Pharmacokinetics and Safety of Letermovir and Midazolam Coadministration in Healthy Subjects

Abstract

Letermovir is a human cytomegalovirus (CMV) terminase inhibitor for the prophylaxis of CMV infection and disease in allogeneic hematopoietic stem-cell transplant recipients. In vitro studies have identified letermovir as a potential cytochrome P450 (CYP) 3A inhibitor. Thus, the effect of letermovir on the CYP3A isoenzyme-specific probe drug midazolam was investigated in a phase 1 trial. Healthy female subjects received single-dose intravenous (IV; 1 mg) and oral (2 mg) midazolam on days -4 and -2, respectively. Letermovir 240 mg once daily was administered on days 1 to 6, and further single doses of midazolam 1 mg IV and oral midazolam 2 mg were administered on days 4 and 6, respectively. Pharmacokinetics, tolerability, and safety were monitored throughout the trial. Following coadministration with letermovir, the least square means ratio for maximum plasma concentration and area under the plasma concentrationtime curve from time 0 to the last measurable concentration was 172.4% and 225.3%, respectively, for oral midazolam, and 105.2% and 146.6%, respectively, for midazolam IV. The area under the plasma concentration-time curve from time 0 to the last measurable concentration ratio of midazolam to 1-hydroxymidazolam increased slightly in the presence of letermovir following IV (8.8-13.1; 49% increase) and oral (3.3-5.3; 59% increase) midazolam. Letermovir reached steady state, on average, by days 5 to 6. All treatments were generally well tolerated. Letermovir demonstrated moderate CYP3A inhibition.

Pharmacokinetics, Safety, and Tolerability of Letermovir Following Single‐ and Multiple‐Dose Administration in Healthy Japanese Subjects

“…20 Letermovir was shown in vitro to be an inducer and time-dependent inhibitor of CYP3A4, 9 though in vivo results using a CYP3A probe substrate (midazolam) suggest that letermovir is a net moderate inhibitor of CYP3A. 21 Letermovir increases the plasma concentrations of the immunosuppressants CsA, tacrolimus, and sirolimus and may increase exposures to other sensitive CYP3A substrates when coadministered with letermovir. 14,15 Letermovir appeared to induce CYP2C9/CYP2C19 on the basis of the DDI trial with voriconazole.…”

Drug‐Drug Interaction of Letermovir and Atorvastatin in Healthy Participants

“…The observed approximately 3‐fold increase in ATV exposure may be related to letermovir‐mediated inhibition of CYP3A metabolism in the gut and liver. In comparison, coadministration of once‐daily oral letermovir 240 mg (lower than the clinical dose) with oral midazolam 2 mg resulted in a 2.25‐fold increase in the AUC and 1.72‐fold increase in the C max of midazolam, and with IV midazolam 1 mg resulted in a 1.47‐fold increase in the AUC and 1.05‐fold increase in the C max of midazolam 7,16 . These data indicate that letermovir primarily affects gut metabolism, with a lesser impact on hepatic metabolism of CYP3A substrates.…”

“…Letermovir is a CMV DNA terminase complex inhibitor indicated for the prevention of CMV infection and disease in adult recipients of HSCT. 1 Based on the inhibitory effects of letermovir on CYP3A metabolism [6][7][8] and OATP1B and BCRP transport in vitro, letermovir has the potential to affect the PK of ATV (a CYP3A, an OATP1B, and potentially a BCRP substrate), 15 which is a commonly prescribed HMG-CoA reductase inhibitor 14 that may be coadministered with letermovir. The observed approximately 3-fold increase in ATV exposure may be related to letermovirmediated inhibition of CYP3A metabolism in the gut and liver.…”

“…Therefore, letermovir has the potential to affect the pharmacokinetics (PK) of substrates of CYP3A, OATP1B1/3, and BCRP via inhibition. In clinical drug‐drug interaction (DDI) studies, letermovir was shown to increase exposure of the CYP3A substrates cyclosporine A, tacrolimus, sirolimus, and midazolam up to ≈3‐fold in healthy participants, suggesting that letermovir moderately inhibits CYP3A activity 6–8 . In recipients of HSCT, exposure of tacrolimus is also reportedly increased when coadministered with letermovir 9 .…”

“…In clinical drug-drug interaction (DDI) studies, letermovir was shown to increase exposure of the CYP3A substrates cyclosporine A, tacrolimus, sirolimus, and midazolam up to ≈3-fold in healthy participants, suggesting that letermovir moderately inhibits CYP3A activity. [6][7][8] In recipients of HSCT, exposure of tacrolimus is also reportedly increased when coadministered with letermovir. 9 Coadministration of letermovir with a combined oral contraceptive increased exposure of levonorgestrel and ethinyl estradiol, which is likely due to the inhibition of CYP3A and uridine-5 -diphosphate-glucuronosyltransferase 1A1 (UGT1A1) by letermovir.…”