AIMS: To investigate the pharmacokinetics (PK) and pharmacodynamics (PD) of betaine in the treatment of classical homocystinuria due to cystathionine beta-synthase (CbetaS) deficiency with a view to optimizing the dosage regimen. METHODS: Betaine was given as a single oral dose of 100 mg kg(-1) to six patients (age range 6-17 years) who normally received betaine but whose treatment had been suspended for 1 week prior to the study. Plasma betaine and total homocysteine concentrations were measured by high performance liquid chromatography (h.p.l.c.) at frequent intervals over 24 h. The best-fit PK model was determined using the PK-PD program Win-Nonlin and the concentration-time-effect data analysed by an indirect PD model. Using the PK and PD parameters, simulations were carried out with the aim of optimizing betaine dosage. RESULTS: Betaine PK was described by both mono- and bi-exponential disposition functions with first order absorption and a lag time. The correlation coefficient between betaine oral clearance and body weight was 0.6. Mean betaine clearance was higher in males than in females (P=0.03). PK-PD simulation indicated minimal benefit from exceeding a twice-daily dosing schedule and a 150 mg kg(-1) day(-1) dosage for betaine. CONCLUSIONS: PK-PD modelling allows recommendations for optimal dosage of betaine in the treatment of homocystinuria, that have the potential for improved patient compliance and both therapeutic and pharmacoeconomic benefit.
AIMS: To investigate the pharmacokinetics (PK) and pharmacodynamics (PD) of betaine in the treatment of classical homocystinuria due to cystathionine beta-synthase (CbetaS) deficiency with a view to optimizing the dosage regimen. METHODS:Betaine was given as a single oral dose of 100 mg kg(-1) to six patients (age range 6-17 years) who normally received betaine but whose treatment had been suspended for 1 week prior to the study. Plasma betaine and total homocysteine concentrations were measured by high performance liquid chromatography (h.p.l.c.) at frequent intervals over 24 h. The best-fit PK model was determined using the PK-PD program Win-Nonlin and the concentration-time-effect data analysed by an indirect PD model. Using the PK and PD parameters, simulations were carried out with the aim of optimizing betaine dosage. RESULTS:Betaine PK was described by both mono- and bi-exponential disposition functions with first order absorption and a lag time. The correlation coefficient between betaine oral clearance and body weight was 0.6. Mean betaine clearance was higher in males than in females (P=0.03). PK-PD simulation indicated minimal benefit from exceeding a twice-daily dosing schedule and a 150 mg kg(-1) day(-1) dosage for betaine. CONCLUSIONS: PK-PD modelling allows recommendations for optimal dosage of betaine in the treatment of homocystinuria, that have the potential for improved patient compliance and both therapeutic and pharmacoeconomic benefit.
Authors: S H Mudd; F Skovby; H L Levy; K D Pettigrew; B Wilcken; R E Pyeritz; G Andria; G H Boers; I L Bromberg; R Cerone Journal: Am J Hum Genet Date: 1985-01 Impact factor: 11.025
Authors: Andrew A M Morris; Viktor Kožich; Saikat Santra; Generoso Andria; Tawfeg I M Ben-Omran; Anupam B Chakrapani; Ellen Crushell; Mick J Henderson; Michel Hochuli; Martina Huemer; Miriam C H Janssen; Francois Maillot; Philip D Mayne; Jenny McNulty; Tara M Morrison; Helene Ogier; Siobhan O'Sullivan; Markéta Pavlíková; Isabel Tavares de Almeida; Allyson Terry; Sufin Yap; Henk J Blom; Kimberly A Chapman Journal: J Inherit Metab Dis Date: 2016-10-24 Impact factor: 4.982