Feasibility of biowaiver extension to biopharmaceutics classification system class III drug products cimetidine

• Published in: Clinical pharmacokinetics 2006-01, Vol.45 (4), p.385-399
• Main Authors: JANTRATID, Ekarat, PRAKONGPAN, Sompol, AMIDON, Gordon L, DRESSMAN, Jennifer B
• Format: Article
• Language: English
• Subjects: Adult; Biological and medical sciences; Biological Availability; Biopharmaceutics; Cimetidine - blood; Cimetidine - chemistry; Cimetidine - pharmacokinetics; Drug Approval; Excipients - chemistry; General pharmacology; Humans; Intestinal Absorption; Male; Medical sciences; Permeability; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Polymethacrylic Acids - chemistry; Solubility; Tablets - chemistry; Therapeutic Equivalency; United States; United States Food and Drug Administration
• ISSN: 0312-5963; 1179-1926
• DOI: 10.2165/00003088-200645040-00004

The extension of biowaivers (drug product approval without a pharmacokinetic bioequivalence study) to drugs belonging to Class III of the Biopharmaceutics Classification System (BCS) is currently a subject of much discussion. To assess the relationship between in vitro dissolution characteristics and in vivo absorption performance of immediate-release (IR) products containing cimetidine, a BCS Class III compound, in human subjects. To evaluate the feasibility and appropriateness of an extension of the biowaiver concept to BCS Class III compounds. BCS-conform dissolution tests were carried out on ten marketed cimetidine products from Thailand and Germany, as well as cimetidine tablet formulations containing cimetidine 400mg manufactured by direct compression using methacrylate copolymer (Eudragit) RS PO) as a release-retarding agent to yield three batches with significantly different release profiles. Twelve healthy male subjects were enrolled in a randomised, open-label, single-dose schedule based on a five-way Williams' design balanced for carryover effects. Subjects received the following treatments, with 1-week washout periods between: (i) Tagamet 400mg tablet; (ii) 7.5% methacrylate copolymer cimetidine tablet; (iii) 15% methacrylate copolymer cimetidine tablet; (iv) 26% methacrylate copolymer cimetidine tablet; and (v) Tagamet (300 mg/ 2 mL) intravenous injection. The area under the plasma concentration-time curve from 0 to 12 hours (AUC(12)) and AUC from time zero to infinity (AUC(infinity)), peak plasma concentration (C(max)), absolute bioavailability (F) and mean residence time (MRT) were evaluated and statistically compared among formulations. In vitro-in vivo correlation (IVIVC) analysis was then applied to elucidate the overall absorption characteristics of each tablet formulation. The release properties of the ten marketed cimetidine products were shown to comply with current US FDA criteria for rapidly dissolving drug products. As expected, the in vitro dissolution profiles of the cimetidine tablets containing different percentages of methacrylate copolymer differed considerably from one another. However, in vivo results showed no significant difference in AUC(12), AUC(infinity), C(max) and F between the tablets manufactured with methacrylate copolymer and the innovator. The MRT values obtained from 26% methacrylate copolymer tablets were significantly longer than for the other two methacrylate copolymer formulations and the Tagamet tablets. F