title: Lack of a significant pharmacokinetic interaction between maraviroc and tacrolimus in allogeneic HSCT recipients.
abstract: OBJECTIVE
  Emerging data suggest that the combination of tacrolimus and the CCR5 antagonist maraviroc, both cytochrome P450-3A4 substrates, may be effective in preventing graft-versus-host disease in patients undergoing allogeneic HSCT. This study evaluated whether a pharmacokinetic interaction exists between these agents.
  
  
  METHODS
  The study included 36 allogeneic HSCT recipients who received maraviroc + tacrolimus and 43 recipients of tacrolimus alone. We used a difference-in-differences analysis to examine the change in the concentration/dose ratios of tacrolimus after the discontinuation of maraviroc. In addition, we analysed the concentrations and dose requirements of tacrolimus in the two groups.
  
  
  RESULTS
  There was no significant difference in tacrolimus concentration/dose ratios in patients receiving maraviroc + tacrolimus compared with tacrolimus alone. Upon discontinuation of maraviroc, the change in concentration/dose ratio was small and not significant relative to the control group, and the effect estimate was further attenuated after adjustment for confounders [-0.35 (ng/mL)/(mg/day); P = 0.46]. In addition, the change in mean tacrolimus dose after discontinuation of maraviroc was similar between the groups (0.12 mg/day; P = 0.56), as was the change in mean tacrolimus concentration (0.02 ng/mL; P = 0.97).
  
  
  CONCLUSIONS
  Our findings do not support a significant inhibitory effect of maraviroc on the metabolism of tacrolimus. These data demonstrate that this drug combination is safe and imply that the protective effect of maraviroc against graft-versus-host disease was not mediated through an increase in tacrolimus concentrations. These findings are important for the design of clinical trials that evaluate maraviroc in combination with cytochrome P450-3A4 substrates.
authors.affiliation: Department of Pharmacy, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Ganetsky
authors.affiliation: Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Todd A
authors.initials: TA
authors.lastname: Miano
authors.affiliation: Department of Pharmacy, Hospital of the University of Pennsylvania, Philadelphia, PA, USA Philadelphia College of Pharmacy, University of the Sciences, Philadelphia, PA, USA.
authors.forename: Mitchell E
authors.initials: ME
authors.lastname: Hughes
authors.affiliation: Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA Abramson Cancer Center and the Division of Hematology and Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Vonderheide
authors.affiliation: Abramson Cancer Center and the Division of Hematology and Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Porter
authors.affiliation: Abramson Cancer Center and the Division of Hematology and Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA ran.reshef@uphs.upenn.edu.
authors.forename: Ran
authors.initials: R
authors.lastname: Reshef
mesh_terms: D000328:Adult; D000368:Aged; D003510:Cyclohexanes / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004347:Drug Interactions; D005260:Female; D006086:Graft vs Host Disease / Q000517:prevention & control*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D000077592:Maraviroc; D008875:Middle Aged; D011446:Prospective Studies; D016559:Tacrolimus / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014184:Transplantation, Homologous; D014230:Triazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D003510:Cyclohexanes; D007155:Immunologic Factors; D014230:Triazoles; D000077592:Maraviroc; D016559:Tacrolimus
keywords: chemokine receptors; immunosuppression; pharmacology; transplantation