Abstract
The assessment of bioequivalence (BE) of drug products acting locally within gastrointestinal (GI) tract is one of the biggest challenges generally in generic product development and approval process. In recent years, considerable progress has been made by the FDA in developing alternative bioequivalence approaches to in vivo clinical endpoint studies for locally acting GI products. These BE approaches include in vitro tests, in vivo BE studies with pharmacokinetic (PK) endpoints and in vivo BE studies with pharmacodynamics (PD) endpoints. The selection of the appropriate product-specific BE recommendations depend on a number of factors including biopharmaceutical properties of the drug substance, formulation design, and drug product safety and efficacy profiles. In this chapter, the newly developed BE approaches for a number of locally acting GI products are reviewed. It is expected that the information provided in this chapter will help the industry and regulatory scientists understand the scientific principles for identification of the most appropriate BE methods and thus accelerate the new as well as the generic product development and life-cycle management for locally acting GI products.
The views expressed in this chapter are those of the authors and do not reflect the official policy of the FDA. No official support or endorsement by the FDA is intended or should be inferred.
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References
Aggarwal S, Loomba RS, Arora RR (2012) Efficacy of colesevelam on lowering glycemia and lipids. J Cardiovasc Pharmacol 59:198–205
Albaaj F, Hutchison AJ (2005) Lanthanum carbonate for the treatment of hyperphosphataemia in renal failure and dialysis patients. Expert Opin Pharmacother 6(2):319–328
Alfrey AC, LeGendre GR, Kaehny WD (1976) The dialysis encephalopathy syndrome. Possible aluminum intoxication. N Engl J Med 294(4):184–188
Amidon GL (2004) Bioequivalence testing for locally acting gastrointestinal drugs: scientific principles. Presented at FDA meeting of the Advisory Committee for Pharmaceutical Science and Clinical Pharmacology, Oct 20. Available from http://www.fda.gov/ohrms/dockets/ac/04/slides/2004-4078S2_10_Amidon_files/frame.htm. Accessed Oct 2013
Aumais G, Lefebvre M, Tremblay C, Bitton A, Martin F, Giard A, Madi M, Spénard J (2003) Rectal tissue, plasma and urine concentrations of mesalamine after single and multiple administrations of 500 mg suppositories to healthy volunteers and ulcertive proctitis patients. Aliment Pharmacol Ther 17(1):93–97
Bartlett JG (2008) Historical perspectives on studies of Clostridium difficile and C. difficile infection. Clin Infect Dis 46(suppl 1):S4–S11
Bays HE (2011) Colesevelam hydrochloride added to background metformin therapy in patients with type 2 diabetes mellitus: a pooled analysis from 3 clinical studies. Endocr Pract 17:933–938
Bays HE, Goldberg RB, Truitt KE, Jones MR (2008) Colesevelam hydrochloride therapy in patients with type 2 diabetes mellitus treated with metformin—glucose and lipid effects. Arch Intern Med 168:1975–1983
Behets GJ, Verberckmoes SC, Haese PC, De Broe ME (2004) Lanthanum carbonate: a new phosphate binder. Curr Opin Nephrol Hypertens 13(4):403–409
Bellasi A, Kooienga L, Block GA (2006) Phosphate binders: new products and challenges. Hemodial Int 10(3):225–234
Berner YN, Shike M (1988) Consequences of phosphate imbalance. Annu Rev Nutr 8(1):121–148
Block GA, Hulbert-Shearon TE, Levin NW, Port FK (1998) Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: a national study. Am J Kidney Dis 31(4):607–617
Block GA, Klassen PS, Lazarus JM, Ofsthun N, Lowrie EG, Chertow GM (2004) Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J Am Soc Nephrol 15(8):2208–2218
Braun J, Asmus HG, Holzer H, Brunkhorst R, Krause R, Schulz W, Neumayer HH, Raggi P, Bommer J (2004) Long-term comparison of a calcium-free phosphate binder and calcium carbonate–phosphorus metabolism and cardiovascular calcification. Clin Nephrol 62(2):104–115
Braunlin WH, Holmes-Farley SR, Smisek D, Guo A, Appruzese W, Xu QW, Hook P, Zhorov E, Mandeville H (2000) In vitro comparison of bile acid-binding to colesevelam hydrochloride and other bile acid sequestrants. Abstr Pap Am Chem Soc 219:U409–U410
Brown J, Haines S, Wilding IR (1997) Colonic spread of three rectally administered mesalazine (Pentasa) dosage forms in healthy volunteers as assessed by gamma scintigraphy. Aliment Pharmacol Ther 11(4):685–691
Chow SC, Liu JP (2009) In vitro bioequivalence testing. In: Design and analysis of bioavailability and bioequivalence studies, 3rd edn. Taylor & Francis Group, Boca Raton, FL, pp 451–452
Chow SC, Shao J, Wang HS (2003) In vitro bioequivalence testing. Stat Med 22:55–68
Chuong MC, Christensen JM, Ayres JW (2008) New dissolution method for mesalamine tablets and capsules. Dissolution Technol 15:7–14
Coladonato JA (2005) Control of Hypophosphatemia among Patients with ESRD. J Am Soc Nephrol 16(suppl 2):107–114
Conner DP, Davit BM (2008) Bioequivalence and drug product assessment, in vivo. In: Shargel L, Kanfer I (eds) Generic drug development: solid oral dosage forms. Marcel Dekker, New York, pp 275–277
Damment SJ, Pennick M (2008) Clinical pharmacokinetics of the phosphate binder lanthanum carbonate. J Clin Pharmacokinet 47(9):553–563
Davis GR, Zerwekh JE, Parker TF, Krejs GJ, Pak CTC, Fordtran JS (1983) Absorption of phosphate in the jejunum of patients with chronic renal failure before and after correction of Vitamin D deficiency. Gastroenterology 85(4):908–916
Davit BM (2009) FDA recommendation for vancomycin HCl Capsule BE studies. Presented at FDA Meeting of the Advisory Committee for Pharmaceutical Science and Clinical Pharmacology, 4 Aug 2009. Available from http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AdvisoryCommitteeforPharmaceuticalScienceandClinicalPharmacology/UCM179419.pdf. Accessed Oct 2013
Davit BM (2010) Regulatory perspective on developing dissolution method and specifications for generic drug products in the US. Presented at Informa Life Sciences second annual dissolution conference, Barcelona, Spain, Oct 2010
Davit BM (2013) Regulatory approaches for generic drugs: BE of topical drug product. Presented at PQRI workshop, evaluation of new and generic topical drug product, Bethesda, MD, 11–13 March 2013
FDA (1995) Guidance for industry: immediate release solid oral dosage forms: scale-up and post-approval changes. Available from http://www.fda.gov/downloads/Drugs/Guidances/UCM070636.pdf. Accessed Oct 2013
FDA (2000) Guidance for industry: Waiver of in vivo bioavailability and bioequivalence studies for immediate release solid oral dosage forms based on a biopharmaceutics classification system. Available from http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070246.pdf. Accessed Oct 2013
FDA (2002) Guidance for industry: food-effect bioavailability and fed bioequivalence studies. Available from http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070241.pdf. Accessed Dec 2013
FDA (2003) Guidance for industry: bioavailability and bioequivalence studies for orally administered drug products—general considerations. Available from http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070124.pdf. Accessed Oct 2013
FDA (2004) FDA meeting of the Advisory Committee for Pharmaceutical Science and Clinical Pharmacology, Oct 2004 briefing information. Available from http://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4078B1_07_Bioequivalence-Testing.pdf. Accessed Oct 2013
FDA (2006) FDA approved label: Dipentum® (Olsalazine sodium) capsule. UCB, Inc., Smyrna, GA
FDA (2007) FDA response to Citizen’s Petition for Colazal®, Doc#FDA-2005P-0314, Dec. Available from http://www.regulations.gov/#!documentDetail;D=FDA-2005-P-0314-0004. Accessed Oct 2013
FDA (2008a) FDA meeting of the Advisory Committee for Pharmaceutical Science and Clinical Pharmacology, July 2008 briefing information. http://www.fda.gov/ohrms/dockets/ac/08/briefing/2008-4370b1-01-FDA.pdf. Accessed Oct 2013
FDA (2008b) FDA meeting of the Advisory Committee for Pharmaceutical Science and Clinical Pharmacology, July 2008 summary minutes. http://www.fda.gov/ohrms/dockets/ac/08/minutes/2008-4370m2-Final%20Minutes.pdf. Accessed Oct 2013
FDA (2008c) Draft guidance on vancomycin capsules. Available from http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM082278.pdf. Accessed Oct 2013
FDA (2008d) Draft guidance on balsalazide disodium capsule. Available from http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm082854.pdf. Accessed Oct 2013
FDA (2008e) Draft guidance on olsalazine sodium capsule. Available from http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm089229.pdf. Accessed Oct 2013
FDA (2008f) FDA approved label: Rowasa® (mesalamine) enema. Alaven Pharmaceutical LLC, Marietta, GA
FDA (2008g) Draft guidance on Rowasa. Available from http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM088662.pdf. Accessed Oct 2013
FDA (2008h) Vancomycin solubility study report. Available from http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm082291.pdf. Accessed Oct 2013
FDA (2008i) Vancomycin dissolution study report. Available from http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm082295.pdf. Accessed Oct 2013
FDA (2009a) FDA meeting of the Advisory Committee for Pharmaceutical Science and Clinical Pharmacology, Aug 2009 summary minutes. Available from http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AdvisoryCommitteeforPharmaceuticalScienceandClinicalPharmacology/UCM237493.pdf. Accessed Oct 2013
FDA (2009b) FDA meeting of the Advisory Committee for Pharmaceutical Science and Clinical Pharmacology, Aug, 2009 Briefing information. Available from http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AdvisoryCommitteeforPharmaceuticalScienceandClinicalPharmacology/UCM173220.pdf. Accessed Oct 2013
FDA (2009c) Draft guidance on Acarbose tablets. Available from http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM170242.pdf. Accessed Oct 2013
FDA (2010a) FDA response to Citizen’s Petition for Asacol® and Pentasa®, Doc#FDA-2010-P-0111 and FDA-2008-P-0507, Aug 2010. Available from http://www.regulations.gov/#!documentDetail;D=FDA-2010-P-0111-0011. Accessed Oct 2013
FDA (2010b) Draft guidance on Orlistat capsules. Available from http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM082278.pdf. Accessed Oct 2013
FDA (2010c) Draft guidance on Sulfasalazine DR tablets. Available from http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM199673.pdf. Accessed Oct 2013
FDA (2010d) Draft guidance on Sulfasalazine tablets. Available from http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM199674.pdf. Accessed Oct 2013
FDA (2010e) FDA approved label: Asacol® HD (mesalamine) DR tablets. Warner Chilcott (US) LLC, New Jersey
FDA (2011a) FDA approved label: Asacol® (mesalamine) DR tablet. Warner Chilcott (US) LLC, Rockaway, NJ
FDA (2011b) FDA approved label: Liada® (mesalamine) DR tablet. Shire US manufacturing Inc., Owings Mills, MD
FDA (2011c) FDA approved label: Vancocin® (vancomycin) capsule. ViroPharma Inc, Exton, PA
FDA (2011d) Draft guidance on lanthanum carbonate. Available from http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM270541.pdf. Accessed Oct 2013
FDA (2011e) Draft guidance on calcium acetate capsules. Available from http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM179176.pdf. Accessed Oct 2013
FDA (2011f) Draft guidance on colesevelam hydrochloride. Available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm083337.pdf. Accessed Oct 2013
FDA (2011g) Draft guidance on Sevelamer carbonate tablets. Available from http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM089620.pdf. Accessed Oct 2013
FDA (2012a) Draft guidance on Asacol. Available from http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM320002.pdf. Accessed Oct 2013
FDA (2012b) Draft guidance on Asacol HD. Available from http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM320003.pdf. Accessed Oct 2013
FDA (2012c) Draft guidance on Liada. Available from http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM320004.pdf. Accessed Oct 2013
FDA (2012d) FDA approved label: Xenical® (orlistat) capsule. Roche Laboratories Inc., Basel
FDA (2012e) Draft guidance on Cholestyramine powder. Available from http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM273910.pdf. Accessed Oct 2013
FDA (2012f) FDA response to Citizen’s Petition for Vancocin®, Doc#FDA-2006P-0007, Dec. Available from http://www.regulations.gov/#!documentDetail;D=FDA-2006-P-0007-0051. Accessed Oct 2013
FDA (2013a) FDA approved label: Azufidine EN-Tabs® (mesalamine) DR tablet. Pharmacia and Upjohn Company, Peapack, NJ
FDA (2013b) Draft guidance on Balsalazide Disodium tablets. Available from http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm082854.pdf. Accessed Oct 2013
FDA (2013c) FDA response to Citizen’s Petition for Asacol® and Pentasa®, Doc#FDA-2012-P-1087, March 2013. Available from http://www.regulations.gov/#!documentDetail;D=FDA-2012-P-1087-0005. Accessed Oct 2013
FDA (2013d) Draft guidance on Canasa. Available from http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM088666.pdf. Accessed Oct 2013
Fonseca VA, Rosenstock J, Wang AC, Truitt KE, Jones MR (2008) Colesevelam HCl improves glycemic control and reduces LDL cholesterol in patients with inadequately controlled type 2 diabetes on sulfonylurea-based therapy. Diabetes Care 31:1479–1484
Gao W, Chan J, Farokhzad OC (2010) pH-responsive nanoparticles for drug delivery. Mol Pharm 7(6):1913–1920
Gessner PK, Hasan MM (1987) Freundlich and Langmuir isotherms as models for the adsorption of toxicants on activated charcoal. J Pharm Sci 76(4):319–327
Gillespie WR et al (1997) Bioequivalence assessment based on pharmacodynamics response: application to albuterol metered dose inhalers. Pharm Res 14(11):S139–S140
Goldberg RB, Fonseca VA, Truitt KE, Jones MR (2008) Efficacy and safety of colesevelam in patients with type 2 diabetes mellitus and inadequate glycemic control receiving insulin-based therapy. Arch Intern Med 168:1531–1540
Goodman WG, Goldin J, Kuizon BD, Yoon C, Gales B, Sider D, Wang Y, Chung J, Emerick A, Greaser L, Elashoff RM, Salusky IB (2000) Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med 342(20):1478–1483
Haidar SH, Davit B, Chen ML, Conner D, Lee L, Li QH, Lionberger R, Makhlouf F, Patel D, Schuirmann DJ, Yu LX (2008) Bioequivalence approaches for highly variable drugs and drug products. Pharm Res 25(1):237–241
Heller DP, Burke SK, Davidson DM, Donovan JM (2002) Absorption of colesevelam hydrochloride in healthy volunteers. Ann Pharmacother 36:398–403
Houghton LA, Mangnall YF, Read NW (1990) Effect of incorporating fat into a liquid test meal on the relation between intragastric distribution and gastric emptying in human volunteers. Gut 31(11):1226–1229
Hruska KA, Mathew S, Lund R, Qiu P, Pratt P (2008) Hyperphosphatemia of chronic kidney disease. Kidney Int 74(2):148–157
Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group (2009) KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney Int 76(suppl 113):1–130
Kornbluth A, Sachar DB (2010) Ulcerative colitis practice guidelines in adults: American College of gastroenterology, Practice Parameters Committee. Am J Gastroenterol 105(3):501–523
Krishnaiah YS, Yang Y, Bykadi S, Sayeed VA, Khan MA (2013) Comparative evaluation of in vitro efficacy of colesevelam hydrochloride tablets. Drug Dev Ind Pharm. Early Online: 1–7
Lichtenstein GR, Kamm MA (2008) Review article: 5-aminosalicylate formulations for the treatment of ulcerative colitis-methods of comparing release rates and delivery of 5-aminosalicylate to the colonic mucosa. Aliment Pharmacol Ther 28(6):663–673
Lionberger RA (2008) FDA critical path initiatives: opportunities for generic drug development. AAPS J 10(1):103–109
Loftus EV Jr (2004) Clinical epidemiology of inflammatory bowel disease: incidence, prevalence and environmental influences. Gastroenterology 126(6):1504–1517
Loghman-Adham M (1999) Phosphate binders for control of phosphate retention in chronic renal failure. Pediatr Nephrol 13(8):701–708
Martin P, Wang P, Robinson A, Poole L, Dragone J, Smyth M, Pratt R (2011) Comparison of dietary phosphate absorption after single doses of lanthanum carbonate and sevelamer carbonate in healthy volunteers: a balance study. Am J Kidney Dis 57(5):700–706
McIntyre CW (2007) New developments in the management of hyperphosphatemia in chronic kidney disease. Semin Dial 20(4):337–341
Myers B, Evans DN, Rhodes J, Evans BK, Hughes BR, Lee MG, Richens A, Richards D (1987) Metabolism and urinary excretion of 5-amino salicylic acid in healthy volunteers when given intravenously or released for absorption at different sites in the gastrointestinal tract. Gut 28:196–200
O’Connor D, Adams WP, Chen ML, Daley-Yates P, Davis J, Derendorf H, Ducharme MP, Fuglsang A, Herrle M, Hochhaus G, Holmes SM, Lee SL, Li BV, Lyapustina S, Newman S, Oliver M, Patterson B, Peart J, Poochikian G, Roy P, Shah T, Singh GJ, Sharp SS (2011) Role of pharmacokinetics in establishing bioequivalence for orally inhaled drug products: workshop summary report. J Aerosol Med Pulm Drug Deliv 24(3):119–135
Pai AB, Conner TA, McQuade CR (2009) Therapeutic use of the phosphate binder lanthanum carbonate. Expert Opin Drug Metab 5(1):71–81
Pennick M, Dennis K, Damment SJ (2006) Absolute bioavailability and disposition of lanthanum in healthy human subjects administered lanthanum carbonate. J Clin Pharmacokinet 46(7):738–746
Polli JE (2008) In vitro studies are sometimes better than conventional human pharmacokinetic in vivo studies in assessing bioequivalence of immediate-release solid oral dosage forms. AAPS J 10(2):289–299
Product Monograph (2010) Fosrenol (Lanthanum carbonate hydrate). Available from http://www.shirecanada.com/en/shire-canada/Fosrenol_M_100203_En.pdf. Accessed Oct 2013
Qureshi AI, Cohen RD (2005) Mesalamine delivery system: do they really make much difference? Adv Drug Deliv Rev 57(2):281–302
Read NW, Miles CA, Fischer D, Halgate AM, Konie ND, Mitchell MA, Reeve AM, Roche TB, Walker M (1980) Transit of a meal through the stomach, small intestine and colon in normal subjects and its role in the pathogenesis of diarrhea. Gastroenterology 79(6):1276–1282
Rudolph MW, Klein S, Beckert TE, Petereit H, Dressman JB (2001) A new 5-aminosalicylic acid multi-unit dosage form for the therapy of ulcerative colitis. Eur J Pharm Biopharm 51(3):183–190
Sandborn WJ (2002) Rational selection of oral 5-aminosalicylate formulations and prodrugs for the treatment of ulcerative colitis. Am J Gastroenterol 97(12):2939–2941
Schroder H, Campbell DE (1972) Absorption, metabolism and excretion of salicylazosulfapyridine in man. Clin Pharmacol Ther 13(4):539–551
Shah VP et al (1998) In vitro dissolution profile comparison-statistics and analysis of the similarity factor, f2. Pharm Res 15(6):1998
Sheikh MS, Maguire JA, Emmett M, Santa Ana CA, Nicar MJ, Schiller LR, Fordtran JS (1989) Reduction of dietary phosphorus absorption by phosphorus binders. A theoretical, in vitro, and in vivo study. J Clin Invest 83(1):66–73
Slatopolsky E, Weerts C, Lopez-Hiker S, Norwood K, Zink M, Windus D, Delmez J (1986) Calcium carbonate as a phosphate binder in patients with chronic renal failure undergoing dialysis. N Engl J Med 315(3):157–161
Sprague SM (2007) A comparative review of the efficacy and safety of established phosphate binders: calcium, sevelamer, and lanthanum carbonate. Curr Med Res Opin 23(12):3167–3175
Steinmetz KL (2002) Colesevelam hydrochloride. Am J Health Syst Pharm 59:932–939
Tonelli M, Wiebe N, Culleton B, Lee H, Klarenbach S, Shrive F, Manns B (2007) Systematic review of the clinical efficacy and safety of sevelamer in dialysis patients. Nephrol Dial Transplant 22(10):2856–2866
Wilson CG (2010) The transit of dosage forms through the colon. Int J Pharm 395(1–2):17–25
Wrong O, Harland C (2007) Sevelamer and other anion-exchange resins in the prevention and treatment of hyperphosphataemia in chronic renal failure. Nephron Physiol 107(1):17–33
Yang Y, Shah RB, Yu LX, Khan MA (2013a) In vitro bioequivalence approach for a locally acting gastrointestinal drug: lanthanum carbonate. Mol Pharm 10(2):544–550
Yang Y, Bykadi S, Carlin AS, Shah RB, Yu LX, Khan MA (2013b) Comparative evaluation of the in vitro efficacy of lanthanum carbonate chewable tablets. J Pharm Sci 102(4):1370–1381
Younk LM, Davis SN (2012) Evaluation of colesevelam hydrochloride for the treatment of type 2 diabetes. Expert Opin Drug Met 8:515–525
Zhang X, Zheng N, Lionberger RA, Yu LX (2013) Innovative approaches for demonstration of bioequivalence: the US FDA perspective. Ther Deliv 4(6):725–740
Zhi J, Melia AT, Guerciolini R, Chung J, Kinberg J, Hauptman JB, Patel IH (1994) Retrospective population-based analysis of the dose–response (Fecal fat excretion) relationship of orlistat in Normal and obese volunteers. Clin Pharmacol Ther 56(1):82–85
Zhi J, Melia AT, Eggers H, Joly R, Patel IH (1995) Review of limited systemic absorption of orlistat, a lipase inhibitor, in healthy human volunteers. J Clin Pharmacol 35(11):1103–1108
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Jiang, X., Yang, Y., Stier, E. (2014). Bioequivalence for Drug Products Acting Locally Within Gastrointestinal Tract. In: Yu, L., Li, B. (eds) FDA Bioequivalence Standards. AAPS Advances in the Pharmaceutical Sciences Series, vol 13. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1252-0_12
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