181: Relative Bioavailability & Food Effect of Phase 2 Formulations of Zimlovisertib in Healthy Participants

Statement of Purpose: Zimlovisertib (PF-06650833), a selective interleukin-1 receptor kinase 4 (IRAK4) inhibitor, which is the first-in-class to enter clinical phase of development. The first-in-human study was conducted using an extemporaneously prepared suspension. Subsequently, a modified release formulation using swellable core technology (SCT) was developed and used in a Phase 2 study (NCT02996500) evaluating efficacy and safety of zimlovisertib in patients with rheumatoid arthritis (RA). In order to increase the drug load, another modified release formulation using extrudable swellable core (ECS) technology was developed. The objective of this study (NCT03308110) was to evaluate relative bioavailability and food effect of ECS tablets to be used to support future clinical development of the molecule.

Description of Methods & Materials: A Phase 1, open-label, randomized, 5-period, 8-sequence, cross-over, single-dose study was conducted in 24 healthy participants to assess the bioavailability of ECS tablets relative to SCT tablets at two dose levels ie 100 mg and 400 mg. In addition, the effect of a high fat meal on the PK of ECS tablet was evaluated. At least 8-day washout duration was given before dosing in each period. Serial plasma samples were collected for the measurement of zimlovisertib and PK parameters were calculated by non-compartmental analysis. Natural log-transformed dose normalized AUC_inf, AUC_last and C_max were analyzed using a mixed effect model with treatment, sequence and period as fixed effect and subject within sequence as a random effect.

Data & Results: All participants were male with a mean (range) age of 35.92 (24 to 51) years. The majority of participants were white (22 out of 24). The relative bioavailability of zimlovisertib ECS 100 mg fasted compared to SCT 100 mg fasted were 81.41%, 85.32% and 90.75% for dose normalized AUC_inf, AUC_last and C_max, respectively. The relative bioavailability of zimlovisertib ECS 400 mg fasted compared to SCT 400 mg fasted were 96.32%, 95.41% and 88.96% for dose normalized AUC_inf, AUC_last and C_max, respectively. Compared to the exposures of zimlovisertib in the fasted state, the exposures of zimlovisertib increased when administered with high-fat meal. The dose-normalized AUC_inf, AUC_last and C_max of zimlovisertib ECS 100 mg administered with high-fat meal compared to these in fasted state were 127.26%, 125.55% and 240.84%, respectively. Similarly at 400 mg, the dose normalized AUC_inf, AUC_last and C_max of zimlovisertib ECS administered with a high-fat meal compared to these in fasted state were 159.81%, 147.72% and 340.55%, respectively. All treatments were safe and well-tolerated in healthy participants in this study.

Interpretation, Conclusion or Significance: The PK of ECS tablets was comparable to SCT tablets. Administration of ECS tablets with a high fat meal increased the exposure of zimlovisertib and thus administration in fasted state was recommended in efficacy studies.

Disclosures: All authors are employees of Pfizer Inc and may hold stock or stock options.