3.2.2 Multiple Ascending Dose Study
Mean plasma emodepside concentration-time profiles are shown in Figure 2 and PK parameters are presented in Table 5. Rapid absorption of emodepside and the median tmax seen in the SAD study were confirmed across all dosing groups and regimens in the MAD study. Emodepside levels were still quantifiable in all subjects at the final sampling timepoint, 507 hours after the last morning dose, which was consistent with the findings in the SAD study.
Cmax and AUC increased in a dose-proportional manner after once daily (OD) dosing of 5 and 10 mg emodepside LSF. Exposure was higher after dosing with 10 mg twice daily (BID) than with 10 mg OD. Compared to pre-dose concentrations on Days 1–8, Ctrough levels in the 5 mg OD, 10 mg OD and 10 mg BID groups before the last dose on Day 9 indicated that steady state had still not been reached.
Elimination t½ was independent of dose with a geometric mean terminal t½ on Day 9 of 419 hours in the 5 mg OD group, 450 hours in the 10 mg OD group and 508 hours in the 10 mg BID group (Table 5). Plasma concentrations declined from Cmax more rapidly during the 24 hours post-dose than subsequently, again consistent with the findings in the SAD study.
The increase in plasma emodepside concentrations after the last dose on Day 9 was lower after 10 mg BID than after 10 mg OD, with Cmax/Ctrough ratios of 1.9 and 3.0, respectively. Although the total daily dose in the 10 mg BID group was double that in the 10 mg OD group on Days 0–8, geometric mean Cmax on Day 9 was only 1.2-fold higher in the 10 mg BID group than in the 10 mg OD group.