Pharmacokinetics
Single ascending dosingThe main pharmacokinetic parameters are summarized in Table 2. The first administration of the low doses showed that Org 48775-0 was rapidly absorbed and eliminated (see Figure 3A). Based on these results a rational sampling scheme was designed for the remainder of the study. From the 100 mg dose upward, a second peak at approximately 4 hrs after dosing was observed. The pharmacokinetics were linear up to a dose of 400 mg and after the 600 mg dose a lower than expected increase in Cmax and AUC was noted.
Evaluation of food effectTmax of Org 48775-0 in fasted condition was 1.6 ± 0.4 hours and in fed condition 3.3 ± 1.0 hours. The T1/2 was 12.6 ± 7.1 hours in fasted condition and 9.5 ± 0.6 hours in fed condition. Dosing of 100 mg Org 48775-0 in the fasted condition resulted in Cmax of 4490 ±949 ng/mL compared to the fed condition (3810 ± 967 ng/mL). With respect to the AUC no relevant differences were observed between fasted (32900 ± 8060 ng/mL) and fed condition (33300 ± 7430 ng/mL) (Figure 3C).
Evaluation of gender differencesThe pharmacokinetic behavior of Org 48775-0 for females was comparable to males (Figure 3D). T1/2 in females was 15.1 ± 6.3 hours and in males 11.4 ± 5.8 hours. The Cmax in females was 5390 ± 2140 and in males 4474 ± 891 ng/mL. The main pharmacokinetic parameters are summarized in Table 2.
Multiple ascending dosingThe pharmacokinetic results showed no accumulation of Org 48775-0 plasma levels after treatment with 30, 70 or 150 mg (see Figure 3B). Steady state concentrations were reached on Day 2 after twice daily dosing of 30-150 mg. Based on the dose-normalized Cmax values after multiple dose administration, the absorption rate approached its maximum: Cmax increased less than dose-proportional. This is confirmed by the prolonged Tmax at 150 mg bid. However, the AUC increased dose-proportionally in the dose range studied. Steady state was reached after 24 hours for all three dose levels.