Table 1.
Summary of clinical studies contributing to the pooled pharmacokinetic analysis.
Table 2.
Summary of baseline demographic and clinical data for the study populations contributing to the present analysis.
Fig 1.
Graphical representation of the final structural model describing the pharmacokinetics of emodepside in healthy volunteers.
Absorption from the gut compartment is described by a 4-transit-compartment absorption model, followed by a 3-compartment disposition model. F is the relative oral bioavailability, ktr is the rate constant between absorption compartments, Vc is the apparent volume of distribution of the central compartment, Vp is the apparent volume of distribution of the peripheral compartments, Q is the inter-compartmental clearance between the central and peripheral compartments, and CL is the apparent elimination clearance.
Fig 2.
Prediction-corrected visual predictive checks of the final population pharmacokinetic model for emodepside.
Strata by formulation of emodepside. a: LSF oral solution; b: amorphous solid dispersion tablet A; c: amorphous solid dispersion tablet B (1 data point at 240 h time after dose was censored). Open circles represent observed plasma emodepside concentrations. The solid red line represents the 50th percentile (median) and the blue dashed lines represent the 5th and 95th percentiles of the observed data. The shaded area represents the 95% confidence interval around the simulated 5th, 50th, and 95th percentiles. The horizontal dashed line represents the lower limit of quantification of emodepside (1 ng/mL). The inset shows the absorption phase between 0 and 12 h.
Table 3.
Parameter estimates of the final population pharmacokinetic model of emodepside in healthy male subjects.
Fig 3.
Relationship between emodepside exposure and drug-related TEAEs of interest.
Boxplots (upper panel) showing the distribution of Cmax for study participants without (TEAE of interest = 0) and with (TEAE of interest = 1) occurrence of drug-related TEAE of interest (a), as well as eye disorders (b) and nervous system disorders separately (c). The midline indicates the median, the box corresponds to the interquartile range, and the whiskers extend up to 1.5 times the interquartile range. The lower panel show corresponding predicted probabilities of drug-related TEAE of interest, eye disorder and nervous system disorder, respectively, based on the final logistic Cmax−adverse events regression model. The solid blue line indicates the median and the shaded area the 95% CI around predicted probabilities.
Fig 4.
Overview of study arms planned for a phase II clinical trial.
Proposed body-weight based dosing regimens for administration of amorphous solid dispersion (ASD) tablet formulation B.
Fig 5.
Simulations of emodepside exposure and probability of adverse events for study arm 1–4.
Maximum emodepside plasma exposure (Cmax, upper panel), corresponding predicted probability of drug-related TEAE of interest (middle panel) and total time above the target concentration of 100 ng/mL (lower panel), stratified by body weight. The midline of the boxplots indicates the median, the box corresponds to the interquartile range, and the whiskers extend from the 5th to the 95th percentile. The red dotted line in the middle panel indicates a 50% probability threshold for any drug-related TEAE of interest. The red dotted line in the lower panel indicates the minimum number of days (5 days) above the target concentration. Simulations are based on administration of amorphous solid dispersion (ASD) tablet formulation B and the proposed body weight-based dosing regimen for a: study arm 1 (single dose of emodespide), b: study arm 2 (once daily dosing for 7 days), c: study arm 3 (once daily dosing for 14 days) and d: study arm 4 (twice daily dosing for 10 days) as described in Fig 4.