Figure 2 – Schematic illustration of the pharmacokinetic model of ivacaftor and its main metabolites ivacaftor-M1 and ivacaftor-M6. Abbreviations: D1; zero-order absorption into the gut compartment, KA; absorption rate constant, Vc IVA/F; apparent ivacaftor central volume of distribution, Vp IVA/F; apparent ivacaftor peripheral volume of distribution, Q/F; apparent intercompartmental clearance, CLIVA/F; apparent ivacaftor clearance, Vc M1/6/(F*fm); apparent ivacaftor-M1/6 central volume of distribution of the fraction metabolized, CLM1/6/(F*fm); apparent ivacaftor-M1/6 clearance of the fraction metabolized, Qm/fm; intercompartmental clearance of the fraction metabolized.
Figure 3 – Prediction corrected visual predictive checks (VPC) of the final models. The open circles represent the prediction correct concentrations of tezacaftor, tezacaftor-M1, ivacaftor, ivacaftor-M1 and ivacaftor-M6. The solid black line represents the observed median and the dashed black lines represent the 5th and 95th percentiles of the observed prediction-corrected data. The blue areas represent the 80% confidence interval of the model-predicted 5th and 95thpercentiles. The orange area represents the 80% confidence interval of the model-predicted median. For tezacaftor, tezacaftor-M1, ivacaftor and ivacaftor-M6, the solid black line slightly rises above the orange shaded area at the end of the dosing interval, indicating a minor underestimation of the observed 50th percentile. For ivacaftor-M1, the dashed black line slightly rises above the blue shaded area at the beginning of the dosing interval, indicating a minor underestimation of the observed 5th percentile. For ivacaftor-M6, the dashed black line slightly rises above the blue shaded area in the middle of the dosing interval, indicating a minor underestimation of the observed 95th percentile.
Figure 4 – AUC0-24h and AUC0-12h versus Cmin for tezacaftor and ivacaftor. Tezacaftor Pearson’s r = 0.931 (95% CI = 0.837 – 0.971, P<0.0001), R2 = 0.866, regression equation: y=20.68x+37.48. Ivacaftor Pearson’s r = 0.942 (95% CI = 0.848 – 0.979, P<0.0001), R2 = 0.887, regression equation: y=9.14x+5.69.
AUC, area under the curve; Cmin, trough concentration; CI, confidence interval.