Ziftomenib Population PK Simulator
Explore ziftomenib exposure after oral dosing in relapsed/refractory NPM1-mutated AML, including food, PPI, strong CYP3A4 inhibitor, healthy volunteer, and active metabolite scenarios.
Published model
Mitra et al. 2026, CPT:PSP
Recommended dose
600 mg once daily
Model family
2-compartment parent + linked metabolites
What this ziftomenib simulator models
The model describes ziftomenib and the KO-739 / KO-516 metabolites using an oral absorption model for the parent drug plus linked two-compartment disposition for each metabolite. It is designed for scientific exploration of exposure trends rather than individual clinical dosing.
| Feature | Model value | Interpretation |
|---|---|---|
| Model structure | 2-compartment oral parent model | First-order absorption with lag time and first-order elimination |
| Bioavailability | F1 = 0.129 | Food increases F1 ~6.09-fold; PPI multiplier 0.627 |
| Absorption | Ka = 0.0928 h⁻¹; lag = 0.325 h | PPI lowers Ka; fed state increases lag time |
| Parent clearance | CL = 11.6 L/h | Strong CYP3A4 inhibitor multiplier 0.459 |
| Distribution | Vc = 54.6 L; Q = 27.7 L/h; Vp = 1106 L | Large peripheral volume consistent with extensive distribution |
| Metabolites | KO-739 and KO-516 | Sequential linked metabolite exposure simulated with separate 2-compartment kinetics |
Built for clinically relevant scenarios
600 mg once daily
Supported dose in adult R/R NPM1-mutated AML patients
Fed vs fasted
Explore bioavailability and absorption lag effects
Proton pump inhibitor
Explore lower F1 and Ka assumptions from the published model
Strong CYP3A4 inhibitor
Explore parent and metabolite clearance changes
Healthy volunteer vs AML patient
Compare population setting effects on clearance and metabolite parameters
Why ziftomenib PK matters
Ziftomenib targets the menin-KMT2A interaction, a disease-relevant transcriptional dependency in NPM1-mutated AML. For an oral targeted oncology therapy, understanding exposure under food, acid-reducing agent, and CYP3A4 inhibitor conditions is central to dose selection and clinical pharmacology strategy.
The published Mitra et al. analysis reported flat exposure-response profiles across evaluated efficacy and safety endpoints over the studied exposure range, supporting a wide therapeutic margin and the 600 mg once-daily dose in adult R/R NPM1-mutated AML.
Educational/research use only. Not intended for patient-specific treatment decisions.
Frequently asked questions
What is ziftomenib?
Ziftomenib is an oral, highly selective menin inhibitor being developed for genetically defined acute myeloid leukemia, including relapsed/refractory NPM1-mutated AML. Menin inhibition disrupts the menin-KMT2A interaction and downstream leukemogenic transcriptional programs.
What dose does the simulator focus on?
The landing page and simulator emphasize 600 mg once daily, the dose supported by the Mitra et al. population PK and exposure-response analysis for adult relapsed/refractory NPM1-mutated AML patients.
Does ziftomenib require dose adjustment with azole antifungals?
In the published exposure-response analysis, antifungal azoles had no clinically meaningful impact on efficacy or safety profiles, supporting co-administration without dose adjustment in the studied population. This simulator is for research and education, not individual clinical dosing.
What does the PK model include?
The simulator uses a 2-compartment parent ziftomenib model with first-order absorption, lag time, and linked KO-739 and KO-516 metabolite compartments. It includes covariate switches for food, PPI use, strong CYP3A4 inhibition, and healthy volunteer versus AML patient population.
Reference
Mitra A, Yang X, Ortiz RH, Jomphe C, Leoni M, Gosselin NH. Population Pharmacokinetics and Exposure-Response Analysis of Ziftomenib in Relapsed or Refractory Acute Myeloid Leukemia Patients With NPM1 Mutation. CPT: Pharmacometrics & Systems Pharmacology. 2026;15:e70244.