Olaf Lichtenberger (1), Friedrich-Karl Trefz (2), Alain Munafo (3)
(1) Merck KGaA, Darmstadt, Germany, (2) Pediatric Clinic Reutlingen, Germany, (3) Merck Institute for Pharmacometrics, Lausanne, Switzerland
Objectives: Hyperphenylalaninemia (HPA) is the most common dysfunction of metabolism of amino acids, caused by a missing or reduced activity of either the enzyme phenylalanine hydroxylase (PAH) or one of four enzymes involved in the tetrahydrobiopterin (BH4) metabolism. Mutations or deficiencies of any of these enzymes may give rise to pathologically increased phenylalanine concentrations, which can lead to intellectual disability, seizures, and other serious medical problems [1,2].
This paper presents a phenylalanine turn-over model in neonates with HPA receiving a BH4 loading test.
Methods: Neonatal phenylalanine concentrations from 375 patients with PAH deficiency and 194 with BH4 synthesis deficiency receiving a BH4 test dose were modeled against time and dose using nonlinear mixed-effect approach (NONMEM). A kinetic pharmacodynamic (KPD) approach was chosen to describe the phenylalanine concentration vs. time, since no PK of BH4 was available. Out of the different types of turn-over model, the closest one to the mechanism of action is the “Stimulation of Loss”, driven by the dose of BH4 delivered to the effect compartment. Inter-individual variability terms on KDE (the elimination of BH4 concentration from effect compartment), Kout (loss from phenylalanine compartment) and on slope effect parameters have been considered.
A mixture population approach, with 2 different populations has been used in order to differentiate response (Re) from non-response (NRe). In the model the slope parameter of NRe was set to zero, whereas the slope of Re was estimated, according to the sub-population estimated by NONMEM.
Results: The KPD turnover model describes appropriately the phenylalanine concentration vs. time. Using the model we found that 193 out of 194 patients with deficiency of BH4 synthesis are responders. In contrast, among patients with PAH deficiency, 42.4 % are estimated to be non-responders.
Diagnostic plots show that the model fits the data well, with good precision and without bias. The mixture model differentiation between Re and NRe was externally qualified by comparing the responsiveness with a 48-h based prognostic test [3].
Conclusions: The KPD model “Stimulation of Loss” coupled with mixture model for classification between Re and NRe allows a more objective description of the BH4 effect than previous analyses and could facilitate further correlation studies investigating various demographic, laboratory, and genetic parameters.
References:
[1] Okano Y, Eisensmith RC, Güttler F, Lichter-Konecki U, Konecki DS, Trefz FK, Dasovich M, Wang T, Henriksen K, Lou, H, Woo S: Molecular Basis of Phenotypic Heterogeneity in Phenylketonuria, N Engl J Med. 1991, 324: 1232-1238
[2] Levy HL, Milanowski A, Chakrapani A, Cleary M, Lee P, Trefz KF, Whitley CB, Feillet F, Feigenbaum AS, Bebchuk JD, Christ-Schmidt H, Dorenbaum A: Efficacy of sapropterin dihydrochloride (tetrahydrobiopterin, 6R-BH4) for reduction of phenylalanine concentration in patients with phenylketonuria: a phase III randomized placebo-controlled study. The Lancet 2007, 370(9586): 504-510
[3] Fiege B, Bonafé L, Ballhausen D, Baumgartner M, Thöny B, Meili D, Fiori L, Giovanni M, Blau N: Extended tetrahydrobiopterin loading test in the diagnosis of cofactor-responsive phenylketonuria: A pilot study; Mol Gen Metab 2005, 86: 91-95
Reference: PAGE 23 (2014) Abstr 3149 [www.page-meeting.org/?abstract=3149]
Poster: Drug/Disease modeling - Paediatrics