The Influence of Renal Function on the Pharmacokinetics and Pharmacodynamics and Simulated Time Course of Doxacurium

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Abstract
Doxacurium's clearance (C1) is markedly decreased in patients with renal failure undergoing kidney transplantation. However, no studies have determined the influence of renal function (as assessed by creatinine clearance [CrCl]) on its pharmacokinetics in patients without renal failure. We studied 53 patients aged 19-59 yr. During N2O/isoflurane anesthesia, doxacurium was infused over 10 min, plasma was sampled for up to 6 h, and twitch tension was measured. A three-compartment model was fit to plasma concentration data and an effect compartment model to twitch data. Mixed-effects modeling was used to determine the influence of covariates, including CrC1, on doxacurium's pharmacokinetic/pharmacodynamic parameters. Obesity decreased both doxacurium's Cl (1.1% per percent above ideal body weight [IBW]) and its neuromuscular junction sensitivity (0.4% per percent above IBW). Cl increased 0.6% per mL/min increase in CrCl. In addition, the rate constant for equilibration between plasma concentration and effect decreased 46% per 1% increase in isoflurane, central compartment volume decreased 86% per 1% increase in isoflurane concentration, and slow distributional Cl decreased 69% per mg/ 100 mL increase in serum albumin. Simulations showed that the latter two covariates influence the time course of bolus doxacurium administration minimally. Both obesity and renal dysfunction prolong doxacurium's recovery markedly. When dosing is based on IBW, effects of CrCl on neuromuscular recovery are smaller compared with dosing based on actual weight. Therefore, obese patients should be dosed based on IBW. No further dosage adjustment is necessary for patients with renal dysfunction; however, recovery will take longer in patients with moderate-to-severe renal dysfunction. We examined the factors influencing doxacurium's pharmacokinetic and pharmacodynamic characteristics. Both creatinine clearance and obesity significantly influence its time course. The effect of obesity is minimized if patients are dosed based on ideal body weight.