Pharmacokinetics of Sapropterin in Patients with Phenylketonuria
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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age and had received ≥80% of the scheduled doses in a previous 6-week, randomized, placebo-controlled study or had been withdrawn from that study after exceeding a plasma phenylalanine concentration of ≥1500 μmol/L to ≥1800 μmol/L, depending on the subject’s age and baseline plasma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.
KeywordsInterindividual 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.
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