Pharmacokinetics and pharmacodynamics of TF-505, a novel nonsteroidal 5alpha-reductase inhibitor, in normal subjects treated with single or multiple doses.
OBJECTIVE
To assess the tolerability, pharmacokinetics and pharmacodynamics of a novel nonsteroidal and noncompetitive inhibitor of type I and type II 5alpha-reductases, (-)-(S)-4-[1-[4-[1-(4-isobutylphenyl) butoxy]benzoyl]indolizin-3-yl]butyric acid (TF-505), after single and multiple oral doses in healthy volunteers.


METHODS
In the single-dose study, six young adult males in each dose group received 25 mg or 50 mg of TF-505, and six older males (>or= 40 years) in each dose group received 75 mg or 100 mg of TF-505. The subjects were given the drug in ascending dose and in the fasting state. Six subjects also received 50 mg of TF-505 after breakfast in a two-period crossover manner. In the multiple-dose study, six older males in each dose group received 12.5 mg or 25 mg TF-505 after breakfast daily for 7 days. Plasma concentrations of TF-505, dihydrotestosterone (DHT) and testosterone were measured. The pharmacokinetics of TF-505 were analysed by a compartment model with first-order absorption, first-order elimination and a lag time. Pharmacokinetic and pharmacodynamic relationships were evaluated by indirect response modelling with inhibition of input.


RESULTS
Maximum plasma concentration (Cmax) and the area under the concentration-time curve (AUC) increased proportionately after the single dose up to 50 mg and with the multiple doses. Linearity was not detected between 75 and 100 mg of TF-505. Dose dependency was also noted for the effect of TF-505 on DHT concentrations following single doses up to 50 mg and multiple doses. Plasma DHT concentrations decreased maximally to 58.2, 49.5, 54.2 and 49.8% of basal values at 8-12 h after single administration of 25, 50, 75 and 100 mg TF-505, respectively, and to 60.5 and 49.4% at the 7th and 5th dose following multiple doses of 12.5 and 25 mg TF-505, respectively. The predicted effect curves matched the observed data when the indirect response model was applied to the time course of the suppressant effect of TF-505 on plasma DHT concentrations after both the single and multiple studies. Fifty percent inhibitory concentrations (IC50) of 0.82, 1.48, 1.31 and 0.88 micro g ml(-1), zero-order rate constants for the onset of plasma DHT concentration changes (kin) of 17.8, 17.4, 17.0 and 10.7% h(-1) and first-order rate constants for increase in plasma DHT concentrations to basal values (kout) of 0.17, 0.16, 0.17 and 0.10 h(-1) for the single study at doses of 25, 50, 75 and 100 mg, respectively, were attained. In the multiple-dose study, IC50s were 1.74 and 1.49 micro g ml(-1) for the 12.5 and 25 mg doses, respectively. No serious adverse events related to TF-505 were observed.


CONCLUSIONS
TF-505 was well tolerated in healthy male volunteers. Accumulation of TF-505 in plasma was not observed during multiple dosing. The indirect response model described the relationships between pharmacokinetics and pharmacodynamics of TF-505. Such modelling is expected to yield an appropriate dosage regimen in subsequent clinical trials.
Fujita
Tomoe
T
Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Japan. f-tomo@pd6.so-net.ne.jp
Matsumoto
Yoshiaki
Y
Kimura
Toshimi
T
Yokota
Shinichi
S
Sawada
Mika
M
Majima
Masataka
M
Ohtani
Yoshio
Y
Kumagai
Yuji
Y
D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000493:pharmacokinetics / Q000494:pharmacology; D058891:5-alpha Reductase Inhibitors; D000284:Administration, Oral; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000328:Adult; D000368:Aged; D003687:Dehydroepiandrosterone / Q000097:blood; D013196:Dihydrotestosterone / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005640:Follicle Stimulating Hormone / Q000097:blood; D006801:Humans; D007212:Indolizines / Q000494:pharmacology*; D007986:Luteinizing Hormone; D008297:Male; D008875:Middle Aged
D058891:5-alpha Reductase Inhibitors; C106324:FR 146687; D007212:Indolizines; D013196:Dihydrotestosterone; D003687:Dehydroepiandrosterone; D000324:Adrenocorticotropic Hormone; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase