Dose dumping

Dose dumping is a phenomenon of drug metabolism in which environmental factors can cause the premature and exaggerated release of a drug. This can greatly increase the concentration of a drug in the body and thereby produce adverse effects or even drug-induced toxicity.[1]

Dose dumping is most commonly seen in drugs taken by mouth and digested in the gastrointestinal tract. Around the same time patients take their medication, they can also ingest other substances like fatty meals or alcohol that increase drug delivery. The substances may act on the drug's capsule to speed up drug release, or they may stimulate the body's absorptive surfaces to increase the rate of drug uptake.

Dose dumping is a disadvantage found in extended release dosage form.

In general, drug companies try to avoid drugs with significant dose dumping effects. Such drugs are prone to problems and are often pulled from the market. Such was the case with the pain medication Palladone Once Daily formulation due to its dose-dumping effects when taken with alcohol.[2]

Types of dose dumping

Alcohol-induced dose dumping (AIDD)

It is by definition an unintended rapid release in large amounts of a modified-release dosage due to a co-ingestion with ethanol.[3]

Some interactions between alcohol, biological factors and the presentation of the drug can influence the apparition of AIDD by:

Food-induced dose dumping (FIDD)

Food intake produces dynamic changes in digestion and pharmacokinetics through a variety of mechanisms, which can produce an unintended release of modified-release dosages under certain circumstances. Usually, high fat diets are the most associated with this phenomenon, but there is evidence that standard-composition food can cause this even in immediate release formulations, such as the case of methylphenidate.[9]

Some of the mechanisms involved in FIDD are:[10][11]

  • Changes in composition and volumes of luminal fluid.
  • Modification in gastrointestinal motility and consequently transit time of the stomach.
  • Variation in concentration of bile salts and lipids.
  • Loss of drug's matrix integrity due to changes in pH, fat and bile.

References
  1. Hendeles L, Weinberger M, Milavetz G, Hill III M, Vaughan L (1985). "Food-induced "dose-dumping" from a once-a-day theophylline product as a cause of theophylline toxicity". Chest. 87 (6): 758–765. doi:10.1378/chest.87.6.758. PMID 3996063. A landmark 1985 study on dose dumping observed when theophylline was taken with fatty meals.
  2. Palladone Pain Drug Pulled Off the Market as reported by WebMD in July 2005.
  3. D’Souza, Susan; Mayock, Stephen; Salt, Alger (2017-06-07). "A review of in vivo and in vitro aspects of alcohol-induced dose dumping". AAPS Open. 3 (1). doi:10.1186/s41120-017-0014-9. ISSN 2364-9534.
  4. Johnson, Franklin K.; Ciric, Sabrina; Boudriau, Sophie; Kisicki, James; Stauffer, Joseph (May 2012). "Effects of Alcohol on the Pharmacokinetics of Morphine Sulfate and Naltrexone Hydrochloride Extended Release Capsules". The Journal of Clinical Pharmacology. 52 (5): 747–756. doi:10.1177/0091270011403740. ISSN 0091-2700.
  5. Franke, A.; Teyssen, S.; Harder, H.; Singer, M. V. (January 2004). "Effect of ethanol and some alcoholic beverages on gastric emptying in humans". Scandinavian Journal of Gastroenterology. 39 (7): 638–644. doi:10.1080/00365520410005009. ISSN 0036-5521.
  6. Fagerberg, Jonas H.; Al-Tikriti, Yassir; Ragnarsson, Gert; Bergström, Christel A.S. (2012-06-20). "Ethanol Effects on Apparent Solubility of Poorly Soluble Drugs in Simulated Intestinal Fluid". Molecular Pharmaceutics. 9 (7): 1942–1952. doi:10.1021/mp2006467. ISSN 1543-8384.
  7. Jedinger, N.; Khinast, J.; Roblegg, E. (July 2014). "The design of controlled-release formulations resistant to alcohol-induced dose dumping – A review". European Journal of Pharmaceutics and Biopharmaceutics. 87 (2): 217–226. doi:10.1016/j.ejpb.2014.02.008.
  8. Missaghi, Shahrzad; Fegely, Kurt A.; Rajabi-Siahboomi, Ali R. (2009-01-16). "Investigation of the Effects of Hydroalcoholic Solutions on Textural and Rheological Properties of Various Controlled Release Grades of Hypromellose". AAPS PharmSciTech. 10 (1): 77–80. doi:10.1208/s12249-008-9181-2. ISSN 1530-9932.
  9. Midha, K. K.; McKay, G.; Rawson, M. J.; Korchinski, E. D.; Hubbard, J. W. (2001). "Effects of food on the pharmacokinetics of methylphenidate". Pharmaceutical Research. 18 (8): 1185–1189. doi:10.1023/A:1010987212724.
  10. Koziolek, Mirko; Kostewicz, Edmund; Vertzoni, Maria (2018-08-28). "Physiological Considerations and In Vitro Strategies for Evaluating the Influence of Food on Drug Release from Extended-Release Formulations". AAPS PharmSciTech. 19 (7): 2885–2897. doi:10.1208/s12249-018-1159-0. ISSN 1530-9932.
  11. Klein, Sandra (2009). "Predicting Food Effects on Drug Release from Extended-Release Oral Dosage Forms Containing a Narrow Therapeutic Index Drug". Dissolution Technologies. 16 (3): 28–40. doi:10.14227/dt160309p28. ISSN 1521-298X.


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