MP45-02 POPULATION PHARMACOKINETIC MODELING AND SIMULATION TO ASSESS THE IMPACT OF AN 8-WEEK MAINTENANCE DOSING REGIMEN FOR INTRAMUSCULAR TESTOSTERONE UNDECANOATE

Abstract

INTRODUCTION AND OBJECTIVE: Intramuscular (IM) testosterone undecanoate (TU) is indicated for testosterone (T) replacement in adult males with a deficiency or absence of endogenous T. IM TU is currently approved to be administered at initiation and at 4 weeks (wks) followed by a maintenance dose every 10 wks (750 mg/dose). However, a more frequent maintenance regimen (every 8 wks) may improve the management of symptoms of low T at the end of each dosing interval. The objective of this work was to develop a population pharmacokinetic (popPK) model for IM TU and to perform PK simulations to assess the impact of an 8-wk maintenance regimen on T exposures. METHODS: A popPK model was developed to characterize the PK of serum total T using data from 130 hypogonadal men receiving the approved 10-wk maintenance regimen of IM TU in Study IP157-001 Part C. T profiles were then simulated for 8-wk and 10-wk maintenance regimens (10 doses/regimen) based on the population size and demographics of Study IP157-001 Part C. Using simulated T concentrations, the following parameters were calculated: average concentration (Cavg), maximum concentration (Cmax), and trough concentration (Ctrough). Responder rates of clinical interest were determined for each parameter. RESULTS: The PK of TU was well-described by a 1-compartment model with 1st-order absorption and elimination kinetics. The model included a rapid suppression and gradual recovery of endogenous T production during TU administration. Lower clearance (CL/F) and volume of distribution (V/F) were associated with lower body weight, more rapid IM absorption with lower body weight, and greater CL/F with lower sex hormone binding globulin levels. Simulated T PK profiles and responder rates for Dose 10 are presented in Figure 1. Improved responder rates for Cavg and Ctrough were predicted for the 8-wk regimen compared to the 10-wk regimen with no increase in Cmax excursions >2500 ng/dL. CONCLUSIONS: Simulations indicate that the absolute percent of Ctrough responders (Ctrough >300 ng/dL) increased by 9.4% (95% confidence interval: 8.5% – 10.3%) for the 8-wk regimen compared to the 10-wk regimen. Smaller impacts of the 8-wk regimen were calculated for Cavg and Cmax with no increase in Cmax excursions >2500 ng/dL for the 8-wk regimen.Source of Funding: Endo Pharmaceuticals Inc.