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

Clin Pharmacol Ther. 2021 Oct 21. doi: 10.1002/cpt.2456. Online ahead of print.ABSTRACTThe 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.PMID:34674258 | DOI:10.1002/cpt.2456
Source: Clinical Pharmacology and Therapeutics - Category: Drugs & Pharmacology Authors: Source Type: research