Dahan Arik, Wolk Omri, Zur Moran, Amidon Gordon L, Abrahamsson Bertil, Cristofoletti Rodrigo, Groot D W, Kopp Sabine, Langguth Peter, Polli James E, Shah Vinod P, Dressman Jennifer B
Department of Clinical Pharmacology, School of Pharmacy, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel.
J Pharm Sci. 2014 Jun;103(6):1592-600. doi: 10.1002/jps.23977. Epub 2014 May 1.
The present monograph reviews data relevant to applying the biowaiver procedure for the approval of immediate-release multisource solid dosage forms containing codeine phosphate. Both biopharmaceutical and clinical data of codeine were assessed. Solubility studies revealed that codeine meets the "highly soluble" criteria according to World Health Organization (WHO), the European Medicines Agency (EMA), and the United States Food and Drug Administration (US FDA). Codeine's fraction of dose absorbed in humans was reported to be high (>90%) based on cumulative urinary excretion of drug and drug-related material following oral administration. The permeability of codeine was also assessed to be high in both Caco-2 monolayers and rat intestinal perfusion studies. The main risks associated with codeine, that is, toxicity (attributed to CYP2D6 polymorphism) and its abuse potential, are present irrespective of the dosage form, and do not need to be taken into account for bioequivalence (BE) considerations. Taken together, codeine is a class 1 drug with manageable risk and is a good candidate for waiver of in vivo BE studies.
本专著回顾了与应用生物豁免程序批准含磷酸可待因的速释多源固体剂型相关的数据。对可待因的生物药剂学和临床数据均进行了评估。溶解度研究表明，根据世界卫生组织（WHO）、欧洲药品管理局（EMA）和美国食品药品监督管理局（US FDA）的标准，可待因符合“高溶解性”标准。据报道，基于口服给药后药物及药物相关物质的累积尿排泄量，可待因在人体中的剂量吸收分数较高（>90%）。在Caco-2单层细胞和大鼠肠道灌注研究中，可待因的渗透性也被评估为较高。与可待因相关的主要风险，即毒性（归因于CYP2D6基因多态性）及其滥用可能性，无论剂型如何均存在，在生物等效性（BE）考量中无需考虑。综上所述，可待因是一种风险可控的1类药物，是豁免体内BE研究的良好候选药物。
