ABSTRACT: INTRODUCTION: Acetazolamide is commonly used in chronic obstructive pulmonary disease (COPD) patients with metabolic alkalosis. Little is known of the pharmacodynamics of acetazolamide in the critically ill. We undertook a pharmacodynamic modeling of bicarbonate response to acetazolamide in COPD patients under mechanical ventilation. METHODS: This observationnal, retrospective study included 68 invasively ventilated COPD patients who received one or multiple doses of 250 or 500 mg of acetazolamide during the weaning period. Among the 68 investigated patients, 207 time-serum bicarbonate observations were available for analysis. Population pharmacodynamics was modeled using a non linear mixed effect model. The main covariates of interest were baseline demographic data, simplified acute physiology score II (SAPS II) at intensive care unit (ICU) admission, cause of respiratory failure, co-prescription of drugs interfering with the acid-base equilibrium, and serum concentrations of protein, creatinin, potassium and chloride. The effect of acetazolamide on serum bicarbonate levels at different doses and in different clinical conditions was subsequently simulated in silico. RESULTS: The main covariates interacting with acetazolamide pharmacodynamics were SAPS II at ICU-admission (P = .01), serum chloride (P < .001), and concomitant administration of corticosteroids (P = .02). Co-administration of furosemide significantly decreased bicarbonate elimination. Acetazolamide induced a decrease in serum bicarbonate with a doseresponse relationship. The amount of acetazolamide inducing 50% of the putative maximum effect was 117 mg 21 mg. According to our model, an acetazolamide dosage > 500 mg twice daily is required to reduce serum bicarbonate concentration > 5 mmol/L in presence of high serum chloride levels or co- administration of systemic corticosteroids or furosemide. CONCLUSIONS: This study identified several covariates that influenced acetazolamide pharmacodynamics and could allow a better individualization of acetazolamide dosing when treating COPD patients with metabolic alkalosis.