Results Inhibition of CYP3a4 by ketoconazole increased midostaurin exposure more than tenfold, and induction of CYP3a4 by rifampicin decreased midostaurin exposure by more than tenfold. Midostaurin did not appreciably affect the concentrations of midazolam or its metabolite, 1′-hydroxymidazolam, at single or multiple doses. Conclusion the pharmacokinetics of midostaurin and its metabolites was affected substantially by ketoconazole and rifampicin, suggesting that midostaurin is a sensitive CYP3a4 substrate. Midostaurin did not appear to inhibit or induce CYP3a4 in vivo.
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.
PurposeMidostaurin (PKC412) is a multitargeted tyrosine kinase inhibitor of FMS-like tyrosine kinase 3 receptor (FLT3), c-KIT, and other receptors. Midostaurin is active in patients with acute myeloid leukemia and systemic mastocytosis. Although no substantive risk for cardiac abnormalities has been observed with midostaurin in clinical studies thus far, some TKIs have been shown to affect cardiac repolarization. Here we evaluated midostaurin’s effect on cardiac repolarization.MethodsThis phase I study evaluated the effect of midostaurin (75 mg twice daily for 2 days; 75 mg once on day 3) on the heart rate–corrected QT (QTc) interval in a parallel design with active (moxifloxacin) and placebo control arms in healthy volunteers.ResultsThe maximum mean QTc change from baseline corrected using Fridericia’s correction (QTcF) for midostaurin compared with placebo was 0.7 ms at 24 h post dose on day 3. The highest upper bound of the 1-sided 95% CI was 4.7 ms, which excluded 10 ms, demonstrating a lack of QTcF prolongation effect. Assay sensitivity was demonstrated by modeling the moxifloxacin plasma concentration versus QTcF change from baseline, which showed a clear positive increase in QTcF with increasing moxifloxacin plasma concentrations, as expected based on previous studies. In the 4-day evaluation period, a minority of participants (34.6%) experienced an adverse event; 97.0% were grade 1. No grade 3 or 4 adverse events were reported.ConclusionMidostaurin demonstrated a good safety profile in healthy volunteers, with no prolonged cardiac repolarization or other changes on the electrocardiogram.Electronic supplementary materialThe online version of this article (doi:10.1007/s00280-012-1825-y) contains supplementary material, which is available to authorized users.
Asciminib (Scemblix) is a first-in-class BCR::ABL1 inhibitor that works by specifically targeting the ABL myristoyl pocket (STAMP) and has potent activity against the T315I mutation. This study aimed to characterize the effect of asciminib exposure on disease progression and to elucidate factors influencing efficacy. Our analysis included 303 patients with chronic myeloid leukemia in chronic phase recruited in a phase I study with dose ranging from 10 to 200 mg twice a day (b.i.d.) or 40 to 200 mg once a day (q.d.) (NCT02081378) and in the phase III ASCEMBL (Study of Efficacy of CML-CP Patients Treated With ABL001 Versus Bosutinib, Previously Treated With 2 or More TKIs) study receiving asciminib 40 mg b.i.d. (NCT03106779). A total of 67 patients harbored the T315I mutation. A longitudinal pharmacokinetic/pharmacodynamic model was developed to characterize the exposure-efficacy relationship, in which the efficacy was assessed through BCR::ABL1 transcript levels over time. Specifically, a three-compartment model representing quiescent leukemic stem cells, proliferating bone marrow cells, and resistant cells was developed. Drug killing of the proliferating cells by asciminib was characterized by a power model. A subgroup analysis was performed on the patients with the T315I mutation using a maximum drug effect model to characterize the drug effect. The model demonstrated the appropriateness of a total daily dose of asciminib 80 mg in patients without the T315I mutation and 200 mg b.i.d. in patients with the T315I mutation with further validation in light of safety data. This model captured key characteristics of patients' response to asciminib and helped inform dosing rationale for resistant and difficult-to-treat populations.Chronic myeloid leukemia (CML) is driven by the constitutively active ABL1 tyrosine kinase domain of BCR::ABL1, 1 and studies have shown that BCR::ABL1 transcript levels are correlated with long-term outcomes to tyrosine kinase inhibitors (TKIs) among patients with CML. 2,3 Therefore, BCR::ABL1 and its derived major molecular response (MMR) rate (proportion of patients with BCR::ABL1 ≤ 0.1%), used in phase III studies as a primary end point, is an established surrogate marker to evaluate
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