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© 1999 International Anesthesia Research Society
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Abstract |
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Rapacuronium (Org 9487) is a rapid-onset and short- to intermediate-acting muscle relaxant. Its 3-desacetyl metabolite, Org 9488, also exerts neuromuscular-blocking activity that may become apparent after prolonged maintenance of relaxation with rapacuronium. In this study, the pharmacokinetic behavior (n = 7) of this metabolite and the pharmacokinetic/pharmacodynamic (PK/PD) relationship of rapacuronium (n = 10) and Org 9488 (n = 7) were investigated in humans. Similar protocols were used for three study groups regarding the anesthetic technique, blood and urine sampling, and pharmacokinetic and PK/PD analyses. The time course of action was measured mechanomyographically using the adductor pollicis muscle. The median clearance of rapacuronium was 7.28 mL · kg-1 · min-1 with an excretion fraction in the urine of 6.2%. The clearance (studied in two groups) of Org 9488 was 1.28 and 1.06 mL · kg-1 · min-1 with an excretion fraction in the urine of 51.9% and 53.5%, respectively. The median rate constant of transport between plasma and the biophase of rapacuronium (0.449 min-1) is markedly larger than that for Org 9488 (0.105 min-1). The modeled concentration in the biophase at 50% effect as a measure of potency is higher for rapacuronium (4.70 µg/mL) than for Org 9488 (1.83 µg/mL). The lower clearance of the metabolite will gradually prolong the time course of the neuromuscular blockade during maintenance with rapacuronium.
Implications: We investigated the concentration-time-effect relationship of the relaxant rapacuronium and the contribution of its metabolite. Clearance, rate constant of transport between plasma and the biophase, and modeled concentration in the biophase at 50% effect of rapacuronium are consistent with its rapid onset and short to intermediate duration. The lower clearance of the metabolite will gradually prolong the time course of the neuromuscular blockade during maintenance with rapacuronium.
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Introduction |
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Rapacuronium (Org 9487, the 16N-allyl, 17ß-propionate analog of vecuronium) is the first nondepolarizing muscle relaxant that combines the desirable characteristics of rapid onset of relaxation and a short to intermediate duration of action (1–3). The time course of action of rapacuronium may be prolonged by the formation of its active 3-desacetyl metabolite, Org 9488, when rapacuronium is used for the maintenance of relaxation (3,4). In general, the time course of action of muscle relaxants can be ascribed to a number of factors, including cardiac output, muscle perfusion, and physicochemical (intrinsic) drug properties, including pharmacokinetics and receptor affinity. Ultimately, these factors determine the concentration-time-effect relationship (5,6). Modeling of pharmacokinetic behavior and simultaneous pharmacokinetic-pharmacodynamic (PK/PD) modeling offers a means of quantifying this concentration-time-effect relationship. This information can be used to understand and compare the pharmacology of muscle relaxants. It can also be used to assess the contribution of, for example, active metabolites to the concentration-effect relationship of the parent compound. With this in mind, we investigated the pharmacokinetics of the metabolite of rapacuronium, Org 9488, and the PK/PD relationship of rapacuronium and Org 9488 using Sheiner et al.’s model (7).
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Methods |
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In this article, we describe three studies with similar protocols. Each study protocol was approved by the Medical Ethical Committee of the University Hospital of Groningen. In total, 24 ASA physical status I–III patients, aged 18–65 yr, scheduled for elective surgery participated in the studies after their written, informed consent was obtained. Patients who were breast feeding or pregnant; patients with a history of myocardial ischemia, kidney, liver, or neuromuscular disorders; and those receiving any medication interfering with neuromuscular blockade effect or the high-performance liquid chromatograph assay were excluded.
After premedication with midazolam (7.5–15 mg orally), anesthesia was induced with thiopental (4–6 mg/kg IV) and fentanyl (1–3 µg/kg IV). Anesthesia was maintained with isoflurane 0.6% end-tidal concentration in a mixture of 66% nitrous oxide and oxygen. Incremental doses of 50 µg of fentanyl were administered as required.
Usual monitors were used. After induction, the PETCO2 was kept between 30 and 35 mm Hg. Central and peripheral cutaneous (thumb) temperatures were maintained >36.5°C and >32.5°C, respectively, throughout the period of neuromuscular monitoring by covering the patient with blankets and wrapping the arm in synthetic cotton wool.
After the induction of anesthesia, neuromuscular function was measured by using mechanomyography of the adductor pollicis muscle. The neuromuscular blocking drug was administered after a calibration period of 1 min with single-twitch stimulation (ST). ST (0.1 Hz, supramaximal square-wave pulses of 200 µs) was delivered to the ulnar nerve at the wrist, interposed by train-of-four (TOF) stimulation (four twitches at 2 Hz, T4/T1 = TOF ratio) at 25%, 75%, and 90% ST recovery. Preload was kept constant at 200–400 g. The contraction force of the adductor pollicis muscle was measured by using a force transducer and recorded on line (8).
Group I (n = 10) received rapacuronium in a short-term infusion to model PK/PD simultaneously. The infusion was continued until ST height was decreased by 70% to achieve a maximal block of approximately 90%.
Group II (n = 7) received a single bolus of 200 µg/kg Org 9488. We calculated that a bolus of 200 µg/kg Org 9488 would result in a plasma concentration range that is obtained normally after the administration of 1.5 mg/kg rapacuronium bromide.
Group III (n = 7) received Org 9488 in a short-term infusion to model the PK/PD simultaneously. The infusion was continued until ST height decreased by 70% to achieve a maximal block of approximately 90%. If necessary, vecuronium or rocuronium could be administered after recovery from initial neuromuscular block.
In Group I, after the induction of anesthesia, an arterial line was introduced in an extremity other than the arm used for neuromuscular monitoring. Arterial blood samples were taken before the administration of rapacuronium; 1 and 2 min after the start of the infusion; at approximately 20%, 50%, and 80% neuromuscular block; and at maximal neuromuscular block. Thereafter, samples were drawn at approximately 20%, 55%, and 90% recovery from maximal neuromuscular block and 45, 60, 90, 120, 180, and 240 min after discontinuing the infusion. Samples of 4 mL were collected in standard lithium heparinized test tubes containing 1 mL of 1 M NaH2PO4 solution to prevent the degradation of rapacuronium.
In Group II, venous blood samples (4 mL) were taken from a line not used for the infusion of Org 9488 2, 4, 7, 10, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 min after the administration of Org 9488.
In Group III, after induction, an arterial line was introduced in an extremity other than the arm that was used for neuromuscular monitoring. Arterial blood samples were taken before the administration of Org 9488; 1 and 2 min after the start of the infusion; at approximately 20%, 50%, and 80% neuromuscular block; and at maximal neuromuscular block. Thereafter, samples were drawn at approximately 20%, 55%, and 90% recovery from neuromuscular block and 30, 60, 90, 120, 180, 240, 300, and 360 min after discontinuing the infusion. Samples of 4 mL were collected in standard lithium heparinized test tubes.
The samples of all three groups were centrifuged within 2 h after collection, and the pipetted plasma was stored at -18°C until shipment to an independent, accredited laboratory where the samples were analyzed using liquid chromatography coupled to mass spectrometry for both compounds.
Urine was sampled before the administration of the drug and over the time periods 0–2, 2–4, 4–6, 6–9, 9–12, 12–18, 18–24, 24–36, and 36–48 h after the administration of rapacuronium or Org 9488. The urine for the whole period was collected via a Foley catheter and mixed before it was sampled according to the sampling scheme. In Group I, urine was collected in bags containing 20 mL of 1 M NaH2PO4 solution to prevent hydrolysis of rapacuronium. The volume of urine and the time was noted. The samples were frozen immediately and were stored at -20°C.
Plasma samples were analyzed using high-performance liquid chromatograph with mass selective detection. Rapacuronium (Group I only), Org 9488 (all patients), and the internal standard, d10-Org 9487 were extracted from acidified human plasma into dichloroethane. The dichloroethane was evaporated in nitrogen, and the residue was reconstituted in 250 µL of a 85:15 (vol/vol) mixture of 10 mM ammonium acetate in 1% acetic acid:acetonitrile. Separation was achieved on an Asahipak column with a mobile phase composed of a 75:25 (vol/vol) mixture of 10 mM ammonium acetate in 1% acetic acid:acetonitrile. Detection was by single ion reaction monitoring of the ions 597.7, 555.7, and 607.7 for rapacuronium, Org 9488, and d10-rapacuronium, respectively.
Calibration curves were obtained from eight calibration standards in the concentration range of 2.00–1000 ng/mL. The calibration curves were calculated by using weighted linear regression using a weighting factor of 1/concentration. The precision (within-day variability) and accuracy were calculated from plasma samples spiked with rapacuronium or Org 9488 in concentrations of 6, 30, 300, and 900 ng/mL. The precision ranged from 4.4% to 6.0% for rapacuronium and from 5.1% to 19.9% for Org 9488. The accuracy ranged from -14.5% to -11.0% for rapacuronium and from -9.3% to 9.0% for Org 9488.
The limit of quantification was defined as the lowest calibration standard that could be determined with an accuracy and precision >20% and was 2 ng/mL for both compounds. The stability of rapacuronium and Org 9488 in acidified plasma was tested and found to be relatively low compared with the assay precision. In acidified plasma spiked with rapacuronium, the amount of Org 9488 due to interconversion via hydrolysis increased from 0.4% to 1.8%.
Urine samples were analyzed according to a similar procedure. Calibration curves were obtained from eight calibration standards in the concentration range of 50–10,000 ng/mL. The calibration curves were calculated by using weighted linear regression using a weighting factor of 1/concentration. The precision (within-day variability) and accuracy were obtained from urine samples spiked with rapacuronium or Org 9488 in concentrations of 200, 1500, 8000, and 100,000 ng/mL. The precision ranged from 4.1% to 6.8% for rapacuronium and from 4.3% to 8.1% for Org 9488. The accuracy ranged from -10.1% to -0.3% for rapacuronium and from -3.6% to 6.7% for Org 9488. The limit of quantification in urine was set at 50 ng/mL for both compounds.
Plasma concentration-time data were analyzed by iterative nonlinear regression using the program MultiFit (written by JH Proost). For each individual patient, the variables of a two- and three-exponential equation (adapted for the case of administration by infusion) were fitted to the logarithm of the plasma concentration-time data pairs, assuming homoscedastic error after the logarithmic transformation. The correctness of this assumption was tested by visual inspection of the graphs of the residuals plotted against time and against the concentration. Moreover, the relative error of the bioanalysis was almost independent of concentration over the entire concentration range.
Because mixing of the administered drug throughout the central volume may be incomplete during the first 2 min after administration, samples taken within 2 min of administration of a bolus dose or after starting the infusion were discarded. Goodness-of-fit was evaluated by visual inspection of the measured and calculated data points and of the residuals plotted against time and against concentration. The residual coefficient of variation and the standard errors of the estimated model variables, determined from the variance-covariance matrix, were also used as measures of goodness-of-fit. The choice between a two- and three-exponential equation was based on the F-test accepting a more complex model as significantly better fitting if P < 0.05.
The volume of the central compartment (V1) and peripheral compartments (V2, V3), steady-state volume of distribution (Vss), plasma clearance (CL), distribution clearance to peripheral compartments (CL12, CL13), half-lives (t1/2
1, t1/22, t1/23), and mean residence time (MRT) were calculated using standard equations, assuming that elimination takes place from the central compartment. MRT was calculated as that after an IV bolus dose.
The amount excreted in urine, expressed as a percentage of the dose, was calculated for each patient. The urinary excretion data were also evaluated by using iterative nonlinear regression, as described above. Instead of the plasma concentration, the fraction excreted in each sampling interval was used. From the variables of the exponential equation, the half-lives and the total amount excreted (calculated as the sum of the measured amounts excreted and the calculated amount to be excreted after the last sampling time, extrapolated to infinity and expressed as a percentage of the dose) were obtained. Renal clearance was calculated as the product of the CL and the fraction excreted in urine.
The twitch height-time data were analyzed by using iterative nonlinear regression using the program PkPdFit (written by JH Proost), using the PK/PD model described by Sheiner et al (7).
For each individual patient, the PK/PD model variables were fitted to the measured twitch height data by minimizing the sum of squared differences between the measured and calculated twitch height, using equal weights for each measurement. The plasma concentration-time profile was described by the best fitting polyexponential function, calculated by using MultiFit.
The PK/PD analysis of rapacuronium (Group I) is confounded by the presence of Org 9488, which may contribute to the neuromuscular block and thus may interfere with the assessment of the PK/PD variables rate constant of transport between plasma and the biophase (ke0), modeled concentration in the biophase at 50% effect (EC50), and the steepness of the concentration-effect relationship or Hill coefficient (
). The "true" PK/PD variables of rapacuronium were estimated for each patient in Group I using the following procedure. For each patient, the plasma-concentration-time profile of Org 9488 was described by the best-fitting polyexponential function, obtained from the measured plasma concentrations of Org 9488. Using the mean value of ke0 obtained in Group III, the effect compartment concentration-time profile of Org 9488 was then estimated. It was assumed that the neuromuscular blocking effects of rapacuronium and Org 9488 were additive as a result of binding to the same receptor, i.e., the total effect of rapacuronium and Org 9488 can be described by the sigmoid Emax model or Hill equation, relating drug effect to an apparent drug concentration calculated from 
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) for both compounds. For EC50 of Org 9488, the mean value obtained in Group III was used. The PK/PD variable ke0, EC50, and of rapacuronium were then estimated as previously described. The Kruskal-Wallis test was used to compare the demographic data of all three groups. P < 0.05 was considered significant.
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Results |
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Twenty-four patients were investigated. There were no differences in demographic variables among the three study groups (Table 1). The administered dose, duration of infusion, and pharmacodynamic data are presented in Table 1.
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The results of the pharmacokinetic analysis of the plasma concentration data are summarized in Table 2.
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In 9 of 10 patients of Group I, the three-exponential equation fitted the data significantly better than the two-exponential equation (Figures 1 and 2 ); in 1 patient, the difference was not significant (P = 0.064). In each of the patients, the goodness-of-fit of the three-exponential equation was satisfactory, with a residual coefficient of variation of 11%–21%. The pharmacokinetic variables of the three-compartment model are presented in Table 2.
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) in a typical patient from Group I and of Org 9488 (
) in a typical patient from Group III. Squares indicate the measured plasma concentration, and the solid line represents the calculated plasma concentration profiles after fitting to three exponential equations.In Group I, the plasma concentration data of the metabolite Org 9488 were analyzed according to the same procedure. In one patient, the three-exponential equation fitted the data significantly better than the two-exponential equation. In each of the patients, the goodness-of-fit of the two-exponential fit was satisfactory, with a residual coefficient of variation of 15%–26%. The initial and terminal half-lives and the MRT of Org 9488 in Group I were 4.5 (1.4–9.1), 179 (123–248), and 219 (170–340) min, respectively.
For both Groups II and III, the three-exponential equation fitted the data significantly better than the two-exponential equation in four of seven patients (Figure 2); in the remaining three patients, the three-exponential equation did not result in a satisfactory fit. The pharmacokinetic variables of the best-fitting model for each patient are summarized in Table 2. For the patients in whom the two-exponential equation was applied, it was assumed that the second phase was not identified; the median values of CL12, V2, and t1/22 therefore refer to the remaining four patients in each of Groups II and III. The residual coefficient of variation ranged from 6% to 18% in Group II and from 8% to 20% in Group III.
The results of the pharmacokinetic analysis of the urinary excretion data are summarized in Table 3.
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In one patient in Group I, the urine was only collected for a period of 14 h. In seven of the remaining patients in Group I, the two-exponential equation fitted significantly better than the monoexponential equation; the median initial half-life was 53 (26–142) min. The fraction excreted unchanged in urine was 6.3% of the dose; the amount estimated to be excreted after the last sampling time was 0.1% of the dose.
In Group I, the urinary excretion of the metabolite Org 9488 amounted to 3.5% (2.2%–7.7%) of the dose of rapacuronium. The two-exponential equation did not result in an acceptable fit in any of the patients. A monoexponential fit resulted in a half-life of 922 (628–1773) min. The estimated total amount excreted at an infinite time was 3.9% (2.5%–9.5%) of the dose of rapacuronium.
For both Groups II and III, the two-exponential equation did not result in an acceptable fit in any of the patients; the results of the monoexponential equation are therefore presented in Table 3. The fraction excreted in urine was 51.9% and 53.5% of the dose in Groups II and III, respectively; the median amount estimated to be excreted after the last sampling time was 4.7% and 0.3% of the dose in Groups II and III, respectively.
In Table 4 , the results of the PK/PD analysis are summarized for Groups I and III. The goodness-of-fit was satisfactory, with a residual standard deviation of 2.8%–8.3% in Group I and 1.7%–7.7% in Group III. Figures 2 and 3 illustrate the plasma concentration-time relationship and the time-effect relationship of rapacuronium and Org 9488 in typical patients from Groups I and III, respectively.
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Discussion |
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A rapid clearance, low potency, and large rate constant for the equilibration of the effect compartment concentration with plasma concentration (ke0) are assumed to be properties of a muscle relaxant with a fast onset and offset (5,9,10). As shown in this study, rapacuronium does have these properties.
However, the lower clearance of its metabolite may be responsible for slowly progressive delay in recovery when rapacuronium is used to prolong neuromuscular blockade. This delay in recovery, seen only after infusions of 
1 h, leads to significantly decreased dose requirements, as reported previously (4).
The clearance of rapacuronium (Group I), 7.28 mL · kg-1 · min-1, is higher than that of vecuronium or rocuronium, both 4.0 mL · kg-1 · min-1 (11,12). These differences in clearance are consistent with the shorter duration of action of rapacuronium compared with those of vecuronium and rocuronium. In both animal and in vitro experiments, rapacuronium is eliminated mainly by the liver (13), as was found for vecuronium (13,14) and rocuronium (13,15). Org 9488 (Groups II and III) was found to have a clearance of 1.1–1.3 mL · kg-1 · min-1, which is similar to that of pancuronium, as reported by Sohn et al. (11). This low clearance must be held responsible for a longer duration of action of pancuronium and Org 9488 compared with that of vecuronium and rocuronium. Like pancuronium, Org 9488 is mainly eliminated by the kidneys (Table 3).
The value for ke0 obtained from arterial samples was considerably larger for rapacuronium (Group I) than for rocuronium (16), 0.45 min-1 and 0.16 min-1, respectively. This indicates a more rapid equilibration of plasma and effect compartment concentration for rapacuronium and therefore a more rapid establishment of the effect. In contrast to its parent compound, Org 9488 has a low ke0 (0.11 min-1), with an EC50 (1.8 µg/mL) between that of rapacuronium and rocuronium. The intrinsic potency of rapacuronium is lower than that of other steroidal muscle relaxants. This is reflected by the higher EC50 for rapacuronium of 4.7 µg/mL, compared with 0.8 µg/mL for rocuronium (16), 0.15 µg/mL for vecuronium (11), and 0.18 µg/mL for pancuronium (11).
The values for ke0 and EC50 of rapacuronium corrected for the presence of Org 9488 are higher than the uncorrected values (Table 4). The corrected values may be regarded as the best estimates of the intrinsic properties of rapacuronium. To obtain the corrected PK/PD variables of rapacuronium, we assumed that the steepness of the concentration-effect relationship () is the same for rapacuronium and its metabolite Org 9488. Because of their competitive mode of action, one would expect the same value for for each nondepolarizing neuromuscular blocking drug, regardless of its receptor affinity (reflected in EC50). However, our data indicate that the steepness for the metabolite Org 9488 is larger than that for rapacuronium. We do not believe this difference in steepness significantly affected our results because the concentrations of Org 9488 were relatively small and the corrected PK/PD variables of rapacuronium differed only slightly from the uncorrected values.
After the administration of rapacuronium (Group I), the compound Org 9488 was found in each plasma sample. The ratio of concentrations (in molar units) of Org 9488 and rapacuronium increased from 0.042 ± 0.015 during the first 5 min to values of 1–4 at 180–360 min after administration. Part of this Org 9488 was already present in the ampoule of rapacuronium, which contained 1% Org 9488 as an impurity.
Assuming that approximately 50% of the formed metabolite is eliminated via the urine (Table 3), the fraction of rapacuronium metabolized to Org 9488 may be estimated to be approximately 7%. This fraction will be higher if Org 9488 is excreted into bile, as has been found in studies with rapacuronium in cats (unpublished data) and in isolated perfused rat livers (13). However, hepatic and renal excretion have yet to be determined in humans.
The terminal half-life of rapacuronium was found to be much longer in urine than that in plasma. It is therefore likely that the true terminal half-life in plasma is also much longer than the observed value, because this terminal phase is reached after the plasma concentration has dropped below the limit of quantification. From this longer half-life, it may be inferred that the true steady-state volume of distribution is much larger than the value obtained from the plasma concentration data (Table 2). These findings are in agreement with the observed longer terminal half-life and larger steady-state volume of distribution in intensive care unit patients receiving long-term infusions of rocuronium compared with values found in normal surgical patients (17).
We aimed to obtain the effect data under circumstances that mimic intubation in daily clinical practice as closely as possible. We therefore had to drop the period necessary for stabilization of the twitch response. It could be argued that the use of isoflurane may have influenced our observations. However, because we used only a low end-tidal concentration of isoflurane (0.6%), potentiation was restricted to the effect data of the recovery. This was marginal due to the duration of the submaximal blockade by rapacuronium, which is much shorter than the equilibration time for isoflurane at the neuromuscular junction. In addition, this slight degree of potentiation may, in part, counteract the staircase phenomenon of the ulnar nerve-adductor pollicis system, a gradual increase of the twitch response occurring over approximately 30 min in the absence of a stabilization period. We therefore assume our calculated value for the potency for rapacuronium to be a reliable estimate for the determination of the intubating dose.
In conclusion, the characteristics of rapid clearance, low potency, and large ke0 of rapacuronium found in this study are consistent with the observations that rapacuronium is a muscle relaxant with a rapid onset and short to intermediate duration of action. Initially, its active metabolite, Org 9488, may not influence the time course of action after a single dose of rapacuronium because of its low plasma concentration. However, it may be responsible for the delayed recovery from rapacuronium after an infusion of 1 h due to cumulation of the metabolite because of its continuous formation and lower clearance.
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Acknowledgments |
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This study was supported by Organon Teknika BV, Boxtel, The Netherlands.
We thank Anna B. Buchthal, MD, for correcting the manuscript for the English language.
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Footnotes |
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Presented in part at the 1997 ASA annual meeting, San Diego, CA.
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References |
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