Abstract B148: Population pharmacokinetics (PK) of the investigational NEDD8-activating enzyme (NAE) inhibitor pevonedistat (TAK-924/MLN4924) administered alone or in combination with azacitidine in patients (pts) with solid or hematologic malignancies
Authors: Faessel Hélène M. , Mould Diane R. , Dezube Bruce J. , Santillana Sergio , Venkatakrishnan Karthik 
Published: May 2016

Introduction: Pevonedistat is a first-in-class small molecule inhibitor of NAE that is currently in phase 1b clinical development across multiple solid tumors and in acute myeloid leukemia (AML). Here we report a population modeling analysis to describe pevonedistat IV PK in cancer pts and identify potential predictors of interpatient variability in pevonedistat exposures when given alone or combined with azacitidine.

Methods: Plasma concentration-time data were analyzed using nonlinear mixed effects modeling (NONMEM 7.2). Two- and 3-compartment linear disposition with zero-order input models were tested. Subsequently, effects of selected demographic (age, sex, race, and body size) and physiologic (hepatic transaminases, bilirubin, blood parameters, and creatinine clearance [CRCL]) covariates were evaluated. First Order Conditional Estimation method with log transform-both-sides was used. Model goodness-of-fit and performance (visual predictive check and nonparametric bootstrapping) were also assessed.

Results: A total of 250 pts (64% male; 80% white) from 5 completed or ongoing phase 1/1b dose-escalation clinical studies contributed 2882 observations. Of these, 42% were 65 yrs or older and 18% were 75 yrs or older. Half of pts had normal renal function, while 34% and 17% had mild (CRCL 60-89 mL/min) to moderate (CRCL 30-59 mL/min) renal impairment, respectively. Data were described by a 2-compartment PK model parameterized in terms of systemic clearance (CL), intercompartmental clearance (Q), and central (Vc) and peripheral (Vp) volumes of distribution with associated between-subject variability (BSV). Terms describing correlations between BSV for CL, Q, and Vp were included. Body size was described as an allometric function with the effect of body surface area (BSA, range 1.38-3.00 m2) on all parameters. Age (range 19-90 yrs) on CL was included as a power function normalized by the reference age of 65 yrs. Categorical covariates (sex and race) were modeled to estimate the proportional change in the typical value of the PK parameter. Consistent with observations of dose-proportional increases in pevonedistat exposures within each study, CL was constant across doses. Pevonedistat PK was unaffected after daily dosing with azacitidine in pts with AML. Final population mean parameter estimates (95% bootstrap confidence interval [CI]) were CL = 29.0 L/h (25.8, 32.7); Vc = 93.5 L (79.1, 110); Vp = 107 L (99.3, 115); and Q = 20.1 L/h (18.3, 22.2). Proportional residual variability was 28%. Upon exploration of patient-specific covariate effects, body size influenced CL (interindividual variability [IIV] ∼25% CV) and volume of distribution (IIV∼22% CV). Pevonedistat CL tended to gradually decrease with age (∼25% over the 30-90 yrs age range). There was no apparent effect of renal function status (CRCL &gt;30 mL/min) on pevonedistat PK.

Conclusions: The clinical PK profile of pevonedistat is comparable in pts with solid tumors, lymphomas, or AML. No changes were observed in the presence of azacitidine when compared to historical single-agent data. Elderly pts may have reduced pevonedistat CL; additional monitoring of these pts is recommended.

Citation Format: Hélène M. Faessel, Diane R. Mould, Bruce J. Dezube, Sergio Santillana, Karthik Venkatakrishnan. Population pharmacokinetics (PK) of the investigational NEDD8-activating enzyme (NAE) inhibitor pevonedistat (TAK-924/MLN4924) administered alone or in combination with azacitidine in patients (pts) with solid or hematologic malignancies. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B148.