Semi-mechanistic Modeling of Hypoxanthine, Xanthine, and Uric Acid Metabolism in Asphyxiated Neonates

Wan-Yu Chu, Karel Allegaert, Thomas P. C. Dorlo, Alwin D. R. Huitema*, ALBINO Study Grp

*Corresponding author for this work

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Abstract

Background and Objective: Previously, we developed a pharmacokinetic-pharmacodynamic model of allopurinol, oxypurinol, and biomarkers, hypoxanthine, xanthine, and uric acid, in neonates with hypoxic-ischemic encephalopathy, in which high initial biomarker levels were observed suggesting an impact of hypoxia. However, the full pharmacodynamics could not be elucidated in our previous study. The current study included additional data from the ALBINO study (NCT03162653) placebo group, aiming to characterize the dynamics of hypoxanthine, xanthine, and uric acid in neonates with hypoxic-ischemic encephalopathy. Methods: Neonates from the ALBINO study who received allopurinol or placebo mannitol were included. An extended population pharmacokinetic-pharmacodynamic model was developed based on the mechanism of purine metabolism, where synthesis, salvage, and degradation via xanthine oxidoreductase pathways were described. The initial level of the biomarkers was a combination of endogenous turnover and high disease-related amounts. Model development was accomplished by nonlinear mixed-effects modeling (NONMEM ®, version 7.5). Results: In total, 20 neonates treated with allopurinol and 17 neonates treated with mannitol were included in this analysis. Endogenous synthesis of the biomarkers reduced with 0.43% per hour because of precursor exhaustion. Hypoxanthine was readily salvaged or degraded to xanthine with rate constants of 0.5 1/h (95% confidence interval 0.33–0.77) and 0.2 1/h (95% confidence interval 0.09–0.31), respectively. A greater salvage was found in the allopurinol treatment group consistent with its mechanism of action. High hypoxia-induced initial levels of biomarkers were quantified, and were 1.2-fold to 2.9-fold higher in neonates with moderate-to-severe hypoxic-ischemic encephalopathy compared with those with mild hypoxic-ischemic encephalopathy. Half-maximal xanthine oxidoreductase inhibition was achieved with a combined allopurinol and oxypurinol concentration of 0.68 mg/L (95% confidence interval 0.48–0.92), suggesting full xanthine oxidoreductase inhibition during the period studied. Conclusions: This extended pharmacokinetic-pharmacodynamic model provided an adequate description of the complex hypoxanthine, xanthine, and uric acid metabolism in neonates with hypoxic-ischemic encephalopathy, suggesting a positive allopurinol effect on these biomarkers. The impact of hypoxia on their dynamics was characterized, underlining higher hypoxia-related initial exposure with a more severe hypoxic-ischemic encephalopathy status.

Original languageEnglish
Pages (from-to)1545-1558
Number of pages14
JournalClinical Pharmacokinetics
Volume61
Issue number11
Early online date30 Aug 2022
DOIs
Publication statusPublished - Nov 2022

Bibliographical note

Funding Information:
The ALBINO Study Group involved in this project consists of the coordinating investigators, the pharmacokinetic study group, and the beneficiaries and national coordinators. Coordinating investigators are Axel R. Franz (University Hospital Tuebingen, Tuebingen, Germany) and Mario Rüdiger (University Hospital CG Carus, Medizinische Fakultät der TU Dresden, Dresden, Germany). The contributors to the pharmacokinetic study group are Laura Nijstad and Kim Annink (Utrecht, the Netherlands), Christian Maiwald (Tuebingen, Germany), Michael Schroth and Anja Hagen (Nuremberg, Germany) and Loubna el Bakkali and Mirjam M. van Weisenbruch (Amsterdam, the Netherlands). The beneficiaries and national coordinators are Axel R. Franz and Christian F. Poets (Tuebingen, Germany), Mario Rüdiger (Dresden, Germany), Manon Benders and Frank van Bel (Utrecht, the Netherlands), Karel Allegaert and Gunnar Naulaers (Leuven, Belgium), Dirk Bassler (Zurich, Switzerland), Katrin Klebermass-Schrehof (Vienna, Austria), Maximo Vento (Valencia, Spain), Hercilia Guimaraes (Porto, Portugal), Tom Stiris (Oslo, Norway), Isabella Mauro (Udine, Italy), Marjo Metsäranta (Helsinki, Finland), Sampsa Vanhatalo (Helsinki, Finland), Jan Mazela (Poznan, Poland), Tuuli Metsvaht (Tartu, Estonia), and Roselinda van der Vlugt-Meijer (ACE Pharmaceuticals, Zeewolde, the Netherlands).

Funding Information:
The ALBINO study is funded under the Horizon 2020 Framework EU Program call H2020-PHC-2015-two-stage grant 667224. The research on the pharmacokinetics during whole body hypothermia (KA) is further supported by the iPREDICT project (FWO Senior research project, fundamental research, G0D0520N).

Publisher Copyright:
© 2022, The Author(s).

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