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.

Pharmacokinetics, pharmacodynamics, and safety of lesinurad, a selective uric acid reabsorption inhibitor, in healthy adult males.

Lesinurad is a selective uric acid reabsorption inhibitor under investigation for the treatment of gout. Single and multiple ascending dose studies were conducted to evaluate pharmacokinetics, pharmacodynamics, and safety of lesinurad in healthy males. Lesinurad was administered as an oral solution between 5 mg and 600 mg (single ascending dose; N=34) and as an oral solution or immediate-release capsules once daily (qday) between 100 mg and 400 mg for 10 days under fasted or fed condition (multiple ascending dose; N=32). Following single doses of lesinurad solution, absorption was rapid and exposure (maximum observed plasma concentration and area under the plasma concentration-time curve) increased in a dose-proportional manner. Following multiple qday doses, there was no apparent accumulation of lesinurad. Urinary excretion of unchanged lesinurad was generally between 30% and 40% of dose. Increases in urinary excretion of uric acid and reductions in serum uric acid correlated with dose. Following 400 mg qday dosing, serum uric acid reduction was 35% at 24 hours post-dose, supporting qday dosing. A relative bioavailability study in healthy males (N=8) indicated a nearly identical pharmacokinetic profile following dosing of tablets or capsules. Lesinurad was generally safe and well tolerated.