Dataset Information

Multi-dose enteral L-citrulline administration in premature infants at risk of developing pulmonary hypertension associated with bronchopulmonary dysplasia.

ABSTRACT:

Objective

Information is needed to guide the design of randomized controlled trials (RCTs) evaluating L-citrulline therapy for premature infants with pulmonary hypertension associated with bronchopulmonary dysplasia (BPD-PH). Based on our single-dose pharmacokinetic study, we evaluated the ability of a multi-dose enteral L-citrulline strategy to achieve a target trough steady-state L-citrulline plasma concentration and its tolerability in premature infants.

Study design

Plasma L-citrulline concentrations were measured in six premature infants receiving 60 mg/kg L-citrulline every 6 h for 72 h before the first and last L-citrulline doses. L-citrulline concentrations were compared to concentration-time profiles from our previous study.

Results

Target trough plasma L-citrulline concentrations were achieved in 2/6 subjects. No serious adverse events occurred.

Conclusions

Multi-dose L-citrulline was well tolerated. These results will assist in the design of phase II RCTs evaluating L-citrulline dosage strategies to achieve target plasma L-citrulline concentrations in infants at risk for BPD-PH.

Clinical trials

gov ID: NCT03542812.

SUBMITTER: Fike CD

PROVIDER: S-EPMC10844094 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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Publications

Multi-dose enteral L-citrulline administration in premature infants at risk of developing pulmonary hypertension associated with bronchopulmonary dysplasia.

Fike Candice D CD Aschner Judy L JL Avachat Charul C Birnbaum Angela K AK Sherwin Catherine M T CMT

Journal of perinatology : official journal of the California Perinatal Association 20231031 2

<h4>Objective</h4>Information is needed to guide the design of randomized controlled trials (RCTs) evaluating L-citrulline therapy for premature infants with pulmonary hypertension associated with bronchopulmonary dysplasia (BPD-PH). Based on our single-dose pharmacokinetic study, we evaluated the ability of a multi-dose enteral L-citrulline strategy to achieve a target trough steady-state L-citrulline plasma concentration and its tolerability in premature infants.<h4>Study design</h4>Plasma L-c ...[more]

PMID: 37907796

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Project description:BackgroundOptions 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.ObjectivesThis 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 resultsTen 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 volume of distribution (V/F) and clearance (CL/F) were 302.89 ml and 774.96 ml/h, respectively, with the drug exhibiting a 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.ConclusionThis 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.RegistrationClinical trials.gov Identifier: NCT03542812.

Dataset Information

Multi-dose enteral L-citrulline administration in premature infants at risk of developing pulmonary hypertension associated with bronchopulmonary dysplasia.

Objective

Study design

Results

Conclusions

Clinical trials

Publications

Multi-dose enteral L-citrulline administration in premature infants at risk of developing pulmonary hypertension associated with bronchopulmonary dysplasia.

Similar Datasets

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