Population Pharmacokinetics and Pharmacodynamics of Oral Propranolol in Pediatric Patients With Infantile Hemangioma

Abstract

This study aimed to characterize the population pharmacokinetics and exposure‐response relationship of propranolol (Hemangiol® Syrup for Pediatric) in infants with infantile hemangioma. Using nonlinear mixed‐effects modeling with 63 pooled sets of plasma concentration‐time data from 32 Japanese patients aged 35‐150 days, we described the disposition of propranolol adequately by a 1‐compartment model with first‐order absorption. The estimated population mean apparent clearance and apparent central volume of distribution were 9.34 L/h and 146 L, respectively. Body weight and postnatal age influenced the population pharmacokinetic model. The clinical end points—success (complete or nearly complete resolution of the target hemangioma) and failure—at weeks 12 and 24 were characterized by logistic regression using the area under the concentration‐time curve (AUC), estimated from the final population pharmacokinetic model, as an exposure predictor. The logistic regression showed that a higher AUC was associated with a higher probability of successful treatment. At each exposure level, probability of successful treatment was correlated with gestational age and treatment duration. Model‐predicted probabilities of successful treatment were consistent with actual results in the clinical trial. Simulations using several dosing regimens indicated that oral propranolol at 3 mg/kg per day was effective and would be appropriate for treating Japanese infants. These simulation results can support optimization of dosing regimens, such as selecting amounts, treatment durations, and dosing intervals, for clinical use.

Hemangiol® in infantile haemangioma: A paediatric post-marketing surveillance drug study

“…Of note, SAEs occurred in two prematurely born children, who may be more prone to hypoglycaemia and bronchial hyperreactivity as previously reported 32 . Therefore, low dose of Hemangiol(r) (2mg/kg/day) could be of interest in such high-risk children 23,28 , however the dosage of 3mg/kg/day has been more investigated in pharmacokinetics and pharmacodynamics studies 33,34 based on the manufacturer's clinical trial 18 . For all SAEs, causality scores concluded to possible to strong relation to Hemangiol(r).…”

An Open-Label Single-Arm Clinical Trial of Propranolol Cream in Infantile Hemangioma

“…The cream was shown to be safe with no serious side effects such as hypotension, bradycardia, or hypoglycemia, unlike the oral formulation. In a clinical study of an oral liquid formulation in Japanese subjects, the median simulated trough concentrations in the plasma after repeated oral administration of 3 mg/kg/day propranolol twice daily for 168 h were 16.7, 20.8, and 26.4 ng/mL at 6, 9, and 12 h, respectively [9]. In the present study, plasma concentrations were measured at weeks 4 and 24; both of the highest values were considerably lower than the simulated trough concentration, suggesting that the drug had little systemic effect and was only locally effective.…”

Commentary:Beta‐blockers and sleep problems

“…Moreover, two separate pharmacokinetic studies demonstrated that irregular twice daily dosing with as short as a 6hour interval does not affect propranolol's efficacy. 11,12 In fact, this is probably the stronger conclusion I would derive from the study.…”

“…If given in the early afternoon, less propranolol will be in the blood stream at night, potentially causing less sleep disturbance. Moreover, two separate pharmacokinetic studies demonstrated that irregular twice daily dosing with as short as a 6‐hour interval does not affect propranolol's efficacy 11,12 . In fact, this is probably the stronger conclusion I would derive from the study.…”