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

Tomoki Takechi, Tadao Kumokawa, Rumiko Kato, Takeshi Higuchi, Tsuyoshi Kaneko, Ichiro Ieiri

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1361-1370
Number of pages10
JournalJournal of Clinical Pharmacology
Volume58
Issue number10
DOIs
Publication statusPublished - Oct 1 2018

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Hemangioma
Propranolol
Pharmacokinetics
Pediatrics
Population
Logistic Models
Therapeutics
Gestational Age
Body Weight
Clinical Trials

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

Cite this

Population Pharmacokinetics and Pharmacodynamics of Oral Propranolol in Pediatric Patients With Infantile Hemangioma. / Takechi, Tomoki; Kumokawa, Tadao; Kato, Rumiko; Higuchi, Takeshi; Kaneko, Tsuyoshi; Ieiri, Ichiro.

In: Journal of Clinical Pharmacology, Vol. 58, No. 10, 01.10.2018, p. 1361-1370.

Research output: Contribution to journalArticle

Takechi, Tomoki ; Kumokawa, Tadao ; Kato, Rumiko ; Higuchi, Takeshi ; Kaneko, Tsuyoshi ; Ieiri, Ichiro. / Population Pharmacokinetics and Pharmacodynamics of Oral Propranolol in Pediatric Patients With Infantile Hemangioma. In: Journal of Clinical Pharmacology. 2018 ; Vol. 58, No. 10. pp. 1361-1370.
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