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.
IMPLICATIONS: 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.