Deniz Ozdin1,2, Isadore Kanfer3,4, Murray P Ducharme5,6. 1. Faculté de pharmacie, Université de Montréal, Pavillon Jean Coutu, 2940 Chemin de la polytechnique, Montréal, Quebec, Canada. 2. Learn and Confirm Inc., 750 Marcel-Laurin Suite 235, St-Laurent, Quebec, Canada. 3. Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College St, Toronto, Ontario, Canada. 4. Faculty of Pharmacy, Rhodes University, Grahamstown, South Africa. 5. Faculté de pharmacie, Université de Montréal, Pavillon Jean Coutu, 2940 Chemin de la polytechnique, Montréal, Quebec, Canada. murray.ducharme@learnandconfirm.ca. 6. Learn and Confirm Inc., 750 Marcel-Laurin Suite 235, St-Laurent, Quebec, Canada. murray.ducharme@learnandconfirm.ca.
Abstract
PURPOSE: The purpose of this study was (a) to suggest a novel dermatopharmacokinetic (DPK) approach from which pharmacokinetic parameters relevant to the bioequivalence (BE) assessment of a topical formulation can be deduced while circumventing the need for numerous measurements and assumptions, and (b) to investigate whether this approach enables the correct conclusion of BE and bioinequivalence (BIE). METHODS: Bioequivalent and bioinequivalent formulations of acyclovir were compared versus a reference product (Zovirax®). Tape Stripping was conducted at only one dose duration during the uptake phase to generate drug content in stratum corneum versus time profiles, each time point corresponding to one stripped layer. Nonlinear mixed effect modeling (ADAPT5®) (MLEM algorithm) was used to fit the DPK data and to estimate the rate (Kin) and extent (FS) of drug absorption/input into the skin. Results were evaluated using the average BE approach. RESULTS: Estimated exposure metrics were within the usual BE limits for the bioequivalent formulation (FS: 102.4 [90%CI: 97.5-107.7]; Kin: 94.2 [90%CI: 83.7-106.0]), but outside those limits for the bioinequivalent formulation (FS: 43.4 [90%CI: 27.9-67.6]; Kin: 54.5 [90%CI: 36.6-81.1]). CONCLUSIONS: The proposed novel DPK approach was shown to be successful, robust and applicable to assess BE and BIE correctly between topical formulations.
PURPOSE: The purpose of this study was (a) to suggest a novel dermatopharmacokinetic (DPK) approach from which pharmacokinetic parameters relevant to the bioequivalence (BE) assessment of a topical formulation can be deduced while circumventing the need for numerous measurements and assumptions, and (b) to investigate whether this approach enables the correct conclusion of BE and bioinequivalence (BIE). METHODS: Bioequivalent and bioinequivalent formulations of acyclovir were compared versus a reference product (Zovirax®). Tape Stripping was conducted at only one dose duration during the uptake phase to generate drug content in stratum corneum versus time profiles, each time point corresponding to one stripped layer. Nonlinear mixed effect modeling (ADAPT5®) (MLEM algorithm) was used to fit the DPK data and to estimate the rate (Kin) and extent (FS) of drug absorption/input into the skin. Results were evaluated using the average BE approach. RESULTS: Estimated exposure metrics were within the usual BE limits for the bioequivalent formulation (FS: 102.4 [90%CI: 97.5-107.7]; Kin: 94.2 [90%CI: 83.7-106.0]), but outside those limits for the bioinequivalent formulation (FS: 43.4 [90%CI: 27.9-67.6]; Kin: 54.5 [90%CI: 36.6-81.1]). CONCLUSIONS: The proposed novel DPK approach was shown to be successful, robust and applicable to assess BE and BIE correctly between topical formulations.
Entities:
Keywords:
bioequivalence and bioinequivalence; population PK modeling; regulatory sciences; tape stripping; topical dermatological formulations
Authors: V P Shah; G L Flynn; A Yacobi; H I Maibach; C Bon; N M Fleischer; T J Franz; S A Kaplan; J Kawamoto; L J Lesko; J P Marty; L K Pershing; H Schaefer; J A Sequeira; S P Shrivastava; J Wilkin; R L Williams Journal: Pharm Res Date: 1998-02 Impact factor: 4.200
Authors: S F Cordery; A Pensado; W S Chiu; M Z Shehab; A L Bunge; M B Delgado-Charro; R H Guy Journal: Int J Pharm Date: 2017-06-19 Impact factor: 5.875
Authors: Thalita Pedon de Araujo; Isabelle Moura Fittipaldi; Danilo Cesar Galindo Bedor; Maira Ludna Duarte; Sarah F Cordery; Richard H Guy; M Begoña Delgado-Charro; Davi Pereira de Santana; Leila Bastos Leal Journal: Int J Pharm Date: 2018-02-17 Impact factor: 5.875