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Erschienen in: Cancer Chemotherapy and Pharmacology 5/2020

25.09.2020 | Original Article

Physiologically based pharmacokinetic modeling and simulation to predict drug–drug interactions of ivosidenib with CYP3A perpetrators in patients with acute myeloid leukemia

verfasst von: Chandra Prakash, Bin Fan, Alice Ke, Kha Le, Hua Yang

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 5/2020

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Abstract

Purpose

Develop a physiologically based pharmacokinetic (PBPK) model of ivosidenib using in vitro and clinical PK data from healthy participants (HPs), refine it with clinical data on ivosidenib co-administered with itraconazole, and develop a model for patients with acute myeloid leukemia (AML) and apply it to predict ivosidenib drug–drug interactions (DDI).

Methods

An HP PBPK model was developed in Simcyp Population-Based Simulator (version 15.1), with the CYP3A4 component refined based on a clinical DDI study. A separate model accounting for the reduced apparent oral clearance in patients with AML was used to assess the DDI potential of ivosidenib as the victim of CYP3A perpetrators.

Results

For a single 250 mg ivosidenib dose, the HP model predicted geometric mean ratios of 2.14 (plasma area under concentration–time curve, to infinity [AUC0-∞]) and 1.04 (maximum plasma concentration [Cmax]) with the strong CYP3A4 inhibitor, itraconazole, within 1.26-fold of the observed values (2.69 and 1.0, respectively). The AML model reasonably predicted the observed ivosidenib concentration–time profiles across all dose levels in patients. Predicted ivosidenib geometric mean steady-state AUC0-∞ and Cmax ratios were 3.23 and 2.26 with ketoconazole, and 1.90 and 1.52 with fluconazole, respectively. Co-administration of the strong CYP3A4 inducer, rifampin, predicted a greater DDI effect on a single dose of ivosidenib than on multiple doses (AUC ratios 0.35 and 0.67, Cmax ratios 0.91 and 0.81, respectively).

Conclusion

Potentially clinically relevant DDI effects with CYP3A4 inducers and moderate and strong inhibitors co-administered with ivosidenib were predicted. Considering the challenges of conducting clinical DDI studies in patients, this PBPK approach is valuable in ivosidenib DDI risk assessment and management.
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Metadaten
Titel
Physiologically based pharmacokinetic modeling and simulation to predict drug–drug interactions of ivosidenib with CYP3A perpetrators in patients with acute myeloid leukemia
verfasst von
Chandra Prakash
Bin Fan
Alice Ke
Kha Le
Hua Yang
Publikationsdatum
25.09.2020
Verlag
Springer Berlin Heidelberg
Erschienen in
Cancer Chemotherapy and Pharmacology / Ausgabe 5/2020
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-020-04148-3

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