Related Experiment Video
Updated: Mar 7, 2026
Quantification of the Immunosuppressant Tacrolimus on Dried Blood Spots Using LC-MS/MS
Published on: November 8, 2015
Developmental pharmacokinetics of sirolimus: Implications for precision dosing in neonates and infants with
Tomoyuki Mizuno1, Tsuyoshi Fukuda1,2, Chie Emoto1,2
1Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Insights
This study developed age-appropriate sirolimus dosing regimens for infants and neonates with vascular anomalies. The new dosing strategy aims to improve therapeutic drug management and precision dosing in young children.
Area of Science:
- Pharmacometrics and Systems Pharmacology
- Pediatric Pharmacology
- Vascular Anomaly Treatment
Background:
- Sirolimus demonstrates efficacy in pediatric patients with complicated vascular anomalies.
- Limited dosing information exists for neonates and infants, necessitating further research.
- Developmental changes in drug elimination capacity impact dosing in young children.
Purpose of the Study:
- To develop an age-appropriate sirolimus starting dosing regimen for neonates and infants.
- To address the limited dosing data in this vulnerable pediatric population.
- To optimize sirolimus therapy based on developmental pharmacokinetics.
Main Methods:
- Utilized a sirolimus maturation model to simulate drug clearance in neonates and infants (0-24 months).
- Generated steady-state predose concentrations and simulated dose requirements for target trough concentrations (5-15 ng/ml).
- Selected starting doses to maximize the probability of achieving target sirolimus concentrations across age cohorts.
Main Results:
- Simulated sirolimus clearance increased with age, consistent with prior findings.
- Proposed dosing regimens for eight age cohorts achieved target attainment rates of 75-95%.
- Identified specific dosing strategies tailored to different age groups within the first two years of life.
Conclusions:
- Established age-appropriate sirolimus dosing regimens for neonates and infants with vascular anomalies.
- The developed algorithm, coupled with therapeutic drug management, supports precision dosing in pediatric patients.
- A prospective evaluation of these dosing regimens is planned to confirm their clinical utility.
Background:
Sirolimus has recently been shown to be efficacious and tolerable in pediatric patients with complicated vascular anomalies. Nevertheless, dosing information remains very limited especially for neonates and infants. The purpose of this study was to develop an age-appropriate sirolimus starting dosing regimen based on the developmental changes in drug elimination capacity using data collected in neonates and infants.
Procedure:
A recently developed sirolimus maturation model [Emoto et al. CPT Pharmacometrics Syst Pharmacol, 2016] was used to simulate clearance estimates using realistic age and weight covariates for age cohorts aged 0-24 months. Next, predose concentrations at steady state were generated for each age cohort of neonates and infants. Dose requirements to attain predefined target trough concentration ranges (10-15 and 5-10 ng/ml) were simulated across the different age groups. Starting doses were chosen to maximize the likelihood of achieving sirolimus-targeted concentrations.
Results:
The trajectory of simulated sirolimus clearances increased with age and was in agreement with the previous findings in the Phase 2 study. The proposed dosing regimens covered eight age cohorts and resulted in target attainment of more than 75-95% across selected regimens.
Conclusions:
This study identified age-appropriate sirolimus dosing regimens for neonates and infants. The algorithm in combination with therapeutic drug management will facilitate sirolimus precision dosing in young children with vascular anomalies. A prospective evaluation is being planned.
Related Concept Videos
01:26Pharmacokinetics in Pediatric Patients: Drug Excretion
01:17Pharmacokinetics in Pediatric Patients: Drug Distribution
01:29Drug Dosing: Infants and Children
01:24Pharmacokinetics in Pediatric Patients: Drug Metabolism
01:23Pharmacokinetics in Pediatric Patients: Overview and Drug Absorption
01:21Factors Affecting Drug Response: Overview