Population Pharmacokinetic/Pharmacodynamic Modeling of Depot Testosterone Cypionate in Healthy Male Subjects

Abstract

A randomized, double-blind clinical trial was conducted to investigate long-term abuse effects of testosterone cypionate (TC). Thirty-one healthy men were randomized into a dose group of 100, 250, or 500 mg/wk and received 14 weekly injections of TC. A pharmacokinetic/pharmacodynamic (PK/PD) model was developed to characterize testosterone concentrations and link exposure to change in luteinizing hormone and spermatogenesis following long-term TC administration. A linear one-compartment model best described the concentration-time profile of total testosterone. The population mean estimates for testosterone were 2.6 kL/day for clearance and 14.4 kL for volume of distribution. Weight, albumin, and their changes from baseline were identified as significant covariates for testosterone. The estimated potency of total testosterone (tT) with respect to suppression of luteinizing hormone (LH) synthesis was 9.33 ng/mL. Simulation based on the indirect response model suggests the suppression of endogenous testosterone secretion, LH synthesis, and spermatogenesis was more severe and of greater duration in the 250 mg and the 500 mg dose groups.

Figure 1

Effect of baseline and time‐varying covariates on pharmacokinetic parameters (clearance (CL) and volume (V)) and pharmacodynamic parameters for suppression of luteinizing hormone (half‐maximal inhibitory concentration (IC₅₀), K_in) and spermatogenesis ( $\mathrm{C}\mathrm{a}\mathrm{v}{\mathrm{g}}_{50}$). Error bars indicate 95% confidence interval based on a nonparametric bootstrap.

Figure 2

Prediction‐corrected visual predictive check for total testosterone obtained from 1,000 simulations stratified on dose and sampling period. Black solid points are observed concentrations. Red solid and dashed lines represent 2.5th, 50th, and 97.5th percentiles of observed data. The shaded areas indicate simulation‐based 95% confidence intervals around the median (orange) and the 2.5th and 97.5th percentiles (blue) from 1,000 simulations with the final model. Note: All subjects received 14 weekly injections of testosterone cypionate (TC) from week 2 to week 15. Intensive pharmacokinetic sampling was collected immediately postdose, at 8 hours, and then daily for 26 consecutive days after the last active TC injection (week 15).

Figure 3

Visual predictive checks for luteinizing hormone (left) and sperm counts (right) obtained from 1,000 simulations. Black solid points are observed concentrations. Red solid and dashed lines represent 2.5th, 50th, and 97.5th percentiles of observed data. The shaded areas indicate simulation‐based 95% confidence intervals around the median (orange) and the 2.5th and 97.5th percentiles (blue) from 1,000 simulations with the final model.

Figure 4

Summary of level of suppression of endogenous testosterone secretion (top), luteinizing hormone synthesis (LH; middle), and sperm counts (bottom) over time during and after testosterone cypionate dosing based on post hoc parameters from 31 subjects. Colored solid lines represent the median suppression level. Horizontal dashed line represents basal endogenous testosterone secretion independent of LH upregulation. Shaded areas indicate 95% confidence interval of the suppression level. Blue: 100 mg, Red: 250 mg, and Green: 500 mg. Black solid points represent the observed percentage change of variable of interest (LH30 or sperm counts) from baseline. The size of black points represents the frequency of observations.