Lack of a significant pharmacokinetic interaction between maraviroc and tacrolimus in allogeneic HSCT recipients.
OBJECTIVES
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.
['Ganetsky|Alex|A|', 'Miano|Todd A|TA|', 'Hughes|Mitchell E|ME|', 'Vonderheide|Robert H|RH|', 'Porter|David L|DL|', 'Reshef|Ran|R|']
D000328:Adult D000368:Aged D003510:Cyclohexanes D004347:Drug Interactions D005260:Female D006086:Graft vs Host Disease D018380:Hematopoietic Stem Cell Transplantation D006801:Humans D007155:Immunologic Factors D008297:Male D000077592:Maraviroc D008875:Middle Aged D011446:Prospective Studies D016559:Tacrolimus D014184:Transplantation, Homologous D014230:Triazoles D055815:Young Adult
chemokine receptors immunosuppression pharmacology transplantation