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

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.