(M1430-05-27) An Oseltamivir Phosphate Case Study–Use of Mechanistic IVIVE Based PBPK Model for Assessment of Dissolution Safe Space in Adults and Extrapolation to Paediatric Subjects

Purpose: Paediatric Research Equity Act (PREA) gives FDA the authority to require paediatric studies in certain drugs and biological products. Studies must use appropriate formulations for each age group.  A recent work by Mausa¹ and Mioa² on oseltamivir phosphate (OSP) propose a stringent dissolution limit of 6% and 4% slower dissolution difference for adolescents and neonates respectively as the lower limits for bioequivalence safe space. The purpose of this work is to re-evaluate dissolution safe space recommendations via virtual BE (VBE) simulations using a verified PBPK model.

Methods: The Advanced Dissolution, Absorption and Metabolism (ADAM) model of the Simcyp population-based PBPK simulator (V21, Certara) was used for Physiologically-Based Biopharmaceutics (PBBM) modelling. A full PBPK model for i.v. infusion dosing in adults was developed for OSP and its metabolite oseltamivir carboxylate (OSC) using literature data where tissue distribution Kp scalar was fitted. Metabolism of OSP by carboxylesterase was incorporated using the reported hepatic S9 incubations data. Renal clearance was optimized for OSP and OSC. Regional permeability (P_eff) was predicted using the bottom-up Mechanistic Permeability (MechPeff) model without any adjustments to simulate capsule and suspension absorption. Drug dissolution was modelled using two approaches: (1) Direct input of in vitro dissolution profiles (Figure 1a) and, (2) Using a mechanistic IVIVE approach. For the latter, the Diffusion Layer Model (DLM) parameterised using in vitro dissolution profiles under three conditions (Figure 1b) using the SIVA toolkit (V4, Certara UK). The verified model was extended to paediatric subjects applying the built-in ontology for metabolism and absorption. Virtual BE of the slower dissolution batches against reference was assessed using the Simcyp VBE Module with a cross over design with 5 replicates for adult (N=50) and paediatric (N=25) populations, and compared to a 10% slower dissolution profile for evaluation of safe space approach.

Results: The plasma PK profiles for OSP and OSC were well captured for both the i.v. infusion and oral route of administration in adults. The observed vs. predicted PK parameters for adults and paediatric subjects are given in Table 1. The T/R (90% Confidence interval) ratios from VBE analysis for each of the two approaches for various populations are given in Table 2 for OSP. As expected, direct input of in vitro dissolution profiles (Approach 1) has comparative impact on ratio of PK parameters (i.e,. incomplete release as input would result in similar lower ratio for the AUC), while the mechanistic DLM model as input does not have such limitation (Table 2). The mechanistic approach would likely yield more clinically relevant dissolution safe space assessment. This is also evident from the fact that the suspension and immediate release formulations have been found to be bioequivalent (SPC, Tamiflu), thus demonstrating lower impact of solid vs liquid formulation on PK of OSP.

Conclusion: Assumption of in vitro dissolution measured in 900mL of 0.1N HCl being valid throughout the GI tract and assessing less than 10% difference in such dissolution to define clinically relevant dissolution criteria is uncertain. DLM based IVIVE approach is informed by the relevant parameters from in vitro experiments and applies in vivo physiological differences along the GI tract. Mechanistic absorption modelling approaches can give more realistic assessment of safe space compared to direct use of in vitro dissolution (fixed pH and large volume (900mL)) into PBPK models for BCS Class III drugs. Such empirical PBPK models should cautiously be used specifically when extrapolating to paediatric subjects where relevance of such in vitro dissolution is questionable.

References: 1. Mousa, Youssef. Modeling for Success: A Case Example for Oseltamivir Phosphate. Complex generics. [Online] October 1, 2021.
2. Miao, Lei, et al. Using a Physiologically Based Pharmacokinetic Absorption Model to Establish Dissolution Bioequivalence Safe Space for Oseltamivir in Adult and Pediatric Populations. The AAPS Journal, Vol. 22:107.

Acknowledgments: Authors have no conflict of interest for the carried research work, and they are all Certara employees.

Figure 1: (a) OGD dissolution for reference and a point by point 10% slower and lower profile; (b): In vitro dissolution in multiple media with 10% slower profile.



Table 1: Observed vs Predicted (Mean (min-max)) pharmacokinetic parameters



T/R ratios with 90% CI for Adults, Adolescents and Neonates