An Evaluation of a Pharmacokinetic Interaction Between Tacrolimus and Maraviroc in Allogeneic Stem Cell Transplant Recipients

Background: Acute graft-versus-host disease (GVHD) remains a leading complication in allogeneic hematopoietic stem cell transplant (HSCT) recipients. Recently, our group demonstrated a low rate of visceral acute GVHD with the addition of maraviroc (MVC), a CCR5 antagonist, to tacrolimus (TAC) and methotrexate (MTX) in HSCT recipients (Reshef et al, NEJM 2012). MVC was initiated two days prior to HSCT and continued until day +30. Limited data are available regarding whether a pharmacokinetic interaction exists between TAC and MVC, both CYP3A4 substrates. A recent case report suggested an increase in TAC exposure when combined with MVC in a liver transplant recipient (Dufty et al, J Antimicrob Chemother 2013). We conducted a retrospective analysis to evaluate whether a pharmacokinetic interaction exists between TAC and MVC in HSCT recipients. 

Methods: We retrospectively compared TAC concentrations and concentration/dose ratios in 36 HSCT recipients receiving GVHD prophylaxis with TAC/MTX/MVC with a matched control population of 43 HSCT recipients receiving TAC/MTX. Ratios were compared at 2 weeks and 6 weeks following HSCT. Within group comparisons were made using the Wilcoxon signed-rank test and between-group comparisons were analyzed using the Wilcoxon rank-sum test or Student's t-test as appropriate. A p-value of ≤ 0.05 was considered significant.

Results: The median TAC concentration/dose ratio in the TAC/MTX/MVC group at week 2 was 2.8 (IQR 1.6 – 4.1) vs. 3.2 (IQR 2 to 4.2) in the TAC/MTX group (p=0.31). At week 6 (2 weeks after MVC discontinuation), the median TAC concentration/dose ratio increased in both groups, however the within group changes were not significant (TAC/MTX/MVC week 2 vs. week 6: 2.8 vs. 3.1, p=0.071; TAC/MTX week 2 vs. week: 6 3.2 vs. 4.4, p=0.077). Concentration/dose ratios at week 6 were similar between groups: TAC/MTX/MVC 3.1 (IQR 1.8 to 5.1) vs. TAC/MTX 4.4 (IQR 2.5 to 5.8), p=0.1. Change from baseline was also similar between groups: TAC/MTX/MVC 0.2 vs. TAC/MTX 0.5, p=0.54. The weekly mean TAC concentrations were similar between groups at week 1: 11.1 ng/mL vs. 10.7 ng/mL; week 3: 10.1 ng/mL vs. 10.6 ng/mL; and week 4: 10.9 ng/mL vs. 11.8 ng/mL; (p>0.05 for each week). At week 2, TAC levels were lower in the TAC/MTX/MVC group (9.5 ng/mL vs. 11 ng/mL; p=0.045).

Conclusion: With the exception of week 2, we observed no significant differences in TAC concentrations or concentration/dose ratios over time in patients receiving MVC compared to controls, implying that the protective effect of maraviroc was not mediated through an increase in TAC levels. However, the trend towards a decrease in concentration/dose ratio of TAC upon discontinuation of MVC suggests an inhibitory effect of MVC on TAC metabolism. Further evaluation of this potential interaction in larger studies is warranted and close monitoring of TAC levels is required when the TAC and MVC are co-administered.