Pharmacokinetics and safety of letermovir, a novel anti-human cytomegalovirus drug, in patients with renal impairment

British Journal of Clinical Pharmacology

5 years ago

Pharmacokinetics and safety of letermovir, a novel anti-human cytomegalovirus drug, in patients with renal impairment

Katharina Erb-Zohar, Helga Rübsamen-Schaeff, Arne Schanke, Ellen G. J. Hulskotte, Jürgen Scheuenpflug, Holger Zimmermann, Hans-Peter Stobernack, Dirk Kropeit, Atef Halabi

Aims Human cytomegalovirus remains a significant issue for immunocompromised patients and existing viral polymerase targeting therapies are associated with significant toxicity. Accordingly, the viral terminase complex inhibitor, letermovir, is in development. We assessed letermovir pharmacokinetics in renal impairment. Methods This was a Phase 1, open-label, nonrandomised trial. Estimated glomerular filtration rate based on the Modification of Diet Renal Disease equation was used to create three groups of eight subjects: healthy function (estimated glomerular filtration rate ≥ 90 ml min–1 1.73m–2), moderate (30–59 ml min–1 1.73m–2) and severe (<30 ml min–1 1.73m–2) impairment. Oral letermovir 120 mg was dosed once-daily for 8 days and blood collected for pharmacokinetic analyses. Results All 24 subjects enrolled completed the trial. Moderate and severe renal impairment increased mean unbound letermovir fractions by 11% and 26%, respectively, vs. healthy subjects. Exposure (AUCτ,ss and Css,max) was increased with renal impairment [least square mean ratios (90% confidence intervals) total letermovir vs. healthy subjects, AUCτ,ss 192% (143–258%) and 142% (83–243%) for moderate and severe impairment, respectively; Css,max 125% (87–182%) and 106% (75–151%), respectively]. Clearance was decreased vs. healthy subjects. Correlation analyses indicated a correlation between decreasing renal function and increased unbound letermovir concentration (R2 = 0.5076, P < 0.0001). Correlations were identified between decreased clearance with both decreased renal function (R2 = 0.0662, P = 0.2249 and R2 = 0.1861, P = 0.0353 total and unbound clearance, respectively) and increased age (R2 = 0.3548, P = 0.0021 and R2 = 0.3166, P = 0.0042 total and unbound clearance, respectively). Multiple-dose letermovir 120 mg was well tolerated across groups. Conclusions Renal impairment increased exposure to letermovir, although age was a confounding factor.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/bcp.13292