A review of in vivo and in vitro aspects of alcohol-induced dose dumping

Abstract

This review provides a comprehensive list of in vivo and in vitro studies that have investigated alcohol induced dose dumping (AIDD) in modified release dosage forms. Of the numerous classes of drugs commercially available as modified release products, opioids, centrally acting drugs, and drugs with a narrow therapeutic index present high risks from dose dumping, despite being formulated in a manner that releases drug in a tailored or delayed fashion. Awareness of AIDD has led to the withdrawal of a few marketed products by Regulatory Agencies, and black box warnings on others. Since then, significant effort has focused on proving the robustness of a formulation when co-ingested with alcohol. Patient risk is deemed to be low if the formulation and its performance is unimpaired by the presence of 0-40% alcohol under in vivo and in vitro conditions.

Does the Intake of Ethanol Affect Oral Absorption of Poorly Soluble Drugs?

“…In contrast with our hypothesis, increased bioavailability, due to increasing drug dissolution and solubility in GI fluids in rats, is unlikely to occur. The literature suggests the same situation for humans where intragastric and intraduodenal concentrations (1) are expected to be relatively low as compared to ingested ethanol concentrations and (2) rapidly decline. This most likely results in GI ethanol concentrations that are too low to affect local solubility.…”

“…29 The pharmacokinetic profile can be affected by dose dumping, as mentioned before. 1,19 However, most ethanol-drug interactions at the pharmacokinetic level result from interference with metabolizing enzymes. Ethanol is both a substrate and inducer of cytochrome P450 (CYP) 2E1, and a substrate of alcohol dehydrogenase, and it can therefore interact with drugs that are substrates, inducers, or inhibitors of these enzymes.…”

“…The concomitant intake of ethanol has been shown to affect the bioavailability of several commercially available drug products. 1 Ethanol in the gastrointestinal (GI) tract can result in the premature disintegration of modified-release dosage forms, referred to as "dose dumping," leading to (1) rapid drug dissolution, (2) an increased rate of drug absorption, and (3) higher plasma concentrations. In the case of Pallodone XL™, a once-daily formulation of hydromorphone hydrochloride, the potential for ethanol-induced dose dumping even prompted market withdrawal.…”

“…In the case of Pallodone XL™, a once-daily formulation of hydromorphone hydrochloride, the potential for ethanol-induced dose dumping even prompted market withdrawal. 1,2 Alternatively, ethanol in the GI tract may affect absorption by increasing drug dissolution and solubility in GI fluids, because ethanol can act as a cosolvent. We have previously shown that the presence of 20% ethanol in simulated human gastric and intestinal fluids significantly increased the apparent solubility (S app ) of poorly water-soluble compounds; moreover, in silico simulations based on these solubility measurements predicted increased plasma concentrations of nonionizable lipophilic compounds.…”

Imaging of the Effect of Alcohol-Containing Media on the Performance of Hypromellose Hydrophilic Matrix Tablets: Comparison of Direct Compression and Regular Grades of Polymer

“…Palladone ® , a hydromorphone hydrochloride extended release narcotic analgesic, was removed from the US market by the Food and Drug Administration (FDA) after clinical studies indicated an interaction when ingested with alcohol. The plasma concentration of hydromorphone exceeded therapeutic levels and potentially reached hazardous levels because of the alcohol-induced failure of the extended release component [ 1 , 2 ]. This loss of controlled release property phenomenon, termed dose dumping, is defined as the unintended fast release of drug with consequent undesired rapid absorption from extended release formulations [ 3 ].…”