madman
Super Moderator
Introduction: Intramuscular testosterone undecanoate is indicated for testosterone replacement in adult males with a deficiency or absence of endogenous testosterone. Intramuscular testosterone undecanoate is currently approved to be administered at initiation and at 4 weeks followed by a maintenance dose every 10 weeks (750 mg on each dosing occasion). However, a more frequent maintenance regimen (every 8 weeks) may improve the management of symptoms of low testosterone at the end of each dosing interval.
Objective: To develop a population pharmacokinetic model for intramuscular testosterone undecanoate and to perform pharmacokinetic simulations to assess the impact of an 8-week maintenance regimen on testosterone exposure.
Methods: A population pharmacokinetic model was developed to characterize the pharmacokinetics of serum total testosterone using data from 130 hypogonadal men receiving the approved 10-week maintenance regimen of intramuscular testosterone undecanoate in Study IP157-001 Part C. Following model development, testosterone profiles were simulated for 8-week and 10-week maintenance regimens (10 doses/regimen) based on the population size and demographics of Study IP157?001 Part C. Using simulated testosterone 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 pharmacokinetics of testosterone undecanoate was well-described by a 1-compartment model with first-order absorption and elimination kinetics. The model incorporated a rapid suppression and gradual recovery of endogenous testosterone production during testosterone undecanoate administration. Lower clearance (CL/F) and volume of distribution (V/F) were associated with lower body weight, more rapid intramuscular absorption with lower body weight, and greater CL/F with lower sex hormone-binding globulin levels. Simulated testosterone pharmacokinetic profiles and responder rates for Dose 10 are presented in the Figure. Improved responder rates for Cavg and Ctrough were predicted for the 8-week regimen compared with the 10-week regimen, with no increase in Cmax excursions >2500 ng/dL.
Conclusions: Model simulations indicate that dosing intramuscular testosterone undecanoate every 8 weeks versus 10 weeks increases the percentage of subjects with Ctrough >300 ng/dL by approximately 10% (76.1% vs 66.7%, respectively). Smaller impacts of the 8-week regimen were predicted for Cavg and Cmax, with no increase in Cmax excursions >2500 ng/dL with the 8-week regimen.
Objective: To develop a population pharmacokinetic model for intramuscular testosterone undecanoate and to perform pharmacokinetic simulations to assess the impact of an 8-week maintenance regimen on testosterone exposure.
Methods: A population pharmacokinetic model was developed to characterize the pharmacokinetics of serum total testosterone using data from 130 hypogonadal men receiving the approved 10-week maintenance regimen of intramuscular testosterone undecanoate in Study IP157-001 Part C. Following model development, testosterone profiles were simulated for 8-week and 10-week maintenance regimens (10 doses/regimen) based on the population size and demographics of Study IP157?001 Part C. Using simulated testosterone 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 pharmacokinetics of testosterone undecanoate was well-described by a 1-compartment model with first-order absorption and elimination kinetics. The model incorporated a rapid suppression and gradual recovery of endogenous testosterone production during testosterone undecanoate administration. Lower clearance (CL/F) and volume of distribution (V/F) were associated with lower body weight, more rapid intramuscular absorption with lower body weight, and greater CL/F with lower sex hormone-binding globulin levels. Simulated testosterone pharmacokinetic profiles and responder rates for Dose 10 are presented in the Figure. Improved responder rates for Cavg and Ctrough were predicted for the 8-week regimen compared with the 10-week regimen, with no increase in Cmax excursions >2500 ng/dL.
Conclusions: Model simulations indicate that dosing intramuscular testosterone undecanoate every 8 weeks versus 10 weeks increases the percentage of subjects with Ctrough >300 ng/dL by approximately 10% (76.1% vs 66.7%, respectively). Smaller impacts of the 8-week regimen were predicted for Cavg and Cmax, with no increase in Cmax excursions >2500 ng/dL with the 8-week regimen.
