Publication: Feasibility of biowaiver extension to Biopharmaceutics Classification System Class III drug products: Cimetidine
Issued Date
2006-04-10
Resource Type
ISSN
03125963
03125963
03125963
Other identifier(s)
2-s2.0-33645503065
Rights
Mahidol University
Rights Holder(s)
SCOPUS
Bibliographic Citation
Clinical Pharmacokinetics. Vol.45, No.4 (2006), 385-399
Suggested Citation
Ekarat Jantratid, Sompol Prakongpan, Gordon L. Amidon, Jennifer B. Dressman Feasibility of biowaiver extension to Biopharmaceutics Classification System Class III drug products: Cimetidine. Clinical Pharmacokinetics. Vol.45, No.4 (2006), 385-399. doi:10.2165/00003088-200645040-00004 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/23772
Research Projects
Organizational Units
Authors
Journal Issue
Thesis
Title
Feasibility of biowaiver extension to Biopharmaceutics Classification System Class III drug products: Cimetidine
Other Contributor(s)
Abstract
Background: 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. Objectives: 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. Study design and participants: 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® (300mg/2mL) intravenous injection. The area under the plasma concentration-time curve from 0 to 12 hours (AUC12) and AUC from time zero to infinity (AUC∞), peak plasma concentration (Cmax), 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. Results: 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 AUC12, AUC∞, Cmaxand 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. Furthermore, IVIVC analysis showed that the 26% methacrylate copolymer tablets exhibited dissolution rate-limited absorption, whereas the other formulations showed permeability rate-limited absorption. Conclusion: The results of the present study indicated that the absorption of cimetidine from IR tablets is, in general, limited by permeability rather than dissolution. IVIVC analysis demonstrated that only when the release was deliberately retarded (tablets containing 26% methacrylate copolymer), did the dissolution represent the rate-limiting step to drug absorption. On the in vitro side, it seems that 85% dissolution within 30 minutes, as currently required by the US FDA Guidance, is more than sufficient to guarantee bioequivalence of IR cimetidine products. For cimetidine and other BCS Class III drugs with a similar intestinal absorption pattern, application of the biowaiver concept seems to present little risk of an inappropriate bioequivalence decision. © 2006 Adis Data Information BV. All rights reserved.