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The Effects of Food on Drug Bioavailability and Bioequivalence

Chapter
Part of the AAPS Advances in the Pharmaceutical Sciences Series book series (AAPS, volume 13)

Abstract

The effects of food on the drug absorption of orally dosed drug products are complex. These food effects can be specific, direct interactions between components of the food ingested and the drug substance or excipients themselves, or the food-effects can be secondary to the physiological changes in the gastrointestinal (GI) tract, which occur after ingesting the meal. These food-effects often have clinical significance. Food can change the bioavailability (BA) of a drug, which can in turn, alter its safety and/or efficacy profile. Likewise, food can influence the bioequivalence (BE) between a proposed generic drug product and its innovator counterpart (i.e., the reference listed drug product, or RLD). This chapter focuses on the complex effects of food on the absorption of drugs from the GI tract. In particular, it discusses the current US regulatory framework set forth by the Food and Drug Administration (FDA) in determining the impact of food on the absorption of orally dosed drug products. Case studies are discussed in order to show specific examples of the complex effects of food on drug absorption and BA, and how modified formulations might overcome at least some of these effects. After reading this chapter, the reader should have a general understanding of (1) how food can affect drug absorption from the GI tract, (2) why these food–drug interactions are relevant to the FDA and to US consumers, and (3) what types of BA and BE studies are recommended by the FDA for determining potential food-effects on drug absorption.

Keywords

Gastric Emptying Drug Product Drug Substance Splanchnic Blood Flow Reference Listed Drug 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. Adkin DA, Davis SS, Sparrow RA, Huckle PD, Phillips AJ, Wilding IR (1995) The effects of pharmaceutical excipients on small intestinal transit. Br J Clin Pharmacol 39(4):381–387PubMedCentralPubMedCrossRefGoogle Scholar
  2. Amidon GL, Lennernas H, Shah VP, Crison JR (1995) A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res 12:413–420PubMedCrossRefGoogle Scholar
  3. Astellas Pharma US, Inc (2012) Myrbetriq® Tablets package insertGoogle Scholar
  4. Astrazeneca Pharmaceuticals LP, Wilmington DE (2012) Tenormin® Tablets package insertGoogle Scholar
  5. AstraZeneca Pharmaceuticals LP, Wilmington DE 19850 (2012) Nexium® Delayed-Release Capsules package insertGoogle Scholar
  6. Barnwell SG, Laudanski T, Dwyer M, Story MJ, Guard P, Cole S, Attwood D (1993) Reduced bioavailability of atenolol in man: the role of bile acids. Int J Pharm 89(3):245–250CrossRefGoogle Scholar
  7. Bayer Pharmaceuticals Corporation, 400 Morgan Lane, West Haven CT 06516 (2005) Cipro® Tablets and Cipro® Oral Suspension package insertGoogle Scholar
  8. Bayer Pharmaceuticals Corporation, 400 Morgan Lane, West Haven CT 06516 (2005) Cipro® XL Tablets package insertGoogle Scholar
  9. Birkebaek NH, Memmert K, Mortensen J, Dirksen H, Christensen MF (1990) Fractional gastrointestinal transit time: intra- and interindividual variation. Nucl Med Commun 11(3):247–252PubMedCrossRefGoogle Scholar
  10. Bristol-Myers Squibb Virology, Bristol-Myers Company, Princeton, NJ 08543 (2006) Videx® Buffered Tablets package insertGoogle Scholar
  11. Bristol-Myers Squibb Virology, Bristol-Myers Company, Princeton, NJ 08543 (2011) Videx® EC package insertGoogle Scholar
  12. Camilleri M, Malagelada JR, Brown ML, Becker G, Zinsmeister AR (1985) Relation between antral motility and gastric emptying of solids and liquids in humans. Am J Physiol 249(5 Pt 1):G580–G585PubMedGoogle Scholar
  13. Charman WN, Porter CJH, Mithani S, Dressman JB (1997) Physicochemical and physiological mechanisms for the effects of food on drug absorption: the role of lipids and pH. J Pharm Sci 86(3):269–282PubMedCrossRefGoogle Scholar
  14. Collins PJ, Horowitz M, Maddox A, Myers JC, Chatterton BE (1996) Effects of increasing solid component size of a mixed solid/liquid meal on solid and liquid gastric emptying. Am J Physiol 271(4 Pt 1):G549–G554PubMedGoogle Scholar
  15. Daneshmend TK, Roberts CJC (1982) The influence of food on the oral and intravenous pharmacokinetics of a high clearance drug: a study with labetalol. Br J Clin Pharmacol 14:73–78PubMedCentralPubMedCrossRefGoogle Scholar
  16. Davit BM, Conner DP (2008) Food effects on drug bioavailability: implications for new and generic drug development. Biopharmaceutics Applications in Drug Development pp. 317–335Google Scholar
  17. Deferme S, Augustijns P (2003) The effect of food components on the absorption of P-gp substrates: a review. J Pharm Pharmacol 55:153–162PubMedCrossRefGoogle Scholar
  18. Dressman JB, Berardi RR, Dermentzoglou LC, Russell TL, Schmaltz SP, Barnett JL, Jarvenpaa KM (1990) Upper gastrointestinal (GI) pH in young, healthy men and women. Pharm Res 7(7):756–761PubMedCrossRefGoogle Scholar
  19. Dressman J, Butler J, Hempenstall J, Reppas C (2001) The BCS: where do we go from here? Pharm Technol 25:68–76Google Scholar
  20. Dressman JB, Vertzoni M, Goumas K, Reppas C (2007) Estimating drug solubility in the gastrointestinal tract. Adv Drug Deliv Rev 59(7):591–602PubMedCrossRefGoogle Scholar
  21. Evans DF, Pye G, Bramley R, Clark AG, Dyson TJ, Hardcastle JD (1988) Measurement of gastrointestinal pH profiles in normal ambulant human subjects. Gut 29(8):1035–1041PubMedCentralPubMedCrossRefGoogle Scholar
  22. FDA News (2005) FDA asks Purdue Pharma to withdraw Palladone® for safety reasons (July 12, 2005) http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2005/ucm108460.htm
  23. Fleisher D, Li C, Zhou Y, Pao L, Karim A (1999) Drug, meal and formulation interactions influencing drug absorption after oral administration: clinical implications. Clin Pharmacokinet 36:233–254PubMedCrossRefGoogle Scholar
  24. Gai MN, Isla A, Andonaeugui MT, Thielemann AM, Seitz C (1997) Evaluation of the effect of three different diets on the bioavailability of two sustained release theophylline matrix tablets. Int J Clin Pharm Ther 35:565–571Google Scholar
  25. Grattan T, Hickman R, Darby-Dowman A, Hayward M, Boyce M, Warrington S (2000) A five way crossover human volunteer study to compare the pharmacokinetics of paracetamol following oral administration of two commercially available paracetamol tablets and three development tablets containing paracetamol in combination with sodium bicarbonate or calcium carbonate. Eur J Pharm Biopharm 49(3):225–229PubMedCrossRefGoogle Scholar
  26. Grundy JS, Foster RT (1996) The nifedipine gastrointestinal therapeutic system (GITS). Evaluation of pharmaceutical, pharmacokinetic and pharmacologic properties. Clin Pharmacokinet 30:28–51PubMedCrossRefGoogle Scholar
  27. Hendeles L, Weingerger M, Milavetz G, Hill M, Vaughan L (1985) Food-induced “dose-dumping” from a once-a-day theophylline product as a cause of theophylline toxicity. Chest 87:758–765PubMedCrossRefGoogle Scholar
  28. Hörter D, Dressman JB (2001) Influence of physicochemical properties on dissolution of drugs in the gastrointestinal tract. Adv Drug Deliv Rev 46(1–3):75–87PubMedCrossRefGoogle Scholar
  29. Huupponen R, Seppälä P, Iisalo E (1984) Effect of guar gum, a fibre preparation, on digoxin and penicillin absorption in man. Eur J Clin Pharmacol 26(2):279–281PubMedCrossRefGoogle Scholar
  30. Jones HM, Parrott N, Ohlenbusch G, Lavé T (2006) Predicting pharmacokinetic food effects using biorelevant solubility media and physiologically based modelling. Clin Pharmacokinet 45(12):1213–1226PubMedCrossRefGoogle Scholar
  31. Karim A, Burns T, Wearley L, Streicher J, Palmer M (1985) Food-induced changes in theophylline absorption from controlled-release formulations. I. Substantial increased and decreased absorption with Uniphyl tablets and Theo-Dur Sprinkle. Clin Pharmacol Ther 38:77–83PubMedCrossRefGoogle Scholar
  32. Klein S (2010) The use of biorelevant dissolution media to forecast the in vivo performance of a drug. AAPS J 12(3):397–406PubMedCentralPubMedCrossRefGoogle Scholar
  33. Lee J, Zhang W, Moy S, Kowalski D, Kerbusch V, van Gelderen M, Sawamoto T, Grunenberg N, Keirns J (2013) Effects of food intake on the pharmacokinetic properties of mirabegron oral controlled-absorption system: a single-dose, randomized, crossover study in healthy adults. Clin Ther 35(3):333–341PubMedCrossRefGoogle Scholar
  34. Lentz KA (2008) Current methods for predicting human food effect. AAPS J 10(2):282–288PubMedCentralPubMedCrossRefGoogle Scholar
  35. Maka DA, Murphy LK (2000) Drug-nutrient interactions: a review. AACN Clin Issues 11:580–589PubMedCrossRefGoogle Scholar
  36. Malagelada JR, Longstreth GF, Summerskill WH, Go VL (1976) Measurement of gastric functions during digestion of ordinary solid meals in man. Gastroenterology 70(2):203–210PubMedGoogle Scholar
  37. Malagelada JR, Longstreth GF, Deering TB, Summerskill WH, Go VL (1977) Gastric secretion and emptying after ordinary meals in duodenal ulcer. Gastroenterology 73(5):989–994PubMedGoogle Scholar
  38. Martinez MN, Amidon GL (2002) A mechanistic approach to understanding the factors affecting drug absorption: a review of fundamentals. J Clin Pharmacol 42:620–643PubMedCrossRefGoogle Scholar
  39. Mathias NR, Crison J (2012) The use of modeling tools to drive efficient oral product design. AAPS J 14(3):591–600PubMedCentralPubMedCrossRefGoogle Scholar
  40. McLean AJ, McNamara PJ, du Souich P, Gibaldi M, Laika D (1978) Food, splanchnic blood flow, and bioavailability of drugs subject to first-pass metabolism. Clin Pharmacol Ther 24:5–10PubMedGoogle Scholar
  41. Melander A, McLean A (1983) Influence of food intake on presystemic clearance of drugs. Clin Pharmacokinet 8(4):286–296PubMedCrossRefGoogle Scholar
  42. Melander A, Danielson K, Schersten B, Wahlin E (1977) Enhancement of the bioavailability of propranolol and metoprolol by food. Clin Pharmacol Ther 22(1):108–112PubMedGoogle Scholar
  43. Meyer JH, Dressman J, Fink A, Amidon G (1985) Effect of size and density on canine gastric emptying of nondigestible solids. Gastroenterology 89(4):805–813PubMedGoogle Scholar
  44. Neuhofel AL, Wilton JH, Victory JM, Hejmanowski LG, Amsden GW (2002) Lack of bioequivalence of ciprofloxacin when administered with calcium-fortified orange juice: a new twist on an old interaction. J Clin Pharmacol 42:461–466PubMedCrossRefGoogle Scholar
  45. Novartis Pharmaceuticals Corporation (2004) Myfortic® (mycophenolic acid) Delayed Release Tablet package insertGoogle Scholar
  46. Parrott N, Lukacova V, Fraczkiewicz G, Bolger MB (2009) Predicting pharmacokinetics of drugs using physiologically based modeling—application to food effects. AAPS J 11(1):45–53PubMedCentralPubMedCrossRefGoogle Scholar
  47. Pfizer, Inc. v. Shalala, 1 F.Supp.2d 38 (D.D.C. 1998)Google Scholar
  48. Procter & Gamble Pharmaceuticals, Inc., Cincinnati, OH 45202 (2009) Macrobid® Capsules package insertGoogle Scholar
  49. Purdue Pharmaceutical Products L.P., Stamford, CT 09601-3431 (2004) Uniphyl® Tablets package insertGoogle Scholar
  50. Reliant Pharmaceuticals, Inc., Liberty Corner, NJ 07938 (2005) InnoPran® XL package insertGoogle Scholar
  51. Russell TL, Berardi RR, Barnett JL, Dermentzoglou LC, Jarvenpaa KM, Schmaltz SP, Dressman JB (1993) Upper gastrointestinal pH in seventy-nine healthy, elderly, North American men and women. Pharm Res 10(2):187–196PubMedCrossRefGoogle Scholar
  52. Schug BS, Brendel E, Chantraine E, Wolf D, Martin W, Schall R, Blume HH (2002a) The effect of food on the pharmacokinetics of nifedipine in two slow release formulations: pronounced lag-time after a high fat breakfast. J Clin Pharmacol 53:582–588CrossRefGoogle Scholar
  53. Schug BS, Brendel E, Wonnemann M, Wolf D, Wargenau M, Dikngler A, Blume HH (2002b) Dosage form-related food interaction observed in a marketed once-daily nifedipine formulation after a high-fat American breakfast. Eur J Clin Pharmacol 58:119–125PubMedCrossRefGoogle Scholar
  54. Semple HA, Fangming X (1995) Interaction between propranolol and amino acids in the single-pass isolated, perfused rat liver. Drug Metab Dispos 23:794–798PubMedGoogle Scholar
  55. Shionogi Inc (2013) Keflex® Capsules package insertGoogle Scholar
  56. Tam YK (1993) Individual variation in first-pass metabolism. Clin Pharmacokinet 25:300–328PubMedCrossRefGoogle Scholar
  57. Toothaker RD, Welling PG (1980) The effect of food on drug bioavailability. Annu Rev Pharmacol Toxicol 20:173–199PubMedCrossRefGoogle Scholar
  58. U.S. Code of Federal Regulations, Title 21, Part 320—Bioavailability and Bioequivalence Requirements, Subpart A—General Provisions, Section 320.1 (2006) Definitions. U.S. Government Printing Office, Washington (April 2011), p 190Google Scholar
  59. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (2000) Waiver of in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms based on a biopharmaceutics classification system (August 31, 2000)Google Scholar
  60. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (2003) Guidance for industry: bioavailability and bioequivalence studies for orally administered drug products—general considerations (March 19, 2003)Google Scholar
  61. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (2003) Guidance for industry: food-effect bioavailability and fed bioequivalence studies (2002)Google Scholar
  62. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (2012) Guidance for industry: size of beads in drug products labeled for sprinkle (May 2012)Google Scholar
  63. Weinberger MM (1984) Theophylline QID, BID and now QD? A report on 24-hour dosing with slow-release theophylline formulations with emphasis on analysis of data used to obtain Food and Drug approval for Theo-24. Pharmacotherapy 4:181–198PubMedGoogle Scholar
  64. Welling PG (1996) Effects of food on drug absorption. Annu Rev Nutr 16:383–415PubMedCrossRefGoogle Scholar
  65. Yin L, Qin C, Chen K, Zhu C, Cao H, Zhou J, He W, Zhang Q (2013) Gastro-floating tablets of cephalexin: preparation and in vitro/in vivo evaluation. Int J Pharm 452(1–2):241–248PubMedCrossRefGoogle Scholar
  66. Yu LX, Lipka E, Crison JR, Amidon GL (1996) Transport approaches to the biopharmaceutical design of oral drug delivery systems: prediction of intestinal absorption. Adv Drug Deliv Rev 19(3):359–376PubMedCrossRefGoogle Scholar
  67. Yu LX, Straughn AB, Faustino PJ, Yang Y, Parekh A, Ciavarella AB, Asafu-Adjaye E, Mehta MU, Conner DP, Lesko LJ, Hussain AS (2004) The effect of food on the relative bioavailability of rapidly dissolving immediate-release solid oral products containing highly soluble drugs. Mol Pharm 1(5):357–362PubMedCrossRefGoogle Scholar
  68. Yuen KH (2010) The transit of dosage forms through the small intestine. Int J Pharm 395(1–2):9–16PubMedCrossRefGoogle Scholar

Copyright information

© The United States Government 2014

Authors and Affiliations

  1. 1.Center for Drug Evaluation and ResearchU.S. Food and Drug AdministrationSilver SpringUSA

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