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.