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

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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 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.

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.

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Acknowledgements

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).

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Authors and Affiliations

  1. Department of Pediatrics, The University of Utah Health, Salt Lake City, UT, USA

    Candice D. Fike & Angela K. Birnbaum

  2. Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA

    Charul Avachat, Angela K. Birnbaum & Catherine M. Sherwin

  3. Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY, USA

    Judy L. Aschner

  4. Department of Pediatrics, Hackensack Meridian School of Medicine, Nutley, NJ, USA

    Judy L. Aschner

  5. Department of Pediatrics, Wright State University Boonshoft School of Medicine, Dayton, OH, USA

    Catherine M. Sherwin

  6. Dayton Children’s Hospital, Dayton, OH, USA

    Catherine M. Sherwin

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  1. Candice D. Fike
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Corresponding author

Correspondence to Catherine M. Sherwin.

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Funding

This study was supported by a National Heart, Lung, and Blood Institute Grant R34-Hl-142995 (CDF).

Conflicts of Interest

Candice D. Fike and Judy L. Aschner are inventors on a patent at Vanderbilt University Medical Center that has been licensed to Asklepion pharmaceuticals for the “Therapeutic treatment for bronchopulmonary dysplasia”. Angela K. Birnbaum, and Charul Avachat, declare that they have no conflicts of interest. Catherine M. Sherwin is on the Editorial Board for Pediatric Drugs and has no other conflicts of interest to declare

Ethics Approval

All procedures performed in this study involving human participants were in accordance with the 1964 Helsinki Declaration and its later amendments. The study design was approved by the institutional review boards of The University of Utah and Intermountain Healthcare.

Consent to Participate

All participants or legal guardians of participants in the clinical trial included in these analyses provided written informed consent.

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Not applicable.

Availability of Data and Material

All the raw data are available from the first author, who is ready to share it with any researcher.

Code availability

Not applicable.

Author Contributions

Candice D. Fike, Judy L. Aschner, and Catherine M. Sherwin contributed to the conception and design of the study. Data collection was performed by Candice D. Fike. Formal data analysis was performed by Angela K. Birnbaum, Charul Avachat, and Catherine M. Sherwin. Candice D. Fike wrote the first draft of the manuscript. All authors reviewed and edited drafts of the manuscript and approved the final manuscript.

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Fike, C.D., Avachat, C., Birnbaum, A.K. et al. Pharmacokinetics of l-Citrulline in Neonates at Risk of Developing Bronchopulmonary Dysplasia-Associated Pulmonary Hypertension. Pediatr Drugs 25, 87–96 (2023). https://doi.org/10.1007/s40272-022-00542-x

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