Population pharmacodynamic model of bicarbonate response to acetazolamide in mechanically ventilated chronic obstructive pulmonary disease patients

Abstract

Introduction: 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.

Figures

Figure 1

Differences between pre-acetazolamide dose bicarbonate level and bicarbonate level at 24 hours in all patients, plotted according to the total dosage of acetazolamide administered. Boxplots show the medians, first and third quartiles and 10th and 90th percentiles. The zero level at predose indicates that these values are based on intrapatient differences (repeated measures). Predose values: median 37.5; 25th and 75th percentiles 34 and 41, respectively; and 10th and 90th percentiles 30 and 45 mmol/L, respectively.

Figure 2

Goodnees-of-fit plots for the final model of acetazolamide pharmacodynamics. Shown are the results for 68 weaning chronic obstructive pulmonary disease patients. Observed versus model-predicted serum bicarbonate concentrations for (A) mean and (B) individual predictions and (C) normalized prediction distribution errors (NPDEs) versus predicted serum bicarbonate concentrations. The solid lines represent the identity lines and the dotted lines represent the regression lines. The mean and variance of the NPDE distribution were not significantly different from 0 and 1, respectively (P = 0.66 and P = 0.60, respectively; Wilcoxon signed-rank test and Fisher variance test, respectively) and from normality (P = 0.052, Shapiro-Wilks test), illustrating the robusteness of serum bicarbonate prediction after acetazolamide administration.

Figure 3

Model-predicted effect of 125 mg, 250 mg, 500 mg or 1, 000 mg of acetazolamide. Shown are the effects of acetazolamide (ACET) administered once daily on serum bicarbonate in the presence of (A) low or high levels of serum chloride, (B) coprescription or not of 20 to 160 mg/day furosemide or (C) coprescription or no coprescription of 1 mg/kg/day systemic cortocosteroids. Modelization of ACET pharmacodynamics was derived from 68 chronic obstructive pulmonary disease patients during the weaning period with metabolic alkalosis (Simplified Acute Physiology Score II at ICU admission was standardized at 50 and is shown in all parts of the figure). A higher ACET dosage is required to reduce serum bicarbonate concentrations > 5 mmol/L when high chloride or coprescription of systemic corticosteroids or furosemide occurs.