N. Kassir,1 R. Dudley,2 J. Longstreth,3 S. Mouksassi,1 J. F. Marier,1 T. Danoff2; 1Pharsight, a Certara Company, Montreal, QC, Canada, 2Clarus Therapeutics, Northbrook, IL, 3Longstreth & Associates, Mundelein, IL

BACKGROUND: A phase IIIa dose-titration trial was performed to assess efficacy, safety and pharmacokinetics (PK) of testosterone (T) following oral administration of testosterone undecanoate (TU) to ~160 hypogonadal men. Average concentration (Cavg) and maximum concentration (Cmax) of T were slightly higher than desired. The objective of this project was to develop a population PK model of T and perform simulations to support an optimal dosing regimen that would result in Cavg and Cmax of T within targeted ranges in a novel phase IIIb trial. The phase IIIb trial PK results were compared to simulation predictions.
METHODS: A population PK model of T was constructed based on phase IIIa data. Simulations were performed to determine a revised dosing rationale for a phase IIIb trial that would result in Cavg and Cmax of T within target ranges associated to efficacy and safety, respectively. External validation was performed by comparing model predicted Cavg and Cmax to observed values in the phase IIIb trial.
RESULTS: A one-compartment model with inter-occasion variability fitted T concentrations adequately in the phase IIIa trial. Based on simulations, a phase IIIb trial was proposed that included dose titration based on monitoring serum T levels within a prescribed time window, and a titration scheme with a starting dose of 200 mg BID. Based on external validation, Cavg values predicted with the model were within 5% of those observed in the phase IIIb trial. Differences in predicted vs. observed Cmax percentages ranged from -2.8% to +7.9%.
CONCLUSION: Modeling and simulations were performed to support an optimized dose titration scheme within a phase IIIb study designed to assess efficacy and safety of TU in hypogonadal men. Regulatory targets for efficacy and safety of T were achieved in the phase IIIb study.