IntegratingIn Vitro, Modeling, andIn VivoApproaches to Investigate Warfarin Bioequivalence

Abstract

We demonstrate the use of modeling and simulation to investigate bioequivalence (BE) concerns raised about generic warfarin products. To test the hypothesis that the loss of isopropyl alcohol and slow dissolution in acidic pH has significant impact on the pharmacokinetics of warfarin sodium tablets, we conducted physiologically based pharmacokinetic absorption modeling and simulation using formulation factors or in vitro dissolution profiles as input parameters. Sensitivity analyses indicated that warfarin pharmacokinetics was not sensitive to solubility, particle size, density, or dissolution rate in pH 4.5, but was affected by dissolution rate in pH 6.8 and potency. Virtual BE studies suggested that stressed warfarin sodium tablets with slow dissolution rate in pH 4.5 but having similar dissolution rate in pH 6.8 would be bioequivalent to the unstressed warfarin sodium tablets. A four‐way, crossover, single‐dose BE study in healthy subjects was conducted to test the same hypothesis and confirmed the simulation conclusion.

Generating Model Integrated Evidence for Generic Drug Development and Assessment

“…Stressed tablets represent tablets stored in the typical home bathroom condition, which represented a worst‐case scenario that was not recommended for drug product storage (e.g., under 40°C/75% relative humidity for 24 hours). The in vivo PK BE study results following a four‐way, crossover, single‐dose design in healthy subjects confirmed the PK simulation predictions …”

Establishing virtual bioequivalence and clinically relevant specifications using in vitro biorelevant dissolution testing and physiologically-based population pharmacokinetic modeling. case example: Naproxen

“…Virtual bioequivalence studies have been already published in the recent past (Babiskin and Zhang, 2015;Doki et al, 2017;Pathak et al, 1997;Pepin et al, 2016;Wedagedera et al, 2017;Zhang et al, 2017) However, in most of those studies the intra-subject (IIV) and inter-occasion (IOV) variability is either ignored or added directly to the PK metrics (i.e. Cmax and AUC) as random error terms.…”

“…Physiologically-based population pharmacokinetic (popPBPK) modelling has been implemented successfully to support and inform drug product development and regulatory decisionmaking. (Babiskin and Zhang, 2015;Doki et al, 2017;Heimbach et al, n.d.;Mitra, 2019;Olivares-Morales et al, 2016;Parrott et al, 2014;Pepin et al, 2016;Stillhart et al, 2017;Suarez-Sharp et al, 2018;Zhang et al, 2017) Patient-centric, model-informed drug product development necessitates an in vitro-in vivo-in silico link to establish clinically relevant specifications and thus guarantee the quality of the drug product with respect to safety and efficacy. By encompassing model-informed formulation selection and prediction of clinical performance, modeling and simulation (M & S) provides a way forward to the design of "safe spaces", and thus offer regulatory relief.…”

“…Although the current PBPK regulatory guidelines still mainly focus on the prediction of drug-drug interactions (DDIs),(European Medicines Agency (EMA), 2018a; U.S.FDA Center for Drug Evaluation and Research (CDER), 2018a) the integration of translational biopharmaceutical modeling and dissolution testing has been attracting increased attention from leading pharmaceutical industries as well as regulatory bodies and over the last few years, the regulatory impact of mechanistic absorption modeling has significantly increased. (Babiskin and Zhang, 2015;Heimbach et al, 2019;Pepin et al, 2016;Zhang et al, 2017) Establishing bioequivalence (BE) has been a critical component of and remains a challenge during development of both new drug and generic products. In the context of quality by design (QbD) and the biopharmaceutics risk assessment roadmap (BioRAM), (Selen et al, 2014) , (Dickinson et al, 2008) the importance of linking in vitro with in vivo data bi-directionally has received greater emphasis.…”

Development and validation of an ultra‐high‐performance liquid chromatography–tandem mass spectrometry method to determine the bioavailability of warfarin and its major metabolite 7‐hydroxy warfarin in rats dosed with oral formulations containing different polymorphic forms

“…A preclinical in vivo study was conducted to evaluate bioavailability profiles of a crystalline warfarin sodium [United States Pharmacopeia (USP)‐grade warfarin sodium containing 8%–8.5% IPA] and an amorphous warfarin sodium (warfarin sodium containing 1%–3% IPA) in a Sprague Dawley (SD) rat model. This current preclinical study complements the FDA clinical study conducted with both the crystallin and amorphous forms of the marketed warfarin drug products (Zhang et al, ). The current preclinical study is focused on bioanalytical method development for bioavailability and metabolism studies in rats (Saengtienchai, Ikenaka, Watanabe, Ishida, & Ishizuka, ).…”