Figure 1.
Key pharmacokinetic parameters.
Figure 2.
Ivermectin AUC ratio (AUC in interaction phase/AUC in baseline phase) versus azithromycin AUC in interaction phase.
Solid line serves as a reference point of no change of ivermectin bioavailability; dotted line is Loess fit (local regression fit) to indicate lack of linear relationship. Circles are the observed individual values.
Figure 3.
Two-compartment pharmacokinetic structural model for ivermectin.
The best fit was obtained by models for two subpopulation (A and B), characterized by different F values, relative to the baseline model that included all subjects. Parameters: central and peripheral compartment volumes, total body clearance (CL), inter-compartmental clearance (Q), rate of absorption, and relative bioavailability (F). Note that albendazole was administered in both baseline and interaction phases.
Figure 4.
Goodness-of-fit plots for the final population mixture model.
Observed versus predicted and individual predicted plasma ivermectin levels. The solid line represents the line of identity (top panels). Residual versus predicted plasma ivermectin levels and weighted residual versus time, (bottom panels).
Table 1.
Final Non-Mixture Model Parameter Estimates and Their Variabilities.
Table 2.
Final Mixture Model Parameter Estimates and Their Variabilities.
Figure 5.
Observed, population predicted, and individual predicted ivermectin concentrations of individual subjects following ivermectin alone (No AZ) and after co-administration with azithromycin (AZ) for Subpopulation B, where increased bioavailability is observed in the interaction period.
The solid line represents the fit predicted by the typical pharmacokinetic mixture model parameters. The dashed line shows the fit of the post hoc estimates of the population model. Circles represent the observed concentrations.
Figure 6.
Observed data plotted as individual points.
The solid center lines represent the median values of the 1000 simulated data sets, whereas the upper and lower lines represent the 97.5th and 2.5th quantiles of the simulated data, respectively.
Figure 7.
Upper panel: Observed maximum ivermectin concentration data in baseline and interaction arms from all subjects (open boxes) and from subpopulations A and B (shaded and hatched boxes).
Lower panel: Maximum concentration data from 1000 simulation replicates using the non-mixture model in all subjects (open boxes) and from the mixture model in subpopulations A and B (shaded and hatched boxes). The line in the interior of the box denotes the median, the bottom and top edges denote the first and third quartiles, respectively. The lines from the top and bottom edges extend to 1.5 times the interquartile range. Values exceeding the interquartile range are plotted as individual points.