Propranolol pharmacokinetics in infants treated for Infantile Hemangiomas requiring systemic therapy: Modeling and dosing regimen recommendations.

Propranolol pharmacokinetics in infants treated for Infantile Hemangiomas requiring systemic therapy: Modeling and dosing regimen recommendations.

Del Frari, Laurence;Léauté-Labrèze, Christine;Guibaud, Laurent;Barbarot, Sébastien;Lacour, Jean-Philippe;Chaumont, Christine;Delarue, Alain;Voisard, Jean-Jacques;Brunner, Valérie;
pharmacology research & perspectives 2018 Vol. 6 pp. e00399
303
del-frari2018propranololpharmacology

Abstract

Propranolol has become the first choice therapy for complicated Infantile Hemangiomas (IH). The pharmacokinetics of propranolol were evaluated after repeated oral administration of a new pediatric solution of propranolol at 3 mg kg day given twice daily (BID) in infants (77-243 days) with IH. A population model was built to describe the pharmacokinetics of propranolol in infants and to simulate different dosing regimens. One hundred and sixty-seven plasma concentrations from 22 infants were used in the population analysis. Weight effect was tested on apparent clearance and volume of distribution. Monte-Carlo simulations were performed for 4 dosing regimens: BID dosing with irregular or strict 12-hour intervals and 2 different 3 time daily dosing (TID) regimens. The best model was a one-compartment model with first-order absorption and elimination rates. The weight affected the clearance but not the volume. Typical oral clearance was estimated at 3.06 L hour kg (95% CI: 1.14-8.61 L hour kg), close to adult clearance data. When regular BID dosing was compared to TID or irregular BID regimens, simulated median Cmin and Cmax were <20% different. To conclude, a model using a weight allometric function on clearance was established and confirmed that the dose in mg/kg should be used without adaptation by range of age in treatment of complicated IH. The simulations support the use of a BID dosing preferably to a TID dosing thanks to close Cmin and Cmax at steady state between both regimen and showed the possibility of irregular BID dosing, allowing early administration in the evening when needed.

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