Evaluation of iberdomide and cytochrome p450 drug-drug interaction potential in vitro and in a phase 1 study in healthy
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PHARMACOKINETICS AND DISPOSITION
Evaluation of iberdomide and cytochrome p450 drug-drug interaction potential in vitro and in a phase 1 study in healthy subjects Allison Gaudy 1 & Christian Atsriku 2 & Ying Ye 1 & Kimberly MacGorman 1 & Liangang Liu 3 & Yongjun Xue 2 & Sekhar Surapaneni 2 & Maria Palmisano 1 Received: 5 May 2020 / Accepted: 16 September 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Purpose Iberdomide is a cereblon E3 ligase modulator capable of redirecting the protein degradation machinery of the cell towards the elimination of target proteins potentially driving therapeutic effects. In vitro studies demonstrated that iberdomide predominantly undergoes oxidative metabolism mediated by cytochrome P450 (CYP) 3A4/5 but had no notable inhibition or induction of CYP enzymes. Consequently, the potential of iberdomide as a victim of drug-drug interactions (DDI) was evaluated in a clinical study with healthy subjects. Methods A total of 33 males and 5 females with 19 subjects per part were enrolled. Part 1 evaluated the pharmacokinetics (PK) of iberdomide alone (0.6 mg) and when administered with the CYP3A and P-gp inhibitor itraconazole (200 mg twice daily on day 1 and 200 once daily on days 2 through 9). Part 2 evaluated the PK of iberdomide alone (0.6 mg) and with CYP3A4 inducer rifampin (600 mg QD days 1 through 13). Plasma concentrations of iberdomide and the active metabolite M12 were determined by validated liquid chromatography-tandem mass spectrometry assay. Results Coadministration of iberdomide with itraconazole increased iberdomide peak plasma concentration (Cmax) 17% and area under the concentration curve (AUC) approximately 2.4-fold relative to administration of iberdomide alone. The Cmax and AUC of iberdomide were reduced by approximately 70% and 82%, respectively, when iberdomide was administered with rifampin compared with iberdomide administered alone. Exploratory assessment of metabolite M12 concentrations demonstrated that CYP3A is responsible for M12 formation. Conclusions Caution should be taken when coadministering iberdomide with strong CYP3A inhibitors. Coadministration of iberdomide with strong CYP3A inducers is not advised. Clinical trial registration Clinical trial identification number is NCT02820935 and was registered in July 2016. Keywords Pharmacokinetics . Drug-drug interaction . Iberdomide . CC-220 . Clinical pharmacology
Introduction Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00228-020-03004-w) contains supplementary material, which is available to authorized users. * Allison Gaudy [email protected] 1
Clinical Pharmacology, Bristol Myers Squibb, Princeton, NJ, USA
2
Nonclinical Development, Bristol Myers Squibb, Princeton, NJ, USA
3
Global Biometrics and Data Sciences, Bristol Myers Squibb, Princeton, NJ, USA
Iberdomide (CC-220) is an orally available immunomodulatory compound under development for the treatment of systemic lupus erythematosus (SLE) and relapsed/ refractory multi
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