Population pharmacokinetic analysis of sildenafil in term and preterm infants with pulmonary arterial hypertension

Figures

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  Figure 1. Goodness-of-fit plots for sildenafil. (a) Population predictions versus observed concentrations; (b) Individual predictions versus observed concentrations; (c) Conditional weighted residuals (CWRES) versus population predictions; and (d) CWRES versus time. The solid lines represent the line of unity. The dashed lines represent the linear regression fit.

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  Figure 2. Goodness-of-fit plots for N-desmethyl sildenafil. (a) Population predictions versus observed concentrations; (b) Individual predictions versus observed concentrations; (c) Conditional weighted residuals (CWRES) versus population predictions; and (d) CWRES versus time. The solid lines represent the line of unity. The dashed lines represent the linear regression fit.

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  Figure 3. Prediction-corrected visual predictive check for sildenafil and N-desmethyl sildenafil. The solid lines represent the 5th, 50th, and 95th percentiles of the observed data. The shaded areas represent the 90% confidence interval of the 5th, 50th, and 95th percentiles of the predicted data.

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  Figure 4. Simulated sildenafil concentration–time profiles after multiple administrations of sildenafil every 6 h: (a) 0.5 mg/kg; (b) 0.75 mg/kg; (c) 1 mg/kg; and (d) 2 mg/kg. The solid lines represent the 50th percentiles, and the dotted lines represent the 5th and 95th percentiles of the simulated data. The dashed lines represent the therapeutic exposure references for Cmax: 47, 140, and 373 ng/mL are expected to inhibit type 5 phosphodiesterase activity in vitro by approximately 53%, 77%, and 90%, respectively14.

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  Figure 5. The predicted (a) Cmax and (b) AUC at a steady state after multiple administrations of 0.5–2 mg/kg of sildenafil every 6 h. The dashed lines represent the therapeutic exposure references: the Cmax, 47, 140, and 373 ng/mL are expected to inhibit type 5 phosphodiesterase activity in vitro by approximately 53%, 77%, and 90%, respectively14; and the AUC, sildenafil and N-desmethyl sildenafil combined with an AUC > 2650 ng∙h/mL which previously showed clinical efficacy in infant patients15.

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  Figure 6. Percentage of reaching therapeutic exposure according to sildenafil dose. The therapeutic exposure for the (a) Cmax and (b) AUC were set as follows: the Cmax, 47, 140, and 373 ng/mL, which are expected to inhibit type 5 phosphodiesterase activity in vitro by approximately 53%, 77%, and 90%, respectively14; and the AUC, sildenafil and N-desmethyl sildenafil combined with an AUC > 2650 ng∙h/mL, which previously showed clinical efficacy in infant patients15.