Cytomegalovirus prophylaxis with letermovir in pediatric (birth to <18 years of age) hematopoietic cell transplant recipients: pharmacokinetics, efficacy, and safety results of a Phase 2b study

Abstract

Letermovir, a cytomegalovirus (CMV) terminase complex inhibitor, was first approved for prophylaxis of CMV infection and disease in adult CMV-seropositive allogeneic hematopoietic cell transplant (HCT) recipients (R+). This study evaluated the pharmacokinetics (PK), efficacy, and safety of letermovir in pediatric R+ allogeneic HCT recipients. In this Phase 2b, single-arm, open-label study, 65 participants were enrolled sequentially in three age groups (AG; AG1, 12 to <18 years; AG2, 2 to <12 years; and AG3, birth to <2 years). PK was evaluated in an initial cohort in each AG using intensive PK data to confirm or modify dosing before enrolling the remaining participants. Adult HCT population PK (PopPK) data were used to establish the exposure reference range. The adult letermovir dose evaluated in AG1 and AG2 participants achieved exposures generally within the adult HCT reference range. In AG3, the initial cohort (letermovir with cyclosporin A) achieved exposures trending lower than the median exposure target; the letermovir dose was increased for the remaining participants. Efficacy and safety in pediatric participants were generally consistent with adult HCT data. A pediatric HCT PopPK model was developed to determine dose recommendations to be included in patient prescribing information. The doses evaluated achieved exposures generally within the adult HCT reference range. At exposures achieved, letermovir was efficacious and safe in preventing clinically significant CMV infection in pediatric allogeneic HCT recipients. The observed concentration data informed a pediatric PopPK model to optimize final letermovir dose recommendations in this population.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT03940586.

Keywords: cytomegalovirus; hematopoietic cell transplantation; letermovir; pediatric; pharmacokinetics.

Fig 1

(a) Study design and (b) sequential pharmacokinetic (PK) evaluation of age groups. AG, age group; CSA±, may receive concomitant cyclosporin A; CSA−, cannot receive concomitant cyclosporin A; HCT, hematopoietic cell transplant; IV, intravenous; LET, letermovir; PO, oral. Intensive PK sampling was performed pre-dose and 1, 2.5, 8, and 24 h post-dose. Sparse PK sampling took place at Weeks 2, 4, 6, 8, 10, 12, and 14 post-HCT during the treatment phase. ^aNumber of PK-evaluable participants. ^bInterim PK analysis occurred at three time points: when all evaluable participants had completed intensive PK sampling in AG1 Panel A, when all evaluable participants had completed intensive PK sampling in AG2 Panel A, and when the first three evaluable participants had completed intensive PK sampling in AG3.

Fig 2

Participant disposition (all randomized and treated participants): (a) status for trial and (b) status for study medication in trial. AE, adverse event; AG, age group.

Fig 3

Individual letermovir exposures for all participants who underwent intensive PK sampling compared with reference adult values (n = 36). AG, age group; AUC0–24, area under the concentration-time curve for the dosing interval (0–24 h) (logarithmic scale); CsA, cyclosporin A; IV, intravenous; NG, nasogastric; PK, pharmacokinetic; PO, oral; PopPK, population PK. CsA above the symbol indicates CsA was coadministered with the letermovir dose. Vertical dotted lines show the dosing weight-band boundaries for 2 to < 12 years (AG2) and birth to < 2 years (AG3); there are no dosing weight boundaries for 12 to < 18 years (AG1). The upper and lower bounds of the adult reference exposure range were prespecified based on the Phase 3 PopPK model (9).