A Physiologically Based Pharmacokinetic Model for Studying the Biowaiver Risk of Biopharmaceutics Classification System Class I Drugs With Rapid Elimination: Dexketoprofen Trometamol Case Study

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 C_max. 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 C_max 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.

Keywords: bioequivalence; biowaiver; dexketoprofen trometamol; gastric emptying; physiologically based pharmacokinetic model.

FIGURE 1

Schematic diagram of four equivalent test results.

FIGURE 2

Structure of the compartmental absorption and transit (CAT) model and two- compartment model; the parameter used in the models include: K _dis is the dissolution rate constant; K _a is the absorption rate constant; K _tgl is the liquid gastric emptying rate constant, K _tgs is the solid gastric emptying rate constant; K _t is the intestinal gastric emptying rate constant; K ₁₂ is the transit rate constant from the central compartment to the peripheral compartment; K ₂₁ is the transit rate constant from the peripheral compartment to the central compartment; K ₁₀ is the first-order elimination rate constant.

FIGURE 3

Prediction results of the mean plasma concentration of dexketoprofen after oral administration of 37 mg dexketoprofen trometamol (corresponding to 25 mg dexketoprofen) (black line), dexketoprofen plasma concentration (solid circles, n = 18), and the result of 1,000 simulations after the addition of the gastric emptying variation model (gray shaded region).

FIGURE 4

Effect of changes in drug permeability, dissolution, liquid gastric emptying time, and solid gastric emptying time on the C_max and AUC_tlast changes for dexketoprofen, and the results of plasma profiles of various parameters simulated by the PBPK model. Changes in parameters were normalized to the baseline value of reference value, whereas the C_max and AUC_tlast changes were normalized to the baseline C_max (A) and AUC_tlast (B) values and the BE limits of 80–125% boundary for the C_max and AUC_tlast (dashed lines), respectively. 3D surface response plot to show the relationship of dexketoprofen liquid gastric emptying time (min) with dissolution (C) and absorption (D) effects on the C_max.

FIGURE 5

Distribution of the GMR in 1,000 virtual BE simulations, (A): C_max (24 subjects in each trial); (B): AUC_tlast (24 subjects in each trial), (C): C_max (48 subjects in each trial); (D): AUC_tlast (48 subjects in each trial).

FIGURE 6

The first 50 virtual simulation in the 1,000 virtual BE trials. Error bars represent the 90% confidence intervals. Green indicates that the results successfully showed BE, yellow indicates that the results failed to show BE, and red indicates that the results failed to show BIE. (A): 24 subjects were included; (B): 48 subjects were included.

FIGURE 7

(A): Compartmental dissolution of the three DEX formulations in the PBPK model; (B): compartmental absorption of the three DEX formulations in the PBPK model.