# Pharmacokinetics of oral L-citrulline in infants at high risk of developing pulmonary hypertension associated with bronchopulmonary dysplasia

> **NIH NIH R34** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2020 · $230,754

## Abstract

PROJECT SUMMARY
Our long-term objective is to provide a therapy to ameliorate pulmonary hypertension (PH) in infants with
bronchopulmonary dysplasia (BPD). Current treatment for infants with PH associated with BPD (BPD-PH) is
limited to attempts to resolve the underlying respiratory disorder, provide optimal nutrition for lung growth and
development, and use of oxygen as a vasodilator. Using this management approach, the survival rates at 6-24
months of age for infants with BPD-PH is only 50-60%. There is evidence that vasodilators other than oxygen
may be beneficial for the treatment of these infants. In particular, inhaled nitric oxide (NO) has been shown to
function effectively as an acute pulmonary vasodilator in infants with BPD-PH. There is also data showing
clinical improvement when inhaled NO is used long term, for 8-90 days. Inhaled NO is expensive and
cumbersome expecially when used long-term. An alternate source of NO can be provided with the NO-L-
arginine precursor, L-citrulline. Of note, oral L-citrulline has been shown to be bioavailable in adult humans and
in the Fike lab newborn piglet model of PH. A safety profile for using oral L-citrulline in neonatal patients with
inborn errors of metabolism is already established. Moreover, the Fike lab has shown that treatment with oral
L-citrulline ameliorates PH in the newborn piglet model in a dose-dependent fashion. Furthermore, results from
studies with the piglet model of PH and from some limited data available from human infants undergoing
cardiac bypass surgery, indicate that a circulating plasma L-citrulline trough of 100-150 µM in human infants
will be needed to ameliorate BPD-PH. The overarching goal of this proposal is to develop oral L-citrulline
clinically as a treatment to ameliorate BPD-PH in human infants. Prior to large scale efficacy studies,
pharmacokinetic (PK) studies of oral L-citrulline are needed in order to determine the doses and treatment
intervals to be used that will achieve target plasma levels of 100-150 µM in infants at high risk of developing
BPD-PH. The aims of this proposal are to: 1) Characterize the PK profile of oral L-citrulline in infants at high
risk of developing BPD-PH in order to define an appropriate dose range (dose and treatment interval) that
achieves trough plasma L-citrulline levels of 100-150 µM and 2) Evaluate the ability to achieve the target L-
citrulline plasma levels in infants at high risk of developing BPD-PH treated for 72 hours with oral L-citrulline.
The results of these studies will define the oral L-citrulline dosing strategies to be used in a subsequent large
scale efficacy treatment trial for human infants at high risk of developing BPD-PH, an understudied population
of patients in desperate need of new therapies.

## Key facts

- **NIH application ID:** 9962983
- **Project number:** 5R34HL142995-03
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** CANDICE D FIKE
- **Activity code:** R34 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $230,754
- **Award type:** 5
- **Project period:** 2018-07-05 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9962983

## Citation

> US National Institutes of Health, RePORTER application 9962983, Pharmacokinetics of oral L-citrulline in infants at high risk of developing pulmonary hypertension associated with bronchopulmonary dysplasia (5R34HL142995-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9962983. Licensed CC0.

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