EUROPEAN JOURNAL OF DRUG METABOUSM AND PHARMACOKINETICS, 1990, VoL IS, No.3, pp. 231-237
Pharmacokinetics of oxiracetam in patients with renal impairment after a 800 mg single oral dose J.B. LECAILLON 1, J.P. DUBOIS 1, H. COPPENS 1, T. DARRAGON 1, G. REUMOND2, N. POZET3, 1. 1RAEGER3 and G. LAMBREy4 lBiopharmaceutical Research Center and Medical Department, Laboratoires CIBA-GEIGY, Rueil-Malmaison, France 2Centre Hospitalier General, Evreux, France 3H"pital Edouard Herriot, Lyon, France 4Centre Hospitalier, Beauvais, France
Receivedfor publication: September 29, 1989
Keywords: Oxiracetam, renal impainnent, pharmacokinetics, maintenance dose
SUMMARY The pharmacokinetics of oxiracetam in patients with renal impairment were investigated after administration of a 800 mg single oral dose of oxiracetam. The renal insufficiency was estimated on the basis of the creatinine clearance (CLcr) which ranged from 9 to 95 mlImin among the 20 patients. In plasma, the terminal elimination half-life (TIll) ranged from 10.6 to 68.1 h, the highest Tlfl corresponding to the patients with a high degree of renal impairment In urine, the amounts of oxiracetam excreted during the 48 h postdosing represented 8.3 to 82.6% of the dose. They were lower in patients with a high degree of renal impairment. The correlations between the total clearance of oxiracetam, the renal clearance, the terminal apparent elimination rate constant in plasma, and CLcr were estimated by linear regression analysis. The correlation coefficients were 0.916, 0.985 and 0.803 respectively. The apparent volume of distribution of the central compartment V(l) and the total volume of distribution at the steady-state V(SS) were not dependent on the degree of renal impairment The mean values ± SD were 25.9 ± 13.0 litres and 48.3 ± 21.5 litres respectively. Oxiracetam concentrations in plasma of patients were estimated for repeated administration of 800 mg of oxiracetam. The estimations showed that the steady-state concentrations would be obtained after 6-10 days of repeated administration for patients whose CLcr is 9-15 mlImin and 3-5 days for patients with CLcr between 15 and 40 mlImin. The dosage of oxiracetam in renal insufficient patients was evaluated in order to reach a mean steady-state concentration level of oxiracetam in plasma close to that in patients with normal renal function. For patients with CLcr between 40 and 60 mlImin, the adjusted daily dose would be 50% of the dose given to a patient with normal renal function. For patients with CLcr between 15 and 40 mlImin, the adjusted daily dose would be 25% of the dose given to a patient with normal renal function. For patients whose CLcr was below 40 ml/min, one daily administration in agreement with the dosage reduction, could be given.
INTRODUCTION Oxiracetam (4-hydroxy-2-oxo-l-pyrrolidine acetamide) is a new nootropic drug. In normal volunteers Please send reprint requests to : J.B. Lecaillon, Laboratoires CIDA-GEIGY, B.P. 308, F-92506 Rueil-Malmaison Cedex, France
given oxiracetam, quantitative phannaco-EEG data demonstrated significant CNS effects (1). In elderly patients with organic brain syndrome, oxiracetam exhibited a significant improvement of the memory function (2). In patients with mild to moderate dementia, 800 mg of oxiracetam twice daily was effective in enhancing both attentional activities and other, more complex neuropsychological functions (3).
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Eur. J. Drug Metab. Pharmacokinet., 1990, No.3
Table I: Creatinine clearance, diagnoses of diseases and associated medications Patient CLcr (mlimin) 8.9
Associated diseases
Associated medications
Hypertension
Furosemide, propranolol, gluconolactate and calcium carbonate dihydralazine, atenolol
9
Undernutrition, hyperuricemia, troubles of behaviour, peptic ulcer
Haloperidol, allopurinol, ranitidine
10
Hypertension
Polystyrene sodium sulfonate, allopurinol, aluminium phosphate, calcifediol, nifedipine, calcium carbonate
11
Hypertension
Atenolol, nifedipine, polystyrene sodium sulfonate, calcium carbonate, allopurinol, calcifediol, simethicone + aluminium hydroxide + sorbitol
13.7
Hypertension
Allopurinol, cynara scolymus + citroflavonotdes, sodium bicarbonate
IS,S
Congestive hC81t failure, arteriopathy of lower limbs
Nifedipine,clonidine, pentoxifylline, furosemide, dihydralazine, digoxine
Hypertension, frequent urinary infections
Clonidine
18
20
Nitrazepam
21
Allopurinol, pipemidic acid
22
Hypertension
Furosemide, methyldopa, indometacine
25
Atheromatosic polyvasculitis
Clonidine,fUrosemide
26
Dihydralazine, captopril Hypertension
Acebutolol
Left congestive heart failure, oesophagitis
Cimetidine, magnesium and aluminium hydroxides, methyldopa, sulfamethoxazole and trimethoprim
45
Gout
Colchicine.Iysine acetylsalicylate
48
Cerebral atheromatosis, mitral regurgitation
Disopyramide phosphate, naftidrofuryl flurbiprofene, pygeum africanum
31 35.5
36.3
Pipemidic acid
61 81
95
Renal lithiasis
Cefotaxime, amikacine Pipemidic acid
J. E. Lecaillon et al., Oxiracetam & renal impairment The pharmacokinetics of the drug have been studied in healthy male volunteers (4) and in elderly patients (5, 6), but not yet in patients with impaired renal function. Twenty patients (two of them having normal creatinine clearance value) participated in the present study.
METHODS Patients Twenty patients (13 males and 7 females), aged 30 to 79 years with body weights from 56 to 85 kg gave their written informed consent to participate in the study. Their creatinine clearance (CLcr), the diseases other than renal insufficiency and the associated medications which could not be interrupted are reported in Table 1. The subjects had hepatic functions in the normal range.
Protocol In the morning, after an overnight fast, the subjects were given a 800 mg film-coated tablet orally with 100 ml of water. About two hours after medication, the subjects had a light standardized breakfast Blood (4 ml) was collected into heparinized tubes before dosing and 0.5, I, 2, 4, 6, 10, 24, 32 and 48 h afterwards. The samples were immediately centrifuged, plasma was separated and stored at -20·C until analysis. Urine was collected before administration and quantitatively in the time intervals 0-10, 10-24, 24-48 h after administration. The volumes were recorded and aliquots of about 15 ml were immediately stored at -20·C until analysis.
Analytical method Oxiracetam concentrations were determined by column-switching high performance liquid chromatography (7). The limit of quantitation of oxiracetam was 1.2 umol/l (about 200 ng/ml) in plasma and 9.5 umol/l (about 1.5 ug/ml) in urine. The accuracy and precision of the method were tested by analysing every day, biological samples spiked with known amounts of oxiracetam.
233
Data treatment Oxiracetam peak concentrations in plasma and time to peak were directly obtained from the individual concentration-time profile. The area under concentration-time curve (AUC(O-inf» was calculated by the trapezoidal rule and extrapolated to time infinity, The apparent elimination half-life (TlIZ) was determined from the slope of the last log-linear segment of the concentration-time curve. The apparent elimination rate constant in plasma (beta) during the terminal phase was calculated as ln2 I (TIn). The total plasma clearance (CLT) was obtained from the ratio FD/AUC, where F is the fraction of the dose (0) absorbed after oral administration; F was taken as equal to 1, assuming a complete availability of the oral dose. If only 75% of the dose of oxiracetam were absorbed after oral administration as described previously (4), the total plasma clearance values found in this study would have to be multiplied by 0.75. The renal clearance (CLR) was obtained from the ratio U(0-48 h)/AUC(O-48 h), where U(O-48h) is the cumulated amount of unchanged drug excreted in urine and AUC(0-48h) the area under the curve in plasma calculated over 48 h after dosing. The mean (Cmeans), maximum (Cmaxss) and minimum (Cmins.;1 concentrations at the steady-state in plasma, corrected for a body weight of 75 kg were estimated as AUC(O-int)/time interval between two consecutive doses during chronic treatment for Cmeans, and by using the superposition technique with the concentrations measured after the single dose and the corresponding Tin value for Cmaxs, and Cmins, The kinetics were also studied by the incremental method (8) which applies to drugs whose pharmacokinetics can be described by a two-compartment open model with linear kinetics as previously shown for oxiracetam (4). The method permits the determination of the characteristics of the model and of the absorption kinetics. K(10)
elimination rate constant from the central compartment (h- 1)
K(12)
transfer rate constant from the central to the peripheral compartment (h- 1)
K(21)
transfer rate constant from the peripheral to the central compartment (h- 1)
V(1)
apparent volume of distribution (1) of the central compartment (assuming complete availability of the orally administered dose)
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234
Table II : Oxiracetam pharmacokinetic parameters Patient CLcr (mlimin)
8.9 9 10 11 13.7 15.5 18 20 21 22 25 26 31 35.5 36.3 45 48 61 81 95
Cl1* (mUmin)
T1I2 (h)
12.9 15.6 11.1 9.6 14.0 15.0 19.7 19.3 24.3 17.2 24.8 48.3 25.5 62.3 29.5 34.7 42.5 47.6 76.0 92.0
41.4 54.9 68.1 60.6 31.0 32.5 22.3 13.2 21.6 28.7 18.0 27.6 22.8 19.5 15.9 20.4 16.2 13.3 10.6 13
AUC(O-inf) (pnwl.hJl)
Beta (h- 1)
0.014 0.012 0.010 0.008 0.020 0.021 0.034 0.051 0.025 0.023 0.039 0.025 0.029 0.035 0.043 0.033 0.042 0.049 0.064 0.051
U(0-48h) (%dose)
ClR (mUmin)
6521 5414 7575 8797 6045 5631 4291 4345 3463 4919 3397 1743 3297 1353 2861 2430 1987 1770 1108 916
7.11 2.87 3.07 6.37 7.76
32.6 8.34 11.8 31.5 38.1
14.1 11.6 14.3 11.3 17.3 8.9 14.5 26.7 20.9
57.4 55.0 48.7 48.7 60.0 13.3 47.7 36.0 65.2
28.6 40.9 57.6 71.4
61.7 82.6 74.0 75.9
• : maximum value assuming complete availability of the administered dose
V(SS) total steady-state apparent volume of distribution (I) (assuming a complete availability of the orally administered dose)
1000
CONCENTRATION (~MOL/L)
RESULTS The model independent phannacokinetic parameters and those obtained by using a two-compartment open model are given in Tables II & III, respectively. The maximum of concentration appeared between 1 and 4 h postdosing and its magnitude (mean Cmax ± SD = 158 ± 55 umol/l) was not influenced by the degree of renal impairment. The decrease of concentration was slowed down in patients with low CLcr as shown by the increase of the TlI2 up to 68 h and the log-linear plot of the concentrations for patients with CLcr of II, 22,45 and 81 ml/min (Fig. 1). The amount of oxiracetam excreted in urine over 48 h ranged from 8.3 to 82.6% of the administered dose among the subjects and was lower in subjects with a high degree of renal impairment (Table 11). The correlations between CLT, CLR, beta (terminal apparent elimination rate constant in plasma) and CLcr were estimated by linear regression analysis. The
12
24
6
48 TIME(H)
Fig. 1 : Log-linear plot of the oxiracetam concentrations in plasma for patients with CLer of 11 (0),22 (*),45 (#) and 81 (x) mlImin
equations and coefficients of correlation (r) are: CLT= 0.876
CLer + 4.4,
r
=
0.916
CLR = 0.75
CLer - 3.54,
r
=
0.985
beta = 0.00052
CLer + 0.015,
r = 0.803
The apparent volume of distribution of the central
235
J. E. Lecaillon et al., Oxiracetam & renal impairment
Table 1lI : Oxiracetam two-compartment model characteristics calculated by the incremental method from the plasma concentrations Characteristics ofthe model
Subject CLcr (mlJmin)
8.9 9 10 11 13.7 15.5 18 20 21 22 25 26 31 35.5 36.3 45 48 61 81 95
K(lO)
K(l2)
K(2l)
V(l)*
(h- 1)
(h- 1)
(h- 1)
(I)
0.03 0.02 0.02 0.02 0.03 0.05 0.08 0.09 0.06 0.07 0.08 0.04 0.09 0.09 0.12 0.09 0.10 0.16 0.18 0.32
Mean ±SD
V(SS)* (l)
0.05 0.42 0.06 0.08 0.03 0.10 0.27 0.20 0.04 0.12 0.12 0.07 0.09 0.13 0.09 0.09 0.07 0.06 0.07 0.05
0.07 0.42 0.08 0.05 0.07 0.10 0.21 0.31 0.06 0.08 0.17 0.'12 0.07 0.12 0.09 0.09 0.09 0.08 0.10 0.06
26.2 36.9 35.4 21.7 26.0 19.8 14.5 13.4 24.5 15.3 20.3 69.4 17.7 44.5 15.9 25.2 25.6 18.9 27.9 18.9
46.0 74.3 63.9 53.8 37.0 38.2 32.9 21.8 42.8 36.9 35.2 109 39.7 91.4 30.5 50.3 45.6 34.4 47.2 35.3
0.11 0.09
0.12 0.09
25.9 13.0
48.3 21.5
• : maximum value assuming complete availability of the administered dose
compartment, the total volume of distribution at the steady-state and the transfer rate constants between the central and the peripheral compartment were not influenced by the degree of renal insufficieny. The elimination rate constant from the central compartment K(10) was influenced by the degree of renal impairment and the equation of the curve obtained by linear regression analysis: K(10) = 0.00275 CLer 0.000009, r = 0.936, indicated a good proportionality between K(10) and CLer.
DISCUSSION A dependency of the elimination rate of oxiracetam in plasma with CLcr was observed and this is rather common for a drug whose elimination occurred in the unchanged form almost exclusively by the renal route. The pharmacokinetic model: two compartment model
described for healthy subjects (4) and the volume of distribution were not modified in patients with renal impairment
Estimation of steady-state concentrations The study of oxiracetam concentrations after repeated administration in elderly patients with CLcr down to 23 rnIlmin has previously been reported (6) and indicates that the pharmacokinetics of the drug are not modified by repeated administration. Therefore, the results of the present study after single administration can be used to predict the steady-state concentrations during repeated administration. The oxiracetam concentrations in plasma were estimated for each patient on the basis of the administration of 800 mg of the drug twice daily. The predicted concentration profiles for subjects with CLer of 15.5, 45 and 95 ml/min are shown in Figure 2. These estimations
Eur. J. DrugMetab. Pharmacokinet., 1990,No.3
236
showed that the steady-state concentrations would be obtained after 6-10 days of repeated administration for patients with CLer of 9-15 mlImin and 3-5 days for patients with CLcr between 15 and 40 mlImin. The maximum, minimum and mean concentrations at the steady-state, corrected for a body weight of 75 kg, are reported in Table IV.
600
CONCENTRATION (IJMOL/L)
Dosage of oxiracetam in renal insufficient patients The slow elimination of oxiracetam in patients with renal impainnent would lead to an increase of the steady-state level of oxiracetam (Fig. 2). A reduction of the dosage in these patients appeared necessary. The dosage of oxiracetam in renal insufficient patients Table N : Predicted maximum, minimum and mean concentrations at the steady-state on the basis of two 800 mg daily doses of oxiracetam, normalized for a 75 kg body weight. Maintenance dose calculated * for the patients Subject CLcr
Cmax..
(mllmin)
(jU1IOlIl)
Cmillu (1J1II01il)
MaintenCmean.. ance (lJ1IIOlIl) dosage* (%)
8.9 9 10 11 13.7 15.5 18 20 21 22 25 26 31 35.5 36.3 45 48 61 81 95
600 461 648 567 536 396 340 369 290 423 334 147 337 145 311 299 234 195 129 118
456 398 556 464 389 305 206 208 171 270 174 108 150 89.1 112 167 94.8 56.7 37.9 19.6
528 428 606 518 466 356 266 284 230 344 246 130 228 113 191 230 152 118 80.0 59.8
12 15 11 12 14 18 24 23 28 19 26 49 28 57 33 28 42 54 80 100
* : calculated as the ratio (Crneans. in patient with normal renal functionlCmeana. renal insufficient patient) x 100. The reference taken for a patient with normal renal function was that of a patient whose CLcr - 100 mlImin. Its Cmeallssvalue (63.8 JUIloVl) was calculated from the linear regression analysis of lICmeallss values as a function of CLer
1
2
3
4
567 8 TIME (DAYS)
Fig. 2 : Simulated concentration profiles of oxira.cetam in plasma for the subjects with CLcr of 15:5. (0), .45 (*) and 95 (#) mJ/min based on the administration of 800 mg of the drug twice daily. The results after single administration were used to simulate the profiles during repeated administration
was evaluated in order to reach a mean steady-state concentration level of oxiracetam in plasma close to that in a patient with normal renal function. The maintenance dose in these patients (Table IV) was obtained by dividing the mean oxiracetam level in a patient with normal renal function (CLcr = 100 mlImin) by the mean level in the patients with renal impairment and expressing the result in percent Figure 3 shows the individual maintenance dose as a function of CLer. The straight line was obtained by linear least-squares regression analysis and could serve as a nomograph for the graphical determination of the dose reduction. Nevertheless for practical reasons and by considering the values of maintenance dose for each individual (Table IV) and the good tolerability of the drug (3, 9), it appeared easier to propose a maintenance dose within two intervals of CLcr: 25% of normal dose for patients whose CLcr is 15-40 mlImin, and 50% of normal dose for patients whose CLcr is 40-60 mlImin. For patients whose CLcr is above 60 mlImin no special adjustment appeared necessary. For patients whose CLer is below 40 mlImin, it is possible to administer the maintenance dose of oxiracetam once daily instead of twice daily. In that case the minimum concentrations would be similar or higher than those recorded in a patient with normal renal function receiving the normal dose of oxiracetam twice daily.
J. E. Lecaillon et al., Oxiracetam & renalimpairment C MEAN (NORMAL)I CMEAN (REN.IMP.)
100 90
%
/' /
//
80 70 60
237
For patients whose CLer is above 60mVmin no special adjustment appeared necessary. For patients whose CLcr is below 40 ml/min, it is possible to administer the maintenance dose of oxiracetam once daily instead of twice daily.
o
50
ACKNOWLEDGEMENTS
o
40 30 20
The authors are grateful to Mrs C. Souppart for technical assistance.
o
20
40
60
80
100
CLCR (ML/MIN) Fig. 3 : Ratio of mean concentration levels: normal
patient/patient with a renal impairment as a function of CLcr. The straight line, obtained by linear least squares regression analysis, could serve as a nomograph for the graphical determination of the dose reduction. The maintenance dose in % of the normal dose could be read on the Y axis. The equation was: Dose (%) = 0.97 CLer + 3.2; r = 0.932
CONCLUSIONS The elimination rate of oxiracetam is reduced in patients with renal impairment, The phannacokinetic model: two-compartment model described for healthy subjects and the volume of distribution were not modified in patients with renal impairment. A dependency of the elimination rate in plasma, of the renal and of the total clearances of oxiracetam with CLer was observed. A reduction of the dosage in patients with renal impairment appeared necessary. The dose to be given is as follows: 25% of normal dose for patients whose CLer is 15-40 ml/min. 50% of normal dose for patients whose CLer is 40-60 ml/min.
REFERENCES 1. ltil T.M., Soldatos c., Bozak M., et al. (1979): CNS effects of ISF-2522. A new nootropic (a phase 1 safety and CNS efficacy study with quantitative pharmaco-EEG and pharmaco-psychology study). Curr. TIter. Res., 26, 525-538. 2. ltil TM., Menon GN., Bozak M., Songar A. (1982): The effects of oxiracetam (ISF 2522) in patients with organic brain syndrome (a double blind controlled study with Piracetam). Drug Dev. Res., 2,447-461. 3. Villardita G., Parini I., Grioli S., Quattropani M, Lomeo., Scapagnini U. (1987): Clinical and neuropsychological study with oxiracetam versus placebo in patients with mild to moderate dementia. I. Neural. Transm. Suppl., 24, 293-298. 4. Perucca E., Albrici A., Gatti G., Spalluto R., Visconti M, Crema A. (1984): Pharmacokinetics of oxiracetam following intravenous and oral administration in healthy volunteers. Eur. I. Drug Metab. Pharmacokinet., 3,267-274. 5. Perucca E., Parini I., Albrici A., Visconti M., Ferrero E. (1987) : Oxiracetam pharmacokinetics following single and multiple dose administration in the elderly. Eur. I. Drug Metab. Pharmacokinet., 2,145-148. 6. Lecaillon I.B., Dubois I.P., Coppens R., Theobald W., Reumond G., Beck R. (1990) : Pharmacokinetics of oxiracetam in elderly patients after 800 mg oral doses, comparison with non-geriatric healthy subjects. Eur. I. Drug Metab. Pharmacokinet., This issue 7. Lecai1lon I.B., Souppart C., F. Le Duigow, Dubois I.P. (1989) : Determination of oxiracetam in plasma and urine by column-switching high performance liquid chromatography. I. Chromatogr., 497, 223-230. 8. Gerardin A., Wantiez D., Jaouen A. (1983): An incremental method for the study of the absorption of drugs whose kinetics are described by a two-compartment model: estimation of the microscopic rate constants. I. Pharmacokinet. Biopharm. 11, 401-424. 9. Ferrero E., (1984) : Controlled clinical trial of oxiracetam in the treatment of chronic cerebrovascular insufficiency in the elderly. Curr. Ther. Res. 36, 298-308.
Pharmacokinetics of oxiracetam in patients with renal impairment after a 800 mg single oral dose J.B. LECAILLON 1, J.P. DUBOIS 1, H. COPPENS 1, T. DARRAGON 1, G. REUMOND2, N. POZET3, 1. 1RAEGER3 and G. LAMBREy4 lBiopharmaceutical Research Center and Medical Department, Laboratoires CIBA-GEIGY, Rueil-Malmaison, France 2Centre Hospitalier General, Evreux, France 3H"pital Edouard Herriot, Lyon, France 4Centre Hospitalier, Beauvais, France
Receivedfor publication: September 29, 1989
Keywords: Oxiracetam, renal impainnent, pharmacokinetics, maintenance dose
SUMMARY The pharmacokinetics of oxiracetam in patients with renal impairment were investigated after administration of a 800 mg single oral dose of oxiracetam. The renal insufficiency was estimated on the basis of the creatinine clearance (CLcr) which ranged from 9 to 95 mlImin among the 20 patients. In plasma, the terminal elimination half-life (TIll) ranged from 10.6 to 68.1 h, the highest Tlfl corresponding to the patients with a high degree of renal impairment In urine, the amounts of oxiracetam excreted during the 48 h postdosing represented 8.3 to 82.6% of the dose. They were lower in patients with a high degree of renal impairment. The correlations between the total clearance of oxiracetam, the renal clearance, the terminal apparent elimination rate constant in plasma, and CLcr were estimated by linear regression analysis. The correlation coefficients were 0.916, 0.985 and 0.803 respectively. The apparent volume of distribution of the central compartment V(l) and the total volume of distribution at the steady-state V(SS) were not dependent on the degree of renal impairment The mean values ± SD were 25.9 ± 13.0 litres and 48.3 ± 21.5 litres respectively. Oxiracetam concentrations in plasma of patients were estimated for repeated administration of 800 mg of oxiracetam. The estimations showed that the steady-state concentrations would be obtained after 6-10 days of repeated administration for patients whose CLcr is 9-15 mlImin and 3-5 days for patients with CLcr between 15 and 40 mlImin. The dosage of oxiracetam in renal insufficient patients was evaluated in order to reach a mean steady-state concentration level of oxiracetam in plasma close to that in patients with normal renal function. For patients with CLcr between 40 and 60 mlImin, the adjusted daily dose would be 50% of the dose given to a patient with normal renal function. For patients with CLcr between 15 and 40 mlImin, the adjusted daily dose would be 25% of the dose given to a patient with normal renal function. For patients whose CLcr was below 40 ml/min, one daily administration in agreement with the dosage reduction, could be given.
INTRODUCTION Oxiracetam (4-hydroxy-2-oxo-l-pyrrolidine acetamide) is a new nootropic drug. In normal volunteers Please send reprint requests to : J.B. Lecaillon, Laboratoires CIDA-GEIGY, B.P. 308, F-92506 Rueil-Malmaison Cedex, France
given oxiracetam, quantitative phannaco-EEG data demonstrated significant CNS effects (1). In elderly patients with organic brain syndrome, oxiracetam exhibited a significant improvement of the memory function (2). In patients with mild to moderate dementia, 800 mg of oxiracetam twice daily was effective in enhancing both attentional activities and other, more complex neuropsychological functions (3).
232
Eur. J. Drug Metab. Pharmacokinet., 1990, No.3
Table I: Creatinine clearance, diagnoses of diseases and associated medications Patient CLcr (mlimin) 8.9
Associated diseases
Associated medications
Hypertension
Furosemide, propranolol, gluconolactate and calcium carbonate dihydralazine, atenolol
9
Undernutrition, hyperuricemia, troubles of behaviour, peptic ulcer
Haloperidol, allopurinol, ranitidine
10
Hypertension
Polystyrene sodium sulfonate, allopurinol, aluminium phosphate, calcifediol, nifedipine, calcium carbonate
11
Hypertension
Atenolol, nifedipine, polystyrene sodium sulfonate, calcium carbonate, allopurinol, calcifediol, simethicone + aluminium hydroxide + sorbitol
13.7
Hypertension
Allopurinol, cynara scolymus + citroflavonotdes, sodium bicarbonate
IS,S
Congestive hC81t failure, arteriopathy of lower limbs
Nifedipine,clonidine, pentoxifylline, furosemide, dihydralazine, digoxine
Hypertension, frequent urinary infections
Clonidine
18
20
Nitrazepam
21
Allopurinol, pipemidic acid
22
Hypertension
Furosemide, methyldopa, indometacine
25
Atheromatosic polyvasculitis
Clonidine,fUrosemide
26
Dihydralazine, captopril Hypertension
Acebutolol
Left congestive heart failure, oesophagitis
Cimetidine, magnesium and aluminium hydroxides, methyldopa, sulfamethoxazole and trimethoprim
45
Gout
Colchicine.Iysine acetylsalicylate
48
Cerebral atheromatosis, mitral regurgitation
Disopyramide phosphate, naftidrofuryl flurbiprofene, pygeum africanum
31 35.5
36.3
Pipemidic acid
61 81
95
Renal lithiasis
Cefotaxime, amikacine Pipemidic acid
J. E. Lecaillon et al., Oxiracetam & renal impairment The pharmacokinetics of the drug have been studied in healthy male volunteers (4) and in elderly patients (5, 6), but not yet in patients with impaired renal function. Twenty patients (two of them having normal creatinine clearance value) participated in the present study.
METHODS Patients Twenty patients (13 males and 7 females), aged 30 to 79 years with body weights from 56 to 85 kg gave their written informed consent to participate in the study. Their creatinine clearance (CLcr), the diseases other than renal insufficiency and the associated medications which could not be interrupted are reported in Table 1. The subjects had hepatic functions in the normal range.
Protocol In the morning, after an overnight fast, the subjects were given a 800 mg film-coated tablet orally with 100 ml of water. About two hours after medication, the subjects had a light standardized breakfast Blood (4 ml) was collected into heparinized tubes before dosing and 0.5, I, 2, 4, 6, 10, 24, 32 and 48 h afterwards. The samples were immediately centrifuged, plasma was separated and stored at -20·C until analysis. Urine was collected before administration and quantitatively in the time intervals 0-10, 10-24, 24-48 h after administration. The volumes were recorded and aliquots of about 15 ml were immediately stored at -20·C until analysis.
Analytical method Oxiracetam concentrations were determined by column-switching high performance liquid chromatography (7). The limit of quantitation of oxiracetam was 1.2 umol/l (about 200 ng/ml) in plasma and 9.5 umol/l (about 1.5 ug/ml) in urine. The accuracy and precision of the method were tested by analysing every day, biological samples spiked with known amounts of oxiracetam.
233
Data treatment Oxiracetam peak concentrations in plasma and time to peak were directly obtained from the individual concentration-time profile. The area under concentration-time curve (AUC(O-inf» was calculated by the trapezoidal rule and extrapolated to time infinity, The apparent elimination half-life (TlIZ) was determined from the slope of the last log-linear segment of the concentration-time curve. The apparent elimination rate constant in plasma (beta) during the terminal phase was calculated as ln2 I (TIn). The total plasma clearance (CLT) was obtained from the ratio FD/AUC, where F is the fraction of the dose (0) absorbed after oral administration; F was taken as equal to 1, assuming a complete availability of the oral dose. If only 75% of the dose of oxiracetam were absorbed after oral administration as described previously (4), the total plasma clearance values found in this study would have to be multiplied by 0.75. The renal clearance (CLR) was obtained from the ratio U(0-48 h)/AUC(O-48 h), where U(O-48h) is the cumulated amount of unchanged drug excreted in urine and AUC(0-48h) the area under the curve in plasma calculated over 48 h after dosing. The mean (Cmeans), maximum (Cmaxss) and minimum (Cmins.;1 concentrations at the steady-state in plasma, corrected for a body weight of 75 kg were estimated as AUC(O-int)/time interval between two consecutive doses during chronic treatment for Cmeans, and by using the superposition technique with the concentrations measured after the single dose and the corresponding Tin value for Cmaxs, and Cmins, The kinetics were also studied by the incremental method (8) which applies to drugs whose pharmacokinetics can be described by a two-compartment open model with linear kinetics as previously shown for oxiracetam (4). The method permits the determination of the characteristics of the model and of the absorption kinetics. K(10)
elimination rate constant from the central compartment (h- 1)
K(12)
transfer rate constant from the central to the peripheral compartment (h- 1)
K(21)
transfer rate constant from the peripheral to the central compartment (h- 1)
V(1)
apparent volume of distribution (1) of the central compartment (assuming complete availability of the orally administered dose)
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Table II : Oxiracetam pharmacokinetic parameters Patient CLcr (mlimin)
8.9 9 10 11 13.7 15.5 18 20 21 22 25 26 31 35.5 36.3 45 48 61 81 95
Cl1* (mUmin)
T1I2 (h)
12.9 15.6 11.1 9.6 14.0 15.0 19.7 19.3 24.3 17.2 24.8 48.3 25.5 62.3 29.5 34.7 42.5 47.6 76.0 92.0
41.4 54.9 68.1 60.6 31.0 32.5 22.3 13.2 21.6 28.7 18.0 27.6 22.8 19.5 15.9 20.4 16.2 13.3 10.6 13
AUC(O-inf) (pnwl.hJl)
Beta (h- 1)
0.014 0.012 0.010 0.008 0.020 0.021 0.034 0.051 0.025 0.023 0.039 0.025 0.029 0.035 0.043 0.033 0.042 0.049 0.064 0.051
U(0-48h) (%dose)
ClR (mUmin)
6521 5414 7575 8797 6045 5631 4291 4345 3463 4919 3397 1743 3297 1353 2861 2430 1987 1770 1108 916
7.11 2.87 3.07 6.37 7.76
32.6 8.34 11.8 31.5 38.1
14.1 11.6 14.3 11.3 17.3 8.9 14.5 26.7 20.9
57.4 55.0 48.7 48.7 60.0 13.3 47.7 36.0 65.2
28.6 40.9 57.6 71.4
61.7 82.6 74.0 75.9
• : maximum value assuming complete availability of the administered dose
V(SS) total steady-state apparent volume of distribution (I) (assuming a complete availability of the orally administered dose)
1000
CONCENTRATION (~MOL/L)
RESULTS The model independent phannacokinetic parameters and those obtained by using a two-compartment open model are given in Tables II & III, respectively. The maximum of concentration appeared between 1 and 4 h postdosing and its magnitude (mean Cmax ± SD = 158 ± 55 umol/l) was not influenced by the degree of renal impairment. The decrease of concentration was slowed down in patients with low CLcr as shown by the increase of the TlI2 up to 68 h and the log-linear plot of the concentrations for patients with CLcr of II, 22,45 and 81 ml/min (Fig. 1). The amount of oxiracetam excreted in urine over 48 h ranged from 8.3 to 82.6% of the administered dose among the subjects and was lower in subjects with a high degree of renal impairment (Table 11). The correlations between CLT, CLR, beta (terminal apparent elimination rate constant in plasma) and CLcr were estimated by linear regression analysis. The
12
24
6
48 TIME(H)
Fig. 1 : Log-linear plot of the oxiracetam concentrations in plasma for patients with CLer of 11 (0),22 (*),45 (#) and 81 (x) mlImin
equations and coefficients of correlation (r) are: CLT= 0.876
CLer + 4.4,
r
=
0.916
CLR = 0.75
CLer - 3.54,
r
=
0.985
beta = 0.00052
CLer + 0.015,
r = 0.803
The apparent volume of distribution of the central
235
J. E. Lecaillon et al., Oxiracetam & renal impairment
Table 1lI : Oxiracetam two-compartment model characteristics calculated by the incremental method from the plasma concentrations Characteristics ofthe model
Subject CLcr (mlJmin)
8.9 9 10 11 13.7 15.5 18 20 21 22 25 26 31 35.5 36.3 45 48 61 81 95
K(lO)
K(l2)
K(2l)
V(l)*
(h- 1)
(h- 1)
(h- 1)
(I)
0.03 0.02 0.02 0.02 0.03 0.05 0.08 0.09 0.06 0.07 0.08 0.04 0.09 0.09 0.12 0.09 0.10 0.16 0.18 0.32
Mean ±SD
V(SS)* (l)
0.05 0.42 0.06 0.08 0.03 0.10 0.27 0.20 0.04 0.12 0.12 0.07 0.09 0.13 0.09 0.09 0.07 0.06 0.07 0.05
0.07 0.42 0.08 0.05 0.07 0.10 0.21 0.31 0.06 0.08 0.17 0.'12 0.07 0.12 0.09 0.09 0.09 0.08 0.10 0.06
26.2 36.9 35.4 21.7 26.0 19.8 14.5 13.4 24.5 15.3 20.3 69.4 17.7 44.5 15.9 25.2 25.6 18.9 27.9 18.9
46.0 74.3 63.9 53.8 37.0 38.2 32.9 21.8 42.8 36.9 35.2 109 39.7 91.4 30.5 50.3 45.6 34.4 47.2 35.3
0.11 0.09
0.12 0.09
25.9 13.0
48.3 21.5
• : maximum value assuming complete availability of the administered dose
compartment, the total volume of distribution at the steady-state and the transfer rate constants between the central and the peripheral compartment were not influenced by the degree of renal insufficieny. The elimination rate constant from the central compartment K(10) was influenced by the degree of renal impairment and the equation of the curve obtained by linear regression analysis: K(10) = 0.00275 CLer 0.000009, r = 0.936, indicated a good proportionality between K(10) and CLer.
DISCUSSION A dependency of the elimination rate of oxiracetam in plasma with CLcr was observed and this is rather common for a drug whose elimination occurred in the unchanged form almost exclusively by the renal route. The pharmacokinetic model: two compartment model
described for healthy subjects (4) and the volume of distribution were not modified in patients with renal impairment
Estimation of steady-state concentrations The study of oxiracetam concentrations after repeated administration in elderly patients with CLcr down to 23 rnIlmin has previously been reported (6) and indicates that the pharmacokinetics of the drug are not modified by repeated administration. Therefore, the results of the present study after single administration can be used to predict the steady-state concentrations during repeated administration. The oxiracetam concentrations in plasma were estimated for each patient on the basis of the administration of 800 mg of the drug twice daily. The predicted concentration profiles for subjects with CLer of 15.5, 45 and 95 ml/min are shown in Figure 2. These estimations
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236
showed that the steady-state concentrations would be obtained after 6-10 days of repeated administration for patients with CLer of 9-15 mlImin and 3-5 days for patients with CLcr between 15 and 40 mlImin. The maximum, minimum and mean concentrations at the steady-state, corrected for a body weight of 75 kg, are reported in Table IV.
600
CONCENTRATION (IJMOL/L)
Dosage of oxiracetam in renal insufficient patients The slow elimination of oxiracetam in patients with renal impainnent would lead to an increase of the steady-state level of oxiracetam (Fig. 2). A reduction of the dosage in these patients appeared necessary. The dosage of oxiracetam in renal insufficient patients Table N : Predicted maximum, minimum and mean concentrations at the steady-state on the basis of two 800 mg daily doses of oxiracetam, normalized for a 75 kg body weight. Maintenance dose calculated * for the patients Subject CLcr
Cmax..
(mllmin)
(jU1IOlIl)
Cmillu (1J1II01il)
MaintenCmean.. ance (lJ1IIOlIl) dosage* (%)
8.9 9 10 11 13.7 15.5 18 20 21 22 25 26 31 35.5 36.3 45 48 61 81 95
600 461 648 567 536 396 340 369 290 423 334 147 337 145 311 299 234 195 129 118
456 398 556 464 389 305 206 208 171 270 174 108 150 89.1 112 167 94.8 56.7 37.9 19.6
528 428 606 518 466 356 266 284 230 344 246 130 228 113 191 230 152 118 80.0 59.8
12 15 11 12 14 18 24 23 28 19 26 49 28 57 33 28 42 54 80 100
* : calculated as the ratio (Crneans. in patient with normal renal functionlCmeana. renal insufficient patient) x 100. The reference taken for a patient with normal renal function was that of a patient whose CLcr - 100 mlImin. Its Cmeallssvalue (63.8 JUIloVl) was calculated from the linear regression analysis of lICmeallss values as a function of CLer
1
2
3
4
567 8 TIME (DAYS)
Fig. 2 : Simulated concentration profiles of oxira.cetam in plasma for the subjects with CLcr of 15:5. (0), .45 (*) and 95 (#) mJ/min based on the administration of 800 mg of the drug twice daily. The results after single administration were used to simulate the profiles during repeated administration
was evaluated in order to reach a mean steady-state concentration level of oxiracetam in plasma close to that in a patient with normal renal function. The maintenance dose in these patients (Table IV) was obtained by dividing the mean oxiracetam level in a patient with normal renal function (CLcr = 100 mlImin) by the mean level in the patients with renal impairment and expressing the result in percent Figure 3 shows the individual maintenance dose as a function of CLer. The straight line was obtained by linear least-squares regression analysis and could serve as a nomograph for the graphical determination of the dose reduction. Nevertheless for practical reasons and by considering the values of maintenance dose for each individual (Table IV) and the good tolerability of the drug (3, 9), it appeared easier to propose a maintenance dose within two intervals of CLcr: 25% of normal dose for patients whose CLcr is 15-40 mlImin, and 50% of normal dose for patients whose CLcr is 40-60 mlImin. For patients whose CLcr is above 60 mlImin no special adjustment appeared necessary. For patients whose CLer is below 40 mlImin, it is possible to administer the maintenance dose of oxiracetam once daily instead of twice daily. In that case the minimum concentrations would be similar or higher than those recorded in a patient with normal renal function receiving the normal dose of oxiracetam twice daily.
J. E. Lecaillon et al., Oxiracetam & renalimpairment C MEAN (NORMAL)I CMEAN (REN.IMP.)
100 90
%
/' /
//
80 70 60
237
For patients whose CLer is above 60mVmin no special adjustment appeared necessary. For patients whose CLcr is below 40 ml/min, it is possible to administer the maintenance dose of oxiracetam once daily instead of twice daily.
o
50
ACKNOWLEDGEMENTS
o
40 30 20
The authors are grateful to Mrs C. Souppart for technical assistance.
o
20
40
60
80
100
CLCR (ML/MIN) Fig. 3 : Ratio of mean concentration levels: normal
patient/patient with a renal impairment as a function of CLcr. The straight line, obtained by linear least squares regression analysis, could serve as a nomograph for the graphical determination of the dose reduction. The maintenance dose in % of the normal dose could be read on the Y axis. The equation was: Dose (%) = 0.97 CLer + 3.2; r = 0.932
CONCLUSIONS The elimination rate of oxiracetam is reduced in patients with renal impairment, The phannacokinetic model: two-compartment model described for healthy subjects and the volume of distribution were not modified in patients with renal impairment. A dependency of the elimination rate in plasma, of the renal and of the total clearances of oxiracetam with CLer was observed. A reduction of the dosage in patients with renal impairment appeared necessary. The dose to be given is as follows: 25% of normal dose for patients whose CLer is 15-40 ml/min. 50% of normal dose for patients whose CLer is 40-60 ml/min.
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