappeared at a slower rate. No strikingly apparent difference in the urinary metabolic profile was observed between two gender groups. It is concluded that the disposition of orlistat appears to be similar between normal and obese/overweight subjects. Of the minimal fraction of the dose that was absorbed systemically, the presence of two major metabolites accounts for ∼42%.

The Effect of Orlistat, an Inhibitor of Dietary Fat Absorption, on the Pharmacokinetics of β-Carotene in Healthy Volunteers

To assess the influence of orlistat, a lipase inhibitor, on the absorption of β‐carotene, an open‐label, parallel, placebo‐controlled, randomized, two‐way crossover study was performed in 48 healthy volunteers between the ages of 19 and 58 years. Each subject received a single oral dose of 0, 30, 60, or 120 mg β‐carotene (12 subjects per dose level) on the fourth day of treatment with orlistat (120 mg) or placebo 3 times a day for 6 days. The treatments were separated by a washout period of at least 5 weeks. Serial blood samples were collected before and at appropriate intervals after administration of β‐carotene to determine plasma concentrations of unchanged β‐carotene. Short‐term (3 to 6 days) treatment with orlistat did not alter endogenous profiles of β‐carotene in plasma. When β‐carotene was given during orlistat treatment, its absorption was reduced by approximately one‐third. This reduction was consistent for all three dose levels of β‐carotene studied; however, the results for the 30‐mg dose level were subject to greater variability, particularly for area under the concentration—time curve (AUC). It was concluded that two thirds of a supplemental dose of β‐carotene will be absorbed during orlistat treatment; this may be sufficient to achieve physiologic levels of β‐carotene with an appropriate dose of β‐carotene, should supplementation be needed in obese patients who have developed β‐carotene deficiency during therapy with orlistat.

The Effect of Orlistat on the Pharmacokinetics and Pharmacodynamics of Warfarin in Healthy Volunteers

To assess the effect of orlistat on the pharmacokinetics and pharmacodynamics of warfarin, a third‐party blind, placebo‐controlled, randomized, two‐way crossover study was performed in 12 healthy volunteers. Each participant received single 30‐mg oral doses of racemic warfarin sodium (Coumadin; DuPont Pharma, Wilmington, DE) administered on the eleventh day of treatment with 120 mg orlistat (treatment A) and placebo (treatment B) three times a day for 16 days; the two treatments were separated by a 3‐week washout period. Serial blood samples were collected before and at appropriate intervals after each dose of warfarin to determine plasma concentrations of R‐warfarin and S‐warfarin and blood prothrombin time (PT) and plasma Factor VII concentration. In addition, serum concentrations of vitamin K1 and its epoxide and of osteocalcin and its undercarboxylated form were measured before breakfast on days −7, 1, 4, 6, and 10. Equivalent results between treatments with orlistat and placebo were found with regard to all pharmacokinetic parameters of R– and S‐warfarin (except for time to maximum concentration of R‐warfarin). Pharmacodynamic parameters of warfarin (PT and Factor VII) and vitamin K nutritional status parameters (ratios of vitamin K1 to vitamin K1 epoxide and undercarboxylated osteocalcin to osteocalcin) also were unaltered by orlistat. Orlistat administered at doses of 120 mg three times daily did not significantly alter the pharmacokinetics and pharmacodynamics of a single 30‐mg oral dose of warfarin in healthy volunteers.

The Influence of Orlistat on the Pharmacokinetics and Pharmacodynamics of Glyburide in Healthy Volunteers

To assess the influence of orlistat on the pharmacokinetics and pharmacodynamics (the blood glucose‐lowering effect) of glyburide, an open‐label, placebo‐controlled, randomized, two‐way crossover study was done in 12 healthy male volunteers. Each subject received single 5‐mg oral doses of glyburide (Micronase; The Upjohn Company, Kalamazoo, MI) on the fifth day of treatment with placebo (treatment A) and 80‐mg orlistat (treatment B) three times a day for 4 1/3 days; the two treatments were separated by a five‐day washout period. Serial blood samples were collected before and at appropriate intervals after each glyburide dose to determine plasma concentrations and blood glucose levels. Values of Cmax and AUC of glyburide showed an equality of the two treatments by the analysis of variance. There was an apparent correlation between blood glucose level and the logarithm of plasma glyburide concentration; this relationship appeared to not be altered when glyburide was administered with orlistat. In conclusion, orlistat administered at doses of 80‐mg three times daily does not significantly alter the pharmacokinetics and blood glucose‐lowering effect of a single 5‐mg oral dose of glyburide in healthy volunteers.

The Influence of Reduced Dietary Fat Absorption Induced by Orlistat on the Pharmacokinetics of Digoxin in Healthy Volunteers

To assess the influence of an orlistat‐induced reduction in dietary fat absorption on the pharmacokinetics of digoxin, an open‐label, placebo‐controlled, randomized, two‐way crossover study was performed in 12 healthy volunteers. Each subject received single 0.4‐mg doses of digoxin (soft gelatin capsules) administered orally on the fourth day of orlistat (120 mg three times daily for 6 days) and placebo (three times daily for 6 days) treatment, separated by at least an 11‐day washout period. Serial blood samples were collected before and at appropriate intervals after each digoxin dose to determine plasma concentrations of unchanged digoxin. The 90% confidence intervals for the ratio of geometric least‐squares means (for Cmax, AUC0–48, AUC0‐t, and AUC) and for the difference of arithmetic least‐squares means (for tmax and Λz) indicate that the pharmacokinetics of digoxin was not altered by treatment with orlistat. This result suggests that a ∼30% reduction in dietary fat absorption will not change the efficacy of digoxin in cardiac patients.

The Effect of Orlistat on the Pharmacokinetics of Phenytoin in Healthy Volunteers

To assess the effect of an orlistat‐induced reduction in dietary fat absorption on the pharmacokinetics of phenytoin, a third‐party blind, placebo‐controlled, randomized, two‐way crossover study was performed in 12 healthy volunteers. Each participant received single 300‐mg oral doses of phenytoin administered on the fourth day of treatment with 120 mg orlistat (treatment A) or placebo (treatment B) three times a day for 7 days. The two treatments were separated by a 2‐week washout period. Serial blood samples were collected before and up to 96 hours after each dose of phenytoin to determine serum concentrations of phenytoin. The 90% confidence intervals (CI) for the ratio of geometric least‐squares means for maximum concentration (Cmax) and area under the concentration‐time curve (AUC) and for the difference of arithmetic least‐squares means for time of maximum concentration (tmax) and elimination rate constant (λg) showed the two treatments of phenytoin to be equal by analysis of variance. An approximately 30% reduction in dietary fat absorption induced by orlistat administered at doses of 120 mg three times daily did not significantly alter the pharmacokinetics of a single 300‐mg oral dose of phenytoin in healthy volunteers.

Lack of Effect of Orlistat on the Bioavailability of a Single Dose of Nifedipine Extended-Release Tablets (Procardia XL) in Healthy Volunteers

Orlistat, a lipase inhibitor, reduces dietary fat absorption, and thus could potentially alter the absorption of some concomitantly administered drugs, such as the nifedipine gastrointestinal therapeutic system (GITS). To assess the effect of orlistat on the bioavailability of nifedipine GITS, a third party‐blind, placebo‐controlled, randomized, two‐way crossover study was performed in 18 healthy volunteers. Each participant received single 60‐mg oral doses of nifedipine GITS (Procardia XL; Pfizer Labs, New York, NY) on the fourth day of treatment with 120 mg of orlistat or placebo three times a day for 6 days. The two treatments were separated by a washout period of at least 1 week. Serial blood samples were collected before and at appropriate intervals after each nifedipine dose to determine plasma concentrations of nifedipine. The 90% confidence intervals for the ratio of geometric least‐square means for maximum concentration (Cmax) and area under the concentration‐time curve (AUCo‐t) and for the difference of arithmetic least‐square means for time to maximum concentration (tmax) indicate that the bioavailability of nifedipine was not altered by treatment with orlistat. Therapeutic doses of 120 mg of orlistat three times daily do not significantly alter the bioavailability of a single 60‐mg oral dose of nifedipine GITS in healthy volunteers.