Pharmacokinetics of 2 novel formulations of modified-release oral testosterone alone and with finasteride in normal men with experimental hypogonadism

Abstract

Oral administration of testosterone might be useful for the treatment of testosterone deficiency. However, current "immediate-release" formulations of oral testosterone exhibit suboptimal pharmacokinetics, with supraphysiologic peaks of testosterone and its metabolite, dihydrotestosterone (DHT), immediately after dosing. To dampen these peaks, we have developed 2 novel modified-release formulations of oral testosterone designed to slow absorption from the gut and improve hormone delivery. We studied these testosterone formulations in 16 normal young men enrolled in a 2-arm, open-label clinical trial. Three hundred-mg and 600-mg doses of immediate-release and modified fast-release or slow-release formulations were administered sequentially to 8 normal men rendered hypogonadal by the administration of the gonadotropin-releasing hormone antagonist acyline. Blood for measurement of serum testosterone, DHT, and estradiol was obtained before and 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours after each dose. A second group of 8 men was studied with the coadministration of 1 mg of the 5α-reductase inhibitor finasteride daily throughout the treatment period. Serum testosterone was increased with all formulations of oral testosterone. The modified slow-release formulation significantly delayed the postdose peaks of serum testosterone and reduced peak concentrations of serum DHT compared with the immediate-release formulation. The addition of finasteride further increased serum testosterone and decreased serum DHT. We conclude that the oral modified slow-release testosterone formulation exhibits superior pharmacokinetics compared with immediate-release oral testosterone both alone and in combination with finasteride. This formulation might have efficacy for the treatment of testosterone deficiency.

Trial registration: ClinicalTrials.gov NCT00663793.

Figures

Figure 1

Study design.

Figure 2

Serum testosterone 300 mg (A and B) and 600 mg (C and D) after dosing with the immediate-release, modified fast-release, and modified slow-release formulations of oral testosterone in normal men rendered experimentally hypogonadal with acyline in the testosterone-only (A and C) and testosterone plus finasteride (B and D) groups (n = 8/group). The dotted lines represent the upper and lower limits of the normal range. All values are means ± SEM. * indicates P < .05 compared with both modified fast release and modified slow release; Φ, P < .05 compared with modified fast release; Ψ, P < .05 compared with modified slow release.

Figure 3

Serum dihydrotestosterone (DHT) after dosing with 300 mg of the immediate-release, modified fast-release, and modified slow-release formulations of oral testosterone in normal men rendered experimentally hypogonadal with acyline in the testosterone-only (A) and testosterone plus finasteride (B) groups (n = 8/group). The dotted lines represent the upper and lower limits of the normal range. All values are means ± SEM. Ψ indicates P < .05 compared with modified slow release.

Figure 4

Serum estradiol levels after dosing with 300 mg of the immediate-release, modified fast-release, and modified slow-release formulations of oral testosterone in normal men rendered experimentally hypogonadal with acyline in the testosterone-only (A) and testosterone plus finasteride (B) groups (n = 8/group). The dotted lines represent the upper and lower limits of the normal range. All values are means ± SEM.