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TIMM October 20-23, 2023

Global DDI Solutions

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The edition of TIMM 2023 was held in Athens Greece. A couple of interesting presentations about drug-drug interactions (DDIs) are summarized in this post.

Potential drug-drug interactions of antifungal prophylaxis and midostaurin in FLT3-mutated acute myeloid leukemia – clinical implications of therapeutic drug monitoring

Joisten et al.

The aim of this study is to determine the clinical relevance of the drug-drug interaction (DDI) between midostaurin and posaconazole. Midostaurin is a FLT3-inhibitor (inhibitor of a cytokinereceptor in the liver) and used in treatment of acute myeloid leukemia. It is metabolized by CYP3A4 and is therefore a potential victim of a DDI. Posaconazole is used in these patients for prophylaxis of invasive fungal disease and is a strong inhibitor of CYP3A4.

In this study, blood trough concentrations of midostaurin and posaconazole and occurred adverse reactions were determined. From 24 patients twice-weekly trough concentrations were measured. A greater inter- and intra-variability was found ranged from <0.01 mg/l to 24.5 mg/l for midostaurin and from <30 µg/l to 2571 µg/l for posaconazole, respectively. Five patients had excessively high midostaurin concentrations over 15 mg/L.

In addition, exanthema was determined as possible related adverse event of midostaurin toxicity and prolonged QTc interval, perimyocarditis, hyperbilirubinemia/liver cell necrosis, diarrhea and nausea were determined as probably related adverse event. Which can be explained by the high concentrations of midostaurin.

In conclusion, midostaurin and posaconazole is a clinical relevant DDI. Therapeutic drug monitoring can be used for decision-making dose adjustment of both drugs and reducing toxicity of midostaurin.

Physiological-based pharmacokinetic analysis of drug–drug interactions between isavuconazole and vincristine in pediatric subjects

Choules et al.

In this study, the influence of isavuconazole on vincristine is researched in pediatric cancer population. Vincristine is used for treatment of leukemia in pediatric. Secondary, fungal infections are common in this patient population. These infections are treated with isavuconazole. Known is that isavuconazole is a moderate inhibitor of CYP3A4, inducer of CYP2B6 and potential inhibitor of P-gp and OCT-2 transporter. On the other hand, vincristine is metabolized by CYP3A4 and excreted in biliary by P-gp. The combination of isavuconazole and vincristine is potential for a DDI.

A PBPK model for isavuconazole and vincristine in pediatric cancer population was built in Simcyp©. This model can predict the vincristine exposure when coadministered with isavuconazole. The dose regimen started with a loading dose of isavuconazole. After 12 hours the maintenance dose regimen of isavuconazole daily was given. Vincristine was coadministered at day 5. This model predicted a geometric mean AUC ratio of vincristine coadministered with isavuconazole ranged from 1.54- to 1.69-fold depending on the dosing scheme. The largest magnitude of DDI was predicted when a dose of 372 mg of isavuconazole was administered. No effect was predicted on the geometric mean of Cmax ratio.

In conclusion, isavuconazole is a weak inhibitor when coadministered with vincristine in pediatric cancer population. A slight increase in vincristine exposure can be expected when vincristine is coadministered with isavuconazole.