Pharmacokinetic-pharmacodynamic modeling of the respiratory depressant effect of alfentanil

Background: Although respiratory depression is the most well-known and dangerous side effect of opioids, no pharmacokinetic-pharmacodynamic model exists for its quantitative analysis. The development of such a model was the aim of this study. Methods: After institutional approval and informed consent were obtained, 14 men (American Society of Anesthesiologists physical status I or II; median age, 42 yr [range, 20-71 yr]; median weight, 82.5 kg [range, 68-108 kg]) were studied before they underwent major urologic surgery. An intravenous infusion of alfentanil (2.3 mu g . kg(-1). min(-1)) was started while the patients were breathing oxygen-enriched air (fraction of inspired oxygen [FIO2] = 0.5) over a tightly fitting continuous positive airway pressure mask The infusion was discontinued when a cumulative dose of 70 mu g/kg had been administered, the end-expiratory partial pressure of carbon dioxide (PECO2) exceeded 65 mmHg, or apneic periods lasting more than 60 s occurred. During and after the infusion, frequent arterial blood samples were drawn and analyzed for the concentration of alfentanil and the arterial carbon dioxide pressure (Pa-CO2). A mamillary tno-compartment model was fitted to the pharmacokinetic data. The Pa-CO2 data were described by an indirect response model The model accounted for the respiratory stimulation resulting from increasing Pa-CO2. The model parameters were estimated using NONMEM. Simulations were performed to define the respiratory response at steady state to different alfentanil concentrations. Results: The indirect response model adequately described the time course of the Pa-CO2. The following pharmacodynamic parameters were estimated (population means and Interindividual variability): EC50, 60.3 mu g/l (32%); the elimination rate constant of carbon dioxide (K-cl), 0.088 min(-1) (44%); and the gain in the carbon dioxide response, 4 (28%) (fixed according to literature values). Simulations revealed the pronounced role of Pa-CO2 in maintaining alveolar ventilation in the presence of opioid. Conclusions: The model described the data for the entire opioid-Pa-CO2 response surface examined. Indirect response models appear to be a promising tool for the quantitative evaluation of drug-induced respiratory depression.