Population Pharmacokinetics and Exposure-Response Relationships of Maribavir in Transplant Recipients With First Episode or Refractory Cytomegalovirus.

Abstract

Maribavir's anti-cytomegalovirus (CMV) activity and favorable safety/tolerability profile is a welcomed addition to the CMV treatment armamentarium. To further characterize pharmacokinetic (PK) and exposure-response relationships of maribavir in transplant recipients with CMV, a population PK model was updated with data from the AURORA study, using non-linear mixed-effect modeling. Covariates were tested using a stepwise procedure. In exposure-response analyses, relationships between maribavir exposure metrics and the primary and key secondary response endpoints and safety data from AURORA were characterized. The final model was a two-compartment disposition model with first-order elimination, first-order absorption and an absorption lag-time. Exposure levels were similar irrespective of transplant type and in patients with refractory CMV infection versus those receiving first-line maribavir. Concomitant administration of proton-pump inhibitors resulted in reduced maribavir exposure that was not clinically significant. There was no apparent relationship between maribavir exposure and the primary or key secondary endpoints of the AURORA study. Steady-state maribavir exposures were not significantly associated with any adverse events other than nausea and vomiting. In conclusion, maribavir's efficacy, safety, and favorable tolerability profile in transplant recipients with first CMV infection after transplant or refractory CMV infection is supported by PK exposure metrics. Higher maribavir steady-state concentrations were not associated with greater efficacy or a higher frequency of adverse events other than nausea and vomiting.