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

Abstract

Background: Physiologically-based population pharmacokinetic modeling (popPBPK) coupled with in vitro biopharmaceutics tools such as biorelevant dissolution testing can serve as a powerful tool to establish virtual bioequivalence and set clinically relevant specifications. One of several applications of popPBPK modeling is in the emerging field of virtual bioequivalence (VBE), where it can be used to streamline drug development by implementing model-informed formulation design and to inform regulatory decision-making e.g., with respect to evaluating the possibility of extending BCS-based biowaivers beyond BCS Class I and III compounds in certain cases. Methods: In this study, Naproxen, a BCS class II weak acid was chosen as the model compound. In vitro biorelevant solubility and dissolution experiments were performed and the resulting data were used as an input to the PBPK model, following a stepwise workflow for the confirmation of the biopharmaceutical parameters. The naproxen PBPK model was developed by implementing a middleout approach and verified against clinical data obtained from the literature. Once confidence in the performance of the model was achieved, several in vivo dissolution scenarios, based on model-based analysis of the in vitro data, were used to simulate clinical trials in healthy adults. Inter-occasion variability (IOV) was also added to critical physiological parameters and mechanistically propagated through the simulations. The various trials were simulated on a "worst/best case" dissolution scenario and average bioequivalence was assessed according to Cmax, AUC and tmax. Results: VBE results demonstrated that naproxen products with in vitro dissolution reaching 85% dissolved within 90 minutes would lie comfortably within the bioequivalence limits for Cmax and AUC. Based on the establishment of VBE, a dissolution "safe space" was designed and a clinically relevant specification for naproxen products was proposed. The interplay between formulation-related and drug-specific PK parameters (e.g., t1/2) to predict the in vivo performance was also investigated. Conclusion: Over a wide range of values, the in vitro dissolution rate is not critical for the clinical performance of naproxen products and therefore naproxen could be eligible for BCS-based biowaivers 3 based on in vitro dissolution under intestinal conditions. This approach may also be applicable to other poorly soluble acidic compounds with long half-lives, providing an opportunity to streamline drug development and regulatory decision-making without putting the patient at a risk.

Evaluation of Differences in Dosage Form Performance of Generics Using BCS-Based Biowaiver Specifications and Biopharmaceutical Modeling–Case Examples Amoxicillin and Doxycycline

“…The pH in the acceptor compartment was frequently monitored and, when necessary, adjusted with defined volumes of 1 M sodium hydroxide solution in order to maintain a stable pH. Sampling at specified time points (1,3,5,7,9,11,15,20,25,30,35,45,60,70,80, 90, 120 min) from the acceptor compartment and quantification of the API content was performed analogous to the procedure described in the previous section.…”

“…In contrast to amoxicillin, doxycycline has a long pharmacokinetic elimination half-life (12e25 h 27 ), high permeability (P app [Â10 À6 cm/s] ¼ 17.5 ± 0.3 in a Caco-2 monolayer system 28 ) and a late t max of 1.5e3.5 h. 27 For such APIs, it was suggested that wider dissolution criteria could be acceptable for a BCS-based biowaiver, as minor differences in dissolution are unlikely to have an influence on pharmacokinetic outcome parameters for the assessment of bioequivalence. 26,29,30 Commercially available formulations of doxycycline contain the API in the form of either the monohydrate or the hyclate salt. The bioavailability of a 200 mg dose is high for both forms (mean fraction absorbed of 95% 27 ).…”

Scientific considerations to move towards biowaiver for biopharmaceutical classification system class III drugs: How modeling and simulation can help

“…In another words, the average value of relative bioavailability can be protected through the cross-over design, however, overlooking the intraindividual variability may fail to capture the true confidence interval around the mean. Thus, to prevent any crossover virtual bioequivalence trials (VBE) becoming associated with false positive or false negative results (compared to any real large scale BE results), it is crucial to inform the models with correct estimates of within subject variability (11). Furthermore, this iterative modeling workflow can accommodate the IVIVC for various in vivo conditions (patients vs healthy subjects, stratified populations, etc.)…”

“…The second option is to include the intraindividual variability in the system parameters and to propagate it through simulations (Wedagedera et al., 2017). In one of the recent examples of VBE with naproxen where intraindividual variability was propagated through simulations, its value was arbitrarily chosen to be 30% and it was added to selected GI parameters, for example, mean gastric emptying time, gastric and intestinal pH and bile salts concentration (Loisios‐Konstantinidis et al., 2020). In that way, predicted variability and derived 90% confidence intervals may get inflated.…”

Physiologically‐based pharmacokinetic modeling to support bioequivalence and approval of generic products: A case for diclofenac sodium topical gel, 1%

“…12-15 PBPK models with enhanced population simulation capabilities can be used to support virtual BE (VBE) assessments. [16][17][18][19][20] Previously, mechanistic dermal PBPK models have been used to describe the permeation through the skin for environmental and other chemicals and perform risk-based assessments. 21,22 For locally acting drug products, including those applied on the skin, although administered at or close to the site of action, quantification of active ingredient amounts at the site of action for BE assessments is often not feasible.…”