Investigation into CYP3A4-mediated drug–drug interactions on midostaurin in healthy volunteers

Dutreix, Catherine; Munarini, Florence; Lorenzo, Sebastien; Roesel, Johannes; Wang, Yanfeng

doi:10.1007/s00280-013-2287-6

Cited by 75 publications

(81 citation statements)

References 20 publications

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“…The non-linear pharmacokinetics of CGP62221 follows the same pattern as that of midostaurin, whereas the second metabolite, CGP52421, rises over time until reaching steady-state concentrations after one month of daily treatment (33)(34)(35)(36)(37). Our data show that CGP52421 is less effective in producing growth inhibition and apoptosis in neoplastic MC when compared to midostaurin.…”

Section: Discussionmentioning

confidence: 55%

“…A remarkable phenomenon is that even in patients who have resistant disease or relapse, mediator-related symptoms improve or disappear during therapy (30). treatment, followed by a significant decrease, before reaching a stable plateau after 3-4 weeks (33)(34)(35)(36)(37). The drug has two active metabolites (Supplementary Figure S1), which result from cytochrome CYP3A4-mediated oxidation of the parent-drug (36,37).…”

Section: Introductionmentioning

confidence: 99%

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Target interaction profiling of midostaurin and its metabolites in neoplastic mast cells predicts distinct effects on activation and growth

et al. 2015

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Proteomic-based drug testing is an emerging approach to establish the clinical value and antineoplastic potential of multi-kinase inhibitors. The multikinase inhibitor midostaurin (PKC412) is a promising new agent used to treat patients with advanced systemic mastocytosis (SM). We examined the target interaction-profiles and the mast cell (MC)-targeting effects of two pharmacologically relevant midostaurin metabolites, CGP52421 and CGP62221. All three compounds, midostaurin and the two metabolites, suppressed IgE-dependent histamine secretion in basophils and MC with reasonable IC 50 values. Midostaurin and CGP62221 also produced growth-inhibition and dephosphorylation of KIT in the MC leukemia cell line HMC-1.2, whereas the second metabolite, CGP52421, that accumulates in vivo, showed no substantial effects.Chemical proteomic profiling and drug-competition experiments revealed that midostaurin interacts with KIT and several additional kinase-targets. The key downstream-regulator FES was recognized by midostaurin and CGP62221, but not by CGP52421 in MC lysates, whereas the IgEreceptor-downstream target SYK was recognized by both metabolites. Together, our data show that the clinically relevant midostaurin metabolite CGP52421 inhibits IgE-dependent histamine release, but is a weak inhibitor of MC proliferation which may have clinical implications and may explain why mediator-related symptoms improve in SM patients even when disease progression occurs.

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Section: Discussionmentioning

confidence: 55%

Section: Introductionmentioning

confidence: 99%

Target interaction profiling of midostaurin and its metabolites in neoplastic mast cells predicts distinct effects on activation and growth

et al. 2015

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“…The selected study set consisted of 53 separate DDI studies taken from 46 publications between 2005 and 2015, which included 971 subjects with systemic ketoconazole exposure (Table ). A majority of the studies were conducted at study centers in the United States and Germany (Table ).…”

Section: Resultsmentioning

confidence: 99%

Ketoconazole‐Associated Liver Injury in Drug‐Drug Interaction Studies in Healthy Volunteers

Banankhah

Garnick

Greenblatt

2016

The Journal of Clinical Pharma

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Ketoconazole is a potent CYP3A inhibitor in vivo, and frequently serves as an index CYP3A inhibitor in drug-drug interaction (DDI) studies with healthy volunteers. Limitations restricting the use of systemic ketoconazole in such studies have been recently imposed by regulatory agencies in the United States, the European Union, and elsewhere. A risk of ketoconazole-associated liver injury in the context of DDI studies was cited as the primary justification for these measures. To evaluate the basis for these restrictions, we analyzed a series of published DDI studies identified from a review of existing literature. The study set consisted of 53 DDI studies, and included 971 healthy volunteers with systemic ketoconazole exposure in addition to the victim drug under study. Ketoconazole-associated abnormalities in serum chemistry values indicative of liver injury were observed in 4 subjects, representing a prevalence of 0.41% within the study population. There were no major adverse reactions or instances of hepatic failure. All abnormalities indicative of liver injury resolved upon discontinuation of ketoconazole treatment. The findings from this review do not support restriction of ketoconazole as an index CYP3A inhibitor in DDI studies involving healthy volunteers.

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“…Previously, we assessed plasma 4βHC level and urinary 6βCR in the rifampicin induction part of a drug–drug interaction study [20]. The goals of this analysis were to further evaluate the dynamic range of these biomarkers upon strong induction with rifampicin and to compare and evaluate whether these biomarkers can serve as covariates to explain intersubject variability of midostaurin pharmacokinetics in a clinical setting.…”

Section: Introductionmentioning

confidence: 99%

Comparison of two endogenous biomarkers of CYP3A4 activity in a drug–drug interaction study between midostaurin and rifampicin

Dutreix

Lorenzo

Wang

2014

Eur J Clin Pharmacol

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PurposeMidostaurin, a multitargeted tyrosine kinase inhibitor, is primarily metabolized by CYP3A4. This midostaurin drug–drug interaction study assessed the dynamic response and clinical usefulness of urinary 6β-hydroxycortisol to cortisol ratio (6βCR) and plasma 4β-hydroxycholesterol (4βHC) for monitoring CYP3A4 activity in the presence or absence of rifampicin, a strong CYP3A4 inducer.MethodsForty healthy adults were randomized into groups for either placebo or treatment with rifampicin 600 mg QD for 14 days. All participants received midostaurin 50 mg on day 9. Midostaurin plasma pharmacokinetic parameters were assessed. Urinary 6βCR and plasma 4βHC levels were measured on days 1, 9, 11, and 15.ResultsBoth markers remained stable over time in the control group and increased significantly in the rifampicin group. In the rifampicin group, the median increases (vs day 1) on days 9, 11, and 15 were 4.1-, 5.2-, and 4.7-fold, respectively, for 6βCR and 3.4-, 4.1-, and 4.7-fold, respectively, for 4βHC. Inter- and intrasubject variabilities in the control group were 45.6 % and 30.5 %, respectively, for 6βCR, and 33.8 % and 7.5 %, respectively, for 4βHC. Baseline midostaurin area under the concentration–time curve (AUC) correlated with 4βHC levels (ρ = −0.72; P = .003), but not with 6βCR (ρ = 0.0925; P = .6981).ConclusionsBoth 6βCR and 4βHC levels showed a good dynamic response range upon strong CYP3A4 induction with rifampicin. Because of lower inter- and intrasubject variability, 4βHC appeared more reliable and better predictive of CYP3A4 activity compared with 6βCR. The data from our study further support the clinical utility of these biomarkers.Electronic supplementary materialThe online version of this article (doi:10.1007/s00228-014-1675-0) contains supplementary material, which is available to authorized users.

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Investigation into CYP3A4-mediated drug–drug interactions on midostaurin in healthy volunteers

Cited by 75 publications

References 20 publications

Target interaction profiling of midostaurin and its metabolites in neoplastic mast cells predicts distinct effects on activation and growth

Target interaction profiling of midostaurin and its metabolites in neoplastic mast cells predicts distinct effects on activation and growth

Ketoconazole‐Associated Liver Injury in Drug‐Drug Interaction Studies in Healthy Volunteers

Comparison of two endogenous biomarkers of CYP3A4 activity in a drug–drug interaction study between midostaurin and rifampicin

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