Drug Interactions between letermovir and ropivacaine / sufentanil

MONITOR: Coadministration with letermovir may increase the plasma concentrations of drugs that are substrates of CYP450 2C8, CYP450 3A4, and/or organic anion transporting polypeptide protein (OATP) 1B1 and 1B3. Letermovir has been shown to be a reversible inhibitor of CYP450 2C8 in vitro, although its effect on CYP450 2C8 substrates has not been evaluated clinically. Letermovir is also a time-dependent inhibitor and inducer of CYP450 3A4 in vitro. According to the product labeling, midazolam peak plasma concentration (Cmax) and systemic exposure (AUC) increased by an average of 1.7- and 2.3-fold, respectively, when a single 2 mg oral dose of midazolam was coadministered with letermovir 480 mg orally once daily. The Cmax did not change when midazolam 1 mg was administered intravenously with letermovir 240 mg orally once daily, but AUC increased by 1.5-fold and concentration at 24 hours postdose (C24hr) increased by 2.7-fold. The increased AUC of midazolam, a CYP450 3A4 probe substrate, indicates that net effect of letermovir on the isoenzyme is moderate inhibition. In addition, letermovir is an inhibitor of the hepatic uptake transporters, OATP 1B1 and 1B3. When a single 20 mg dose of atorvastatin, a CYP450 3A4 and OATP1B1/1B3 substrate, was coadministered with letermovir 480 mg orally once daily, atorvastatin Cmax, AUC and C24hr increased by an average of 2.2-, 3.3- and 3.6-fold, respectively. Additional use of cyclosporine is likely to further increase the magnitude of these interactions, since it is an inhibitor of CYP450 3A4 and a strong inhibitor of OATP 1B1 and 1B3.

MANAGEMENT: Caution is advised when letermovir is used concurrently with drugs that are substrates of CYP450 2C8, CYP450 3A4, and/or OATP 1B1 and 1B3, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever letermovir is added to or withdrawn from therapy. Moreover, clinicians should be aware that the magnitude of CYP450 3A- and OATP1B1/3-mediated drug interactions with coadministered drugs may be different when letermovir is used with cyclosporine. The combined effect of the two drugs on CYP450 3A4 may be similar to that of a strong CYP450 3A4 inhibitor, hence clinicians should refer to the prescribing information for dosing recommendations of the CYP450 3A4 substrate with a strong CYP450 3A4 inhibitor. Similarly, letermovir and cyclosporine may demonstrate some additive effects on OATP1B1 inhibition, although cyclosporine by itself is already a strong OATP1B1/3 inhibitor.

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.