Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction

Potential pharmacodynamic interactions
Co-administration of osilodrostat with other therapies known to affect the QT interval can lead to QT prolongation in patients with known cardiac rhythm disorders (see sections 4.4 and 5.1). A washout period should be considered when switching from other products known to affect the QT interval such as pasireotide or ketoconazole.

Effects of other medicinal products on the pharmacokinetics of osilodrostat 
The potential for clinical drug-drug interactions (DDI) with concomitantly administered medicinal products that inhibit transporters or a single CYP or UGT enzyme is low (see section 5.2).

Strong enzyme inhibitors
Caution is advised when co-administered medicinal products that strongly inhibit multiple enzymes are introduced or discontinued during osilodrostat treatment (see section 4.4).

Strong enzyme inducers
Caution is advised when co-administered medicinal products that strongly induce multiple enzymes (e.g. rifampin) are introduced or discontinued during osilodrostat treatment (see section 4.4).

Effects of osilodrostat on the pharmacokinetics of other medicinal products 
Because osilodrostat and its major metabolite M34.5 may inhibit and/or induce multiple enzymes and transporters, general caution is advised when osilodrostat is co-administered with sensitive enzyme or transporter substrates with a narrow therapeutic index. Available interaction data is summarised below (see also section 5.2).

Clinical studies
In a healthy volunteer study (n=20) using a single dose of 50 mg osilodrostat and a probe drug cocktail, osilodrostat was found to be a mild inhibitor of CYP2D6 and CYP3A4/5, a mild to moderate inhibitor of CYP2C19, and a moderate inhibitor of CYP1A2.
-      CYP2D6 – AUC geometric mean ratio of 1.5 for dextromethorphan (CYP2D6 substrate) when dosed with osilodrostat compared to when dosed alone.

-     CYP3A4 – AUC geometric mean ratio of 1.5 for midazolam (CYP3A4 substrate) when dosed with osilodrostat compared to when dosed alone.
-     CYP2C19 –AUC geometric mean ratio of 1.9 for omeprazole (CYP2C19 substrate) when dosed with osilodrostat compared to when dosed alone. However, an in vitro signal of time-dependent inhibition has been observed, thus the consequence following repeated dosing is unclear.
Osilodrostat should be used with caution when co-administered with sensitive CYP2C19 substrates with a narrow therapeutic index.
-     CYP1A2 –AUC geometric mean ratio of 2.5 for caffeine (CYP1A2 substrate) when dosed with osilodrostat compared to when dosed alone. However, an in vitro signal of CYP1A2 induction has been observed, thus the consequence following repeated dosing is unclear. Osilodrostat should be used with caution when co-administered with sensitive CYP1A2 substrates with a narrow therapeutic index such as theophylline and tizanidine.

In a healthy volunteer study (n=24), osilodrostat (30 mg twice daily for 7 days before concomitant administration with a combined oral contraceptive containing 0.03 mg ethinyl oestradiol and 0.15 mg levonorgestrel and continued for another 5 days) did not have a clinically meaningful effect on the AUC and Cmax of ethinyl estradiol (geometric mean ratio: 1.03 and 0.88, respectively) and AUC of levonorgestrel (geometric mean ratio: 1.02). The Cmax of levonorgestrel fell slightly outside the bioequivalence acceptance range (geometric mean ratio: 0.86; 90% confidence interval : 0.737-1.00).
The effects of a longer induction period and an interaction with other hormonal contraceptives have not been studied (see also sections 4.4 and 4.6).

In vitro data
In vitro data for osilodrostat and its major metabolite M34.5 suggest a potential for both inhibition and induction for CYP1A2, CYP2B6 and CYP3A4/5, a potential for time-dependent inhibition of CYP2C19, and an inhibitory potential for CYP2E1 and UGT1A1. It cannot be excluded that osilodrostat may affect the exposure of sensitive substrates for these enzymes.

In vitro data for osilodrostat and its major metabolite M34.5 suggest an inhibitory potential for OATP1B1, OCT1, OCT2, OAT1, OAT3 and MATE1. It cannot be excluded that osilodrostat may affect the exposure of sensitive substrates for these transporters.