Clinical Pharmacokinetics

, Volume 47, Issue 12, pp 817–825 | Cite as

Pharmacokinetics of Sapropterin in Patients with Phenylketonuria

  • François Feillet
  • Lorne Clarke
  • Concetta Meli
  • Mark Lipson
  • Andrew A. Morris
  • Paul Harmatz
  • Diane R. Mould
  • Bruce Green
  • Alex Dorenbaum
  • Marcello Giovannini
  • Erik Foehr
Original Research Article


Background and objective: Untreated phenylketonuria is characterized by neurocognitive and neuromotor impairment, which result from elevated blood phenylalanine concentrations. To date, the recommended management of phenylketonuria has been the use of a protein-restricted diet and the inclusion of phenylalanine-free protein supplements; however, this approach is often associated with poor compliance and a suboptimal clinical outcome. Sapropterin dihydrochloride, herein referred to as sapropterin, a synthetic formulation of 6R-tetrahydrobiopterin (6R-BH4), has been shown to be effective in reducing blood phenylalanine concentrations in patients with phenylketonuria. The objective of the current study was to characterize the pharmacokinetics and pharmacokinetic variability of sapropterin and to identify the characteristics that influence this variability.

Patients and methods: This was a 12-week, fixed-dose phase of an open-label extension study. The study was conducted at 26 centres in North America and Europe.

Patients with phenylketonuria were eligible to participate if they were ≥8 years of age and had received ≥80% of the scheduled doses in a previous 6-week, randomized, placebo-controlled study or had been withdrawn from that study after exceeding a plasma phenylalanine concentration of ≥1500 μmol/L to ≥1800 μmol/L, depending on the subject’s age and baseline plasma phenylalanine concentration. A total of 78 patients participated. Patients received oral once-daily doses of sapropterin (Kuvan®) 5, 10 or 20 mg/kg/day.

Blood samples for the pharmacokinetic analysis were obtained during weeks 6, 10 and 12. A D-optimal sparse sampling strategy was used, and data were analysed by population-based, nonlinear, mixed-effects modelling methods.

Main outcome measure: In a prospectively planned analysis, the apparent clearance, apparent volume of distribution, absorption rate constant and associated interindividual variabilities of each parameter were estimated by modelling observed BH4 plasma concentration-time data.

Results: The best structural model to describe the pharmacokinetics of sapropterin was a two-compartment model with first-order input, first-order elimination and a baseline endogenous BH4 concentration term. Total bodyweight was the only significant covariate identified, the inclusion of which on both the apparent clearance (mean = 2100 L/h/70 kg) and central volume of distribution (mean = 8350 L/70 kg) substantially improved the model’s ability to describe the data. The mean (SD) terminal half-life of sapropterin was 6.69 (2.29) hours and there was little evidence of accumulation, even at the highest dose.

Conclusion: These findings, taken together with the observed therapeutic effect, support bodyweight-based, once-daily dosing of sapropterin 5–20 mg/kg/day.


Interindividual Variability Phenylketonuria Visual Predictive Check Pharmacokinetic Variability Phenylalanine Concentration 



This study was sponsored by BioMarin Pharmaceutical Inc., which had a significant role in the study design; the collection, analysis and interpretation of data; and the writing of the report. The study protocol was drafted and developed by the study sponsor. Representatives or employees of the sponsor were responsible for the administration and monitoring of the study. Analysis of plasma samples for pharmacokinetic analysis was performed by Quest Pharmaceutical Services (Newark, DE, USA). Data management was undertaken by Pacific Data Designs, Inc. (San Francisco, CA, USA) and the population pharmacokinetic evaluations were conducted by Projections Research Inc. (Phoenixville, PA, USA).

François Feillet, assisted by Phillippa Curran, prepared the first draft of the manuscript, which was then modified based on comments and suggestions from all authors. Bruce Green and Diane Mould completed the population pharmacokinetic modelling and contributed towards the writing and interpretation of the data. The final manuscript was approved by all authors.

François Feillet has received honoraria from BioMarin Pharmaceutical Inc. Paul Harmatz has provided consultancy support to BioMarin Pharmaceutical Inc. and has received honoraria or travel support from BioMarin Pharmaceutical Inc. Diane Mould has provided paid consultancy support to BioMarin Pharmaceutical Inc. Bruce Green has provided paid consultancy support to BioMarin Pharmaceutical Inc. Alex Dorenbaum is an employee of BioMarin Pharmaceutical Inc. and owns stock and stock options in BioMarin Pharmaceutical Inc. Erik Foehr is an employee of BioMarin Pharmaceutical Inc. Lorne Clarke, Concetta Meli, Mark Lipson, Andrew Morris and Marcello Giovannini have no conflicts of interest that are directly relevant to the content of this study.

The authors would like to thank their fellow investigators of the Sapropterin Research Group: Canada: A. Feigenbaum, Hospital for Sick Children, Toronto, ON; France: V. Abadie, Hôpital Necker — Enfants Malades, Paris; D. Dobbelaere, CHRU de Lille Hôpital Jeanne de Flandres, Lille; Germany: J. Hennermann, Charité Campus Virchow Klinikum, Otto-Heubner-Centrum fur Kinder und Jugendmedizin, Berlin; F. Trefz, Klinik fur Kinder und Jugendmedizin Reutlingen, Reutlingen; U. Wendel, University Children’s Hospital, Düsseldorf; Ireland: E. Treacy, National Centre for Inherited Metabolic Disorders, The Children’s University Hospital, Dublin; Poland: A. Milanowski, Instytut Matki i Dziecka Apteka, Warsaw; UK: A. Chakrapani, Birmingham Children’s Hospital, Birmingham; M. Cleary, Great Ormond Street Hospital, London; P. Lee, National Hospital for Neurology & Neurosurgery, London; USA: J. Baker, Kaiser Permanente San Jose Medical Center, Oakland, CA; J. Bergoffen, Genetics Department, Kaiser Permanente San Jose Medical Center, San Jose, CA; B.K. Burton, Children’s Memorial Hospital, Chicago, IL; E. Crombez, David Geffen School of Medicine at UCLA, Los Angeles, CA; D. Grange, St Louis Children’s Hospital, St Louis, MO; C. Harding, Oregon Health & Science University, Portland, OR; R. Koch, Children’s Hospital Los Angeles, Los Angeles, CA; H. Levy, Metabolism Research, Children’s Hospital of Boston, Boston, MA; N. Longo, Medical Genetics and Pediatrics, University of Utah, Salt Lake City, UT; L. Randolph, Children’s Hospital Los Angeles, Los Angeles, CA; M. Seashore, Yale University, New Haven, CT; G. Vockley, Division of Medical Genetics, Children’s Hospital of Pittsburgh, Pittsburgh, PA; L. Waber, Children’s Medical Center of Dallas, Dallas, TX; M. Wasserstein, Mount Sinai School of Medicine, New York, NY; C. Whitley, Pharmaceutical Services, Fairview University Medical Center, Minneapolis, MN; J. Wolff, University of Wisconsin, Madison, WI.

The authors would also like to thank William Kramer for his contribution to the design and analysis of the pharmacokinetic trials.


  1. 1.
    Donlon J, Levy HL, Scriver CR. Hyperphenylalaninemia: phenylalanine hydroxylase deficiency. In: Scriver CR, Beaudet AL, Sly WS, et al., editors. The metabolic and molecular bases of inherited disease. 8th ed. New York: McGraw-Hill Companies, Inc., 2001: 1667–724Google Scholar
  2. 2.
    National Institutes of Health Consensus Development Panel. National Institutes of Health Consensus Development Conference statement. Phenylketonuria: screening and management. Pediatrics 2001 Oct; 108(4): 972–82CrossRefGoogle Scholar
  3. 3.
    Hennermann JB, Buhrer C, Blau N, et al. Long-term treatment with tetrahydrobiopterin increases phenylalanine tolerance in children with severe phenotype of phenylketonuria. Mol Genet Metab 2005 Dec; 86 Suppl. 1: S86–90PubMedCrossRefGoogle Scholar
  4. 4.
    Lambruschini N, Perez-Duenas B, Vilaseca MA, et al. Clinical and nutritional evaluation of phenylketonuric patients on tetrahydrobiopterin monotherapy. Mol Genet Metab 2005 Dec; 86 Suppl. 1: S54–60PubMedCrossRefGoogle Scholar
  5. 5.
    Trefz FK, Scheible D, Frauendienst-Egger G, et al. Long-term treatment of patients with mild and classical phenylketonuria by tetrahydrobiopterin. Mol Genet Metab 2005 Dec; 86 Suppl. 1: S75–80PubMedCrossRefGoogle Scholar
  6. 6.
    Lee P, Treacy EP, Crombez E, et al. Safety and efficacy of 22 weeks of treatment with sapropterin dihydrochloride in patients with phenylketonuria. Am J Med Genet A 2008 Oct 16; 146A(22): 2851–9PubMedCrossRefGoogle Scholar
  7. 7.
    Burton B, Grange D, Milanowski A, et al. The response of patients with phenylketonuria and elevated serum phenylalanine to treatment with oral sapropterin dihydrochloride (6R-tetrahydrobiopterin): a phase II, multicentre, open-label, screening study. J Inherit Metab Dis 2007 Oct; 30(5): 700–7PubMedCrossRefGoogle Scholar
  8. 8.
    Levy H, Milanowski A, Chakrapani A, et al. 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 Aug; 370(9586): 504–10PubMedCrossRefGoogle Scholar
  9. 9.
    Green B, Duffull SB. Prospective evaluation of a D-optimal designed population pharmacokinetic study. J Pharmacokinet Pharmacodyn 2003 Apr; 30(2): 145–61PubMedCrossRefGoogle Scholar
  10. 10.
    Fiege B, Ballhausen D, Kierat L, et al. Plasma tetrahydrobiopterin and its pharmacokinetic following oral administration. Mol Genet Metab 2004 Jan; 81(1): 45–51PubMedCrossRefGoogle Scholar
  11. 11.
    Fukushima T, Nixon JC. Analysis of reduced forms of biopterin in biological tissues and fluids. Anal Biochem 1980 Feb; 102(1): 176–88PubMedCrossRefGoogle Scholar
  12. 12.
    Mandema JW, Verotta D, Sheiner LB. Building population pharmacokinetic-pharmacodynamic models: I. Models for covariate effects. J Pharmacokinet Biopharm Oct 1992; 20(5): 511–28CrossRefGoogle Scholar
  13. 13.
    Gobburu JV, Lawrence J. Application of resampling techniques to estimate exact significance levels for covariate selection during nonlinear mixed effects model building: some inferences. Pharm Res 2002 Jan; 19(1): 92–8PubMedCrossRefGoogle Scholar
  14. 14.
    Wahlby U, Jonsson EN, Karlsson MO. Assessment of actual significance levels for covariate effects in NONMEM. J Pharmacokinet Pharmacodyn 2001 Jun; 28(3): 231–52PubMedCrossRefGoogle Scholar
  15. 15.
    Wade JR, Beal SL, Sambol NC. Interaction between structural, statistical, and covariate models in population pharmacokinetic analysis. J Pharmacokinet Biopharm 1994 Apr; 22(2): 165–77PubMedCrossRefGoogle Scholar
  16. 16.
    Yano Y, Beal SL, Sheiner LB. Evaluating pharmacokinetic/pharmacodynamic models using the posterior predictive check. J Pharmacokinet Pharmacodyn 2001 Apr; 28(2): 171–92PubMedCrossRefGoogle Scholar
  17. 17.
    Ritschel W. Handbook of basic pharmacokinetics. 2nd ed. Hamilton (IL): Drug Intelligence Publications, 1980: 413–26Google Scholar
  18. 18.
    Fiege B, Bonafe L, Ballhausen D, et al. Extended tetrahydrobiopterin loading test in the diagnosis of cofactor-responsive phenylketonuria: a pilot study. Mol Genet Metab 2005 Dec; 86 Suppl. 1: S91–5PubMedCrossRefGoogle Scholar
  19. 19.
    Matalon R, Koch R, Michals-Matalon K, et al. Biopterin responsive phenylalanine hydroxylase deficiency. Genet Med 2004 Jan-Feb; 6(1): 27–32PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2008

Authors and Affiliations

  • François Feillet
    • 1
  • Lorne Clarke
    • 2
  • Concetta Meli
    • 3
  • Mark Lipson
    • 4
  • Andrew A. Morris
    • 5
  • Paul Harmatz
    • 6
  • Diane R. Mould
    • 7
  • Bruce Green
    • 7
  • Alex Dorenbaum
    • 8
  • Marcello Giovannini
    • 9
  • Erik Foehr
    • 8
  1. 1.Centre de Référence des Maladies Héréditaires du MétabolismeHôpital d’Enfants, CHU BraboisVandoeuvre les NancyFrance
  2. 2.UBC Department of Medical GeneticsChildren’s Hospital Research InstituteVancouverCanada
  3. 3.Azienda Ospedaliera UniversitariaCataniaItaly
  4. 4.Kaiser Permanente Medical CenterSacramentoUSA
  5. 5.Manchester Children’s HospitalManchesterUK
  6. 6.Children’s Hospital OaklandOaklandUSA
  7. 7.Projections Research Inc.PhoenixvilleUSA
  8. 8.BioMarin Pharmaceutical Inc.NovatoUSA
  9. 9.Department of Pediatrics, San Paolo HospitalUniversity of MilanMilanItaly

Personalised recommendations