Population Pharmacokinetic Modeling and Simulations to Evaluate a Potential Dose Regimen of Testosterone Undecanoate in Hypogonadal Males

Intramuscular testosterone undecanoate is indicated as testosterone replacement in adult males with a deficiency in or absence of endogenous testosterone (hypogonadism). Intramuscular testosterone undecanoate 750 mg is approved to be administered at initiation and at 4 weeks, followed by a maintenance dose every 10 weeks. However, a more frequent maintenance regimen may improve symptom management of low testosterone at the end of each dosing interval. The current objective was to develop a population pharmacokinetic (PK) model for intramuscular testosterone undecanoate 750 mg and to perform PK simulations to assess the impact of an 8‐week maintenance regimen on testosterone exposure. A 1‐compartment model with first‐order absorption and first‐order elimination best described the PK of testosterone undecanoate. The model included time‐dependent suppression and gradual recovery of endogenous testosterone production during testosterone undecanoate administration. Significant covariates included body weight and sex hormone–binding globulin level. With the final PK model, simulations were performed to evaluate the impact of an 8‐week vs a 10‐week maintenance regimen on testosterone exposure. The 8‐week testosterone undecanoate regimen had a predicted 11% increase in average concentration and last observed concentration during a dosing interval before a subsequent dose and a 5% increase in maximum concentration. This translated into an ≈10% increase in the percentage of patients predicted to have a last observed concentration during a dosing interval before a subsequent dose >300 ng/dL, minimal change in the percentage of patients with average concentration in the normal range, and a low likelihood of maximum concentration >2500 ng/dL. These simulations suggest that more frequent administration of intramuscular testosterone undecanoate may be beneficial in some patients. Further clinical evaluation of an 8‐week dose regimen is warranted.