A Semiparametric Deconvolution Model to Establish In Vivo–In Vitro Correlation Applied to OROS Oxybutynin

• Published in: Journal of pharmaceutical sciences Vol. 90; no. 6; pp. 702 - 712
• Main Authors: Pitsiu, Maria, Sathyan, Gayatri, Gupta, Suneel, Verotta, Davide
• Format: Journal Article
• Language: English
• Published: New York Elsevier Inc 01.06.2001; John Wiley & Sons, Inc; Wiley; American Pharmaceutical Association
• Subjects: Biological and medical sciences; Biological Availability; Chemistry, Pharmaceutical; clinical study; controlled release; Digestive system; General pharmacology; Humans; linear systems; Mandelic Acids - pharmacokinetics; Medical sciences; Models, Biological; Pharmaceutical technology. Pharmaceutical industry; Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions; Pharmacology. Drug treatments; Reproducibility of Results; Statistics as Topic; validation data; clinical study; validation data; controlled release; linear systems; Human; Pharmaceutical technology; Healthy subject; Controlled release form; Estimation; Prediction; Oral administration; Bioavailability; In vitro; Modeling; Blood; Blood plasma; In vivo; Antispasmodic agent; Enantiomer; Immediate release form; Dosage form; Active ingredient; Oxybutynin; Mathematical model; Pharmacokinetics; Release
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.1026

In vitro–in vivo correlation (IVIVC) models may be used to predict in vivo drug concentration–time profiles given in vitro release characteristics of a drug. This prediction is accomplished by incorporating in vitro release characteristics as an input function (Avitro) to a pharmacokinetics model. This simple approach often results in biased predictions of observed in vivo drug concentrations, and it can result in rejecting IVIVC. To solve this problem we propose a population IVIVC model that incorporates the in vitro information and allows one to quantify possibly changed in vivo release characteristic. The model assumes linear kinetics and describes the in vivo release as a sum of Avitro and a nonparametric function (Ad, a spline) representing the difference in release due to in vivo conditions. The function Avitro and its variability enter the model as a prior distribution. The function Ad is estimated together with its intersubject variability. The number of parameters associated with Ad defines the model: no parameters indicates perfect IVIVC, a large number of parameters indicates poor IVIVC. The number of parameters is determined using statistical model selection criteria. We demonstrate the approach to solve the IVIVC problem of an oral extended release oxybutynin form (OROS), administered in three pharmacokinetic studies. These studies present a particular challenging case; that is, the relative bioavailability for the OROS administration is >100% compared with that of the immediate‐release form. The result of our modeling shows that the apparent lack of IVIVC can be overcome: in vivo concentration can be predicted (within or across data sets) based on in vitro release rate together with a simple form of systematic deviation from the in vitro release. © 2001 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:702–712, 2001