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[Preprint]. 2023 Jun 9:rs.3.rs-3006963.
doi: 10.21203/rs.3.rs-3006963/v1.

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

Judy Aschner, Charul Avachat  1 , Angela Birnbaum  1 , Catherine Sherwin, Candice Fike  2
Affiliations

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

Judy Aschner et al. Res Sq. .

Update in

Abstract

Objective: Information is needed to guide the design of randomized controlled trials (RCTs) evaluating L-citrulline as a therapy for premature infants with pulmonary hypertension associated with bronchopulmonary dysplasia (BPD-PH). Our goal was to evaluate the tolerability and ability to achieve a target steady-state L-citrulline plasma concentration in prematures treated enterally with a multi-dose L-citrulline strategy based on our single-dose pharmacokinetic study.

Study design: Six prematures received 60 mg/kg of L-citrulline every 6 hours for 72 hours. Plasma L-citrulline concentrations were measured before the first and last L-citrulline doses. L-citrulline concentrations were compared to concentration-time profiles from our previous study.

Results: Plasma L-citrulline concentrations agreed with the simulated concentration-time profiles. No serious adverse events occurred.

Conclusions: Simulations based on single-doses can be used to predict target multi-dose plasma L-citrulline concentrations. These results assist the design of RCTs evaluating the safety and effectiveness of L-citrulline therapy for BPD-PH. Clinical trials.gov ID: NCT03542812.

Keywords: L-arginine; nitric oxide; pharmacokinetics.

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Conflict of interest statement

COMPETING INTERESTS: CDF and JLA are inventors on a patent at Vanderbilt University Medical Center that has been licensed to Asklepion Pharmaceuticals for the “Therapeutic treatment of bronchopulmonary dysplasia.”

Figures

Figure 1
Figure 1
A. Plasma L-citrulline concentrations (mmol/L) of individual subjects collected at baseline and prior to the 12th dose of L-citrulline. B. Plasma arginine concentrations (mmol/L) of individual subjects collected at baseline and prior to the 12th dose of L-citrulline. C. Urine NOx/Urine Cr levels of individual subjects collected before (baseline) and after the 12th dose of L-citrulline.
Figure 2
Figure 2
Observed/predicted plasma L-citrulline concentration (mg/mL) time profiles. Solid black lines represent predicted plasma L-citrulline concentrations. Dotted black lines represent 8.76 mg/ml (50 mmol/L) and 14 mg/mL (80 mmol/L) concentrations. Black dots are the observed L-citrulline concentrations (mg/mL) collected at study time points (i.e. at baseline and prior to the 12th dose of L-citrulline). Note that 2 subjects had the same L-citrulline concentration of 9.3 mg/ml (53 mmol/L) at the second study time point so that dot reflects the data for 2 subjects.
Figure 3
Figure 3
The mean BP measurements (mm Hg) of individual subjects recorded at baseline (dose 0) and with each of the 12 doses of L-citrulline administration.
See this image and copyright information in PMC

References

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