Justification of Drug Product Dissolution Rate and Drug Substance Particle Size Specifications Based on Absorption PBPK Modeling for Lesinurad Immediate Release Tablets

Abstract

In silico absorption modeling has been performed, to assess the impact of in vitro dissolution on in vivo performance for ZURAMPIC (lesinurad) tablets. The dissolution profiles of lesinurad tablets generated using the quality control method were used as an input to a GastroPlus model to estimate in vivo dissolution in the various parts of the GI tract and predict human exposure. A model was set up, which accounts for differences of dosage form transit, dissolution, local pH in the GI tract, and fluid volumes available for dissolution. The predictive ability of the model was demonstrated by confirming that it can reproduce the Cmax observed for independent clinical trial. The model also indicated that drug product batches that pass the proposed dissolution specification of Q = 80% in 30 min are anticipated to be bioequivalent to the clinical reference batch. To further explore the dissolution space, additional simulations were performed using a theoretical dissolution profile below the proposed specification. The GastroPlus modeling indicates that such a batch will also be bioequivalent to standard clinical batches despite having a dissolution profile, which would fail the proposed dissolution specification of Q = 80% in 30 min. This demonstrates that the proposed dissolution specification sits comfortably within a region of dissolution performance where bioequivalence is anticipated and is not near an edge of failure for dissolution, providing additional confidence to the proposed specifications. Finally, simulations were performed using a virtual drug substance batch with a particle size distribution at the limit of the proposed specification for particle size. Based on these simulations, such a batch is also anticipated to be bioequivalent to clinical reference, demonstrating that the proposed specification limits for particle size distribution would give products bioequivalent to the pivotal clinical batches.

Predictive Performance of Physiologically Based Pharmacokinetic Models for the Effect of Food on Oral Drug Absorption: Current Status

“…Sutton 32 suggested that the small and large intestines' water volumes that best fit for several solubility-limited compounds were on average 130 mL and 10 mL (ranged as large as 125 mL), accounting for 10% and 1-10% of organ volumes of small and large intestines, whereas the default corresponding values in the ACAT model of Gastroplus were 40% and 10%. Pepin et al 33 also indicated that the percentage of water content in the small and large intestines for lesinurad, a weak acid, had to be adjusted to 7.5% and 2%, to best characterize the dissolution rates anticipated to occur in the intestines and colon. Sensitivity analysis results showed the volume of luminal water is limiting the absorption in the duodenum through limitation of the amount of drug dissolved but not in the jejunum, and, thus, the amount of water in the GI tract is a key factor to control the drug bioavailability.…”

Biopharmaceutic IVIVE—Mechanistic Modeling of Single- and Two-Phase In Vitro Experiments to Obtain Drug-Specific Parameters for Incorporation Into PBPK Models

“…The SFs permit the specification of the salt-limiting solubility of the API with a default value of 1000 for a monoprotic base such as dipyridamole. The default values within the solubility model are rule-of-thumb values for different ionic species based on observations for a number of drugs in 0.15M KCl or NaCl solutions, 43,44 which are roughly the physiologic concentrations of these ions. Hence as the default value of SF1 underpredicted the acidic medium solubility, SF1 was estimated to be 10,600; this value significantly improved predictions when used with the external solubility data set.…”

Approaches for Establishing Clinically Relevant Dissolution Specifications for Immediate Release Solid Oral Dosage Forms

“…Results from a bioequivalence study confirmed the outcome of the simulations. Finally, Pepin et al recently published their experience with utilizing absorption/PBPK modeling to justify drug product dissolution and drug substance particle size specification for Zurampic® (lesinurad) IR tablets (35). While a detailed review of the development and application of such physiologically based oral absorption/pharmacokinetic models is beyond the scope of this manuscript, the three examples highlighted demonstrate the potential utility of modeling in conjunction with the more traditional IVIVC approaches and the safe space concept discussed in the case studies to develop CRS.…”