An indirect response model of homocysteine suppression by betaine: optimising the dosage regimen of betaine in homocystinuria.

Abstract

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: Angela Matthews, Trevor N Johnson, Amin Rostami-Hodjegan, Anupam Chakrapani, J Edward Wraith, Stuart J Moat, James R Bonham, Geoffrey T Tucker
• Journal: British journal of clinical pharmacology (Br J Clin Pharmacol) Vol. 54 Issue 2 Pg. 140-6 (Aug 2002) ISSN: 0306-5251 [Print] England
• PMID: 12207633 (Publication Type: Journal Article)

Chemical References

• Homocysteine
• Betaine
• Cystathionine beta-Synthase
• Pyridoxine

Topics

• Administration, Oral
• Adolescent
• Betaine (administration & dosage, pharmacokinetics, pharmacology)
• Child
• Cystathionine beta-Synthase (deficiency)
• Dose-Response Relationship, Drug
• Female
• Homocysteine (antagonists & inhibitors, blood)
• Homocystinuria (drug therapy, etiology, metabolism)
• Humans
• Male
• Pyridoxine (therapeutic use)
• Treatment Failure