(W-119) Population pharmacokinetics of revumenib in patients with relapsed/refractory acute leukemias

Yu-Wei Lin, PhD – Director of Pharmacometrics, Certara; Steven Smith, BS – Consultant, Syndax Pharmaceuticals, Inc.; Enoch Cobbina, PhD – Director, Clinical Pharmacology, Syndax Pharmaceuticals, Inc.; S.Y. Amy Cheung, PhD – Vice President, Certara; Nicole McNeer, MD, PhD – Executive Medical Director & Clinical Leader, Syndax Pharmaceuticals, Inc.; Gary Maier, PhD – President and Founder, MaierMetrics and Associates LLC; Peter Ordentlich, PhD – Chief Scientific Officer, Syndax Pharmaceuticals, Inc.

Objectives: Revumenib, a selective, orally bioavailable small molecule inhibitor of the menin-lysine methyltransferase 2A (KMT2A) interaction is under investigation in patients with acute leukemias.¹ Clinical pharmacology of revumenib has been determined in clinical, modeling, and simulation studies. Here, we report the results of PopPK analyses assessing the effects of potential covariates on revumenib exposure.

Methods: AUGMENT-101 Phase 1/2 [NCT04065399] evaluated revumenib in adult and pediatric populations with acute leukemias.¹ Revumenib was administered orally twice daily (BID) in a 28-day cycle via capsule, tablet, or oral solution. A PopPK model was developed using AUGMENT-101 study data. First-order conditional estimation was used with interaction in NONMEM (v7.4.3). Monte-Carlo simulations were conducted in 1000 virtual patients to support dose and regimen justification.

Results: A total of 251 patients had evaluable PK data, consisting of 4,869 revumenib plasma concentrations. Exposures were similar between capsules, tablets, and oral solution. PopPK analysis showed, after taking body weight effect into account, there were no clinically significant differences in the PK for age (9 months–82 years), race, gender, ethnicity, and in patients with body weights of 40-146 kg; differences were observed in patients with < 40 kg (~30–58%), thus dosing in these patients is per body surface area (BSA). Markers of hepatic function (ALT, AST, albumin, bilirubin) had no clinically significant effect on PK; thus, no dose adjustment is recommended for patients with mild or moderate hepatic impairment. Markers of renal function (i.e., serum creatinine) had no clinically significant effect on PK, thus no dose adjustment is recommended for patients with mild or moderate renal impairment. Co-administration with a strong CYP3A4 inhibitor (CYP3A4i) increases plasma concentrations, therefore the dose should be reduced when taken with a strong CYP3A4i. There was minimal effect of a low-fat meal, thus revumenib can be taken fasted or with a low-fat meal.

Conclusions: The clinical pharmacology profile of revumenib has been well characterized in adult and pediatric populations with R/R acute leukemias. There was no clinically meaningful impact of intrinsic factors on revumenib PK except in patients with body weight < 40 kg, hence a BSA adjusted dosing is proposed. Strong CYP3A4i increases plasma concentrations, hence a dose reduction is proposed. Revumenib can be administered under fasted or with a low-fat meal. Pediatric patients and those who cannot swallow a tablet may substitute for the oral solution, as the PK is equivalent.

Citations: [1] Issa GC, et al. Nature. 2023;615:920–24.