Dosing Ethambutol in Obese Patients

Deshpande et al. conclude that ethambutol (EMB) doses of 50 mg/kg of body weight twice a week would be the optimal clinical dose for the treatment of Mycobacterium avium (2). This was based on pharmacokinetic-pharmacodynamic studies using a hollow-fiber system model of intracellular M. avium, mimicking ethambutol human-like pharmacokinetics. This adds important information on the relationship between ethambutol exposure, dose schedule, and M. avium response. Indeed the authors are concerned about the ocular toxicity of EMB in higher doses but suggest that safety is less of a concern because intermittent dosing yields lower toxicity than does daily administration (4), as toxicity is driven by area under the concentration-time curve (AUC) and not by maximum concentration of drug in serum (Cmax) (2). Based on their modeling results, the authors suggest testing their proposed schedule in humans. Clinicians may therefore try this schedule to treat their patients with M. avium infections. However, we are concerned about ocular toxicity in obese patients who may receive EMB in a dose of 50 mg/kg. Earlier we investigated ocular toxicity of EMB and noticed that dosing on the basis of total body weight instead of ideal body weight led to serious overdosing in obese patients (6). This stems from the lower volume of distribution per kg of body weight due to the water-fat partition coefficient of EMB. As the studies cited by the authors lack obese patients (1, 7), the statement that 50 mg/kg is safe cannot be generalized. As with other drugs, not only the volume of distribution but also the clearance of EMB is likely to be different in obese patients, and a weight-normalized maintenance dose, using a size descriptor that corrects for differences in body mass index (BMI), should be given to obese patients (5). As the pharmacokinetics of EMB in obese patients has not been addressed in prospective studies and, therefore, the best size descriptor has not been retrieved, we propose/suggest that chronic drug dosing in the obese subject should be based on lean body weight (3). Since body water is reduced (e.g., from 60% to 30%) in obese patients, it is suggested to use the Devine formula to which a dosing weight correction factor of 0.3 is added to base dosage of hydrophilic antibiotics (8). These weight-based dose corrections result in a significant total dose reduction. For example, the total dose for a male patient of 1.7 m and 90 kg based on 50 mg/kg would result in 3,155 mg using lean body weight, 3,300 mg for ideal body weight, 3,360 mg for adjusted ideal body weight, and 4,500 mg for total body weight. Taking into account the difference of about 30% in total doses, we suggest that the dose of 50 mg/kg should be based on ideal body weight and not on total body weight. Considering that obesity is increasing worldwide, it is important to keep in mind that weight-based dosing in patients with an altered body composition results in higher plasma levels, which can lead to adverse events. A prospective study should evaluate actual pharmacokinetic parameters of EMB and make these empirical dose adjustments superfluous.