Ethambutol pharmacokinetic variability is linked to body mass in overweight, obese, and extremely obese people

Abstract

We conducted a prospective study of 18 adult volunteers (male-to-female ratio of 1) whose body mass index fell into categories of <25, 25 to 40, or >40 kg/m(2), who received a single oral dose of 1,600 mg ethambutol. Only individuals with normal renal function were recruited. The minimum body mass (M) was 45.6 kg, the median was 90.8 kg, and the maximum weight was 160.4 kg. Ethambutol pharmacokinetics were best described by a two-compartment model. Inclusion of weight as a covariate dramatically improved the model, with a relative likelihood approaching infinity. The typical clearance was 42.6 liters/h. Ethambutol systemic clearance was proportional to (M/45.6)(3/4) and thus obeyed fractal geometry-based laws. This means that the area under the concentration-time curve (AUC) actually decreased for obese patients compared to that for leaner patients, reducing chances of concentration-dependent toxicity. On the other hand, such reduced AUCs could lead to therapy failure. Thus, new and individualized ethambutol dosing regimens need to be designed for obese and extremely obese patients.

Figures

Fig 1

Weight distribution in people recruited into the ethambutol study. (A) The recruitment was meant to capture all extremes of weight, and thus the weight is not normally distributed. (B) Distribution of ethambutol dosing indexed to weight (mg/kg) by gender.

Fig 2

Concentrations of ethambutol (mg/liter) achieved after administration of a single dose of ethambutol. This line is the median concentration using naive pooling and demonstrates a biphasic decline consistent with a two-compartment model. The circles represent volunteers with a body mass index classified as normal weight.

Fig 3

Observed versus predicted concentrations of ethambutol in the base model. Concentrations are in mg/liter.

Fig 4

Effect of mass (kg) on ethambutol pharmacokinetic parameters. (A) Weight versus systemic clearance. (B) Weight versus volume of distribution. Vp is represented by open diamonds; Vc is represented by filled squares.