title: Population pharmacodynamic model of bicarbonate response to acetazolamide in mechanically ventilated chronic obstructive pulmonary disease patients.
abstract: BACKGROUND
  Acetazolamide is commonly given to chronic obstructive pulmonary disease (COPD) patients with metabolic alkalosis. Little is known of the pharmacodynamics of acetazolamide in the critically ill. We undertook the pharmacodynamic modeling of bicarbonate response to acetazolamide in COPD patients under mechanical ventilation.
  
  
  METHODS
  This observational, 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 nonlinear mixedeffect model. The main covariates of interest were baseline demographic data, Simplified Acute Physiology Score II (SAPS II) at 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 = 0.01), serum chloride (P < 0.001) and concomitant administration of corticosteroids (P = 0.02). Co-administration of furosemide significantly decreased bicarbonate elimination. Acetazolamide induced a decrease in serum bicarbonate with a dose-response relationship. The amount of acetazolamide inducing 50% of the putative maximum effect was 117 ± 21 mg. According to our model, an acetazolamide dosage > 500 mg twice daily is required to reduce serum bicarbonate concentrations > 5 mmol/L in the presence of high serum chloride levels or coadministration 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.
authors.affiliation: Medical Intensive Care Unit, European Georges Pompidou Hospital (AP-HP), Université Paris Descartes, Sorbonne Paris Cité, 20 rue Leblanc, 75908 Paris, France. nicholas.heming@orange.fr
authors.forename: Nicholas
authors.initials: N
authors.lastname: Heming
authors.forename: Christophe
authors.initials: C
authors.lastname: Faisy
authors.forename: Saïk
authors.initials: S
authors.lastname: Urien
mesh_terms: D000086:Acetazolamide / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000471:Alkalosis / Q000188:drug therapy / Q000378:metabolism; D001639:Bicarbonates / Q000097:blood*; D002257:Carbonic Anhydrase Inhibitors / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism / Q000628:therapy*; D012121:Respiration, Artificial; D012189:Retrospective Studies; D016896:Treatment Outcome
chemical_list: D001639:Bicarbonates; D002257:Carbonic Anhydrase Inhibitors; D000086:Acetazolamide