Population Pharmacokinetic–Pharmacodynamic Modeling of TF-505 Using Extension of Indirect Response Model by Incorporating a Circadian Rhythm in Healthy Volunteers

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 Vc, 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, IC50: 1.01±1.64 (μg/ml), kout: 0.221±0.0486 (h−1), Rm: 20.4±8.08 (% h−1), Ramp: 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.