Abstract
Biowaiver based on the biopharmaceutics classification system (BCS) has been widely used in the global market for the approval of new generic drug products to avoid unnecessary in vivo bioequivalence (BE) studies. However, it is reported that three out of four formulations of dexketoprofen trometamol (DEX) tablets (BCS class I drug) failed the first BE study. The aim of this study was to determine whether the current biowaiver standard is reasonable for DEX. Thus, we successfully established a physiologically based pharmacokinetic (PBPK) model for DEX and examined the effects of dissolution, permeability, and gastric emptying time on DEX absorption under BCS-based biowaiver conditions using sensitivity analyses. Parameter sensitivity analysis showed that the dissolution rate in pH 1.2 media, permeability, and liquid gastric emptying time were sensitive parameters of Cmax. Therefore, gastric emptying variation was introduced into the PBPK model, and virtual BE studys were conducted on original research formulation and the formulation of the boundary dissolution rate (f2 = 50) prescribed by the biowaiver guideline. The virtual BE results showed dissolution rate changes within the biowaiver range will not cause high non-BE ratio, indicate waive of DEX generic drugs would not lead the risk of Cmax when generic products satisfy the requirements of biowaiver guideline. However, the effect of excipients on gastric emptying as a sensitive factor needs to be further studied when the rapid elimination of BCS class I drug is biowaived.
Highlights
Bioequivalence (BE) studies are widely used to evaluate therapeutic equivalence between generic and original drugs
The physiologically based pharmacokinetic (PBPK) model was evaluated by performing simulation to assess the peak plasma drug concentration (Cmax) and AUCtlast of 25 and 12.5 mg dexketoprofen trometamol (DEX) tablets compared with the observed data
For the solid gastric emptying rate, when the Ktgs value was changed in the range of 0.55–4.95 h−1, the Cmax ratio remained in the range of 80–125%
Summary
Bioequivalence (BE) studies are widely used to evaluate therapeutic equivalence between generic and original drugs. A waiver of in vivo BE studies based on the BCS for immediate-release solid oral dosage forms has been proposed and widely accepted by regulators (EMA, 2010; FDA, 2017; ICH, 2019). The biowaiver of oral drugs based on the BCS classification is an effective scientific regulatory tool for granting biowaivers for solid oral immediate-release drug products following in vitro tests (Fagerholm, 2007). Based on the scientific principles of BCS, in vivo differences in the rate and extent of drug absorption between two pharmaceutically equivalent solid oral products may be caused by differences in the in vivo dissolution of the drug. For BCS class I drugs, when the general product meets the requirement of more than 85% release within 30 min and a similar dissolution profile to that of the reference product, unless the general product contains excipients that affect the absorption of active ingredients, the BE test in humans can be waived
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