title: Development and validation of in vitro-in vivo correlation (IVIVC) for estradiol transdermal drug delivery systems.
abstract: The objective of this study was to develop a level A in vitro-in vivo correlation (IVIVC) for drug-in-adhesive (DIA) type estradiol transdermal drug delivery systems (TDDS). In vitro drug permeation studies across human skin were carried out to obtain the percent of estradiol permeation from marketed products. The in vivo time versus plasma concentration data of three estradiol TDDS at drug loadings of 2.0, 3.8 and 7.6mg (delivery rates of 25, 50 and 100μg/day, respectively) was deconvoluted using Wagner-Nelson method to obtain percent of in vivo drug absorption in postmenopausal women. The IVIVC between the in vitro percent of drug permeation (X) and in vivo percent of drug absorption (Y) for these three estradiol TDDS was constructed using GastroPlus® software. There was a high correlation (R(2)=1.0) with a polynomial regression of Y=-0.227X(2)+0.331X-0.001. These three estradiol TDDS were used for internal validation whereas another two products of the same formulation design (with delivery rates of 60 and 100μg/day) were used for external validation. The predicted estradiol serum concentrations (convoluted from in vitro skin permeation data) were compared with the observed serum concentrations for the respective products. The developed IVIVC model passed both the internal and external validations as the prediction errors (%PE) for Cmax and AUC were less than 15%. When another marketed estradiol TDDS with a delivery rate of 100μg/day but with a slight variation in formulation design was chosen, it did not pass external validation indicating the product-specific nature of IVIVC model. Results suggest that the IVIVC model developed in this study can be used to successfully predict the in vivo performance of the same estradiol TDDS with in vivo delivery rates ranging from 25 to 100μg/day.
authors.affiliation: Division of Product Quality Research, Office of Testing and Research, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Division of Product Quality Research, Office of Testing and Research, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Prashanth
authors.initials: P
authors.lastname: Manda
authors.affiliation: Division of Product Quality Research, Office of Testing and Research, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Naresh
authors.initials: N
authors.lastname: Pavurala
authors.affiliation: Division of Product Quality Research, Office of Testing and Research, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Mansoor A
authors.initials: MA
authors.lastname: Khan
authors.affiliation: Division of Product Quality Research, Office of Testing and Research, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA. Electronic address: krishnaiah.yellela@fda.hhs.gov.
authors.forename: Yellela S R
authors.initials: YS
authors.lastname: Krishnaiah
mesh_terms: D000279:Administration, Cutaneous; D000328:Adult; D001682:Biological Availability; D018592:Cross-Over Studies; D016503:Drug Delivery Systems; D004958:Estradiol / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D004967:Estrogens / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D020249:Hormone Replacement Therapy; D006801:Humans; D066298:In Vitro Techniques; D008875:Middle Aged; D008954:Models, Biological; D015203:Reproducibility of Results; D012867:Skin / Q000378:metabolism; D012869:Skin Absorption; D055815:Young Adult
chemical_list: D004967:Estrogens; D004958:Estradiol
keywords: Absorption; Estradiol; In vitro–in vivo correlation (IVIVC); Permeation; Transdermal; Validation