Abstract
Momelotinib (MMB, previously CYT387) is a potent and selective small molecule inhibitor of JAK 1 and JAK 2, and is currently under investigation for the treatment of myelofibrosis (MF). In a Phase 1/2 study of patients with MF, the 300 mg capsule administered once daily was selected as the Phase 3 dose based on a favorable benefit:risk profile. An immediate release tablet formulation (MMB tablet) with better thermodynamic stability and similar biopharmaceutical properties as the capsule formulation (MMB capsule) was developed. The relative bioavailability of MMB tablet vs capsule, effect of food on MMB tablet pharmacokinetics (PK), and the effect of omeprazole on MMB tablet PK were evaluated in a Phase 1 study.
The MMB tablet (dose: 100 to 300 mg) vs MMB capsule PK (300 mg) was evaluated in a Phase 1, single dose study in healthy subjects. MMB tablet PK at supratherapeutic doses (up to 800 mg), under fed and fasted conditions, and with an acid reducing agent (i.e.,. omeprazole) was also evaluated. Intensive PK and PD sampling occurred from 0.5 hour up to 36 hours post dose. Safety was monitored throughout the study. A parametric analysis of variance (ANOVA) using a mixed-effects model was used to fit to the natural logarithmic transformation of PK parameters (AUC and Cmax). The 90% confidence intervals were constructed for the ratio of geometric means of MMB tablet PK at 100, 150, 200 and 300 mg vs MMB capsule 300 mg, using equivalence bounds of 70% to 143% for AUC and Cmax. A similar approach was used to assess the effect of food or omeprazole. MMB tablet PK at supratherapeutic doses of 400 mg and 800 mg were also evaluated.
MMB tablet provided plasma exposures that were less-than dose-proportional from 100 mg to 800 mg (Figure 1). MMB tablet at 200 mg provided plasma exposures that were equivalent to MMB capsule at 300 mg (Table 1). Intake of light and high-fat meal modestly increased Cmax (38% and 28% increase for light and high-fat meals, respectively) and AUCinf (16% and 28% increase for light and high-fat meals, respectively) for MMB tablet. Omeprazole reduced the exposure of MMB tablet by 36% for Cmax and 31% for AUCinf. These differences were not considered clinically relevant.
MMB exposure as a function of dose following single dose administration of MMB tablet formulation
MMB exposure as a function of dose following single dose administration of MMB tablet formulation
Relative bioavailability of MMB phase 3 tablet vs capsule following single dose MMB administration
PK Parameters | 200 mg Tablet: Mean (SD) | 300 mg Capsule: Mean (SD) | GMR [%] (90% CI) |
|---|---|---|---|
| Cmax (ng/mL) | 324 (188) | 356 (196) | 92.0 (79.0, 107) |
| AUCinf (h·ng/mL) | 2570 (1670) | 2670 (1990) | 102 (87.7, 118) |
| AUClast (h·ng/mL) | 2340 (1510) | 2440 (1740) | 101 (86.8, 116) |
PK Parameters | 200 mg Tablet: Mean (SD) | 300 mg Capsule: Mean (SD) | GMR [%] (90% CI) |
|---|---|---|---|
| Cmax (ng/mL) | 324 (188) | 356 (196) | 92.0 (79.0, 107) |
| AUCinf (h·ng/mL) | 2570 (1670) | 2670 (1990) | 102 (87.7, 118) |
| AUClast (h·ng/mL) | 2340 (1510) | 2440 (1740) | 101 (86.8, 116) |
SD=standard deviation; CI=confidence interval ; data rounded as applicable and shown as three significant figures
MMB tablet at 200 mg provides comparable exposure to MMB capsule at 300 mg. MMB tablet plasma exposures increased in a less than dose-proportional manner. No clinically relevant effects of food or acid reducing agent were observed on MMB tablet PK.
Xin:Gilead Sciences: Employment. Off Label Use: GS-9820 is a second-generation, selective, small molecule inhibitor of PI3Kƒ’ƒn under investigation for the treatment of lymphoid malignancies including non-Hodgkin¡¦s lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Shao:Gilead Sciences: Employment, Equity Ownership. Deng:Gilead Sciences: Employment, Equity Ownership. Shaffer:Gilead Sciences: Employment. Stefanidis:Gilead Sciences: Employment. Hemenway:Gilead Sciences: Employment. Li:Gilead Sciences: Employment, Equity Ownership. Jun:Gilead Sciences: Employment, Equity Ownership. Ramanathan:Gilead Sciences: Employment, Equity Ownership.
