Physiologically based pharmacokinetic modeling of tadalafil to inform pediatric dose selection in children with pulmonary arterial hypertension.
CPT Pharmacometrics Syst Pharmacol
; 11(2): 173-184, 2022 02.
Article
en En
| MEDLINE
| ID: mdl-34800000
ABSTRACT
Tadalafil, a phosphodiesterase 5 inhibitor, is being investigated as a treatment for pulmonary arterial hypertension (PAH) in children aged 6 months to less than 18 years. Tadalafil pharmacokinetic (PK) data in children less than 2 years old are unavailable, therefore a physiologically based pharmacokinetic (PBPK) model was developed to enable estimation of tadalafil doses in children less than 2 years old. The model was verified in adults and extended for use in children by modifying CYP3A-mediated intrinsic clearance to include CYP3A7. To account for co-dosing of the commonly prescribed moderate CYP3A4 inducer bosentan, predicted exposures were increased by a factor of 1.54 based on changes in exposure in adults with PAH. This factor was predictable using a bosentan PBPK model. The tadalafil model was verified in children aged greater than or equal to 2 years by comparing predicted and observed exposures. Tadalafil doses for children less than 2 years old were calculated as target area under the concentration curve from zero to 24 h (AUC0-24 )/predicted AUC0-24 , with target AUC0-24 of 10,000 ng*h/ml based on adult 40 mg single dose exposures determined in patients without bosentan background treatment. These doses were 2 mg, 3 mg, 4 mg, and 6 mg, respectively, for children aged birth to less than 1 month, 1 month to less than 6 months, 6 months to less than 1 year, and 1 to less than 2 years. Due to uncertainties in CYP maturation, a nonmechanistic steady-state volume scalar, and lack of PK data in children less than 2 years old, accumulation of tadalafil to steady-state in children less than 2 years was not verifiable. Safety of proposed doses is supported by postmarketing research and investigator-led trials.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Hipertensión Arterial Pulmonar
Tipo de estudio:
Prognostic_studies
Límite:
Adult
/
Child
/
Child, preschool
/
Humans
/
Infant
Idioma:
En
Revista:
CPT Pharmacometrics Syst Pharmacol
Año:
2022
Tipo del documento:
Article
País de afiliación:
Estados Unidos