Drug Interactions between isavuconazonium and ropivacaine / sufentanil

MONITOR: Coadministration with isavuconazonium sulfate (prodrug of isavuconazole) may increase the plasma concentrations of drugs that are substrates of CYP450 3A4 and/or P-glycoprotein (P-gp). The mechanism is decreased clearance due to inhibition of CYP450 3A4 activity and/or P-gp-mediated efflux of these drugs by isavuconazole. In pharmacokinetic studies, isavuconazole increased the systemic exposure (AUC) of sensitive CYP450 3A4 substrates midazolam, sirolimus, and tacrolimus by approximately 2-fold, thus it can be considered a moderate inhibitor of the isoenzyme.

MANAGEMENT: Caution is advised when isavuconazonium sulfate is used concomitantly with drugs that are substrates of the CYP450 3A4 isoenzyme or the P-gp transport protein, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever isavuconazonium sulfate is added to or withdrawn from therapy.

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Coadministration with inhibitors of CYP450 3A4 may modestly increase the plasma concentrations of ropivacaine. Although ropivacaine is primarily metabolized by CYP450 1A2, it has been shown to undergo some metabolism via CYP450 3A4. In eight healthy volunteers, pretreatment with the 3A4 inhibitor erythromycin (500 mg three times a day for 6 days) was found to have only minor effects on the pharmacokinetics of a single dose of ropivacaine (0.6 mg/kg IV over 30 minutes) compared to placebo. However, in combination with the potent 1A2 inhibitor fluvoxamine (100 mg daily), erythromycin further increased the area under the plasma concentration-time curve (AUC) of ropivacaine by 50% compared to fluvoxamine alone, which increased the ropivacaine AUC by 3.7-fold. Fluvoxamine alone prolonged the elimination half-life of ropivacaine from 2.3 to 7.4 hours, while the addition of erythromycin further increased the half-life to 11.9 hours. In another study, pretreatment with the potent 3A4 inhibitor ketoconazole (100 mg twice daily for 2 days) decreased the mean total plasma clearance of ropivacaine (40 mg IV over 20 minutes) by just 15% in 12 healthy volunteers. Thus, it appears that CYP450 3A4 inhibitors may only have a significant effect on the pharmacokinetics of ropivacaine in the presence of a CYP450 1A2 inhibitor such as fluvoxamine, ciprofloxacin, or mexiletine.

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