(M-033) Population Pharmacokinetic Analysis of Possible Drug-Drug Interactions between Mouse Double Minute 2 (MDM2) Inhibitor Navtemadlin and the Bruton's Tyrosine Kinase (BTK) Inhibitor Acalabrutinib in Patients with R/R CLL or R/R DLBCL
Monday, October 20, 2025
7:00 AM - 5:00 PM MDT
Location: Colorado A
Shuang Xu – Certara Inc.; Bill Poland – Certara Inc.; Martine Allard – Kartos Therapeutics; Terry Podoll – Kartos Therapeutics; J. Greg Slatter – Kartos Therapeutics
Objectives: Navtemadlin is a potent, selective, oral MDM2 inhibitor that restores p53 function. In vitro, navtemadlin is a weak, mixed inducer and mechanism-based inhibitor of CYP3A. A physiologically based pharmacokinetic (PK) model estimated that navtemadlin dosed at 240 mg once daily (QD) on Day 1-7 of 28-day cycles could increase the AUC of sensitive CYP3A substrate midazolam in a clinically insignificant manner ( < 1.25-fold) [1].
Acalabrutinib, a covalent BTK inhibitor, is metabolized mainly by CYP3A to active metabolite ACP-5862. Co-administration of acalabrutinib with strong CYP3A inhibitor itraconazole increased AUC by 5.1-fold, indicating acalabrutinib is a sensitive CYP3A substrate [2]. Acalabrutinib is unlikely to perpetrate a drug-drug interaction (DDI) on navtemadlin.
A navtemadlin/acalabrutinib combination study was conducted in patients with Relapsed/Refractory Diffuse Large B-cell Lymphoma (R/R DLBCL) and R/R Chronic Lymphocytic Leukemia (R/R CLL) (NCT04502394). This population PK (PPK) analysis evaluated effects of navtemadlin on acalabrutinib exposure and vice versa.
Methods: Acalabrutinib 100 mg twice daily was combined with navtemadlin dosed at 120, 240, 300 or 360 mg QD on Day 1-7 of 28-day cycles. Patients with DLBCL (N=22) and CLL (N=27) provided 951 navtemadlin and 847 acalabrutinib/ACP-5862 plasma concentrations.
A navtemadlin PPK model [3] was updated with PK from DLBCL/CLL patients. An acalabrutinib/ACP-5862 PPK model [4] was implemented in NONMEM. PPK models were evaluated with standard diagnostic plots. Post hoc individual PK parameters were used to simulate steady-state (SS) exposures for navtemadlin and acalabrutinib/ACP-5862. To compare combination study PK with monotherapy, geometric mean ratios (GMRs) and 90% confidence intervals (90% CI) were calculated.
Results: The navtemadlin PPK model (N=434) adequately fit the PK data from combination patients. DLBCL patients had similar exposure to myelofibrosis and AML patients, higher than patients with solid tumors, MM, and CLL. The difference in SS exposure between DLBCL and CLL patients was not significant (ns). The effect of acalabrutinib on navtemadlin exposure was ns compared to monotherapy, with GMRs [90% CI] of 107.8% [97.4%-119.4%] for AUCss and 119.8% [108.4%-132.3%] for Cmax.
Acalabrutinib and ACP-5862 concentrations were analyzed using the PPK model, which adequately fit the individual PK data. Model-predicted SS exposures were compared between a simulated acalabrutinib monotherapy population (N=10,000) and combination therapy results. The GMR [90% CI] for acalabrutinib PK, when combined with navtemadlin, was 1.27 [1.11-1.44, p=0.005] for AUC0-12, and 1.18 [1.01-1.39, ns] for Cmax. The ACP-5862 GMRs were 1.20 [1.06-1.35, p=0.022] for AUC0-12 and 1.09 [0.95-1.24, ns] for Cmax. There was a significant upward trend of acalabrutinib exposure with navtemadlin dose.
Conclusions: PK data in DLBCL/CLL patients were modeled to assess effects of navtemadlin on acalabrutinib, a sensitive CYP3A substrate. Acalabrutinib and ACP-5862 exposure GMRs of < 1.3 indicate that navtemadlin is unlikely to perpetrate a clinically meaningful DDI on sensitive CYP3A substrates.
Citations: [1] Templeton IE, Podoll T, Krejsa C, Slatter JG. A Mechanistic Physiologically Based Pharmacokinetic (PBPK) Drug Interaction Model for the Mouse Double Minute 2 (MDM2) Inhibitor KRT-232. Blood (2020) 136 (Supplement 1):9-10.
[2] Calquence® (acalabrutinib) Prescribing Information 6/2024.
[3] Zhang L, Poland B, Xu S, Allard M, Krejsa C, Slatter JG. Population Pharmacokinetic and Pharmacodynamic Analysis of Navtemadlin in Patients with Relapsed and Refractory (R/R) Myelofibrosis (MF) and Other Myeloid or Solid Tumor Malignancies. Blood (2023) 142 (Supplement 1): 5755.
[4] Edlund H, Bellanti F, Liu H, et al. Improved characterization of the pharmacokinetics of acalabrutinib and its pharmacologically active metabolite, ACP-5862, in patients with B-cell malignancies and in healthy subjects using a population pharmacokinetic approach. Br J Clin Pharmacal. 2022 Feb;88(2):846-852.
