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PHARMACOKINETICS OF THE INFUSION OF ALFENTANIL IN MAN
Br. J. Anaesth. (1983), 55,1077
PHARMACOKINETICS OF THE INFUSION OF ALFENTANIL IN MAN R. J. FRAGEN, L. H. D. J. BOOIJ, G. J. J. BRAAK, T. B. VREE, J. HEYKANTS AND J. F. CRUL SUMMARY
10 mg by mouth 1 h before the induction of anaesthesia (thiopentone 400- 500 mg i.v.). Intubation of the trachea was facilitated with pancuronium O.Oo^gkg"1 i.v. Ventilation was controlled with 67% nitrous oxide in oxygen to maintain expired carbon dioxide between 4.5 and 5.5 vol% as measured by a calibrated capnograph. If necessary to maintain unconsciousness, enflurane 0.2-0.5% was added to the inspired mixture until the alfentanil was administered. All i.v. drugs were administered through an i.v. cannula in one arm and 5-ml blood samples for drug analysis were taken from a 16gauge cannula placed in a large vein in the opposite arm. A bolus injection of alfentanil O.Smgml"1, 80 Hgkg"1 over 30 s (.Kbotu. = 160 jigkg"1 min"1) and a continuous infusion of alfentanil at a rate of 3 jig kg"1 min"1 ( ^ i ) were started simultaneously. The infusion fluid was 60 ml of alfentanil 0.25 mgml" 1 solution. The infusion was given for 1 h so that each patient received a total alfentanil dose, PATIENTS AND METHODS bolus plus infusion, of 260ngkg" 1 . Venous blood Five healthy patients (two male), scheduled for elective surgery under general anaesthesia, con- samples were withdrawn just before, and 2, 5, 10, sented to participate in this study which was ap- 15, 30, 45 and 60 min after the start of the drug proved by the hospital Ethics committee. The oper- injection, and 2, 5, 10, 15, 30,60,120,240 and 360 ations were expected to last at least 1 h and to be min after the infusion was discontinued. The plasma associated with a blood loss of less than 500 ml. After was separated and stored at -20°C until assayed. Plasma concentrations were measured with a sensifasting overnight, the patients received diazepam tive and specific radioimmunoassay (Michels, Hendricks and Heykants, 1983) by Janssen PharROBERT J. FRAGEN, M.D., Department of Anaesthesia, North- maceutica and kinetic parameters were determined western University Medical School, Chicago, Illinois, U.S.A. L E O H . D. J. BOOIJ, M.D., PH.D. Department of Anaesthesia, Free by NONLIN analysis (Metzler, 1969). Studies of the pharmacokinetics of single bolus doses of alfentanil have been reported recently (Bovill et al., 1982; Bower and Hull, 1982; Camu et al., 1982; Schuttler and Stoeckel, 1982). Compared with fentanyl, alfentanil has a smaller volume of distribution, greater binding to plasma proteins, less binding to red cells, a shorter elimination halflife, a slower total body clearance, and is less lipid soluble—characteristics which suggest that alfentanil would be an appropriate drug to give by continuous i.v. infusion. The purpose of this study was to evaluate an i.v. bolus and infusion regimen as part of a balanced anaesthetic technique, and to determine the pharmacokinetics of alfentanil under these conditions . The bolus and infusion regimen was an empirically derived dose schedule of a bolus of 80 jig kg"1 and a continuous infusion of 3 ng kg"1 min1.
University, Amsterdam, The Netherlands. GERHARD J. J. BRAAK, M.D.; TOM B. VREE, PH.D; JAN F. CRUL, M.D., PH.D.;
Department of Anaesthesia, Catholic University, Nijmegen, The Netherlands. Jos HEYKANTS, PH.D., Janssen Pharmceutica, Beerse, Belgium.
Nitrous oxide was discontinued at the end of the operation which was within 10 min of the end of the infusion of alfentanil. Ventilation was assisted with oxygen until the patient was able to maintain ade© The Macmillan Press Ltd 1983
Downloaded from http://bja.oxfordjournals.org/ at Univ. of Massachusetts/Amherst Library on March 21, 2016
The pharmacokinetics of alfentanil under the conditions of an empirically derived 1 -h continuous infusion of 3ugkg~' mm" 1 , with a bolus of 80 ngkg" 1 , both i.v., were determined in five patients. The distribution half-life (mean±SD) (7.4±3.1min), elimination half-life (86.7± 15.8min), apparent volume of distribu1 1 tion, V"1* (0.44±0.15 litre kg"11) and elimination clearance min"1) were nimilar to those previously reported for a single bolus of alfentanil. These values for apparent volume of distribution and clearance can be used to calculate correct bolus and infusion doses to maintain any desired steady state plasma concentration using standard formulae: for example, to maintain a steady state plasma concentration of 400ngml~', abohisdoseof 176/igkg" 1 and an infusion of 1.3(igkg~ 1 min 1 would be required.
BRITISH JOURNAL OF ANAESTHESIA
1078 quate spontaneous ventilation. Every 2 min the same investigator requested that the patient open his eyes. The time that this occurred was noted for later correlation with the plasma concentrations of alfentanil.
TABLE I. Patina
RESULTS
Patient
Age(yr)
Weight (kg)
Sex
1 2 3 4 5
34 39 48 44 29
84 67 64 66 80
M F F F M
The specific response (plasma concentration-effect relationship) showed that awakening occurred when the plasma concentration decreased by a mean of 68 ±6.4% (range 59-74%) from that measured at the time the infusion was stopped. However, there was considerable variability in the measured plasma concentrations at the time patients opened their eyes to command (178-310 ngml"1). DISCUSSION
The alfentanil elimination half-life of the present study is in agreement with those reported recently (Bovill et al., 1982; Bower and Hull, 1982; Camu et al., 1982; Schuttler and Stoeckel, 1982). The volume of distribution ( V ) and elimination clearance of alfentanil in the present study are in agreement with those reported by Bower and Hull (1982), but are approximately half those reported by other workers. The plasma concentrations of alfentanil at the times the patients responded to verbal command by opening their eyes were fairly consistent when com-
TABLEII. Mcasurtd plasma concentrations of alfentanil (ng ml ') Treatment scheme 80-fig kg"'bolus
+
S-ngkg-'min-' infusion
Infusion stopped After infusion
Time (min)
1
2
3
4
5
Mean
SD
SEM
0 2 5 10 15 30 45 60
<1 898 592 592 672 684 728 760
<1 582 533 336 398 458 544 560
<1 350 382 382 442 420 512 536
<1 630 500 390 426 453 500 532
<1 874 661 612 622 628 750 777
<1 667 534 462 512 529 607 650
227 105 129 125 119 122 119
102 47 58 56 53 55 53
2 5 10 15 30 60 120 240 360
620 620 520 460 394 314 172 58 17
484 384 374 274 238 164 92 38 11
420 366 302 292 210 162 118 65 22
409 374 330 292 208 190 132 56 20
686 652 560 428 428 310 190 80 22
524 479 417 349 296 228 141 59 18
124 144 116 88 107 78 40 15 4
56 64 52 39 48 35 18 7 2
Downloaded from http://bja.oxfordjournals.org/ at Univ. of Massachusetts/Amherst Library on March 21, 2016
The patient characteristics are shown in table I and the measured plasma concentrations for each patient in table II. The time course of the mean plasma concentrations of alfentanil, during and after the infusion, indicate that the decay of the plasma concentrations could be described by a twocompartment model (fig. 1). Plasma concentrations decreased by 30% from their peak values over the first 10 min. Thereafter, the effect of the continuous infusion was a gradual increase in the plasma concentration until the infusion was stopped. No patient responded to painful surgical stimuli during the period of infusion or required any other anaesthetic drug(s). The plasma concentration-time curve was analysed by the NONLIN program and was divided into three parts: part one was the input of the bolus injection plus the infusion; part two was the infusion minus the elimination of the bolus, and part three was the elimination period. The equations used are presented in the appendix. The calculated pharmacokinetic parameters are presented in table III. The individual patient values and the mean ± standard deviation for the group are indicated.
charaatristia
PHARMACOKINETICS OF ALFENTANIL
1079
1000 T
*T 5 0 0 -
c
I 200
CD
I/I
J?
a
50-
c CO
c
20-
60
120
180 240 Time (min)
300
360
420
FIG. 1. Plasma concentrations of alfentanil after a 30-8 bolus injection of 80 figkg ' and a 1-h continuous infusion at a rate of 3 fig kg"1 min- 1 started simultaneously. Each data point represents the mean ± standard deviation from five patients.
pared with the plasma concentrations at the times the infusion was stopped. However, the variability in individual plasma concentrations was as expected in patients of different ages undergoing surgery and receiving multiple drugs (Bowman and Rand, 1980).
Contrary to observations made for fentanyl (Stoeckel, Hengstmann and Schuttler, 1979), there was no rebound increase in the plasma concentration of alfentanil during the elimination period. This suggests that recurrent postoperative ventilatory depression may not be a problem when alfentanil
TABLE III. Calculated pkarmacokinaic indices Parameter
Patient 1 Patient 2 Patient 3 Patient 4 Patient 5
aCmin"1) 0 (min-1) Tj'Cmin) Tj'(min)
0.119 0.009 5.62 73.0 3.61 2.38 1.70 0.09 0.14 701 2.60 218 0.28 23.7
*l2(h-') *2l(h->)
*io(h-') V, (litre kg"1) V2 (tee kg"1) ^(ngml-1)
CfcKmlkg-'min-1) CfeOnlmin-1) V - (litre kg"1) V » (litre)
0.102 0.009 6.83 74.6 2.96 1.85 1.84 0.14 0.22 484 4.09 274 0.45 30.4
0.053 0.005 13.0 U0.1 1.37 1.02 1.19 0.20 0.27 454 3.82 245 0.63 40.5
0.112 0.007 6.20 95.4 3.71 1.57 1.86 0.12 0.29 478 3.68 243 0.52 34.4
0.124 0.008 5.58 80.4 4.01 2.27 1.70 0.09 0.16 671 2.46 197 0.29 23.3
Mean±SD 0.102 ±0.028 0.008 ±0.002 7.44±3.14 86.7±15.8 3.13±1.06 1.82±0.55 1.66±0.27 O.13±O.O5 0.22 ±0.07 558±118 3.33±0.75 235±29.2 0.44±0.15 30.'5±7.30
Downloaded from http://bja.oxfordjournals.org/ at Univ. of Massachusetts/Amherst Library on March 21, 2016
o c o o
1080
BRITISH JOURNAL OF ANAESTHESIA
Total plasma clearance taking into account the body TABLE IV. Calculation of proposed alfentanil bolus and infusion Cfe regimen (Mitenko and Ogilvie, 1972) (ml min"1) weight (kg) of the patient. Apparent vol. of distribution (area) ( V™) Plasma clearance rate (Cfe) Desired alfentanil concentration (C™) Calculated bolus dose ( C - V*™) Calculated infusion rate ( C " - G E )
0.44 litre kg"1 3.33 ml kg"1 min" 400ngml-' 176 fig kg"1 1.3/igkg"'min" 1
APPENDIX DESCWPTION OF PHARMACOKINETIC PARAMETERS
a.PCmin"1)
Slopes of distribution (a) and elimination (0) phases.
Tj", T{f (min)
Half-lives of distribution (a) and elimination (JS) phases, calculated from Tj"- 0.693/
C(ng ml"1)
Average plasma concentration during the infusion period (0-60 min), calculated from: *_
AUCQ_6Q
AUCQ-60
t " 60 in which AUCo-60 i* tric area under the plasma concentration curve from 0 to 60 min (during the infusion period), as calculated by the trapezoidrule. Cfe Total plasma clearance, calculated from: (ml kg"1 min"1) ClE = total dose/AUCo-,0 =- (80 + 180)
V™ (litre)
Apparent volume of distribution taking into account the body weight (kg) of the patient.
*12, *2l (h"1) R«te constants between the central compartment (Q) and the peripheral compartment (Ci). flMt constant for elimination from the central compartment.
Downloaded from http://bja.oxfordjournals.org/ at Univ. of Massachusetts/Amherst Library on March 21, 2016
26Ougkg ' is given i.v. over 1 h. It has been reported that a steady state plasma concentration of 400 ngml"1 is necessary to provide adequate analgesia with 67% nitrous oxide (Carl C. Hug, jr, personal communication). On the basis of the pharmacokinetic results of the present study, the correct loading dose and maintainance infusion rate to maintain a steady state plasma concentration of -WOngml"1 has been determined, using the method of Mitenko and Ogilvie (1972) to be 176ngkg~' and 1.3 ngkg"1 min"1, respectively (table IV). The smaller loading dose used in the present study would account for the early decrease in the plasma concentration-time relationship and, together with the higher maintenance infusion used, for the increases in the plasma concentrations observed for the duration of the infusion; together they fortuitously maintained plasma alfentanil concentrations above the 300ngml~' minimum recommended by Bovill and colleagues (1982). The bolus and infusion procedure recommended above should minimize variations in plasma concentrations, especially those below the therapeutic threshold, during the infusion, and result in a lower plasma concentration at the end of the infusion period and, as a result, more rapid recovery.
V*"* Apparent volume of distribution calculated from: (litre kg"1) V " = <3E x 0.693/7V
Volume of the central compartment (Vi) and vol(litrekg- 1 ) ume of the peripheral compartment (Vi) taking into account the body weight (kg) of the patient. *i2> *2i» *io. V\ and V2 were calculated from: Bolus + infusion (0-30s) dCi/dj = (fctoh,, + kndl Vi + *2, X C2 - (*12 + *10) X Q dC2/dt= *n x Ci - *2i x C2 Infusion (30 stolh) dCi/dt=Mnl/Vi + *2i x C 2 -(*i2 + *io) x Ci dCi/di — same as bolus + infusion (0-30s) Elimination (Into infinity) kzi x C2 - (*i2 + *io) x Q r— same as bolus + infusion (0-30s) where dCi and dC2 are the change in concentration in the central compartment (CO and peripheral compartment (Q),fcbohna the rate constant for the bolus injection,fcfafis the rate constant for the infusion, and df is the rHnng^ in time.
V\, V2
ACKNOWLEDGEMENTS
We thank Mr Robert Woestenborghs and his group (Department of Drug Metabolism, Janssen Pharmaceutica) for analysing the plasma samples and Emiel Termond of the Department of Clinical Pharmacy, Catholic University, Nijmegen for performing the NONLIN analysis. We also thank Michael J. Avram, PH.D. for his help in preparing this manuscript. The project was supported in part by a grant from Janssen Pharmaceutica, Beerse, Belgium.
REFERENCES
Bovill, J. G., Sebel, P. S. Blackburn, C. L. and Heykants, J. (1982). The pharmacokinetics of alfentanil (R39209): A new opioid analgesic. Anathesiology, 57,439. Bower, S., and Hull, C. J. (1982). Comparative pharmacokinetics of fentanyl and alfentanil. Br. J. Anaesth., 54, 871. Bowman, W. C , and Rand, M. J. (1980). Textbook of Pharmacology. Oxford; Blackwell Scientific Publications. Camu, F., Gepts, E., Rucquoi, M., and Heykants, J. (1982). Pharmacokinetics of alfentanil in man. Anesth. Analg.,61,65\. Metzler, C. M. (1969). NONLIN, a Computer Program for Parameter Estimation in Non-linear Situations. Kalamazoo, Michigan: The Upjohn Company Biostatistics Department. Michels, M., Hendricks, R., and Heykants, J. (1983). Radioimmunoassay of the new opiate analgesics alfentanil and sufen-
PHARMACOKINETICS OF ALFENTANIL tanil. Pharmaco-kinetic profile in man. Arch. Int. Pharmacodyn. Th*r., (in press). Mitenko, P. A., and Ogilvie, R. I. (1972). Rapidly achieved plasma concentration plateaus, with observations on theophylline kinetics. Clin. Pharmacol. Thtr., 13, 329. Schuttler, J., and Stoeckel, H. (1982). Alfentanil (R39209) ein neues kurzwirkendes opioid. Anatsthtsist, 31,10. Stoeckel, H., Hengstmann, J. H., and Schuttler, J. (1979). Pharmacokinetics of fentanyl as a possible explanation for recurrence of respiratory depression. Br. J. Anaesth., 51, 741.
Nous avons ttudii la pharmacocinetique de 1'alfentanil adminis trt en perfusion intraveineuse continue d'une heure, ajustee empiriquement a la dose de 3 fig kg"' min"1 apres un bolus de 80 fig kg"' chez cinq patients. La demi-vie de distribution (moyenne±DS) (7,4±3,1 min), la demi-vie domination (86,7 ±15,8 min), le volume apparent de distribution, V** (0,44 ±0,15 litre kg' 1 ) et la clairance d'elimination (3,33± 0,75 ml kg"'min"1) etaient semblables a ceuz pr£cedemment retrouves pour une injection flash unique d'alfentanil. Ces valeurs de clairance et de volume apparent de distribution peuvent etre utilisees pour calculer les doses de charge et d'entretien qui permettent de maintenir, de facon stable, une concentration pUamatiquc souhaitee quelle qu'elle soit, en utilisant les formules usuelles: par ezemple, pour maintenir une concentration plasmatiquc stable de 400ngml~', il faudra une dose de charge de 176 fig kg"1 et une perfusion d'entretien de 1,3 fig kg"1 min"1.
PHARMAKOKINETIK VON ALFENTANILINFUSIONEN BEIM MENSCHEN ZUSAMMENFASSUNG
Bei funf Patienten wurde die Pharmakokinetik von Alfentanil wahrend einer empirisch abgeleiteten einstundigen kontinuierUchen Infusion von 3 fig kg"1 min"' nach einem Bolus von 80 fig kg"1, beides i.v. gegeben, bestimmt. Die VerteilungsHalbwertszeit (mean±SD) (7,4±3,1 min), EUminationsHalbwertszeit (86,7 ± 15,8 min), Verteilungsvolumen (V1™) (0,44±0,15 litrekg"1) und Eliminations-Clearance (3,33±0,75mlkg~'min~ 1 ) entsprachen den friiher berichteten Werten nach einem Einzelbolus. Die Werte nlr Verteilungsvolumen und Clearance konnen zur Errechnung notwendiger Bolusund Infusionsdosen zur Aufrechterhaltung jeder gewflnschten Steady-state-Plasmakonzentrationen dienen. Urn beispielsweise eine Plasmakonzentration von 400ngml"1 aufrechtzuerhalten, sind eine Bolusinjektion von 176 fig kg"1 und eine Infusion von 1,3 fig kg"' min"' notwendig.
FARMACOCINETICA DE LA INFUSION DE ALFENTANILO EN EL HOMBRE SUMARIO
F.n cinco pacientes, de determino la farmacocinetica del alfentanilo bajo las condiciones de una infusion continua de 1 h derivada empiriramente de 3 fig kg"1 min"1, con un bolo de 80figkg~', ambas i.v. La media vida de distribution (promedio±SD) (7,4±3,lmin) la media vida de rliminarion (86,7 ±15,8 min), el vohimen aparente de distribution, V*~ (0,44±0,151itrokg" 1 ) y la evacuacion (3,33±0,75mlkg- 1 min' 1 ) eran similares a los previamente indkados con un bolo unico de alfentanilo. Esos valores del volumen aparente de distribution y de evacuacion pueden usarse para calcular el bolo correcto y las dosis de innmirin necesarios para mantener cualquier concentracion deseada en estado estable en el plasma al usar fdrmulas normales: por ejemplo, para manfenrr una concentracidn en estado estable en el plasma de 400 ng ml"1, se necesitarian una dfntiH dc bolo dc 176 fig kg"' y una infusion dc l,3±figkg- | min" 1 .
Downloaded from http://bja.oxfordjournals.org/ at Univ. of Massachusetts/Amherst Library on March 21, 2016
PHARMACOCINETIQUE D'UNE PERFUSION D'ALFENTANIL CHEZ LHOMME
1081
PHARMACOKINETICS OF THE INFUSION OF ALFENTANIL IN MAN R. J. FRAGEN, L. H. D. J. BOOIJ, G. J. J. BRAAK, T. B. VREE, J. HEYKANTS AND J. F. CRUL SUMMARY
10 mg by mouth 1 h before the induction of anaesthesia (thiopentone 400- 500 mg i.v.). Intubation of the trachea was facilitated with pancuronium O.Oo^gkg"1 i.v. Ventilation was controlled with 67% nitrous oxide in oxygen to maintain expired carbon dioxide between 4.5 and 5.5 vol% as measured by a calibrated capnograph. If necessary to maintain unconsciousness, enflurane 0.2-0.5% was added to the inspired mixture until the alfentanil was administered. All i.v. drugs were administered through an i.v. cannula in one arm and 5-ml blood samples for drug analysis were taken from a 16gauge cannula placed in a large vein in the opposite arm. A bolus injection of alfentanil O.Smgml"1, 80 Hgkg"1 over 30 s (.Kbotu. = 160 jigkg"1 min"1) and a continuous infusion of alfentanil at a rate of 3 jig kg"1 min"1 ( ^ i ) were started simultaneously. The infusion fluid was 60 ml of alfentanil 0.25 mgml" 1 solution. The infusion was given for 1 h so that each patient received a total alfentanil dose, PATIENTS AND METHODS bolus plus infusion, of 260ngkg" 1 . Venous blood Five healthy patients (two male), scheduled for elective surgery under general anaesthesia, con- samples were withdrawn just before, and 2, 5, 10, sented to participate in this study which was ap- 15, 30, 45 and 60 min after the start of the drug proved by the hospital Ethics committee. The oper- injection, and 2, 5, 10, 15, 30,60,120,240 and 360 ations were expected to last at least 1 h and to be min after the infusion was discontinued. The plasma associated with a blood loss of less than 500 ml. After was separated and stored at -20°C until assayed. Plasma concentrations were measured with a sensifasting overnight, the patients received diazepam tive and specific radioimmunoassay (Michels, Hendricks and Heykants, 1983) by Janssen PharROBERT J. FRAGEN, M.D., Department of Anaesthesia, North- maceutica and kinetic parameters were determined western University Medical School, Chicago, Illinois, U.S.A. L E O H . D. J. BOOIJ, M.D., PH.D. Department of Anaesthesia, Free by NONLIN analysis (Metzler, 1969). Studies of the pharmacokinetics of single bolus doses of alfentanil have been reported recently (Bovill et al., 1982; Bower and Hull, 1982; Camu et al., 1982; Schuttler and Stoeckel, 1982). Compared with fentanyl, alfentanil has a smaller volume of distribution, greater binding to plasma proteins, less binding to red cells, a shorter elimination halflife, a slower total body clearance, and is less lipid soluble—characteristics which suggest that alfentanil would be an appropriate drug to give by continuous i.v. infusion. The purpose of this study was to evaluate an i.v. bolus and infusion regimen as part of a balanced anaesthetic technique, and to determine the pharmacokinetics of alfentanil under these conditions . The bolus and infusion regimen was an empirically derived dose schedule of a bolus of 80 jig kg"1 and a continuous infusion of 3 ng kg"1 min1.
University, Amsterdam, The Netherlands. GERHARD J. J. BRAAK, M.D.; TOM B. VREE, PH.D; JAN F. CRUL, M.D., PH.D.;
Department of Anaesthesia, Catholic University, Nijmegen, The Netherlands. Jos HEYKANTS, PH.D., Janssen Pharmceutica, Beerse, Belgium.
Nitrous oxide was discontinued at the end of the operation which was within 10 min of the end of the infusion of alfentanil. Ventilation was assisted with oxygen until the patient was able to maintain ade© The Macmillan Press Ltd 1983
Downloaded from http://bja.oxfordjournals.org/ at Univ. of Massachusetts/Amherst Library on March 21, 2016
The pharmacokinetics of alfentanil under the conditions of an empirically derived 1 -h continuous infusion of 3ugkg~' mm" 1 , with a bolus of 80 ngkg" 1 , both i.v., were determined in five patients. The distribution half-life (mean±SD) (7.4±3.1min), elimination half-life (86.7± 15.8min), apparent volume of distribu1 1 tion, V"1* (0.44±0.15 litre kg"11) and elimination clearance min"1) were nimilar to those previously reported for a single bolus of alfentanil. These values for apparent volume of distribution and clearance can be used to calculate correct bolus and infusion doses to maintain any desired steady state plasma concentration using standard formulae: for example, to maintain a steady state plasma concentration of 400ngml~', abohisdoseof 176/igkg" 1 and an infusion of 1.3(igkg~ 1 min 1 would be required.
BRITISH JOURNAL OF ANAESTHESIA
1078 quate spontaneous ventilation. Every 2 min the same investigator requested that the patient open his eyes. The time that this occurred was noted for later correlation with the plasma concentrations of alfentanil.
TABLE I. Patina
RESULTS
Patient
Age(yr)
Weight (kg)
Sex
1 2 3 4 5
34 39 48 44 29
84 67 64 66 80
M F F F M
The specific response (plasma concentration-effect relationship) showed that awakening occurred when the plasma concentration decreased by a mean of 68 ±6.4% (range 59-74%) from that measured at the time the infusion was stopped. However, there was considerable variability in the measured plasma concentrations at the time patients opened their eyes to command (178-310 ngml"1). DISCUSSION
The alfentanil elimination half-life of the present study is in agreement with those reported recently (Bovill et al., 1982; Bower and Hull, 1982; Camu et al., 1982; Schuttler and Stoeckel, 1982). The volume of distribution ( V ) and elimination clearance of alfentanil in the present study are in agreement with those reported by Bower and Hull (1982), but are approximately half those reported by other workers. The plasma concentrations of alfentanil at the times the patients responded to verbal command by opening their eyes were fairly consistent when com-
TABLEII. Mcasurtd plasma concentrations of alfentanil (ng ml ') Treatment scheme 80-fig kg"'bolus
+
S-ngkg-'min-' infusion
Infusion stopped After infusion
Time (min)
1
2
3
4
5
Mean
SD
SEM
0 2 5 10 15 30 45 60
<1 898 592 592 672 684 728 760
<1 582 533 336 398 458 544 560
<1 350 382 382 442 420 512 536
<1 630 500 390 426 453 500 532
<1 874 661 612 622 628 750 777
<1 667 534 462 512 529 607 650
227 105 129 125 119 122 119
102 47 58 56 53 55 53
2 5 10 15 30 60 120 240 360
620 620 520 460 394 314 172 58 17
484 384 374 274 238 164 92 38 11
420 366 302 292 210 162 118 65 22
409 374 330 292 208 190 132 56 20
686 652 560 428 428 310 190 80 22
524 479 417 349 296 228 141 59 18
124 144 116 88 107 78 40 15 4
56 64 52 39 48 35 18 7 2
Downloaded from http://bja.oxfordjournals.org/ at Univ. of Massachusetts/Amherst Library on March 21, 2016
The patient characteristics are shown in table I and the measured plasma concentrations for each patient in table II. The time course of the mean plasma concentrations of alfentanil, during and after the infusion, indicate that the decay of the plasma concentrations could be described by a twocompartment model (fig. 1). Plasma concentrations decreased by 30% from their peak values over the first 10 min. Thereafter, the effect of the continuous infusion was a gradual increase in the plasma concentration until the infusion was stopped. No patient responded to painful surgical stimuli during the period of infusion or required any other anaesthetic drug(s). The plasma concentration-time curve was analysed by the NONLIN program and was divided into three parts: part one was the input of the bolus injection plus the infusion; part two was the infusion minus the elimination of the bolus, and part three was the elimination period. The equations used are presented in the appendix. The calculated pharmacokinetic parameters are presented in table III. The individual patient values and the mean ± standard deviation for the group are indicated.
charaatristia
PHARMACOKINETICS OF ALFENTANIL
1079
1000 T
*T 5 0 0 -
c
I 200
CD
I/I
J?
a
50-
c CO
c
20-
60
120
180 240 Time (min)
300
360
420
FIG. 1. Plasma concentrations of alfentanil after a 30-8 bolus injection of 80 figkg ' and a 1-h continuous infusion at a rate of 3 fig kg"1 min- 1 started simultaneously. Each data point represents the mean ± standard deviation from five patients.
pared with the plasma concentrations at the times the infusion was stopped. However, the variability in individual plasma concentrations was as expected in patients of different ages undergoing surgery and receiving multiple drugs (Bowman and Rand, 1980).
Contrary to observations made for fentanyl (Stoeckel, Hengstmann and Schuttler, 1979), there was no rebound increase in the plasma concentration of alfentanil during the elimination period. This suggests that recurrent postoperative ventilatory depression may not be a problem when alfentanil
TABLE III. Calculated pkarmacokinaic indices Parameter
Patient 1 Patient 2 Patient 3 Patient 4 Patient 5
aCmin"1) 0 (min-1) Tj'Cmin) Tj'(min)
0.119 0.009 5.62 73.0 3.61 2.38 1.70 0.09 0.14 701 2.60 218 0.28 23.7
*l2(h-') *2l(h->)
*io(h-') V, (litre kg"1) V2 (tee kg"1) ^(ngml-1)
CfcKmlkg-'min-1) CfeOnlmin-1) V - (litre kg"1) V » (litre)
0.102 0.009 6.83 74.6 2.96 1.85 1.84 0.14 0.22 484 4.09 274 0.45 30.4
0.053 0.005 13.0 U0.1 1.37 1.02 1.19 0.20 0.27 454 3.82 245 0.63 40.5
0.112 0.007 6.20 95.4 3.71 1.57 1.86 0.12 0.29 478 3.68 243 0.52 34.4
0.124 0.008 5.58 80.4 4.01 2.27 1.70 0.09 0.16 671 2.46 197 0.29 23.3
Mean±SD 0.102 ±0.028 0.008 ±0.002 7.44±3.14 86.7±15.8 3.13±1.06 1.82±0.55 1.66±0.27 O.13±O.O5 0.22 ±0.07 558±118 3.33±0.75 235±29.2 0.44±0.15 30.'5±7.30
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BRITISH JOURNAL OF ANAESTHESIA
Total plasma clearance taking into account the body TABLE IV. Calculation of proposed alfentanil bolus and infusion Cfe regimen (Mitenko and Ogilvie, 1972) (ml min"1) weight (kg) of the patient. Apparent vol. of distribution (area) ( V™) Plasma clearance rate (Cfe) Desired alfentanil concentration (C™) Calculated bolus dose ( C - V*™) Calculated infusion rate ( C " - G E )
0.44 litre kg"1 3.33 ml kg"1 min" 400ngml-' 176 fig kg"1 1.3/igkg"'min" 1
APPENDIX DESCWPTION OF PHARMACOKINETIC PARAMETERS
a.PCmin"1)
Slopes of distribution (a) and elimination (0) phases.
Tj", T{f (min)
Half-lives of distribution (a) and elimination (JS) phases, calculated from Tj"- 0.693/
C(ng ml"1)
Average plasma concentration during the infusion period (0-60 min), calculated from: *_
AUCQ_6Q
AUCQ-60
t " 60 in which AUCo-60 i* tric area under the plasma concentration curve from 0 to 60 min (during the infusion period), as calculated by the trapezoidrule. Cfe Total plasma clearance, calculated from: (ml kg"1 min"1) ClE = total dose/AUCo-,0 =- (80 + 180)
V™ (litre)
Apparent volume of distribution taking into account the body weight (kg) of the patient.
*12, *2l (h"1) R«te constants between the central compartment (Q) and the peripheral compartment (Ci). flMt constant for elimination from the central compartment.
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26Ougkg ' is given i.v. over 1 h. It has been reported that a steady state plasma concentration of 400 ngml"1 is necessary to provide adequate analgesia with 67% nitrous oxide (Carl C. Hug, jr, personal communication). On the basis of the pharmacokinetic results of the present study, the correct loading dose and maintainance infusion rate to maintain a steady state plasma concentration of -WOngml"1 has been determined, using the method of Mitenko and Ogilvie (1972) to be 176ngkg~' and 1.3 ngkg"1 min"1, respectively (table IV). The smaller loading dose used in the present study would account for the early decrease in the plasma concentration-time relationship and, together with the higher maintenance infusion used, for the increases in the plasma concentrations observed for the duration of the infusion; together they fortuitously maintained plasma alfentanil concentrations above the 300ngml~' minimum recommended by Bovill and colleagues (1982). The bolus and infusion procedure recommended above should minimize variations in plasma concentrations, especially those below the therapeutic threshold, during the infusion, and result in a lower plasma concentration at the end of the infusion period and, as a result, more rapid recovery.
V*"* Apparent volume of distribution calculated from: (litre kg"1) V " = <3E x 0.693/7V
Volume of the central compartment (Vi) and vol(litrekg- 1 ) ume of the peripheral compartment (Vi) taking into account the body weight (kg) of the patient. *i2> *2i» *io. V\ and V2 were calculated from: Bolus + infusion (0-30s) dCi/dj = (fctoh,, + kndl Vi + *2, X C2 - (*12 + *10) X Q dC2/dt= *n x Ci - *2i x C2 Infusion (30 stolh) dCi/dt=Mnl/Vi + *2i x C 2 -(*i2 + *io) x Ci dCi/di — same as bolus + infusion (0-30s) Elimination (Into infinity) kzi x C2 - (*i2 + *io) x Q r— same as bolus + infusion (0-30s) where dCi and dC2 are the change in concentration in the central compartment (CO and peripheral compartment (Q),fcbohna the rate constant for the bolus injection,fcfafis the rate constant for the infusion, and df is the rHnng^ in time.
V\, V2
ACKNOWLEDGEMENTS
We thank Mr Robert Woestenborghs and his group (Department of Drug Metabolism, Janssen Pharmaceutica) for analysing the plasma samples and Emiel Termond of the Department of Clinical Pharmacy, Catholic University, Nijmegen for performing the NONLIN analysis. We also thank Michael J. Avram, PH.D. for his help in preparing this manuscript. The project was supported in part by a grant from Janssen Pharmaceutica, Beerse, Belgium.
REFERENCES
Bovill, J. G., Sebel, P. S. Blackburn, C. L. and Heykants, J. (1982). The pharmacokinetics of alfentanil (R39209): A new opioid analgesic. Anathesiology, 57,439. Bower, S., and Hull, C. J. (1982). Comparative pharmacokinetics of fentanyl and alfentanil. Br. J. Anaesth., 54, 871. Bowman, W. C , and Rand, M. J. (1980). Textbook of Pharmacology. Oxford; Blackwell Scientific Publications. Camu, F., Gepts, E., Rucquoi, M., and Heykants, J. (1982). Pharmacokinetics of alfentanil in man. Anesth. Analg.,61,65\. Metzler, C. M. (1969). NONLIN, a Computer Program for Parameter Estimation in Non-linear Situations. Kalamazoo, Michigan: The Upjohn Company Biostatistics Department. Michels, M., Hendricks, R., and Heykants, J. (1983). Radioimmunoassay of the new opiate analgesics alfentanil and sufen-
PHARMACOKINETICS OF ALFENTANIL tanil. Pharmaco-kinetic profile in man. Arch. Int. Pharmacodyn. Th*r., (in press). Mitenko, P. A., and Ogilvie, R. I. (1972). Rapidly achieved plasma concentration plateaus, with observations on theophylline kinetics. Clin. Pharmacol. Thtr., 13, 329. Schuttler, J., and Stoeckel, H. (1982). Alfentanil (R39209) ein neues kurzwirkendes opioid. Anatsthtsist, 31,10. Stoeckel, H., Hengstmann, J. H., and Schuttler, J. (1979). Pharmacokinetics of fentanyl as a possible explanation for recurrence of respiratory depression. Br. J. Anaesth., 51, 741.
Nous avons ttudii la pharmacocinetique de 1'alfentanil adminis trt en perfusion intraveineuse continue d'une heure, ajustee empiriquement a la dose de 3 fig kg"' min"1 apres un bolus de 80 fig kg"' chez cinq patients. La demi-vie de distribution (moyenne±DS) (7,4±3,1 min), la demi-vie domination (86,7 ±15,8 min), le volume apparent de distribution, V** (0,44 ±0,15 litre kg' 1 ) et la clairance d'elimination (3,33± 0,75 ml kg"'min"1) etaient semblables a ceuz pr£cedemment retrouves pour une injection flash unique d'alfentanil. Ces valeurs de clairance et de volume apparent de distribution peuvent etre utilisees pour calculer les doses de charge et d'entretien qui permettent de maintenir, de facon stable, une concentration pUamatiquc souhaitee quelle qu'elle soit, en utilisant les formules usuelles: par ezemple, pour maintenir une concentration plasmatiquc stable de 400ngml~', il faudra une dose de charge de 176 fig kg"1 et une perfusion d'entretien de 1,3 fig kg"1 min"1.
PHARMAKOKINETIK VON ALFENTANILINFUSIONEN BEIM MENSCHEN ZUSAMMENFASSUNG
Bei funf Patienten wurde die Pharmakokinetik von Alfentanil wahrend einer empirisch abgeleiteten einstundigen kontinuierUchen Infusion von 3 fig kg"1 min"' nach einem Bolus von 80 fig kg"1, beides i.v. gegeben, bestimmt. Die VerteilungsHalbwertszeit (mean±SD) (7,4±3,1 min), EUminationsHalbwertszeit (86,7 ± 15,8 min), Verteilungsvolumen (V1™) (0,44±0,15 litrekg"1) und Eliminations-Clearance (3,33±0,75mlkg~'min~ 1 ) entsprachen den friiher berichteten Werten nach einem Einzelbolus. Die Werte nlr Verteilungsvolumen und Clearance konnen zur Errechnung notwendiger Bolusund Infusionsdosen zur Aufrechterhaltung jeder gewflnschten Steady-state-Plasmakonzentrationen dienen. Urn beispielsweise eine Plasmakonzentration von 400ngml"1 aufrechtzuerhalten, sind eine Bolusinjektion von 176 fig kg"1 und eine Infusion von 1,3 fig kg"' min"' notwendig.
FARMACOCINETICA DE LA INFUSION DE ALFENTANILO EN EL HOMBRE SUMARIO
F.n cinco pacientes, de determino la farmacocinetica del alfentanilo bajo las condiciones de una infusion continua de 1 h derivada empiriramente de 3 fig kg"1 min"1, con un bolo de 80figkg~', ambas i.v. La media vida de distribution (promedio±SD) (7,4±3,lmin) la media vida de rliminarion (86,7 ±15,8 min), el vohimen aparente de distribution, V*~ (0,44±0,151itrokg" 1 ) y la evacuacion (3,33±0,75mlkg- 1 min' 1 ) eran similares a los previamente indkados con un bolo unico de alfentanilo. Esos valores del volumen aparente de distribution y de evacuacion pueden usarse para calcular el bolo correcto y las dosis de innmirin necesarios para mantener cualquier concentracion deseada en estado estable en el plasma al usar fdrmulas normales: por ejemplo, para manfenrr una concentracidn en estado estable en el plasma de 400 ng ml"1, se necesitarian una dfntiH dc bolo dc 176 fig kg"' y una infusion dc l,3±figkg- | min" 1 .
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PHARMACOCINETIQUE D'UNE PERFUSION D'ALFENTANIL CHEZ LHOMME
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