Urinary phenylacetylglutamine as dosing biomarker for patients with urea cycle disorders

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• 作者：M. Mokhtarani^a ; ^{Masoud.mokhtarani@hyperiontx.com} ; G.A. Diaz^b ; W. Rhead^c ; U. Lichter-Konecki^d ; J. Bartley^e ; A. Feigenbaum^f ; N. Longo^g ; W. Berquist^h ; S.A. Berryⁱ ; R. Gallagher^j ; D. Bartholomew^k ; C.O. Harding^l ; M.S. Korson^m ; S.E. McCandlessⁿ ; W. Smith^o ; J. Vockley^p ; S. Bart^q ; D. Kronn^r ; R. Zori^s ; S. Cederbaum^t ; N. Dorrani^t ; J.L. Merritt II^u ; Sandesh Sreenath-Nagamani^v ; M. Summar^d ; C. LeMons^w ; K. Dickinson^a ; D.F. Coakley^a ; T.L. Moors^a ; B. Lee^v ; B.F. Scharschmidt^a
• 关键词：ASL ; argininosuccinate lyase deficiency ; ASS ; argininosuccinate synthetase deficiency ; AUC0&ndash ; 24 ; 24  ; hour area under the curve ; CV % ; coefficient of variation ; DSMB ; Data Safety and Monitoring Board ; GPB ; glycerol phenylbutyrate (generic name for
• 刊名：Molecular Genetics and Metabolism
• 出版年：2012
• 出版时间：November, 2012
• 年：2012
• 卷：107
• 期：3
• 页码：308-314
• 全文大小：402 K

文摘

We have analyzed pharmacokinetic data for glycerol phenylbutyrate (also GT4P or HPN-100) and sodium phenylbutyrate with respect to possible dosing biomarkers in patients with urea cycle disorders (UCD).

Study design

These analyses are based on over 3000 urine and plasma data points from 54 adult and 11 pediatric UCD patients (ages 6-17) who participated in three clinical studies comparing ammonia control and pharmacokinetics during steady state treatment with glycerol phenylbutyrate or sodium phenylbutyrate. All patients received phenylbutyric acid equivalent doses of glycerol phenylbutyrate or sodium phenylbutyrate in a cross over fashion and underwent 24-hour blood samples and urine sampling for phenylbutyric acid, phenylacetic acid and phenylacetylglutamine.

Results

Patients received phenylbutyric acid equivalent doses of glycerol phenylbutyrate ranging from 1.5 to 31.8 g/day and of sodium phenylbutyrate ranging from 1.3 to 31.7 g/day. Plasma metabolite levels varied widely, with average fluctuation indices ranging from 1979 % to 5690 % for phenylbutyric acid, 843 % to 3931 % for phenylacetic acid, and 881 % to 1434 % for phenylacetylglutamine. Mean percent recovery of phenylbutyric acid as urinary phenylacetylglutamine was 66.4 and 69.0 for pediatric patients and 68.7 and 71.4 for adult patients on glycerol phenylbutyrate and sodium phenylbutyrate, respectively. The correlation with dose was strongest for urinary phenylacetylglutamine excretion, either as morning spot urine (r = 0.730, p < 0.001) or as total 24-hour excretion (r = 0.791 p < 0.001), followed by plasma phenylacetylglutamine AUC_24-hour, plasma phenylacetic acid AUC_24-hour and phenylbutyric acid AUC_24-hour. Plasma phenylacetic acid levels in adult and pediatric patients did not show a consistent relationship with either urinary phenylacetylglutamine or ammonia control.

Conclusion

The findings are collectively consistent with substantial yet variable pre-systemic (1st pass) conversion of phenylbutyric acid to phenylacetic acid and/or phenylacetylglutamine. The variability of blood metabolite levels during the day, their weaker correlation with dose, the need for multiple blood samples to capture trough and peak, and the inconsistency between phenylacetic acid and urinary phenylacetylglutamine as a marker of waste nitrogen scavenging limit the utility of plasma levels for therapeutic monitoring. By contrast, 24-hour urinary phenylacetylglutamine and morning spot urine phenylacetylglutamine correlate strongly with dose and appear to be clinically useful non-invasive biomarkers for compliance and therapeutic monitoring.