Yulan Qi (1), Diane R. Mould (2), Huiyu Zhou (1), Markus Merilainen (1), Donald G. Musson (1)
(1) BioMarin Pharmaceutical Inc., Novato, California, USA (2) Projections Research Inc., Phoenixville, Pennsylvania, USA
Objectives: To determine the appropriate dose of sapropterin dihydrochloride, a synthetic preparation of naturally occurring phenylalanine hydroxylase (PAH) cofactor tetrahydrobiopterin (BH4), in pediatric patients (0-6 years) with PKU, a hereditary metabolic disorder caused by a PAH mutation [1,2,3].
Methods: The study design used D-optimization based on a previous model and was prospectively powered to achieve precise estimates of clearance (CL/F) and volume of distribution (V/F) in each age group [4,5]. A series of structural models were evaluated, including 1- and 2-compartment models with 1st-order input, with and without an absorption lag. Decision making during model building was guided by evaluation of change in objective function, magnitude of inter-individual and residual variability, and diagnostic plots. The model was tested and qualified by evaluating precision of the final parameter estimates, evaluating the condition number, and determining both symmetrical 95% confidence intervals (CIs) from asymptotic standard errors of the parameter estimates, as well as stratified non-parametrically bootstrapped 95% CI. Standard diagnostic plots and visual and numerical predictive checks were evaluated. The power to evaluate CL/F and V/F was evaluated using the final model and database to confirm the prospective evaluation. The analysis was performed with NONMEM version 7.2 on pooled data from 114 pediatric and 42 adult PKU patients in 2 phase 3 clinical studies. Oral sapropterin was administered once daily. Sapropterin plasma concentration was measured by a validated LC/MS/MS method.
Results: The best PK model was a 1-compartment model with an absorption lag and 1st order input and 1st order elimination, with a factor describing endogenous BH4 levels. Body weight was the only covariate significantly affecting sapropterin PK. Model evaluations suggested the model was appropriate. Based on recommended weight-based dosing, exposure across age groups was comparable. The absorption half-life of 2.95 hours and elimination half-life of 0.78 hours suggest flip-flop PK behavior in which absorption is rate limiting.
Conclusions: The effect of weight on sapropterin PK was substantial and dose regimens based on weight are appropriate. Overall exposure across all age groups is comparable. Given the absorption and elimination half-life, once daily dosing is justified.
References:
[1] Lambruschini N, Pérez-Dueñas B, Vilaseca MA, Mas A, Artuch R, Gassió R, Gómez L, Gutiérrez A, Campistol J. Clinical and nutritional evaluation of phenylketonuric patients on tetrahydrobiopterin monotherapy. Mol Genet Metab. 2005;86 Suppl 1:S54-60.
[2] Hennermann JB, Bührer C, Blau N, Vetter B, Mönch E.Long-term treatment with tetrahydrobiopterin increases phenylalanine tolerance in children with severe phenotype of phenylketonuria.Mol Genet Metab. 2005;86 Suppl 1:S86-90.
[3] Trefz FK, Scheible D, Frauendienst-Egger G, Korall H, Blau N. Long-term treatment of patients with mild and classical phenylketonuria by tetrahydrobiopterin.Mol Genet Metab. 2005 Dec;86 Suppl 1:S75-80. Epub 2005 Oct 20.
[4] Retout S, Duffull S, Mentre F. Development and implementation of the population Fisher information matrix for the evaluation of population pharmacokinetic designs. Comput Methods Programs Biomed, 2001;65(2):141-151.
[5] Feillet F, Clarke L, Meli C, Baker J, Lipson M, Bergoffen J, Morris A, Harmatz P, MouldDR, Green B, Dorenbaum A, Giovannini M for the Sapropterin Research Group “Pharmacokinetics of Sapropterin Dihydrochloride in Patients with Phenylketonuria” Clin Pharmacokinet. 47(12):817-825 2008
Reference: PAGE 23 (2014) Abstr 3248 [www.page-meeting.org/?abstract=3248]
Poster: Drug/Disease modeling - Paediatrics