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Indravadan H Patel - One of the best experts on this subject based on the ideXlab platform.

  • the effect of Orlistat an inhibitor of dietary fat absorption on the pharmacokinetics of β carotene in healthy volunteers
    The Journal of Clinical Pharmacology, 1996
    Co-Authors: Jianguo Zhi, Angela T Melia, Susan G Kosstwardy, Sujata Arora, Indravadan H Patel
    Abstract:

    To assess the influence of Orlistat, a lipase inhibitor, on the absorption of beta-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 beta-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 beta-carotene to determine plasma concentrations of unchanged beta-carotene. Short-term (3 to 6 days) treatment with Orlistat did not alter endogenous profiles of beta-carotene in plasma. When beta-carotene was given during Orlistat treatment, its absorption was reduced by approximately one-third. This reduction was consistent for all three dose levels of beta-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 beta-carotene will be absorbed during Orlistat treatment; this may be sufficient to achieve physiologic levels of beta-carotene with an appropriate dose of beta-carotene, should supplementation be needed in obese patients who have developed beta-carotene deficiency during therapy with Orlistat.

  • review of limited systemic absorption of Orlistat a lipase inhibitor in healthy human volunteers
    The Journal of Clinical Pharmacology, 1995
    Co-Authors: Jianguo Zhi, Angela T Melia, Herwig Eggers, Raymond Joly, Indravadan H Patel
    Abstract:

    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.

  • retrospective population based analysis of the dose response fecal fat excretion relationship of Orlistat in normal and obese volunteers
    Clinical Pharmacology & Therapeutics, 1994
    Co-Authors: J Zhi, Angela T Melia, Roberto Guerciolini, J Chung, J Kinberg, J B Hauptman, Indravadan H Patel
    Abstract:

    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.

  • retrospective population based analysis of the dose response fecal fat excretion relationship of Orlistat in normal and obese volunteers
    American college of clinical pharmacology. Annual meeting, 1994
    Co-Authors: J Zhi, Angela T Melia, Roberto Guerciolini, J Chung, J Kinberg, J B Hauptman, Indravadan H Patel
    Abstract:

    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 randomizedd 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

Ramasamy Paulmurugan - One of the best experts on this subject based on the ideXlab platform.

  • folate receptor targeted polymeric micellar nanocarriers for delivery of Orlistat as a repurposed drug against triple negative breast cancer
    Molecular Cancer Therapeutics, 2016
    Co-Authors: Ramasamy Paulmurugan, Rohith Bhethanabotla, Kaushik Mishra, Rammohan Devulapally, Kira Foygel, Thillai V Sekar, Jeyarama S Ananta, Tarik F Massoud, Abraham Joy
    Abstract:

    Triple-negative breast cancer (TNBC) is a recalcitrant malignancy with no available targeted therapy. Off-target effects and poor bioavailability of the FDA-approved antiobesity drug Orlistat hinder its clinical translation as a repurposed new drug against TNBC. Here, we demonstrate a newly engineered drug formulation for packaging Orlistat tailored to TNBC treatment. We synthesized TNBC-specific folate receptor-targeted micellar nanoparticles (NP) carrying Orlistat, which improved the solubility (70-80 μg/mL) of this water-insoluble drug. The targeted NPs also improved the delivery and bioavailability of Orlistat to MDA-MB-231 cells in culture and to tumor xenografts in a nude mouse model. We prepared HEA-EHA copolymer micellar NPs by copolymerization of 2-hydroxyethylacrylate (HEA) and 2-ethylhexylacrylate (EHA), and functionalized them with folic acid and an imaging dye. Fluorescence-activated cell sorting (FACS) analysis of TNBC cells indicated a dose-dependent increase in apoptotic populations in cells treated with free Orlistat, Orlistat NPs, and folate-receptor-targeted Fol-HEA-EHA-Orlistat NPs in which Fol-HEA-EHA-Orlistat NPs showed significantly higher cytotoxicity than free Orlistat. In vitro analysis data demonstrated significant apoptosis at nanomolar concentrations in cells activated through caspase-3 and PARP inhibition. In vivo analysis demonstrated significant antitumor effects in living mice after targeted treatment of tumors, and confirmed by fluorescence imaging. Moreover, folate receptor-targeted Fol-DyLight747-Orlistat NP-treated mice exhibited significantly higher reduction in tumor volume compared to control group. Taken together, these results indicate that Orlistat packaged in HEA-b-EHA micellar NPs is a highly promising new drug formulation for TNBC therapy. Mol Cancer Ther; 15(2); 221-31. ©2015 AACR.

  • Orlistat and antisense mirna loaded plga peg nanoparticles for enhanced triple negative breast cancer therapy
    Nanomedicine: Nanotechnology Biology and Medicine, 2016
    Co-Authors: Aarohi Bhargavashah, Kira Foygel, Rammohan Devulapally, Ramasamy Paulmurugan
    Abstract:

    Background: This study explores the use of hydrophilic poly(ethylene glycol)-conjugated poly(lactic-co-glycolic acid) nanoparticles (PLGA-PEG-NPs) as delivery system to improve the antitumor effect of antiobesity drug Orlistat for triple-negative breast cancer (TNBC) therapy by improving its bioavailability. Materials & methods: PLGA-PEG-NPs were synthesized by emulsion-diffusion-evaporation method, and the experiments were conducted in vitro in MDA-MB-231 and SKBr3 TNBC and normal breast fibroblast cells. Results: Delivery of Orlistat via PLGA-PEG-NPs reduced its IC50 compared with free Orlistat. Combined treatment of Orlistat-loaded NPs and doxorubicin or antisense-miR-21-loaded NPs significantly enhanced apoptotic effect compared with independent doxorubicin, anti-miR-21-loaded NPs, Orlistat-loaded NPs or free Orlistat treatments. Conclusion: We demonstrate that Orlistat in combination with antisense-miR-21 or current chemotherapy holds great promise as a novel and versatile treatment agent for TNBC.

Jeffrey W. Smith - One of the best experts on this subject based on the ideXlab platform.

  • inhibition of endothelial cell proliferation and angiogenesis by Orlistat a fatty acid synthase inhibitor
    The FASEB Journal, 2006
    Co-Authors: Cecille D Browne, Elizabeth J Hindmarsh, Jeffrey W. Smith
    Abstract:

    Orlistat, an antiobesity drug, is cytostatic and cytotoxic to tumor cells. The antitumor activity of Orlistat can be attributed to its ability to inhibit the thioesterase domain of fatty acid synthase (FAS). The objective of the present study was to test the effect of Orlistat on endothelial cell proliferation and angiogenesis. Orlistat inhibits endothelial cell FAS, blocks the synthesis of fatty acids, and prevents endothelial cell proliferation. More significantly, Orlistat inhibits human neovascularization in an ex vivo assay, which suggests that it may be useful as an antiangiogenic drug. The mechanism of these effects can be traced to the fact that Orlistat prevents the display of the vascular endothelial growth factor (VEGF) receptor (VEGFR2/KDR/Flk1) on the endothelial cell surface. Thus, Orlistat is an antiangiogenic agent with a novel mechanism of action.

  • Orlistat Is a Novel Inhibitor of Fatty Acid Synthase with Antitumor Activity
    Cancer research, 2004
    Co-Authors: Steven J. Kridel, Fumiko Takada Axelrod, Natasha Rozenkrantz, Jeffrey W. Smith
    Abstract:

    One of the fundamental principles of pharmacology is that most drugs have side effects. Although considerable attention is paid to detrimental side effects, drugs can also have beneficial side effects. Given the time and expense of drug development, it would be particularly exciting if a systematic method could be applied to reveal all of the activities, including the unappreciated actions, of a potential drug. The present study takes the first step along this path. An activity-based proteomics strategy was used to simultaneously identify targets and screen for their inhibitors in prostate cancer. Orlistat, a Food and Drug Administration-approved drug used for treating obesity, was included in this screen. Surprisingly, we find a new molecular target and a potential new application for Orlistat. Orlistat is a novel inhibitor of the thioesterase domain of fatty acid synthase, an enzyme strongly linked to tumor progression. By virtue of its ability to inhibit fatty acid synthase, Orlistat halts tumor cell proliferation, induces tumor cell apoptosis, and inhibits the growth of PC-3 tumors in nude mice.

Aila Rissanen - One of the best experts on this subject based on the ideXlab platform.

  • weight loss hba1c reduction and tolerability of cetilistat in a randomized placebo controlled phase 2 trial in obese diabetics comparison with Orlistat xenical
    Obesity, 2010
    Co-Authors: Peter Kopelman, Stephan Rossner, Soren Toubro, Aila Rissanen, Gerrit H De Groot, Richard N Palmer, Rob Hallam, Andrew Bryson, Roger I Hickling
    Abstract:

    The objective of this multicenter, randomized, double-blind study was to determine the efficacy and safety of cetilistat and Orlistat relative to placebo in obese patients with type 2 diabetes, on metformin. Following a 2-week run-in, patients were randomized to placebo, cetilistat (40, 80, or 120 mg three times daily), or Orlistat 120 mg t.i.d., for 12 weeks. The primary endpoint was absolute change in body weight from baseline. Secondary endpoints included other measures of obesity and glycemic control. Similar reductions in body weight were observed in patients receiving cetilistat 80 or 120 mg t.i.d. or 120 mg t.i.d. Orlistat; these reductions were significant vs. placebo (3.85 kg, P = 0.01; 4.32 kg, P = 0.0002; 3.78 kg, P = 0.008). In the 40 mg t.i.d. and placebo groups, reductions were 2.94 kg, P = 0.958 and 2.86 kg, respectively. Statistically significant reductions in glycosylated hemoglobin (HbA1c) were noted. Cetilistat was well tolerated, and showed fewer discontinuations due to adverse events (AEs) than in the placebo and Orlistat groups. Discontinuation in the Orlistat group was significantly worse than in the 120 mg cetilistat and placebo groups and was entirely due to gastrointestinal (GI) AEs. Treatment with cetilistat 80 or 120 mg t.i.d., or with Orlistat 120 mg t.i.d., significantly reduced body weight and improved glycemic control relative to placebo in obese diabetic patients. Cetilistat was well tolerated with the number of discontinuations due to AEs being similar to placebo.

  • effect of Orlistat on weight regain and cardiovascular risk factors following a very low energy diet in abdominally obese patients a 3 year randomized placebo controlled study
    Diabetes Care, 2007
    Co-Authors: Bjorn Richelsen, Serena Tonstad, Stephan Rossner, Soren Toubro, Leo Niskanen, Steen Madsbad, Pertti Mustajoki, Aila Rissanen
    Abstract:

    OBJECTIVE —To investigate the efficacy of Orlistat on the maintenance of weight loss over 3 years following a major weight loss induced by very-low-energy diet (VLED) in obese patients with metabolic risk factors such as dyslipidemia, impaired fasting glucose, and diet-treated type 2 diabetes. RESEARCH DESIGN AND METHODS —Initially, weight loss was induced by an 8-week VLED (600–800 kcal/day) in 383 patients with a mean BMI of 37.5 kg/m 2 (range 30.0–45.2). Those who lost ≥5% of their body weight (309 of 383 patients) were then randomized to receive lifestyle counseling for 3 years together with either Orlistat 120 mg t.i.d. or matching placebo capsules. Primary end points were the maintenance of ≥5% weight loss after 3 years. Additionally, differences in the development of type 2 diabetes between Orlistat and placebo were analyzed. RESULTS —The VLED induced a mean weight loss of 14.4 ± 2..0 kg among the subsequently randomized patients. The mean weight gain after 3 years was lower with Orlistat than with placebo (4.6 ± 8.6 vs. 7.0 ± 7.1 kg; P P = 0.037). Waist circumference was significantly more reduced in the Orlistat group ( P P = 0.041). CONCLUSIONS —The addition of Orlistat to lifestyle intervention was associated with maintenance of an extra 2.4 kg weight loss after VLED for up to 3 years in obese subjects. The combination of Orlistat and lifestyle intervention was associated with a reduced occurrence of type 2 diabetes.

  • effects of equal weight loss with Orlistat and placebo on body fat and serum fatty acid composition and insulin resistance in obese women
    The American Journal of Clinical Nutrition, 2004
    Co-Authors: Mirja Tiikkainen, Aila Rissanen, Kari Teramo, Robert Bergholm, Antti Aro, Irma Salminen, Marjo Tamminen, Hannele Ykijarvinen
    Abstract:

    Background: Dietary fat has been reported to influence insulin sensitivity. Objective: The objective of the study was to determine how identical weight loss (target: loss of 8% of body weight over 3–6 mo) in women taking Orlistat or placebo combined with a hypocaloric diet influences body composition and insulin sensitivity. Design: Forty-seven obese women [body mass index (in kg/m 2 ): 32.1 0.4] were randomly assigned to receive either Orlistat (120 mg 3 times daily; n 23) or placebo (n 24) with a hypocaloric diet. Whole-body insulin sensitivity (insulin clamp technique), serum fatty acids, and body composition (magnetic resonance imaging) were measured before and after weight loss. Results: The groups did not differ significantly at baseline with respect to age, body weight, intraabdominal and subcutaneous fat volumes, or insulin sensitivity. Weight loss did not differ significantly between the Orlistat (7.3 0.2 kg, or 8.3 0.1%) and placebo (7.4 0.2 kg, or 8.2 0.1%) groups. Insulin sensitivity improved significantly (P 0.001) and similarly after weight loss in the Orlistat (from 4.0 0.3 to 5.1 0.3 mg kg fat-free mass 1 min 1 ) and placebo (from 4.4 0.4 to 5.4 0.4 mg kg fat-free mass 1 min 1 ) groups. Intraabdominal fat and subcutaneous fat decreased significantly in both groups, but the ratio of the 2 decreased significantly only in the Orlistat group. The proportion of dihomo--linolenic acid (20:3n6) in serum phospholipids was inversely related to insulin sensitivity both before ( r 0.48, P 0.001) and after (r 0.46, P 0.001) weight loss, but it did not change significantly in either group. Conclusions: Weight loss rather than inhibition of fat absorption enhances insulin sensitivity. A decrease in fat absorption by Orlistat appears to favorably influence the ratio between intraabdominal and subcutaneous fat, which suggests that exogenous fat or its composition influences fat distribution. Am J Clin Nutr 2004;79: 22–30.

  • effects of weight loss with Orlistat on glucose tolerance and progression to type 2 diabetes in obese adults
    JAMA Internal Medicine, 2000
    Co-Authors: Steven B Heymsfield, Jonathan Hauptman, Charles P Lucas, Mark Boldrin, Karen R Segal, Aila Rissanen, John Wilding, Lars Sjostrom
    Abstract:

    Background: Orlistat is a gastrointestinal lipase inhibitor that reduces dietary fat absorption by approximately 30%, promotes weight loss, and may reduce the risk of developing impaired glucose tolerance and type 2 diabetes in obese subjects. Objective: To test the hypothesis that Orlistat combined with dietary intervention improves glucose tolerance status and prevents worsening of diabetes status more effectively than placebo. Methods: We pooled data from 675 obese (body mass index, 30-43 kg/m 2 ) adults at 39 US and European research centers in 3 randomized, double-blind, placebocontrolled multicenter clinical trials. Subjects received placebo plus a low-energy diet during a 4-week lead-in period. On study day 1, the diet was continued, and subjects were randomized to receive placebo 3 times a day (n=316) or treatment with Orlistat, 120 mg 3 times a day (n=359), for 104 weeks. A standard 3-hour oral glucose tolerance test was performed on day 1 and at the end of treatment. Main Outcome Measures: The categorical assessment of glucose tolerance status (normal, impaired, diabetic) and changes in status from randomization to end of treatment were the primary efficacy measures. The secondary measures were fasting and postchallenge glucose and insulin levels. Results: The mean length of follow-up was 582 days. Subjects who were treated with Orlistat lost more weight (mean±SEM, 6.72±0.41 kg from initial weight) than subjects who received placebo (3.79±0.38 kg; P,.001). A smaller percentage of subjects with impaired glucose tolerance at baseline progressed to diabetic status in the Orlistat (3.0%) vs placebo (7.6%) group. Conversely, among subjects with impaired glucose tolerance at baseline, glucose levels normalized in more subjects after Orlistat treatment (71.6%) vs placebo (49.1%; P=.04). Conclusions: The addition of Orlistat to a conventional weight loss regimen significantly improved oral glucose tolerance and diminished the rate of progression to the development of impaired glucose tolerance and type 2 diabetes.

  • randomised placebo controlled trial of Orlistat for weight loss and prevention of weight regain in obese patients
    The Lancet, 1998
    Co-Authors: Lars Sjostrom, Alain Golay, Mark Boldrin, Aila Rissanen, Teis Andersen, H P F Koppeschaar, Michel Krempf
    Abstract:

    Summary Background We undertook a randomised controlled trial to assess the efficacy and tolerability of Orlistat, a gastrointestinal lipase inhibitor, in promoting weight loss and preventing weight regain in obese patients over a 2-year period. Methods 743 patients (body-mass index 28–47 kg/m 2 ), recruited at 15 European centres, entered a 4-week, single-blind, placebo lead-in period on a slightly hypocaloric diet (600 kcal/day deficit). 688 patients who completed the lead-in were assigned double-blind treatment with Orlistat 120 mg (three times a day) or placebo for 1 year in conjunction with the hypocaloric diet. In a second 52-week double-blind period patients were reassigned Orlistat or placebo with a weight maintenance (eucaloric) diet. Findings From the start of lead-in to the end of year 1, the Orlistat group lost, on average, more bodyweight than the placebo group (10·2% [10·3 kg] vs 6·1% [6·1 kg]; LSM difference 3·9 kg [p Interpretation Orlistat taken with an appropriate diet promotes clinically significant weight loss and reduces weight regain in obese patients over a 2-year period. The use of Orlistat beyond 2 years needs careful monitoring with respect to efficacy and adverse events.

Angela T Melia - One of the best experts on this subject based on the ideXlab platform.

  • the effect of Orlistat an inhibitor of dietary fat absorption on the pharmacokinetics of β carotene in healthy volunteers
    The Journal of Clinical Pharmacology, 1996
    Co-Authors: Jianguo Zhi, Angela T Melia, Susan G Kosstwardy, Sujata Arora, Indravadan H Patel
    Abstract:

    To assess the influence of Orlistat, a lipase inhibitor, on the absorption of beta-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 beta-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 beta-carotene to determine plasma concentrations of unchanged beta-carotene. Short-term (3 to 6 days) treatment with Orlistat did not alter endogenous profiles of beta-carotene in plasma. When beta-carotene was given during Orlistat treatment, its absorption was reduced by approximately one-third. This reduction was consistent for all three dose levels of beta-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 beta-carotene will be absorbed during Orlistat treatment; this may be sufficient to achieve physiologic levels of beta-carotene with an appropriate dose of beta-carotene, should supplementation be needed in obese patients who have developed beta-carotene deficiency during therapy with Orlistat.

  • review of limited systemic absorption of Orlistat a lipase inhibitor in healthy human volunteers
    The Journal of Clinical Pharmacology, 1995
    Co-Authors: Jianguo Zhi, Angela T Melia, Herwig Eggers, Raymond Joly, Indravadan H Patel
    Abstract:

    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.

  • retrospective population based analysis of the dose response fecal fat excretion relationship of Orlistat in normal and obese volunteers
    Clinical Pharmacology & Therapeutics, 1994
    Co-Authors: J Zhi, Angela T Melia, Roberto Guerciolini, J Chung, J Kinberg, J B Hauptman, Indravadan H Patel
    Abstract:

    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.

  • retrospective population based analysis of the dose response fecal fat excretion relationship of Orlistat in normal and obese volunteers
    American college of clinical pharmacology. Annual meeting, 1994
    Co-Authors: J Zhi, Angela T Melia, Roberto Guerciolini, J Chung, J Kinberg, J B Hauptman, Indravadan H Patel
    Abstract:

    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 randomizedd 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