Single ascending dosing study
Administration of 0.3, 1, 3 or 10 mg Org 48775-0 did not result in statistically significant differences in LPS-induced TNFα release versus placebo (Table 3; p>0.05). The observed variability in LPS-induced TNFα release over time was in the range of 25-55% (not shown). However, doses equal to and greater than 30 mg Org 48775-0 significantly inhibited LPS-induced TNFα release compared to placebo (Figure 4A, Table 3: 42.3% increase in inhibition versus placebo, 95% CI -65.2; -4.3, p=0.04; maximal inhibition 63% ± 7% at T=1 hour). Maximal inhibition was observed at dose levels exceeding 100 mg (Figure 4A, maximal inhibition >85% at T=1 hour). Doses of 400 mg and 600 mg did not induce an inhibition of TNFα release that was stronger or longer-lasting compared to 200 mg (Figure 4A). Maximal inhibition of the TNFα release was observed in the first 4 hours after dosing.
The in vitro Org 48775-0 effect, based on concentration-inhibition curves generated for each study participant in a pre-dose blood sample, very well predicted the ex vivo effect of the compound. Figure 5 shows an example of a representative study participant, who received a single dose of 200 mg Org 48775-0. In this subject, the LPS-induced TNFα release was approximately 500 pg/mL at baseline, declining to approximately 100 pg/mL 1 hour after Org 48775-0 administration, after which the TNFα response slowly returned to baseline level over time. This ex vivo drug effect mirrored thein vitro drug effect at drug concentrations corresponding to the observed serum drug concentrations after oral administration.
Evaluation of food effectThere was no significant difference in the LPS-induced TNFα release at baseline between the fasted (361.0 ± 167.1 pg/mL) and fed (290.2± 81.2 pg/mL) condition. No statistically significant effect of food intake was observed on LPS-induced TNFα release after oral administration of 100 mg Org 48755-0 (Figure 4C). In the fasted condition the maximal inhibition of the LPS-induced TNFα release was 80 ± 6% at T=1 hour, in fed condition 73 ± 8%.
Evaluation of gender differencesThere was no significant difference in the LPS-induced TNFα release at baseline between females (305.3 ± 55.2 pg/mL) and males (436.5± 242.5 pg/mL). No statistically significant difference in maximal inhibition of the LPS-induced TNFα release was observed between males and post-menopausal females (Figure 4D). The inhibition by Org 48755-0 was 83.9% ± 6.2% for males and 78.9% ± 4.3% for females (p=0.31, 95% CI -44.2; 21.0 at 1 hr after dosing). The overall inhibition was smaller in the post-menopausal females compared to the males, as demonstrated by a significant difference in the 0-72 hrs inhibition profiles between males and females (p=0.016, 95% CI -49.6; -8.1). Normalized in vitroinhibition curves showed a higher mean EC50 for Org 48775-0 in females than in males (0.88 µM versus 0.64 µM, not shown).
Multiple ascending dosingTreatment with 30 mg Org 48775-0, 70 mg Org 48775-0 and 150 mg Org 48775-0 significantly reduced the LPS-induced TNFα release (Table 3: p=0.04, p=0.001, p<0.0001, versus placebo). Maximal inhibition of the LPS-induced TNFα release was reached after administration of the first Org 48775-0 dose (Figure 4B: 75-85%, dependent on dose). During the entire steady state period the inhibition of the LPS-induced TNFα release remained within a range of approximately 30-75% for 30 mg, 53-80% for 70 mg, and 77-92% for 150 mg Org 48775-0. TNFα release returned to baseline levels within 3 days after the final administration of Org 48775-0. There was a possible rebound effect observed for the TNFα release after the 30 mg Org 48775-0 dose, although this effect was not observed for 70 and 150 mg Org 48775-0 (Figure 4B).