title: Pharmacokinetics and safety of letermovir, a novel anti-human cytomegalovirus drug, in patients with renal impairment.
abstract: OBJECTIVE
  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-11.73m-2), moderate (30-59 ml min-11.73m-2) and severe (<30 ml min-11.73m-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,ssand Css,max) was increased with renal impairment [least square mean ratios (90% confidence intervals) total letermovir vs. healthy subjects, AUCτ,ss192% (143-258%) and 142% (83-243%) for moderate and severe impairment, respectively; Css,max125% (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.
authors.affiliation: AiCuris Anti-infective Cures GmbH, Wuppertal, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Kropeit
authors.affiliation: AiCuris Anti-infective Cures GmbH, Wuppertal, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Scheuenpflug
authors.affiliation: clinphase, Hanau, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Erb-Zohar
authors.affiliation: CRS Clinical Research Services Kiel GmbH, Kiel, Germany.
authors.forename: Atef
authors.initials: A
authors.lastname: Halabi
authors.affiliation: AiCuris Anti-infective Cures GmbH, Wuppertal, Germany.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Stobernack
authors.affiliation: MSD Netherlands, Oss, The Netherlands.
authors.forename: Ellen G J
authors.initials: EGJ
authors.lastname: Hulskotte
authors.affiliation: MSD BV, Oss, The Netherlands.
authors.forename: Arne
authors.initials: A
authors.lastname: van Schanke
authors.affiliation: AiCuris Anti-infective Cures GmbH, Wuppertal, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Zimmermann
authors.affiliation: AiCuris Anti-infective Cures GmbH, Wuppertal, Germany.
authors.forename: Helga
authors.initials: H
authors.lastname: Rübsamen-Schaeff
mesh_terms: D000085:Acetates / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D000368:Aged; D000998:Antiviral Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D008297:Male; D008875:Middle Aged; D011799:Quinazolines / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D051437:Renal Insufficiency / Q000097:blood*
chemical_list: D000085:Acetates; D000998:Antiviral Agents; D011799:Quinazolines; C000588473:letermovir
keywords: antivirals; cytomegalovirus; letermovir; pharmacokinetics; renal insufficiency