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Plasma concentrations of tadalafil in children with pulmonary arterial hypertension
Hiroyuki Kohno1, Fukiko Ichida, Keiichi Hirono
1*Department of Clinical Pharmacy, Graduate School of Medicine and Pharmaceutical Sciences; †Department of Pediatrics and ‡First Department of Surgery, Faculty of Medicine, University of Toyama; and §Department of Pediatrics, Kanazawa Medical University, Ishikawa, Japan.
Insights
This study evaluated tadalafil pharmacokinetics in children with pulmonary arterial hypertension (PAH). Doses achieved sufficient unbound tadalafil concentrations for phosphodiesterase-5 inhibition, despite interindividual variability.
Area of Science:
- Pharmacology
- Pediatrics
- Cardiology
Background:
- Limited data exists on tadalafil plasma concentrations in pediatric populations.
- Pulmonary arterial hypertension (PAH) in children is often managed with tadalafil, necessitating pharmacokinetic understanding.
Purpose of the Study:
- To assess the pharmacokinetic variability of tadalafil in children with PAH.
- To determine plasma concentrations and unbound fractions of tadalafil in this cohort.
Main Methods:
- Bayesian estimation and nonlinear mixed-effects modeling were used to analyze pharmacokinetic parameters (CL/F, V/F).
- Plasma samples were collected pre- and post-dose after repetitive oral administration.
- Ultrafiltration was employed to determine unbound tadalafil concentrations.
Main Results:
- Tadalafil pharmacokinetics were evaluated in 23 children (mean age 3.58 years) with PAH.
- Mean CL/F and V/F values were higher than in adults; no significant effect of age or concomitant bosentan was found.
- Unbound tadalafil concentrations exceeded the in vitro IC50 for phosphodiesterase-5 inhibition.
Conclusions:
- Significant interindividual variability in total and unbound tadalafil plasma concentrations was observed in children with PAH.
- Empirical dosing (mean 0.97 mg·kg-1·d-1) resulted in adequate unbound concentrations for therapeutic effect.
- Findings offer insights for optimizing tadalafil use in pediatric PAH management.
Background:
There is no report documenting the plasma concentrations of tadalafil in children. This study was performed to evaluate the variability in the pharmacokinetics of tadalafil in children with pulmonary arterial hypertension (PAH) treated routinely with the drug.
Methods:
Plasma samples were taken twice (post- and predose) after repetitive oral administration, and the pharmacokinetic parameters (CL/F and V/F) in individual patients were estimated by the Bayesian method using the nonlinear mixed effects model. We also determined the unbound concentration of tadalafil using ultrafiltration.
Results:
Tadalafil was administered to 23 children aged between 0.25 and 17.4 years, with a mean age of 3.58 years. The mean (±SD) daily dose of tadalafil was 0.97 ± 0.41 mg/kg. Sixteen of the 23 children received bosentan concomitantly. The mean CL/F and V/F values of tadalafil were 0.149 L·h-1·kg-1 and 1.87 L/kg, respectively, which were higher than those reported in adults. No effects of age, bosentan, or the estimated glomerular filtration rate were observed on the CL/F value, indicating that other residual factors might account for the interindividual variability among children with PAH. The unbound tadalafil concentrations of the postdose samples ranged from 5.9 to 146 (46.9 ± 37.1) nmol/L, higher than the reported IC50 value of this phosphodiesterase-5 drug for humans (2-4 nmol/L, corresponding to 0.8-1.6 ng/mL).
Conclusions:
We demonstrated variability in the total and unbound plasma concentrations of tadalafil in children. However, all children received the empirical doses of the drug; a mean dose of 0.97 mg·kg-1·d-1 showed sufficient unbound concentrations needed for half-maximal inhibition of human phosphodiesterase-5 in vitro. These observations may provide information for the proper use of tadalafil to treat children with PAH.
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