Assessment of Pharmacokinetic Interaction Between Letermovir and Fluconazole in Healthy Participants

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Letermovir is a human cytomegalovirus terminase inhibitor for the prophylaxis of cytomegalovirus infection and disease in allogeneic hematopoietic stem cell transplant recipients. The pharmacokinetics, safety, and tolerability of letermovir were assessed in healthy Japanese subjects in 2 phase 1 trials: trial 1—single ascending oral doses (240, 480, and 720 mg) and intravenous (IV) doses (240, 480, and 960 mg), and trial 2—multiple oral doses (240 and 480 mg once daily for 7 days). Following administration of oral single and multiple doses, letermovir was absorbed with a median time to maximum plasma concentration of 2 to 4 hours, and concentrations declined in a biphasic manner with a terminal half‐life of ≈10 to 13 hours. The post absorption plasma concentration–time profile of letermovir following oral administration was similar to the profile observed with IV dosing. There was minimal accumulation with multiple‐dose administration. Letermovir exposure in healthy Japanese subjects was ≈1.5‐ to 2.5‐fold higher than that observed in non‐Japanese subjects. Based on the population pharmacokinetic analysis, weight differences primarily accounted for the higher exposures observed in Asians. Letermovir was generally well tolerated following oral and IV administration to healthy Japanese subjects.

Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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

Asari

Ishii

Yoshitsugu

et al. 2022

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“…Therefore, it is reasonable to evaluate the potential for letermovir to cause drug-drug interactions (DDIs), and the clinical development program included a number of studies evaluating potential DDIs. 19,20,[22][23][24][25] The clearance of letermovir in humans is predominantly governed via organic anion transporting polypeptide 1B (OATP1B)-mediated uptake into the liver, the major organ of its elimination. 25 The small amount of metabolites together with negligible amounts of drug-related material recovered in urine in a human absorption, distribution, metabolism, and excretion study supported that metabolism and renal excretion play a minor role in the elimination of letermovir.…”

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confidence: 99%

Pharmacokinetics and Safety of Letermovir and Midazolam Coadministration in Healthy Subjects

Kropeit

McCormick

Erb‐Zohar

et al. 2021

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.

“…11 Fluconazole given as a 400-mg single dose had no meaningful effect on the PK of letermovir, and letermovir given as a single 480-mg dose had no meaningful effect on fluconazole PK. 12 In addition, pharmacogenetic analysis identified a statistically significant but not clinically relevant relationship of OATP1B1 and UGT1A1 polymorphisms to letermovir exposure. 13 Atorvastatin (ATV) is a 3-hydroxy 3-methylglutarylcoenzyme A (HMG-CoA) reductase inhibitor indicated as an adjunct therapy to reduce the risk of angina, hypercholesterolemia, hypertriglyceridemia, myocardial infarction, and stroke, 14 and is a substrate of CYP3A plus the OATP1B1 and BCRP transporters.…”

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confidence: 98%

“…Moreover, concomitant letermovir administration decreased exposure of the antifungal voriconazole (a CYP2C9/19 substrate), suggesting that letermovir may be an inducer of CYP2C9/19‐mediated metabolism; however, the PK of posaconazole were unaffected in the presence of letermovir 11 . Fluconazole given as a 400‐mg single dose had no meaningful effect on the PK of letermovir, and letermovir given as a single 480‐mg dose had no meaningful effect on fluconazole PK 12 . In addition, pharmacogenetic analysis identified a statistically significant but not clinically relevant relationship of OATP1B1 and UGT1A1 polymorphisms to letermovir exposure 13 …”

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confidence: 99%

Drug‐Drug Interaction of Letermovir and Atorvastatin in Healthy Participants

McCrea

Menzel

Adedoyin

et al. 2022

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Letermovir (MK-8228/AIC246) is a cytomegalovirus (CMV) DNA terminase complex inhibitor for CMV prophylaxis in adult patients undergoing hematopoietic stem cell transplant. It is cytochrome P450 (CYP) 3A inhibitor and inhibits organic anion transporting polypeptide 1B1/3 and breast cancer resistance protein transporters. Atorvastatin (ATV), a commonly used treatment for hypercholesterolemia, is a substrate of organic anion transporting polypeptide 1B1, potentially breast cancer resistance protein, and CYP3A. As letermovir may be coadministered with ATV, the effect of multiple-dose letermovir 480 mg once daily on the pharmacokinetics of single-dose ATV 20 mg and its metabolites (ortho-hydroxyatorvastatin [o-OH-ATV] and para-hydroxyatorvastatin [p-OH-ATV]) was evaluated in an open-label trial in healthy female adults (N = 14). ATV area under the plasma concentration-time curve from time 0 to infinity and maximum plasma concentration (C max ) increased ≈3-fold with letermovir coadministration. The time to ATV C max also increased, while apparent clearance decreased. The exposures of o-OH-ATV and p-OH-ATV were comparable in the presence versus absence of letermovir; however, o-OH-ATV C max decreased by 60% with coadministration, while p-OH-ATV C max was similar. Due to the increase in ATV exposure with letermovir coadministration, statin-associated adverse events such as myopathy should be closely monitored following coadministration. The dose of ATV should not exceed 20 mg daily when coadministered with letermovir.