Key result
Ketoconazole coadministration increases omecamtiv mecarbil AUC up to ~51% without clinically significant drug interactions.
Why the study?
Omecamtiv mecarbil is under development for heart failure, requiring assessment of how CYP3A4 and CYP2D6 inhibition affects its pharmacokinetics and its potential to induce CYP3A4.
Does coadministration of CYP3A4/CYP2D6 inhibitors or substrates affect the pharmacokinetics of omecamtiv mecarbil or midazolam in healthy subjects?
Does coadministration of CYP3A4/CYP2D6 inhibitors or substrates affect the pharmacokinetics of omecamtiv mecarbil or midazolam in healthy subjects?
CYP3A4 and CYP2D6 inhibitors do not have a clinically significant effect on omecamtiv mecarbil pharmacokinetics, and omecamtiv mecarbil does not significantly affect CYP3A4 substrates.
Supports minimal DDI risk with CYP3A4/CYP2D6 modulators; leaves open effects in heart failure patients.
Omecamtiv mecarbil (OM) is a cardiac myosin activator under development for the treatment of heart failure. The effect of CYP3A4 and CYP2D6 inhibition on OM pharmacokinetics and the potential for OM to induce CYP3A4 was assessed in 2 studies. Study 1, part A, assessed the effect of ketoconazole 200 mg on the pharmacokinetics of OM 10 mg in CYP2D6 extensive metabolizers (EMs; n = 8) or poor metabolizers (PMs; n = 8). Study 1, part B, assessed the effect of diltiazem 240 mg on the pharmacokinetics of OM 10 mg (EM; n = 8). Study 2 assessed the effect of OM 25 mg on the pharmacokinetics of midazolam 5 mg (n = 14). Coadministration with ketoconazole led to 51% and 31% increases in OM AUC inf in EM and PM subjects, respectively, whereas OM C max remained similar (3% higher and 14% lower for EM and PM subjects, respectively). No changes in OM pharmacokinetics were observed in EM subjects following coadministration with diltiazem. Midazolam AUC inf and C max decreased by 18% and 10%, respectively, when coadministered with OM. In conclusion, CYP3A4 and CYP2D6 inhibitors are unlikely to have a clinically significant effect on the pharmacokinetics of OM. In addition, OM is unlikely to have a clinically relevant effect on the pharmacokinetics of CYP3A4 substrates.
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Trivedi et al. (2021) studied Healthy subjects (n=38). Omecamtiv mecarbil vs. Ketoconazole, diltiazem, or midazolam was evaluated on Pharmacokinetics (AUC and Cmax) of omecamtiv mecarbil and midazolam. Omecamtiv mecarbil coadministration with ketoconazole increased OM AUC by 51% and 31% in CYP2D6 extensive and poor metabolizers, respectively, without clinically significant drug-drug interactions.
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