Pharmacokinetics of l-Citrulline in Neonates at Risk of Developing Bronchopulmonary Dysplasia-Associated Pulmonary Hypertension

Candice D. Fike, Charul Avachat, Angela K. Birnbaum, Judy L. Aschner, Catherine M. Sherwin

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Options to treat pulmonary hypertension (PH) in neonates with bronchopulmonary dysplasia (BPD) are few and largely ineffective. Improving the bioavailability of nitric oxide (NO) might be an efficacious treatment for BPD-PH. When administered orally, the NO-l-arginine precursor, l-citrulline, increases NO production in children and adults, however, pharmacokinetic (PK) studies of oral l-citrulline have not been performed in infants and children. Objectives: This study characterized the PK of enterally administered l-citrulline in neonates at risk of developing BPD-PH to devise a model-informed dosing strategy. Methods and results: Ten premature neonates (≤ 28 weeks gestation) were administered a single dose of 150 mg/kg (powder form solubilized in sterile water) oral l-citrulline at 32 ± 1 weeks postmenstrual age. Due to the need to limit blood draws, time windows were used to maximize the sampling over the dosing interval by assigning neonates to one of two groups (ii) samples collected pre-dose and at 1- and 2.5-h post-dose, and (ii) pre-dose and 0.25- and 3-h post-dose. The l-arginine concentrations (µmol/L) and the l-citrulline (µmol/L) plasma concentration-time data were evaluated using non-compartmental analysis (Phoenix WinNonlin version 8.1). Optimal dosage strategies were derived using a simulation-based methodology. Simulated doses of 51.5 mg or 37.5 mg/kg given four times a day produced steady-state concentrations close to a target of 50 µmol/L. The volumeof distribution (V/F) and clearance (CL/F) were 302.89 ml and 774.96 ml/h, respectively, with the drug exhibitinga half-life of 16 minutes. The AUC from the time of dosing to the time of last concentration was 1473.3 h*μmol/L,with Cmax and Tmax of 799 μmol/L and 1.55 h, respectively. Conclusion: This is the first PK study in neonates presenting data that can be used to inform dosing strategies in future randomized controlled trials evaluating enteral l-citrulline as a potential treatment to reduce PH associated with BPD in premature neonates. Registration: Clinical trials.gov Identifier: NCT03542812.

Original languageEnglish (US)
Pages (from-to)87-96
Number of pages10
JournalPediatric Drugs
Volume25
Issue number1
DOIs
StatePublished - Jan 2023

Bibliographical note

Funding Information:
We thank Asklepion Pharmaceuticals for the generous gift of the l -citrulline used in this study. We also thank the Newborn Clinical Research Nurse Coordinators at the University of Utah and Intermountain Medical Center for their help enrolling patients and performing the study. This work was supported by National Heart, Lung, and Blood Institute Grant R34-HL-142995 (CDF).

Funding Information:
This study was supported by a National Heart, Lung, and Blood Institute Grant R34-H l -142995 (CDF).

Funding Information:
We thank Asklepion Pharmaceuticals for the generous gift of the l -citrulline used in this study. We also thank the Newborn Clinical Research Nurse Coordinators at the University of Utah and Intermountain Medical Center for their help enrolling patients and performing the study. This work was supported by National Heart, Lung, and Blood Institute Grant R34-HL-142995 (CDF).

Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Switzerland AG.

Fingerprint

Dive into the research topics of 'Pharmacokinetics of l-Citrulline in Neonates at Risk of Developing Bronchopulmonary Dysplasia-Associated Pulmonary Hypertension'. Together they form a unique fingerprint.

Cite this