Using Physiologically Based Pharmacokinetic Modeling to Assess the Risks of Failing Bioequivalence Criteria: a Tale of T
- PDF / 519,574 Bytes
- 9 Pages / 595.276 x 790.866 pts Page_size
- 26 Downloads / 200 Views
Research Article Using Physiologically Based Pharmacokinetic Modeling to Assess the Risks of Failing Bioequivalence Criteria: a Tale of Two Ibuprofen Products Ioannis Loisios-Konstantinidis,1 Bart Hens,2 Amitava Mitra,3 Sarah Kim,4 Chang Chiann,5 and Rodrigo Cristofoletti4,6
Received 20 May 2020; accepted 31 July 2020 Abstract. The aims of the proposed study were to develop and verify a quantitative model-based framework to anticipate the in vivo bioequivalence of ibuprofen immediate release formulations. This stepwise approach integrated virtual bioequivalence trials to simulate the test to reference (T/R) ratio for positive (i.e., bioequivalent) and negative (i.e., non-bioequivalent) control formulations containing ibuprofen, approximated distribution of interoccasion variability (IOV) on ibuprofen peak (Cmax) and extent of exposure (AUC) by bootstrapping resampling methods, post hoc incorporation of IOV to simulated T/R ratios, and power curve analysis. After post hoc incorporation of the bootstrapped IOV to the simulated Cmax T/R geometric mean ratios, the resulting 90% confidence intervals overlapped with the in vivo observations for both pairwise comparisons. On the other hand, simulated and observed AUC TNBE/R geometric mean ratios differed, likely due to the lack of propagating clearance-related IOV to the simulations. This approach is in line with modern regulatory initiatives that advocate leveraging quantitative methods and modeling to modernize generic drug development and review. KEY WORDS: bioequivalence; in vitro-in vivo extrapolation; physiology-based pharmacokinetics; quantitative methods; regulatory sciences.
INTRODUCTION Most of the new chemical entities that populate the development pipeline are characterized by a low aqueous solubility (categorized as a Biopharmaceutics Classification System (BCS) class 2 or 4 drugs) which leads to challenges towards their intestinal absorption (1,2). Absorptionrelated parameters of poorly water-soluble drugs may change randomly between subjects (i.e., interindividual variability; IIV) and study occasions (i.e., interoccasion Ioannis Loisios-Konstantinidis and Bart Hens are equal first authors 1
Institute of Pharmaceutical Technology, Goethe University, Frankfurt am Main, Germany. 2 Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium. 3 Clinical Pharmacology and Pharmacometrics, Janssen Pharmaceutical Companies of Johnson & Johnson, Horsham, Pennsylvania, USA. 4 Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy,, University of Florida, 6550 Sanger Road, Office 146, Orlando, Florida 32827, USA. 5 Institute of Mathematics and Statistics, University of Sao Paulo, Sao Paulo, Brazil. 6 To whom correspondence should be addressed. (e–mail: [email protected]fl.edu)
variability; IOV) due to the highly variable conditions within the human gastrointestinal (GI) tract (3). Consequently, demonstrating bioequivalence (BE) between formulations containing these drugs may be challenging. BE
Data Loading...
