Population pharmacokinetics of letermovir following oral and intravenous administration in healthy participants and allogeneic hematopoietic cell transplantation recipients

Abstract

Letermovir is indicated for prophylaxis of cytomegalovirus infection and disease in allogeneic hematopoietic stem cell transplant (HSCT) recipients. Two-stage population pharmacokinetic (PK) modeling of letermovir was conducted to support dose rationale and evaluate the impact of intrinsic/extrinsic factors. Data from healthy phase I study participants over a wide dose range were modeled to evaluate the effects of selected intrinsic factors, including pharmacogenomics; next, phase III HSCT-recipient data at steady-state following clinical doses were modeled. The model in HSCT recipients adequately described letermovir PK following both oral or i.v. administration, and was consistent with the healthy participant model at steady-state clinical doses. Intrinsic factor effects were not clinically meaningful. These staged analyses indicate that letermovir PK in HSCT recipients and healthy participants differ only with respect to bioavailability and absorption rate. The HSCT recipient model was suitable for predicting exposure for exposure-response analysis supporting final dose selection.

Trial registration: ClinicalTrials.gov NCT02137772.

Conflict of interest statement

Marita Prohn is an employee of qPharmetra and a former employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Anders Viberg and Kevin Dykstra are former employees of qPharmetra. Da Zhang, Casey Davis, Sreeraj Macha, Philip Sabato, Dinesh de Alwis, Marian Iwamoto, Craig Fancourt, and Carlyn R. Cho are current or former employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and may own stock and/or stock options in Merck & Co., Inc., Kenilworth, NJ, USA.

© 2021 Merck Sharp & Dohme Corp. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.

Figures

Figure 1

Graphical representation of the (a) healthy participant (phase I model), and (b) HSCT recipient (phase III model) popPK models. Atr, drug amount in a transit compartment; CL, clearance; CLmax, maximal clearance rate; CLmbase, CLmax for a typical 65.8 kg subject; CLMwt, exponent describing the weight effect on CLmax; CP, letermovir plasma concentration; EAI, induction compartment amount; HSCT, hematopoietic stem cell transplant; IMAG, scalar of the induction effect; kin, production rate induction compartment; KMCL, Michaelis‐Menten constant for clearance; KMQ, Michaelis‐Menten constant for intercompartmental clearance; kout, elimination rate induction compartment; Ktr, transit rate constant; MTT, mean transit time; MTTdose, dose effect on MTT; NTR, number of transit compartments; popPK, population pharmacokinetics; Q1, intercompartment clearance to the first peripheral compartment; Q1max, maximal intercompartment clearance to the first peripheral compartment; Q2, intercompartment clearance to the second peripheral compartment; Q3, intercompartment clearance to the third peripheral compartment; TVMTT, MTT for a typical dose of 240 mg; V1, central volume of distribution; V2, first peripheral volume of distribution; V3, second peripheral volume of distribution; V4, third peripheral volume of distribution; V1–4base, V1–4 for a typical 65.8 kg subject; Vd, volume of distribution (sum of V1, V2, V3, and V4); Vdbase, Vd for a typical 65.8 kg subject; Vdjpn, Asian effect on Vdbase; Vdwt, weight effect on Vd; WT, wild type

Figure 2

Simulated letermovir exposure using the healthy participant (phase I) popPK model after single‐dose or multiple‐dose: (a) oral administration; (b) i.v. administration. Box and whisker plot: the dot is the sample median, the boxes define the interquartile range, whiskers extend to 1.5 times the interquartile range. AUC, area under the concentration‐time curve; Cmax, maximum concentration (multiple‐dose Cmax at steady‐state); dn, dose normalized; popPK, population pharmacokinetics

Figure 3

HSCT recipient (phase III) popPK model predictions of letermovir exposure in HSCT recipients: (a) histograms of individual predicted letermovir AUCss and Ctrough; (b) box‐whisker plots of simulated AUCss and Ctrough following different letermovir dosing regimens. AUCss, area under the concentration‐time curve from 0 to 24 h postdose at steady‐state; CSA, cyclosporine A; Ctrough, minimum concentration; HSCT, hematopoietic stem cell transplant; popPK, population pharmacokinetics