EUROPEAN JOURNAL OF DRUG METABOllSM AND PHARMACOKINETICS, 1992, VoL 17, No.3, pp. 213-220
Pharmacokinetics of cadralazine and its hydrazino-metabolite in patients with renal impairment after repeated administration of 5 mg once daily 1 J.F. MARICHAL1, P. BRUNEL2, J.B. LECAILLON3, J. GODBILLON3, B. FALLER, P. BRIGNON 1 and J. MENARD 4 IService de Nephrologie et d'Mmodialyse, Hopitai LouisPasteur, Colmar, France 2Pharmaceutical Research and Development, Ciba-Geigy Limited, Baste, Switzerland 3Laboratoires Ciba-Geigy, Biopharmaceutical Research Center, Rueil-Malmaison, France 4/nstitut National de la Sante et de la Recherche Medico:«, Pathologie Vasculaire et Endocrinologie Renate, U36, Paris, France
Received for publication: July 6, 1991
Keywords: Renal Impairment, cadralazine, hydrazino metabolite
SUMMARY Since the hydrazino-pyridazine metabolite of cadralazine, COP 22 639 is believed to contribute to the activity of the drug, its pharmacokinetics and that of cadralazine were investigated in 8 hypertensive patients with renal impairment The creatinine clearance (CLer) of patients ranged from 10 to 60 mlImin. The concentrations of cadralazine in plasma and urine, and of COP 22 639 (plus its possible hydrazones) in plasma were measured after single and repeated administration of 5 mg of cadralazine once daily. A hypotension possibly linked to cadralazine treatment was recorded on day 3 for the patient with CLer = 10 mlImin. Metabolite concentrations were found to be at least twice as high as in other patients indicating that in this patient. the daily dose of 5 mg was probably too high. The pharmacokinetics of cadralazine were not modified by repeated administration. The drug and its metabolite were eliminated more slowly in patients with low creatinine clearance. The tIn of COP 22 639 was about twice the tll2 of the unchanged drug.
In patients whose CLer ranged from 19-37 mlImin the mean accumulation factor of apparent COP 22 639 was 1.7 times that of the unchanged drug. It shows that the apparent COP 22 639 accumulated more than the unchanged drug. A starting daily dose of 2.5 mg of cadralazine in patients with CLcr < 40 mlImin appears to be suited to take into account the pharmacokinetics of COP 22 639. This dose can be increased by 2.5 mg steps if the antihypertensive effect is not sufficient (maximum dose with CLer < 40 mlImin: 10mg). Haemodynamic parameters recorded during the study showed that cadralazine was effective during 24 h after single and repeated administration.
INTRODUCTION Please send reprint requests to : Mr J.B. Lecaillon, Laboratoires Ciba-Geigy, Biopharmaceutical Research Center, BP 308, 92506 Rueil-Malmaison, France
Cadralazine, 2-(3-[6-(2-hydroxypropyl)ethylaminol pyridazinyl)-ethylcarbazate, is an antihypertensive drug, acting as a peripheral vasodilator. It possesses a
Eur. J. Drug Metab. Pharmacokinet., 1992, No.3
214
cadralazine concentrations (13) after single dose. Since CGP 22 639 could contribute to the antihypertensive effect of the drug, the authors indicated that the proposal of dose reductions needed to be confirmed during a repeated treatment In the meantime, a sensitive HPLC analytical method has been elaborated for the determination of CGP 22 639 (unchanged compound plus its possible hydrazones). The present study investigates the pharmacokinetics of cadralazine and this metabolite after single and repeated administration of 5 mg of cadralazine once daily to hypertensive patients with renal impairment.
~NH-NH2
HSC 2-N
JL . ,N
I
rH2 ~HOH
MATERIALS AND METHODS
N'
C GP
22 639
HYDRAZINO METABOLITE
CH 3 Fig. 1 : Chemical structure of cadralazine and of its hydrazino metabolite, CGP 22 639
slow-onset, long-lasting antihypertensive activity (1-6). The dose of cadralazine given orally judged to be adequately effective in a large enough proportion of hypertensive patients is 10-15 mg once daily (4-6). One of the metabolites of cadralazine (7), the hydrazino-pyridazine metabolite, CGP 22 639 (Fig. 1) is believed to contribute to the antihypertensive effect of the drug (8-11). A recent study in rats substantiated the assumption that the slow onset and long duration of the pharmacological effect of cadralazine is closely related to the distribution pattern of this active metabolite in blood vessels, a target tissue of antihypertensive vasodilator drugs (9). In subjects with normal renal function, cadralazine is mostly eliminated from plasma in the unchanged form by the renal route: 60-80% of the oral dose is recovered in urine (7, 12). The concentrations of the apparent hydrazino metabolite (unchanged compound plus its possible hydrazones) in plasma are low, 1-5% of those of cadralazine (7). In patients with renal failure, cadralazine is eliminated more slowly than in patients with normal renal function (13). Dose reductions (5 mg instead of 10-15 mg once daily) in patients with severe renal impairment had been proposed on the basis of
Patients 8 initially hospitalized patients (4 males and 4 females) suffering from renal impairment with creatinine clearances between 10-60 mlImin were included in this study. They were aged between 22-66 years and had a body weight between 55-97 kg. The causes of renal failure are listed in Table I. 3 patients presented a secondary hypertension consecutive to renal failure and two others an initial essential hypertension; in addition, for the other 3 patients, hypertension and renal failure were discovered at the same time. Antihypertensive treatments with calcium antagonists, vasodilators or converting enzyme inhibitors were stopped during the run-in period. Both beta-blockers and concomitant treatments which were considered necessary for the welfare of the patient (bicarbonates, diuretics, phosphate or aluminium chelating agents) were kept constant for the study duration. The drugs concomitantly used for the treatment of the hypertension are also summarized in Table I.
Protocol The protocol was approved by the Ethics Committee of the Colmar Hospital. After verbal and written information on the test preparation and the procedure of the study, the patients signed a declaration of consent. In the ftrst period on day I, the patients were given at 8 a.m. a single 5 mg dose (half-tablet) of cadralazine after having fasted overnight for at least
J. F. Marichal et 01., Cadralazine & renal impairment
12 h. The half-tablet was taken with 100 mI of water. About 15 min after medication, the patients had a light breakfast No cadralazine was administered on day 2. Blood pressure and heart rate were recorded in the supine position during 15 min before dosing and before the Ist, 4th, 10th, 20th and 48th hours. In the second period, on day 3, and on the following 6 days, at 8 a.m. after an overnight fast, an oral dose of 5 mg of cadralazine was taken by the patients. From days 3-8 they were out of the hospital; on day 9 the protocol was the same as on day 1. For each patient, the total duration of the study including the pre-inclusion period, was about 4 weeks. ECG tracing was recorded during the pre-administration on day 15 and on days 3 and 11 during the active medication. During the trial duration, clinical and biological tolerability were monitored. Arterial blood pressure in the left arm was recorded automatically over 15 min with an oscillometric recorder (Dinamap, Model 1846 SX, Critikon). Heart rate was measured using the same apparatus. Mean arterial pressure was defined as the pressure corresponding to the maximum amplitude of oscillations. Blood was collected in heparinized tubes before dosing and I, 2, 4, 10, 24 and 48 h afterwards, after the single administration on day 1 and after the last administration on day 9. The samples were immediately centrifuged, plasma was separated and stored at -80 until analysis. Urine was collected before dosing (12 h) and thereafter quantitatively in fractions over 0-24 and 24-48 h. The volume of each fraction was measured and aliquots of about 15 mI were immediately stored at -80 until analysis. GC
GC
215
Analytical determinations The concentrations of unchanged drug in plasma and urine were. determined by high performance liquid chromatography (14). For the determination of apparent CGP 22 639 in plasma, the analytical method is summarized as follows. The possible hydrazones of CGP 22 639 in plasma samples were converted back to CGP 22 639 at acidic pH. Then, after addition of hydralazine (internal standard), the compounds were derivatized with sodium nitrite. The derivatives were extracted at basic pH with chloroform. The chloroform phase was evaporated to dryness and the residue was redissolved in 100 Jl.l of mobile phase. The derivatives were chromatographed on a Nucleosil CI8 column, 15 em long, 4.6 nun J.D. using 1.8 x 10-3 mol/I phosphoric acid-acetonitrile (86:14, v/v) as mobile phase and UV detection at 240 nm. The calibration curve was established from plasma samples spiked with CGP 22 639 A (C9H17NsO.2HCI.H20, mol. wt. = 302.21). The limits of quantitation in plasma were 18 nmol of cadralazine per litre (5 nglmI) and 3.3 nmol of CGP 22 639 per litre (1 ng/mI). In urine, the limit of quantitation was 180 nmol of cadralazine per litre (51 ng/ml), The accuracy and precision of the methods were tested every day by analysing biological samples spiked with known amounts of cadralazine (17.1-1765 nmol/l) and CGP 22 639 (1.66-66.2 nmolll). Overall recoveries (found x 100/given value ± SD) were 99.1 ± 11.2% (n = 93) for cadralazine and 101.0 ± 9.7% (n = 122) for CGP 22 639 in plasma. In urine, overall recoveries were 100.6 ± 6.6% (n = 42) for cadralazine.
Table I : Clinical' characteristics of the patients Pat.
CLcr (mllmin)
No.
D/
1
10
2
21
3
Cause ofrenal impairment
D9
Duration (years)
Concomitant antihypertensive treatment (mg per day)
Renal imp.
Hypert.
Right renal hypoplasia with left renal cysts
2
2
Atenolol 100 mg
22
Chronic glomerulonephritis (NSAI)
8
28
Metoprolol 200 mg, furosemide 40 mg
19
28
Right renal hypoplasia
8
8
Acebutolol 400 mg, furosemide 80 mg
4
22
26
Chronic glomerulonephritis (post-inf)
10
22
Metoprolol 200 mg, furosemide 40 mg
5
25
26
Familial nephropathy
7
18
Metoprolol 200 mg
6
31
30
Membrano proliferative glomerulonephritis with vascular disorders
1
1
Atenolol 100 mg, furosemide 40 mg
7
37
27
Hyalin renal deposits
4
4
Acebutolol 200 mg
8
60
44
Membrano proliferative glomerulonephritis
2
2
Metoprolol 200 mg, furosemide 40 mg
Eur. J. Drug Metab. Pharmacokinet., 1992, No.3
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administered dose. This assumption was supported by the fact that more than 90% of the cadralazine was absorbed after oral administration (7). The apparent volume of distribution (Varea) was calculated as (CLT • t1l2)/(1o 2 • body weight). The accumulation factor was calculated as the ratio of the AUC obtained during a dosing interval after repeated administration and after the single dose.
Data treatment Cadralazine and CGP 22 639 peak concentrations in plasma and time to peak (Tmax) were directly obtained from the individual concentration time profiles. The area under the concentration-time curve (AUC(O-inf) was calculated by the trapezoidal rule and extrapolated to time infinity. The apparent elimination half-life (t1l2) was determined from the slope of the last log-linear segment of the concentration time curve. The total plasma clearance (CLT) was obtained from the ratio Fd/AUC, where F is the fraction of the dose (d) absorbed after oral administration. In the case of cadralazine, F was taken to be equal to 1, assuming a complete absorption of the orally
Ace· factor = AUC(0-24 h)day 9/AUC(O-24 h)day 1. The renal clearance (CLR) of cadralazine was calculated as U/AUC in which the amount of cadralazine in urine (U) and AUC are taken over the same time periods.
Table II : Pharmacokinetic values for cadralazine and apparent COP 22 639
Cadralazine
Patient
1 2 3 4 5 6 7 8
Cmax
Tmax
tt/2
AUC
Ace.
(nmolll)
(h)
(h)
(nmol.hll)
Fact.
Varea (Ukg)
U(0-48 h)
(0/0 dose)
VI
V9
VI
V9
VI
V9
VI
V9
V9/VI
VI
V9
VI
V9
513 566 281 360 506 337 356 239
619 300 338 396 407 307 308
1 1 1 1 1 1 1 1
1 2 1 1 1 2 1
8.3 6.1 8.9 9.0 5.6 6.6 4.7 4.7
7.8 11.5 8.8 6.2 8.6 3.8 4.7
6239 5137 4066 4238 4720 3344 3534 1770
5891 4208 3936 4186 3802 2563 2147
1.22 1.33 1.15 0.94 1.23 0.75 1.20
0.408 0.547 0.575 0.616 0.504 0.716 0.598 0.940
0.616 0.719 0.645 0.622 0.825 0.659 0.779
7.7 40.7 24.3 29.2 39.3 15.2 27.9 35.2
41.0 40.3 50.3 40.8 23.3 29.2 46.0
Apparent CGP 22 639
Cmax Patient
1 2 3 4 5 6 7 8
T max (h)
(nmolll)
tin
AUC
Ace.
(h)
(nmol.hll)
Fact.
VI
V9
VI
V9
V9
14.3 14.8 10.9 6.4 9.1 7.2 15.6 6.0
18.8 23.4 23.5 15.1 11.3 6.8 10.2
10 4 10 10 4 10 4 4
4 10 10 2 4 4 4
22.4 19.3 16.8 14.8 20.2 8.5
VI
V9
V9/DI
302 286 243 135 149 150 120 127
350 463 477 281 204 124 131
1.22 1.91 3.53 1.89 1.36 1.03 1.03
AUC: area under the curve (extrapolated toinfinity on day I and over a 24 hdosing interval on day 9) Acc. Fact.: accumulation factor - AUC(0-24h) day 9/AUC(0-24h) day 1 V lIe.: volume ofdistribution U: cadralazine amount excreted inurine during 48 h (% ofthe administered dose)
J. F. Marichal et 01., Cadralazlne & renal impairment
CONCENTRATION (NIIOLlLl
ICADRAlAZINEI
400
217
ICGP 22 6391
CONCENTRATION (Hf'K)LlLl 20
300
15
200
10
100
5
~O
120
160
200
240 TIME (Hl
40
80
120
160
200
240 TIME (Hl
Fig. 2 : Comparison of measured and predicted concentrations of cadralazine and CGP 22 639 in patients with renal impairment (mean of 6 patients with creatinine clearance ranging from 19-37 mlImin). Solid line: predicted from concentrations on day 1 Star: measured on day 9
RESULTS Pharmacokinetics The individual phannacokinetic parameters after the single and the repeated administrations are presented in Table IT for cadralazine and apparent CGP 22 639 in increasing order of CLcr. Due to the outcome of an adverse reaction in patient no. 1 (CLcr = 10 mlImin), hypotension, anuria), the drug was administered to her on days 1, 3 and 4 and discontinued later on. In this subject the concentration proftle was available after the single dose only. The concentrations of CGP 22 639 on days 3 and 4 were two times higher than the highest Cmax value for the other patients after repeated dosing. The phannacokinetic parameters in plasma on days 1 and 9 showed that the drug and its metabolites were eliminated more slowly in patients with low CLcr. The volume of distribution was not related to the CLcr value and was not modified by the repeated dosing. After repeated administration, the cadralazine and CGP 22 639 concentrations were close to those which can be estimated at the steady-state by using the superposition technique. This is exemplified in Figure 2 for the mean concentrations (n = 6) of subjects whose CLcr ranged from 19-37 mlImin. The steady-state concentrations of cadralazine should be reached within 48 h of treatment for all
patients. Those of apparent CGP 22 639 were reached before the 7th daily dose. This is shown by the almost identical predosing CGP 22 639 concentration on day 9 (mean = 7.8 nmol/l) and after a dosing interval, i.e. 24 h later (mean = 8 nmol/l). The Cmax of apparent CGP 22 639 was 1.8-4.4% of the Cmax of unchanged drug after the single dose and 2.2-7.8% after the 7th daily dose in patients No.2 to 8. The AUC(0-48 h) was 3.7-11.1% of that of cadralazine after the single dose and 4.8-12.1 % within a dosing interval after the 7th daily dose. After the single dose, the concentration of the metabolite at 48 h postdosing was below the limit of detection of the analytical method for most subjects. Therefore, t1l2 could not be calculated. The tI/2 of apparent CGP 22 639 after the 7th daily dose was about twice the corresponding tIl2 of the unchanged drug.
Haemodynamics Haemodynamic data are summarized in Table III. During the run-in period, blood pressure and heart rate remained very stable. In the first few hours, the heart rate peaked slightly higher in the chronic than in the acute phase but from 10 h onwards remained at a lower level. After the first drug intake, a slight decrease in blood pressure was observed and it was still present on day 9. There was an initial drop
Eur. J. DrugMetab. Pharmacokinet., 1992, No.3
218
Table III: Haemodynamic parameters (mean ± SD) after cadralazine treatment
Day
1
SBP Time (h post-dose) (mm Hg) Baseline
2 4 10
24
9
Baseline
2 4 10
24
DBP
MBP
(mmHg) (mmHg)
HR (bpm)
148.3 32.9 143.8 28.5 136.2 31.0 136.5 31.0 134.8 22.7 133.6 24.0
92.4 21.7 85.3 20.1 82.5 20.9 82.8 23.1 80.7 15.8 80.7 19.5
113.6 26.1 107.0 25.2 102.3 26.3 101.6 26.7 96.2 17.8 99.5 21.9
67.2 10.0 71.9 12.4 70.7 12.7 68.3 10.8 72.4 10.7 70.6 11.7
132.6 18.0 135.3 15.3 126.8 7.0 126.4 8.5 132.0 11.3 136.2 15.0
81.1 11.0 76.8 8.5 72.9 5.9 77.1 8.2 77.8 10.6 81.7 7.8
99.4 14.7 97.3 10.6 92.6 5.9 95.4 7.0 96.9 10.2 101.3 10.0
67.9 8.8 74.1 8.0 73.5 9.2 67.1 9.4 68.4 9.1 68.0 8.7
SBP: systolic blood pressure DBP: diastolic blood pressure MBP: mean blood pressure HR: heart-rate
following tablet intake with a maximal effect between 2-4 h. In both the acute and chronic curves, there was an initial drop after tablet intake followed by a very slow increase from 10-24 h. No statistical difference was found concerning the maximum drop in blood pressure.
Side-effects Patient no. 5 showed sinus tachycardia 10 h after dosing which disappeared when the daily dose of metoprolol was increased from 100 to 200 mg. In patient no. 7, facial oedema appeared after 1 week of
treatment Patient no. 6 complained of headaches attributed to the rise in blood pressure at the time of the previous treatment discontinuation. After 36 h, oedema of both legs and face appeared. accompanied with a slight increase in weight and a sensation of heat in the body. Patient no. I, a 66-year-old woman with a creatinine clearance of 10 mlImin, complained of muscle and abdominal pains after the third dose. This was associated with gaseous distension and peripheral cyanosis, together with oliguria and worsening of renal function. The blood pressure was 143/89 mm Hg before the first dose of cadralazine and 99/48 mm Hg just before the second dose. The hypotensive response could be related with the higher plasma levels of cadralazine and CGP 22 639 in this patient. No changes in laboratory data due to the drug occurred among the patients. except for a slight increase in transaminases after 1 week of treatment in patient no. 5. Creatinine clearance did not markedly change during the two periods.
DISCUSSION Previous data in patients with renal impairment given a single dose of 10 mg (13) showed a linear dependence of the elimination rate constant, the total clearance and the renal clearance of cadralazine with the creatinine clearance in the range 5-79 ml/min. The present results of CLT and CLR after single and repeated administrations are in good agreement with the previous findings (Fig. 3). After repeated dosing, the Cmax of apparent CGP 22 639 (7-24 nmolll) in patients with CLer from 19-37 ml/min was similar to the Cmax measured in healthy volunteers after a 20 mg single oral dose (7). This represents a relative increase factor of Cmax of about 4 for the hydrazino metabolite in patients with renal impairment. Such an increase was not observed for the unchanged drug. The accumulation factor of apparent CGP 22 639, AUC(0-24h) day 9/AUC(0-24h) day I, in patients whose CLcr was from 19-37 mlImin ranged from 1.03-3.53 (mean ± SD = 1.82 ± 0.91). It was 1.7 times higher as a mean than that of the unchanged drug. This shows that CGP 22 639 accumulated more than the unchanged drug. The accumulation factor of CGP 22 639 was 1.03 for the two patients with the highest CLcr. indicating little or no accumulation in patients whose CLcr is above 40 mlImin.
J. F. Marichal et 01., Cadralazine & renal impairment
TOTAL CLEARANCE (MUMIN)
219
RENAL CLEARANCE {MLIMINl
180
0
80
*
160
Cb
140
0
70 60
120
•
50
100 0
:J 40 ml/min. When the antihypertensive effect is not sufficient, this dose should be increased at 2 week intervals by 2.5 mg steps when CLcr < 40 ml/min (maximum dose:10 mg) or 5 mg steps with CLcr > 40 ml/min (maximum dose: 15 mg). In conclusion, in patients with renal insufficiency, cadralazine is effective over 24 h after single and repeated administration. Despite the absence of
220
Eur. J. DrugMetab. Pharmacokinet., 1992, No.3
accumulation of cadralazine itself, the longer tIn of the active metabolite CGP 22 639 suggests that in patients with creatinine clearance of less than 40 mlImin, a daily dose of 2.5 mg would be appropriate to start the cadralazine treatment
7.
8.
REFERENCES 9.
1. Amann F.W., Biihler F.R. (1979): Long term antihypertensive 2.
3.
4.
5.
6.
therapy with a new vasodilator, ISF 2469, in combination with a beta-blocker and a diuretic. Clin. Eur., 6,1028-1034. Van Bnunmelen P., Biihler FR, Kiowski W., Bertel O. (1979) : Antihypertensive efficacy of a new long acting hydralazine like vasodilator, ISF 2469, in combination with a betablocker and a diuretic. Int, I. Clin. Pharmacol. Biopharm., 17, 380-385. Catalano M., Pacini I., Libretti A. (1983): Cadmlazine (\SF 2469): dose-related antihypertensive activity after single oral administration to patients. Eur. I. Clin. Pharmacol., 24, 157-161. Strocchi E., Costa F.W., Caldari R., et al. (1983) : Comparison of the antihypertensive activity of cadmlazine (ISF 2469) and dihydmlazine during chronic treatment, Int, I. Clin, Pharmacol. Ther. Toxieol., 21, 519-523. Costa F.V., Mamta A.M., Strocchi E., Ambrosioni E. (1983): Efficacy and tolerability of long-acting vasodilator, cadmlazine (ISF 2469) in hypertensive patients: results after one year of treatment, Curr. Ther. Res., 34, 653-661. Salvadeo A., Villa G., Segagni S., et aI. (1985): Cadmlazine, a
10.
11.
12.
13.
14.
new vasodilator, in addition to a beta-blocker for long term treatment of hypertension. Arzneimittelforschung., 35, 623-625. Schiitz H., Faigle I.W., Kiing W., Theobald W. (1985): Disposition and pharmacokinetics of cadmlazine and individual metabolites in man. Eur. I. Drug Metab. Pharmacokinet., 10, 147·153. Carpi C., Dorigotti L., Sememro C. (1981): Cadmlazine and its identified metabolites: comparative effects in blood pressure and on arterial smooth muscle. Br, I. Pharmacol., 72, 188P-189P. Temuchi Y., Watari S., Ishikawa S., et al. (1988): Pharmacokinetics of an active cadmlazine metabolite in plasma and blood vessels of spontaneously hypertensive rats, Arzneimittelforschung., 38, 237-239. Higahsio T., Kuroda K. (1988): Effects of cadmlazine on contmctions induced by norepinephrine, serotonin, angiotensin II and K+ in rabbit aortic and renal arterial strips. Arzneimittelforschung., 38,341-346. Higashio T., Kuroda K. (1988): Effects of cadmlazine on 2+ contractions induced by Ca and norepinephrine in isolated rabbit aortic strips. Arzneimittelforschung., 38, 346-349. Hauffe SA, Dubois I.P., Imhof P.R. (1985) : Human pharmacokinetics of cadra1azine: a new vasodilator. Eur. I. Drug Metab. Pharmacokinel, 10,217-223. Lecaillon I.B., Dubois I.P., Darragon T., Fillastre I.P., Pozet N. (1988): Pharmacokinetics of cadmlazine in patients suffering from renal insufficiency. In: Bres I., Panis G. eds. Interet et limites de la pharmaeocinetique en recherche et developpemenl Montpellier, Troisiemes Joumees Mediterraneennes de Pharmacocinetique, pp. 658-663. Hauffe S.A., Dubois J.P. (1984): Determination of cadmlazine in human plasma and urine by high-performance liquid chromatogmphy. I. Ouomatogr., 290, 223-230.
Pharmacokinetics of cadralazine and its hydrazino-metabolite in patients with renal impairment after repeated administration of 5 mg once daily 1 J.F. MARICHAL1, P. BRUNEL2, J.B. LECAILLON3, J. GODBILLON3, B. FALLER, P. BRIGNON 1 and J. MENARD 4 IService de Nephrologie et d'Mmodialyse, Hopitai LouisPasteur, Colmar, France 2Pharmaceutical Research and Development, Ciba-Geigy Limited, Baste, Switzerland 3Laboratoires Ciba-Geigy, Biopharmaceutical Research Center, Rueil-Malmaison, France 4/nstitut National de la Sante et de la Recherche Medico:«, Pathologie Vasculaire et Endocrinologie Renate, U36, Paris, France
Received for publication: July 6, 1991
Keywords: Renal Impairment, cadralazine, hydrazino metabolite
SUMMARY Since the hydrazino-pyridazine metabolite of cadralazine, COP 22 639 is believed to contribute to the activity of the drug, its pharmacokinetics and that of cadralazine were investigated in 8 hypertensive patients with renal impairment The creatinine clearance (CLer) of patients ranged from 10 to 60 mlImin. The concentrations of cadralazine in plasma and urine, and of COP 22 639 (plus its possible hydrazones) in plasma were measured after single and repeated administration of 5 mg of cadralazine once daily. A hypotension possibly linked to cadralazine treatment was recorded on day 3 for the patient with CLer = 10 mlImin. Metabolite concentrations were found to be at least twice as high as in other patients indicating that in this patient. the daily dose of 5 mg was probably too high. The pharmacokinetics of cadralazine were not modified by repeated administration. The drug and its metabolite were eliminated more slowly in patients with low creatinine clearance. The tIn of COP 22 639 was about twice the tll2 of the unchanged drug.
In patients whose CLer ranged from 19-37 mlImin the mean accumulation factor of apparent COP 22 639 was 1.7 times that of the unchanged drug. It shows that the apparent COP 22 639 accumulated more than the unchanged drug. A starting daily dose of 2.5 mg of cadralazine in patients with CLcr < 40 mlImin appears to be suited to take into account the pharmacokinetics of COP 22 639. This dose can be increased by 2.5 mg steps if the antihypertensive effect is not sufficient (maximum dose with CLer < 40 mlImin: 10mg). Haemodynamic parameters recorded during the study showed that cadralazine was effective during 24 h after single and repeated administration.
INTRODUCTION Please send reprint requests to : Mr J.B. Lecaillon, Laboratoires Ciba-Geigy, Biopharmaceutical Research Center, BP 308, 92506 Rueil-Malmaison, France
Cadralazine, 2-(3-[6-(2-hydroxypropyl)ethylaminol pyridazinyl)-ethylcarbazate, is an antihypertensive drug, acting as a peripheral vasodilator. It possesses a
Eur. J. Drug Metab. Pharmacokinet., 1992, No.3
214
cadralazine concentrations (13) after single dose. Since CGP 22 639 could contribute to the antihypertensive effect of the drug, the authors indicated that the proposal of dose reductions needed to be confirmed during a repeated treatment In the meantime, a sensitive HPLC analytical method has been elaborated for the determination of CGP 22 639 (unchanged compound plus its possible hydrazones). The present study investigates the pharmacokinetics of cadralazine and this metabolite after single and repeated administration of 5 mg of cadralazine once daily to hypertensive patients with renal impairment.
~NH-NH2
HSC 2-N
JL . ,N
I
rH2 ~HOH
MATERIALS AND METHODS
N'
C GP
22 639
HYDRAZINO METABOLITE
CH 3 Fig. 1 : Chemical structure of cadralazine and of its hydrazino metabolite, CGP 22 639
slow-onset, long-lasting antihypertensive activity (1-6). The dose of cadralazine given orally judged to be adequately effective in a large enough proportion of hypertensive patients is 10-15 mg once daily (4-6). One of the metabolites of cadralazine (7), the hydrazino-pyridazine metabolite, CGP 22 639 (Fig. 1) is believed to contribute to the antihypertensive effect of the drug (8-11). A recent study in rats substantiated the assumption that the slow onset and long duration of the pharmacological effect of cadralazine is closely related to the distribution pattern of this active metabolite in blood vessels, a target tissue of antihypertensive vasodilator drugs (9). In subjects with normal renal function, cadralazine is mostly eliminated from plasma in the unchanged form by the renal route: 60-80% of the oral dose is recovered in urine (7, 12). The concentrations of the apparent hydrazino metabolite (unchanged compound plus its possible hydrazones) in plasma are low, 1-5% of those of cadralazine (7). In patients with renal failure, cadralazine is eliminated more slowly than in patients with normal renal function (13). Dose reductions (5 mg instead of 10-15 mg once daily) in patients with severe renal impairment had been proposed on the basis of
Patients 8 initially hospitalized patients (4 males and 4 females) suffering from renal impairment with creatinine clearances between 10-60 mlImin were included in this study. They were aged between 22-66 years and had a body weight between 55-97 kg. The causes of renal failure are listed in Table I. 3 patients presented a secondary hypertension consecutive to renal failure and two others an initial essential hypertension; in addition, for the other 3 patients, hypertension and renal failure were discovered at the same time. Antihypertensive treatments with calcium antagonists, vasodilators or converting enzyme inhibitors were stopped during the run-in period. Both beta-blockers and concomitant treatments which were considered necessary for the welfare of the patient (bicarbonates, diuretics, phosphate or aluminium chelating agents) were kept constant for the study duration. The drugs concomitantly used for the treatment of the hypertension are also summarized in Table I.
Protocol The protocol was approved by the Ethics Committee of the Colmar Hospital. After verbal and written information on the test preparation and the procedure of the study, the patients signed a declaration of consent. In the ftrst period on day I, the patients were given at 8 a.m. a single 5 mg dose (half-tablet) of cadralazine after having fasted overnight for at least
J. F. Marichal et 01., Cadralazine & renal impairment
12 h. The half-tablet was taken with 100 mI of water. About 15 min after medication, the patients had a light breakfast No cadralazine was administered on day 2. Blood pressure and heart rate were recorded in the supine position during 15 min before dosing and before the Ist, 4th, 10th, 20th and 48th hours. In the second period, on day 3, and on the following 6 days, at 8 a.m. after an overnight fast, an oral dose of 5 mg of cadralazine was taken by the patients. From days 3-8 they were out of the hospital; on day 9 the protocol was the same as on day 1. For each patient, the total duration of the study including the pre-inclusion period, was about 4 weeks. ECG tracing was recorded during the pre-administration on day 15 and on days 3 and 11 during the active medication. During the trial duration, clinical and biological tolerability were monitored. Arterial blood pressure in the left arm was recorded automatically over 15 min with an oscillometric recorder (Dinamap, Model 1846 SX, Critikon). Heart rate was measured using the same apparatus. Mean arterial pressure was defined as the pressure corresponding to the maximum amplitude of oscillations. Blood was collected in heparinized tubes before dosing and I, 2, 4, 10, 24 and 48 h afterwards, after the single administration on day 1 and after the last administration on day 9. The samples were immediately centrifuged, plasma was separated and stored at -80 until analysis. Urine was collected before dosing (12 h) and thereafter quantitatively in fractions over 0-24 and 24-48 h. The volume of each fraction was measured and aliquots of about 15 mI were immediately stored at -80 until analysis. GC
GC
215
Analytical determinations The concentrations of unchanged drug in plasma and urine were. determined by high performance liquid chromatography (14). For the determination of apparent CGP 22 639 in plasma, the analytical method is summarized as follows. The possible hydrazones of CGP 22 639 in plasma samples were converted back to CGP 22 639 at acidic pH. Then, after addition of hydralazine (internal standard), the compounds were derivatized with sodium nitrite. The derivatives were extracted at basic pH with chloroform. The chloroform phase was evaporated to dryness and the residue was redissolved in 100 Jl.l of mobile phase. The derivatives were chromatographed on a Nucleosil CI8 column, 15 em long, 4.6 nun J.D. using 1.8 x 10-3 mol/I phosphoric acid-acetonitrile (86:14, v/v) as mobile phase and UV detection at 240 nm. The calibration curve was established from plasma samples spiked with CGP 22 639 A (C9H17NsO.2HCI.H20, mol. wt. = 302.21). The limits of quantitation in plasma were 18 nmol of cadralazine per litre (5 nglmI) and 3.3 nmol of CGP 22 639 per litre (1 ng/mI). In urine, the limit of quantitation was 180 nmol of cadralazine per litre (51 ng/ml), The accuracy and precision of the methods were tested every day by analysing biological samples spiked with known amounts of cadralazine (17.1-1765 nmol/l) and CGP 22 639 (1.66-66.2 nmolll). Overall recoveries (found x 100/given value ± SD) were 99.1 ± 11.2% (n = 93) for cadralazine and 101.0 ± 9.7% (n = 122) for CGP 22 639 in plasma. In urine, overall recoveries were 100.6 ± 6.6% (n = 42) for cadralazine.
Table I : Clinical' characteristics of the patients Pat.
CLcr (mllmin)
No.
D/
1
10
2
21
3
Cause ofrenal impairment
D9
Duration (years)
Concomitant antihypertensive treatment (mg per day)
Renal imp.
Hypert.
Right renal hypoplasia with left renal cysts
2
2
Atenolol 100 mg
22
Chronic glomerulonephritis (NSAI)
8
28
Metoprolol 200 mg, furosemide 40 mg
19
28
Right renal hypoplasia
8
8
Acebutolol 400 mg, furosemide 80 mg
4
22
26
Chronic glomerulonephritis (post-inf)
10
22
Metoprolol 200 mg, furosemide 40 mg
5
25
26
Familial nephropathy
7
18
Metoprolol 200 mg
6
31
30
Membrano proliferative glomerulonephritis with vascular disorders
1
1
Atenolol 100 mg, furosemide 40 mg
7
37
27
Hyalin renal deposits
4
4
Acebutolol 200 mg
8
60
44
Membrano proliferative glomerulonephritis
2
2
Metoprolol 200 mg, furosemide 40 mg
Eur. J. Drug Metab. Pharmacokinet., 1992, No.3
216
administered dose. This assumption was supported by the fact that more than 90% of the cadralazine was absorbed after oral administration (7). The apparent volume of distribution (Varea) was calculated as (CLT • t1l2)/(1o 2 • body weight). The accumulation factor was calculated as the ratio of the AUC obtained during a dosing interval after repeated administration and after the single dose.
Data treatment Cadralazine and CGP 22 639 peak concentrations in plasma and time to peak (Tmax) were directly obtained from the individual concentration time profiles. The area under the concentration-time curve (AUC(O-inf) was calculated by the trapezoidal rule and extrapolated to time infinity. The apparent elimination half-life (t1l2) was determined from the slope of the last log-linear segment of the concentration time curve. The total plasma clearance (CLT) was obtained from the ratio Fd/AUC, where F is the fraction of the dose (d) absorbed after oral administration. In the case of cadralazine, F was taken to be equal to 1, assuming a complete absorption of the orally
Ace· factor = AUC(0-24 h)day 9/AUC(O-24 h)day 1. The renal clearance (CLR) of cadralazine was calculated as U/AUC in which the amount of cadralazine in urine (U) and AUC are taken over the same time periods.
Table II : Pharmacokinetic values for cadralazine and apparent COP 22 639
Cadralazine
Patient
1 2 3 4 5 6 7 8
Cmax
Tmax
tt/2
AUC
Ace.
(nmolll)
(h)
(h)
(nmol.hll)
Fact.
Varea (Ukg)
U(0-48 h)
(0/0 dose)
VI
V9
VI
V9
VI
V9
VI
V9
V9/VI
VI
V9
VI
V9
513 566 281 360 506 337 356 239
619 300 338 396 407 307 308
1 1 1 1 1 1 1 1
1 2 1 1 1 2 1
8.3 6.1 8.9 9.0 5.6 6.6 4.7 4.7
7.8 11.5 8.8 6.2 8.6 3.8 4.7
6239 5137 4066 4238 4720 3344 3534 1770
5891 4208 3936 4186 3802 2563 2147
1.22 1.33 1.15 0.94 1.23 0.75 1.20
0.408 0.547 0.575 0.616 0.504 0.716 0.598 0.940
0.616 0.719 0.645 0.622 0.825 0.659 0.779
7.7 40.7 24.3 29.2 39.3 15.2 27.9 35.2
41.0 40.3 50.3 40.8 23.3 29.2 46.0
Apparent CGP 22 639
Cmax Patient
1 2 3 4 5 6 7 8
T max (h)
(nmolll)
tin
AUC
Ace.
(h)
(nmol.hll)
Fact.
VI
V9
VI
V9
V9
14.3 14.8 10.9 6.4 9.1 7.2 15.6 6.0
18.8 23.4 23.5 15.1 11.3 6.8 10.2
10 4 10 10 4 10 4 4
4 10 10 2 4 4 4
22.4 19.3 16.8 14.8 20.2 8.5
VI
V9
V9/DI
302 286 243 135 149 150 120 127
350 463 477 281 204 124 131
1.22 1.91 3.53 1.89 1.36 1.03 1.03
AUC: area under the curve (extrapolated toinfinity on day I and over a 24 hdosing interval on day 9) Acc. Fact.: accumulation factor - AUC(0-24h) day 9/AUC(0-24h) day 1 V lIe.: volume ofdistribution U: cadralazine amount excreted inurine during 48 h (% ofthe administered dose)
J. F. Marichal et 01., Cadralazlne & renal impairment
CONCENTRATION (NIIOLlLl
ICADRAlAZINEI
400
217
ICGP 22 6391
CONCENTRATION (Hf'K)LlLl 20
300
15
200
10
100
5
~O
120
160
200
240 TIME (Hl
40
80
120
160
200
240 TIME (Hl
Fig. 2 : Comparison of measured and predicted concentrations of cadralazine and CGP 22 639 in patients with renal impairment (mean of 6 patients with creatinine clearance ranging from 19-37 mlImin). Solid line: predicted from concentrations on day 1 Star: measured on day 9
RESULTS Pharmacokinetics The individual phannacokinetic parameters after the single and the repeated administrations are presented in Table IT for cadralazine and apparent CGP 22 639 in increasing order of CLcr. Due to the outcome of an adverse reaction in patient no. 1 (CLcr = 10 mlImin), hypotension, anuria), the drug was administered to her on days 1, 3 and 4 and discontinued later on. In this subject the concentration proftle was available after the single dose only. The concentrations of CGP 22 639 on days 3 and 4 were two times higher than the highest Cmax value for the other patients after repeated dosing. The phannacokinetic parameters in plasma on days 1 and 9 showed that the drug and its metabolites were eliminated more slowly in patients with low CLcr. The volume of distribution was not related to the CLcr value and was not modified by the repeated dosing. After repeated administration, the cadralazine and CGP 22 639 concentrations were close to those which can be estimated at the steady-state by using the superposition technique. This is exemplified in Figure 2 for the mean concentrations (n = 6) of subjects whose CLcr ranged from 19-37 mlImin. The steady-state concentrations of cadralazine should be reached within 48 h of treatment for all
patients. Those of apparent CGP 22 639 were reached before the 7th daily dose. This is shown by the almost identical predosing CGP 22 639 concentration on day 9 (mean = 7.8 nmol/l) and after a dosing interval, i.e. 24 h later (mean = 8 nmol/l). The Cmax of apparent CGP 22 639 was 1.8-4.4% of the Cmax of unchanged drug after the single dose and 2.2-7.8% after the 7th daily dose in patients No.2 to 8. The AUC(0-48 h) was 3.7-11.1% of that of cadralazine after the single dose and 4.8-12.1 % within a dosing interval after the 7th daily dose. After the single dose, the concentration of the metabolite at 48 h postdosing was below the limit of detection of the analytical method for most subjects. Therefore, t1l2 could not be calculated. The tI/2 of apparent CGP 22 639 after the 7th daily dose was about twice the corresponding tIl2 of the unchanged drug.
Haemodynamics Haemodynamic data are summarized in Table III. During the run-in period, blood pressure and heart rate remained very stable. In the first few hours, the heart rate peaked slightly higher in the chronic than in the acute phase but from 10 h onwards remained at a lower level. After the first drug intake, a slight decrease in blood pressure was observed and it was still present on day 9. There was an initial drop
Eur. J. DrugMetab. Pharmacokinet., 1992, No.3
218
Table III: Haemodynamic parameters (mean ± SD) after cadralazine treatment
Day
1
SBP Time (h post-dose) (mm Hg) Baseline
2 4 10
24
9
Baseline
2 4 10
24
DBP
MBP
(mmHg) (mmHg)
HR (bpm)
148.3 32.9 143.8 28.5 136.2 31.0 136.5 31.0 134.8 22.7 133.6 24.0
92.4 21.7 85.3 20.1 82.5 20.9 82.8 23.1 80.7 15.8 80.7 19.5
113.6 26.1 107.0 25.2 102.3 26.3 101.6 26.7 96.2 17.8 99.5 21.9
67.2 10.0 71.9 12.4 70.7 12.7 68.3 10.8 72.4 10.7 70.6 11.7
132.6 18.0 135.3 15.3 126.8 7.0 126.4 8.5 132.0 11.3 136.2 15.0
81.1 11.0 76.8 8.5 72.9 5.9 77.1 8.2 77.8 10.6 81.7 7.8
99.4 14.7 97.3 10.6 92.6 5.9 95.4 7.0 96.9 10.2 101.3 10.0
67.9 8.8 74.1 8.0 73.5 9.2 67.1 9.4 68.4 9.1 68.0 8.7
SBP: systolic blood pressure DBP: diastolic blood pressure MBP: mean blood pressure HR: heart-rate
following tablet intake with a maximal effect between 2-4 h. In both the acute and chronic curves, there was an initial drop after tablet intake followed by a very slow increase from 10-24 h. No statistical difference was found concerning the maximum drop in blood pressure.
Side-effects Patient no. 5 showed sinus tachycardia 10 h after dosing which disappeared when the daily dose of metoprolol was increased from 100 to 200 mg. In patient no. 7, facial oedema appeared after 1 week of
treatment Patient no. 6 complained of headaches attributed to the rise in blood pressure at the time of the previous treatment discontinuation. After 36 h, oedema of both legs and face appeared. accompanied with a slight increase in weight and a sensation of heat in the body. Patient no. I, a 66-year-old woman with a creatinine clearance of 10 mlImin, complained of muscle and abdominal pains after the third dose. This was associated with gaseous distension and peripheral cyanosis, together with oliguria and worsening of renal function. The blood pressure was 143/89 mm Hg before the first dose of cadralazine and 99/48 mm Hg just before the second dose. The hypotensive response could be related with the higher plasma levels of cadralazine and CGP 22 639 in this patient. No changes in laboratory data due to the drug occurred among the patients. except for a slight increase in transaminases after 1 week of treatment in patient no. 5. Creatinine clearance did not markedly change during the two periods.
DISCUSSION Previous data in patients with renal impairment given a single dose of 10 mg (13) showed a linear dependence of the elimination rate constant, the total clearance and the renal clearance of cadralazine with the creatinine clearance in the range 5-79 ml/min. The present results of CLT and CLR after single and repeated administrations are in good agreement with the previous findings (Fig. 3). After repeated dosing, the Cmax of apparent CGP 22 639 (7-24 nmolll) in patients with CLer from 19-37 ml/min was similar to the Cmax measured in healthy volunteers after a 20 mg single oral dose (7). This represents a relative increase factor of Cmax of about 4 for the hydrazino metabolite in patients with renal impairment. Such an increase was not observed for the unchanged drug. The accumulation factor of apparent CGP 22 639, AUC(0-24h) day 9/AUC(0-24h) day I, in patients whose CLcr was from 19-37 mlImin ranged from 1.03-3.53 (mean ± SD = 1.82 ± 0.91). It was 1.7 times higher as a mean than that of the unchanged drug. This shows that CGP 22 639 accumulated more than the unchanged drug. The accumulation factor of CGP 22 639 was 1.03 for the two patients with the highest CLcr. indicating little or no accumulation in patients whose CLcr is above 40 mlImin.
J. F. Marichal et 01., Cadralazine & renal impairment
TOTAL CLEARANCE (MUMIN)
219
RENAL CLEARANCE {MLIMINl
180
0
80
*
160
Cb
140
0
70 60
120
•
50
100 0
:J 40 ml/min. When the antihypertensive effect is not sufficient, this dose should be increased at 2 week intervals by 2.5 mg steps when CLcr < 40 ml/min (maximum dose:10 mg) or 5 mg steps with CLcr > 40 ml/min (maximum dose: 15 mg). In conclusion, in patients with renal insufficiency, cadralazine is effective over 24 h after single and repeated administration. Despite the absence of
220
Eur. J. DrugMetab. Pharmacokinet., 1992, No.3
accumulation of cadralazine itself, the longer tIn of the active metabolite CGP 22 639 suggests that in patients with creatinine clearance of less than 40 mlImin, a daily dose of 2.5 mg would be appropriate to start the cadralazine treatment
7.
8.
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