Exposure-Response Analyses of Letermovir Following Oral and Intravenous Administration in Allogeneic Hematopoietic Cell Transplantation Recipients

The cytomegalovirus (CMV) viral terminase inhibitor letermovir is approved for prophylaxis of CMV infection and disease in adult CMV-seropositive allogeneic hematopoietic stem cell transplantation (HSCT) recipients. In a phase 3 trial (NCT02137772), letermovir significantly reduced clinically significant CMV infection (CS-CMVi) rate versus placebo through week 24 (primary endpoint) and week 14 (secondary endpoint) post-transplantation. Here, exposure-response relationships were investigated using efficacy and selected safety endpoints from the phase 3 trial to inform the proposed clinical dose. Post hoc exposure estimates were derived from a population pharmacokinetic model. No significant exposure dependencies were found for CS-CMVi through week 24 or week 14 among letermovir-treated participants. Evaluated covariates had no impact on exposure-efficacy relationships and letermovir plasma exposure did not affect time of CS-CMVi onset. There was no dependence between adverse event incidence and letermovir exposure. These results support current dosing recommendations in several countries and regions, including the US and EU.