Justin J Wilkins (1), Wilhelmina Bagchus (2), Oezkan Yalkinoglu (3), Claude Oeuvray (4), James McCarthy (5), Akash Khandelwal (3)
(1) Occams, Amstelveen, The Netherlands, (2) Merck Institute for Pharmacometrics, Merck Serono SA, Lausanne, Switzerland, (3) Merck KGaA, Darmstadt, Germany (4) Global Health Institute of Merck, Switzerland (5) QIMR Berghofer Medical Research Institute, Brisbane, Australia
Objectives: M5717 is a translation elongation factor 2 (eEF2) inhibitor in development as an antimalarial. It has a long half-life and duration of action and is active against multiple life-cycle stages of Plasmodium falciparum and Plasmodium vivax. The objective of this study was to describe M5717 pharmacokinetic (PK) concentration versus time data after single ascending oral doses in healthy volunteers, and to assess between-subject PK variability.
Methods: Study MS201618-0013 was a Phase I, first-in-human, randomized, double-blind, placebo-controlled trial of single ascending doses of M5717 to assess the safety, tolerability and pharmacokinetic profile, and to assess the antimalarial activity of M5717 against P. falciparum in healthy male and female adult subjects. So far, a total of 36 subjects received oral M5717 in Part A, a single ascending dose (SAD) part designed to investigate the safety, tolerability and PK properties. A total of 22 healthy subjects were enrolled in Part C, a single-centre, open-label part using the P. falciparum induced blood stage malaria (IBSM) human challenge model to assess the antimalarial activity of M5717 in subjects infected with malaria under controlled conditions. A total of 1166 PK samples from these 58 subjects, who were administered single doses of M5717 (50 mg, 100 mg, 150 mg, 200 mg, 400 mg, 600 mg, 800 mg, 1000 mg), were available for analysis. NONMEM 7.4.3 was used to develop a population PK model to describe the data. Demographic covariate data were incomplete and therefore not used.
Results: M5717 single-dose PK in healthy subjects appear to be complex. PK were not linear with dose, with multiple secondary peaks observable in the concentration-time curve after a single dose. The most parsimonious model that was able to describe M5717 PK was two-compartmental, with a recirculation component to describe the most significant secondary peak; central volume of distribution (V2/F) and absorption rate constant (ka) were strongly inversely correlated with administered dose. Typical values of model parameters were largely well estimated: apparent oral clearance (CL/F) was estimated to be 21.6 L with interindividual variability (IIV) of 37.7%, apparent central volume of distribution (V2/F) was estimated to be 2480 L with an IIV of 19.5%, apparent peripheral volume of distribution (V3/F) was estimated to be 4010 L, apparent intercompartmental clearance (Q/F) was estimated to be 67.9 L/h, absorption rate constant (ka) was estimated to be 0.927 h-1 with an IIV of 66.4%, and relative bioavailability (F1) was fixed to 1 with an IIV of 31.1%. Release of M5717 from the depot compartment for recirculation was estimated to take place 27.2 h after dose administration for a fixed period of 0.5 h. None of the several physiologically-based models describing the relationship between dose and V2 and dose and ka that were tested provided an adequate fit; empirical power models in which dose was treated as a covariate were ultimately used (the coefficients describing the relationships between V2 and dose and between ka and dose were -0.593 and -0.674, respectively). Residual variability was estimated to be 25.7%, applied additively on the logarithmic scale. Diagnostic plots and visual predictive checks were indicative of an acceptable model fit to the data despite the unusual features observed in the PK.
Conclusions: A population PK model was developed to describe the nonlinear dose-exposure relationship for M5717 and its between-subject variability across doses ranging between 50 mg and 1000 mg and was able to describe the observed data acceptably well. Increasing dose was associated with decreasing ka (and therefore slower oral absorption) and decreasing V2/F, suggesting nonlinear distribution.
Reference: PAGE 28 (2019) Abstr 9044 [www.page-meeting.org/?abstract=9044]
Poster: Drug/Disease Modelling - Infection