Population pharmacokinetic-pharmacodynamic modeling of TF-505 using extension of indirect response model by incorporating a circadian rhythm in healthy volunteers

Abstract

The pharmacokinetic-pharmacodynamic (PK-PD) relationship of the newly developed drug, (-)-(S)-4-[1-[4-[1-(4-isobutylphenyl)butoxy]benzoyl]indolizin-3- yl]butyric acid (TF-505), was characterized via a population approach in early human study. Healthy volunteers were divided into six groups. The groups received four single doses (25, 50, 75 or 100 mg) and 2 multiple doses (12.5 or 25 mg) of TF-505, respectively. Dihydrotestosterone (DHT) data were collected to assess TF-505 pharmacodynamics. Population PK/PD modeling of TF-505 was performed via mixed-effects modeling using the NONMEM software package. The final PK-PD model incorporates a two-compartment PK model and an extended indirect PD model. The population PK parameters were 0.197 h-1 for the ka, 0.0678 h-1 for ke, 12.5 l for V c, 0.0645 h-1 for k12, 0.0723 h-1 for k21. Extension of indirect response model by incorporating a time-dependent periodic function for kin takes into account the chronopharmacologic rhythms (Imax: 0.706±0.297, IC 50: 1.01±1.64 (μg/ml), kout: 0.221±0.0486 (h-1), Rm: 20.4±8.08 (% h-1), R amp: 5.06±3.43 (%h-1), Tz: 5.01±0.407 (h) (Population mean±S.E.)). Rm is the mean DHT synthesis rate, Ramp is the amplitude of the DHT synthesis rate, and Tz is the acrophase time, signifying maximum synthesis rate. The present study represents a successful population PK-PD model using the full data from early human studies. The population parameters thus obtained could provide useful indicators for the determination of dosage regimens in exploratory studies in patient populations. © 2005 Pharmaceutical Society of Japan.