Efficacy and Safety of Sapropterin Dihydrochloride in Patients with Phenylketonuria: A Meta-analysis of Randomized Controlled Trials

Overview

Journal Br J Clin Pharmacol

Specialty Pharmacology

Date 2019 Feb 6

PMID 30720885

Citations 11

Authors

Jinghan Qu

Ting Yang

Ente Wang

Min Li

Chaoyang Chen

Lingyun Ma

Ying Zhou

Yimin Cui

Affiliations

Soon will be listed here.

Abstract

Aims: The aim of the present meta-analysis was to evaluate the efficacy and safety of sapropterin dihydrochloride in phenylketonuria (PKU) patients.

Methods: The following databases were searched for randomized controlled trials (RCT) regarding PKU patients treated with sapropterin dihydrochloride: PubMed, Embase, Cochrane Library and clinicaltrials. Two authors independently selected studies, assessed the risk of bias and extracted data. The meta-analysis was performed in RevMan 5.3 provided by the Cochrane Collaboration.

Results: Four studies met the inclusion criteria. In PKU patients with low blood phenylalanine (Phe) concentration, no significant difference was indicated for the decrease of Phe level (weighted mean difference (WMD) = -7.75 μmol L ; 95% confidence intervals (CI): -82.63 to 67.13, P = 0.84, I = 0%), however, the dietary Phe tolerance was significantly improved in the sapropterin group (WMD = 19.89 mg kg d ; 95% CI: 10.26 to 29.52, P < 0.0001, I = 0%). In PKU patients with high blood Phe level, sapropterin showed a significant lowering in blood Phe concentration (WMD = -225.31 μmol L ; 95% CI: -312.28 to -138.34, P < 0.00001, I = 0%). There was no significant difference for adverse events.

Conclusions: Sapropterin could bring benefit for PKU patients with high or low Phe level, due to Phe reduction in a short time or dietary Phe tolerance improvement respectively. Sapropterin has an acceptable safety profile.

Citing Articles

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Long-term safety of sapropterin in paediatric and adult individuals with phenylalanine hydroxylase deficiency: Final results of the Kuvan® Adult Maternal Paediatric European Registry multinational observational study.

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Total Protein Intake in Patients with PKU: Adequacy Evaluation According to the European PKU Guidelines from 2017.

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Expert Consensus on the Long-Term Effectiveness of Medical Nutrition Therapy and Its Impact on the Outcomes of Adults with Phenylketonuria.

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References

Krause W, Halminski M, McDonald L, Dembure P, Salvo R, Freides D . Biochemical and neuropsychological effects of elevated plasma phenylalanine in patients with treated phenylketonuria. A model for the study of phenylalanine and brain function in man. J Clin Invest. 1985; 75(1):40-8. PMC: 423395. DOI: 10.1172/JCI111695. View

Moher D, Liberati A, Tetzlaff J, Altman D . Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009; 6(7):e1000097. PMC: 2707599. DOI: 10.1371/journal.pmed.1000097. View

Huijbregts S, de Sonneville L, Licht R, van Spronsen F, Sergeant J . Short-term dietary interventions in children and adolescents with treated phenylketonuria: effects on neuropsychological outcome of a well-controlled population. J Inherit Metab Dis. 2003; 25(6):419-30. DOI: 10.1023/a:1021205713674. View

Jarnes Utz J, Lorentz C, Markowitz D, Rudser K, Diethelm-Okita B, Erickson D . START, a double blind, placebo-controlled pharmacogenetic test of responsiveness to sapropterin dihydrochloride in phenylketonuria patients. Mol Genet Metab. 2011; 105(2):193-7. DOI: 10.1016/j.ymgme.2011.10.014. View

Burton B, Grant M, Feigenbaum A, Singh R, Hendren R, Siriwardena K . A randomized, placebo-controlled, double-blind study of sapropterin to treat ADHD symptoms and executive function impairment in children and adults with sapropterin-responsive phenylketonuria. Mol Genet Metab. 2014; 114(3):415-24. DOI: 10.1016/j.ymgme.2014.11.011. View

Moyle J, Fox A, Arthur M, Bynevelt M, Burnett J . Meta-analysis of neuropsychological symptoms of adolescents and adults with PKU. Neuropsychol Rev. 2007; 17(2):91-101. DOI: 10.1007/s11065-007-9021-2. View

Lindegren M, Krishnaswami S, Reimschisel T, Fonnesbeck C, Sathe N, McPheeters M . A Systematic Review of BH4 (Sapropterin) for the Adjuvant Treatment of Phenylketonuria. JIMD Rep. 2013; 8:109-19. PMC: 3565680. DOI: 10.1007/8904_2012_168. View

Higgins J, Altman D, Gotzsche P, Juni P, Moher D, Oxman A . The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ. 2011; 343:d5928. PMC: 3196245. DOI: 10.1136/bmj.d5928. View

van Wegberg A, Macdonald A, Ahring K, Belanger-Quintana A, Blau N, Bosch A . The complete European guidelines on phenylketonuria: diagnosis and treatment. Orphanet J Rare Dis. 2017; 12(1):162. PMC: 5639803. DOI: 10.1186/s13023-017-0685-2. View

10.

Aldamiz-Echevarria L, Bueno M, Couce M, Lage S, Dalmau J, Vitoria I . Tetrahydrobiopterin therapy vs phenylalanine-restricted diet: impact on growth in PKU. Mol Genet Metab. 2013; 109(4):331-8. DOI: 10.1016/j.ymgme.2013.05.017. View

11.

Muntau A, Burlina A, Eyskens F, Freisinger P, De Laet C, Leuzzi V . Efficacy, safety and population pharmacokinetics of sapropterin in PKU patients <4 years: results from the SPARK open-label, multicentre, randomized phase IIIb trial. Orphanet J Rare Dis. 2017; 12(1):47. PMC: 5343543. DOI: 10.1186/s13023-017-0600-x. View

12.

Somaraju U, Merrin M . Sapropterin dihydrochloride for phenylketonuria. Cochrane Database Syst Rev. 2015; (3):CD008005. PMC: 6769157. DOI: 10.1002/14651858.CD008005.pub4. View

13.

Smith I, Knowles J . Behaviour in early treated phenylketonuria: a systematic review. Eur J Pediatr. 2000; 159 Suppl 2:S89-93. DOI: 10.1007/pl00014392. View

14.

Loeber J . Neonatal screening in Europe; the situation in 2004. J Inherit Metab Dis. 2007; 30(4):430-8. DOI: 10.1007/s10545-007-0644-5. View

15.

Trefz F, Burton B, Longo N, Martinez-Pardo Casanova M, Gruskin D, Dorenbaum A . Efficacy of sapropterin dihydrochloride in increasing phenylalanine tolerance in children with phenylketonuria: a phase III, randomized, double-blind, placebo-controlled study. J Pediatr. 2009; 154(5):700-7. DOI: 10.1016/j.jpeds.2008.11.040. View

16.

Schmidt E, Rupp A, Burgard P, Pietz J, Weglage J, de Sonneville L . Sustained attention in adult phenylketonuria: the influence of the concurrent phenylalanine-blood-level. J Clin Exp Neuropsychol. 1994; 16(5):681-8. DOI: 10.1080/01688639408402681. View

17.

Shamseer L, Moher D, Clarke M, Ghersi D, Liberati A, Petticrew M . Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ. 2015; 350:g7647. DOI: 10.1136/bmj.g7647. View

18.

Schmidt H, Burgard P, Pietz J, Rupp A . Intelligence and professional career in young adults treated early for phenylketonuria. Eur J Pediatr. 1996; 155 Suppl 1:S97-100. DOI: 10.1007/pl00014262. View

19.

Levy H, Milanowski A, Chakrapani A, Cleary M, Lee P, Trefz F . Efficacy of sapropterin dihydrochloride (tetrahydrobiopterin, 6R-BH4) for reduction of phenylalanine concentration in patients with phenylketonuria: a phase III randomised placebo-controlled study. Lancet. 2007; 370(9586):504-10. DOI: 10.1016/S0140-6736(07)61234-3. View

20.

Waisbren S, Noel K, Fahrbach K, Cella C, Frame D, Dorenbaum A . Phenylalanine blood levels and clinical outcomes in phenylketonuria: a systematic literature review and meta-analysis. Mol Genet Metab. 2007; 92(1-2):63-70. DOI: 10.1016/j.ymgme.2007.05.006. View