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.

Figure 1

The metabolic cycle of methionine and the possible enzyme defects in homocystinuria (cross signs: bold cross indicating patients in this study). The mechanism of action of administered betaine is indicated. R(t) is the concentration of homocysteine at a given time, C(t) is the concentration of betaine at a given time, k_in and k_out are rate constants for the production and loss of homocysteine, respectively, S(t) is a stimulation function for the betaine induced increase in homocysteine elimination.

Figure 2

Representative best fit model (line) to plasma betaine concentrations(•) in subject 1 and subject 2. Biexponential and monoexponential disposition with first-order absorption were assumed for subjects 1 and 2, respectively.

Figure 3

Representative change in plasma total homocysteine as a function of plasma betaine concentration in subject 2 showing counter-clockwise hysteresis.

Figure 4

A representative model fit (solid line) to homocysteine-time data (▴) following administration of 100 mg kg⁻¹ day⁻¹ of betaine to subject 1.

Figure 5

Simulated effects of administering 100 mg kg⁻¹ day⁻¹ of betaine as a twice daily dose on plasma betaine concentration (a) and the predicted effects on plasma total homocysteine concentration (b). Simulation for subject 2.

Figure 6

Simulated effects of increasing dose frequency on the relative decrease in plasma total homocysteine in six patients receiving a fixed dose of 100 mg kg⁻¹ day⁻¹ of betaine (▴ = subject 1, □ = subject 2, ▪ = subject 3, ○ = subject 4, • = subject 5, ▵ = subject 6).

Figure 7

Simulated effects of increasing the betaine dose on the overall reduction in Plasma total homocysteine concentration in 6 patients on a fixed twice-daily dosing schedule (▴ = subject 1, □ = subject 2, ▪ = subject 3, ○ = subject 4, • = subject 5, ▵ = subject 6).