title: 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.
authors.affiliation: Department of Pharmacy Practice, Texas Tech University Health Sciences Center, School of Pharmacy, Dallas, Texas, USA. ronald.hall@ttuhsc.edu
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Hall
authors.forename: Mark A
authors.initials: MA
authors.lastname: Swancutt
authors.forename: Claudia
authors.initials: C
authors.lastname: Meek
authors.forename: Richard D
authors.initials: RD
authors.lastname: Leff
authors.forename: Tawanda
authors.initials: T
authors.lastname: Gumbo
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000995:Antitubercular Agents / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D015992:Body Mass Index; D002851:Chromatography, High Pressure Liquid; D004334:Drug Administration Schedule; D054796:Drug Dosage Calculations; D004977:Ethambutol / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000097:blood; D009767:Obesity, Morbid / Q000097:blood; D050177:Overweight / Q000097:blood*; D011446:Prospective Studies; D012984:Software
chemical_list: D000995:Antitubercular Agents; D004977:Ethambutol