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Pharmacokinetics of rilmenidine in healthy subjects
Pharmacokineticsof Rilmenidinein Healthy Subjects PATRICK GENISSEL, PhD, NORBERT BROMET, PhD, JEAN BERNARD FOURTILLAN, PhD, ALAIN MIGNOT, PhD, and HENRI ALBIN, MD
Rilmenidine is a novel a*-adrenoceptor agonist, used in the treatment of mild or moderate hypertension at the oral dose of 1 mg once or twice daily. The pharmacokinetic parameters were investigated after single or repeated administration in healthy subjects, using labeled and unlabeled compounds. Rilmenidine was rapidly and extensively absorbed, with an absolute bioavailability factor close to 1 and a maximal plasma concentration achieved within 2 hours. Rilmenidine was not subject to presystemic metabolism. Distribution was independent of the free fraction because rilmenidine was weakly bound to plasma proteins (< 10 % ). The volume of distrlbution was approximately 5 hkg-’ (315 liters).
Elimination was rapid with a total body plasma clearance of approximately 450 ml*min-’ and an elimination half-life of approximately 8 hours. Renal excretion was the major elimination process (twothirds of the total clearance). Metabolism was very poor, with a renal elimination of rilmenidine as the parent drug (urinary fraction of rilmenidine was about 65% and no metabolite plasma levels were detected). Linear pharmacokinetics were demonstrated for rilmenidine from 0.5 to 2 mg but, at 3 mg, a slight deviation from linearity was observed. In repeated administration, the linear disposition of rilmenidine with dose was confirmed. (Am J Cardiol 1988;61:47D-53D)
R
ilmenidine or 2-(dicyclopropylmethyl] amino-Z-oxazoline is a novel a2-adrenoceptor agonist1 effective in the treatment of mild and moderate hypertension at the oral dose of 1 mg once or twice daily.2*s Various pharmacologic studies 4,5have revealed a dissociation between the potent hemodynamic properties of rilmenidine, and the adverse effects usually attributed to this therapeutic class. Rilmenidine (Fig. 1) is a weak base of molecular weight of 180.25 with a pKa of approximately 9; at a physiologic pH of 7.4, only 1% exists as the unionized form. However it is mildly lipid soluble, with a true partition coefficient between octanol and water of about 20. Rilmenidine in clinical administration is used as the phosphate salt that is freely soluble in water. Radioactive material was available for human and animal studies, by labeling rilmenidine with carbon 14 on position 2 of the oxazoline ring. The human pharmacokinetics of rilmenidine were studied in 65 healthy subjects, but the various studies
in fact included 173 pharmacokinetic profiles because many of them were performed using a crossover design. The purpose of this report is to present the main pharmacokinetic results found after single and repeated administrations in healthy subjects.
Methods For all studies, drug dosage administered was 1 mg of rilmenidine expressed as base form (1.54 mg rilmenidine phosphate], except for the radiolabeled studies (14Crilmenidine) in which the dosage is indicated later. All subjects underwent full clinical examination including blood pressure, electrocardiography, medical history, blood chemistry and hematology. Each subject gave written informed consent and institutional review board approval was obtained. 14Grilmenidine pharmacokinetics (total radioactivity): Study I: To study the absorption, bioavailability and elimination of 14C-rilmenidine, 4 healthy subjects were given (in crossover design) 14Grilmenidine intravenously (i.v.) (29 &i, which represent 1.1 mg] and orally (26 &i, which represent 0.9 mg of rilmenidine). Blood samples were obtained immediately before dosing and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 24, 36, 48 and 72 hours after administration, Total voided urine was collected over 0 to 0.5, 0.5 to 1, 1 to 2, 2 to 3, 3 to 4, 4 to 6, 6 to 8, 8 to 12,lZ to 24, 24 to 48 and 48 to 72 hours and
From the Institut de Recherche Internationales Servier, Neuilly-sur-Seine, Cephac, Poitiers, and Laboratoire de Pharmacologie, Universiti: de Bordeaux II, Bordeaux, France. Address for reprints: Patrick Genissel, PhD, Institut de Recherches Internationales Servier, 27, rue du Pont, 92202 Neuilly-sur-Seine, France. 47D
48D
A SYMPOSIUM:
RILMENIDINE-A
NOVEL ALPHA2
AGONIST
ANTIHYPERTENSIVE
N‘i’
‘k-N-CH 0’ FIGURE 1. Rilmenidine
formula.
daily until the radioactivity levels decreased to twice background. In the same manner, total feces were collected daily until the radioactivity decreased to twice background. Study II: To study the metabolism and elimination routes of rilmenidine, 4 other healthy subjects were given oral 14Grilmenidine (39 &i, which represent 0.8 mg). Blood samples were obtained immediately before dosing and at 2, 6 and10 hours. Total voided urine was collected over 0 to l,.l to 2,2 to 3,3 to 4,4 to 6, 6 to 8,8 to 12,12 to 24,24 to 32,32 to%,, 48 to 72, 72 to96, 96 to 120, 120 to 144 and 144 to 168 &ours. Total feces were collected daily until 160 hours. Metabolism pathway was studied from blood [Z, 6 and 10 hours) and urinary samples (0 to 48 hours) by using a combination of various analytic methods: thin layer chromatography, liquid chromatography linked with ultraviolet or radioactive detection and further gas chromatography with mass spectrometry for structural analysis. For each study, clinical acceptability was evaluated by gathering adverse effects rey?orted by the subject. Each plasma, urine and fecal sample was analyzed for total radioactivity using liquid scintillation counting after appropriate sample preparation. Absolute bioavailability study: Study of the pharmacokinetics and absolute bioavailability of rilmenidine was undertaken in 12 subjects (6 men and 6 women). Rilmenidine was administered using a crossover design at the single iv. dose of 1 mg (0.01% aqueous solution) and oral (tablet] routes, the order of administration being defined at random and separated by an interval of 2 weeks. Blood samples were obtained before, then 5, 10, 20, 30 and 45 minutes, 1, 2, 3,4, 6, 8, 10, 12, 16, 24, 36, 48 and 60 hours after i.v. administration; and before, then 0.5,1,1.5,2, 2.5, 3,4,6,8,10,12, 16, 24, 36, 48 and 60 hours after oral administration. Urine was collected before, then during the following periods: 0 to 6,6 to 12,12 to 24,24 to 36,36 to 48,48 to 96 and 96 to 144 hours after both administrations. To measure the influence of gender on the pharmacokinetics of rilmenidine, the parameters from men and women were compared by Student t test for nonpaired series; for time to reach the maximal plasma concentration (t,,,], a Mann-Whitney test was performed. Relative bioavailability studies: Tablet versus solution: Relative bioavailability between tablet and oral solution was studied in 12 healthy men. Each subject received an oral dose of 1 mg as a tablet and a single 1 mg dose as 0.2% oral aqueous solution. The washout period between each administration was at least 1 week. Blood samples were obtained before dosing,
AGENT
then 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 16, 24 and 36 hours after dosing. Capsule versus tablet: Relative bioavailability between capsule and tablet was studied in 16 healthy men. Rilmenidine was administered using a crossover design at the single oral dose of 1 mg (capsule or tablet). The order of administration was defined at random and separated by a minimum interval of 1 week. Blood samples were obtained before dosing, then 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24 and 48 hours after dosing. Urine was collected before, then during the following periods: 0 to 24 and 24 to 48 hours after both administrations. Statistical analysis: The comparisons between the pharmacokinetic parameters obtained after tablet vs solution and capsule vs tablet administrations were performed by analysis of variance; for tmax,a Wilcoxon test was performed. Bioequivalence between 2 formulations was tested by total areas under the curve (AUC] and maximal plasma concentrations (C,,,) by the symmetrical confidence interval according to Westlake and Spriet and Beilers7 A less than 25% difference between both formulations (p <0.05) implies bioequivalence between the 2 forms. Influence of food intake: Influence of food intake on rilmenidine pharmacokinetics was studied in 12 healthy subjects. Rilmenidine was administered using a crossover design with the single oral (tablet] dose of 1 mg fasting or 30 minutes after food intake (standardized meal],* the order of administration being defined at random and separated by an interval of 1 week. Blood samples were obtained before dosing then 0.25, 0.5,0.75,1,1.5,2,2.5,3,4,6,10,16,24 and 36 hoursafter dosing. Urine was collected before, then during the following periods: 0 to 12, 12 to 24 and 24 to 48 hours after both administrations. Statistical analysis of pharmacokinetic parameters obtained after rilmenidine administration with or without food was performed by crossover analysis of variance; fort,,,, a Wilcoxon test was performed. Linearity study: Linearity of the pharmacokinetics of rilmenidine was studied after dose ranging administration in 8 healthy men. Rilmenidine was administered orally (capsule] in a double-blind random order at doses of 0.5, 1, 2 or 3 mg. The washout period between each dose was 1 week. Blood samples were obtained before dosing, then 0.5,1,1.5,2,2.5,3,3.5,4,5, 6, 8,10,12, 24 and 48 hours after dosing. A dose-effect relation was sought between C,,, and AUC. This relation was tested by a linear regression analysis: the dose effect was first verified if the significance level was reached (p 10.05] and the difference from linearity was tested. Second, if the difference from linearity was nonsignificant, a probability associated with the regression 50.05 led to the conclusion of a significant dose-effect relation. Finally, in order to conclude the linearity of the pharmacokinetics (AUC = Kdose), the slope of the line of regression was tested with respect to unity and the intercept of the line was tested with respect to zero. The t,,, was compared with a Friedman test. Steady-state study: The pharmacokinetics of rilmenidine were studied at steady state in 12 healthy
February 24, 1988
men. The subjects first received rilmenidine as a single oral dose (one l-mg tablet), then 72 hours after this first administration as repeated doses of 1 tablet every 12 hours for 10 days (2 mg/day). Blood samples were obtained first before dosing, then 0.5, 1,1.5, 2, 2.5, 3,4, 6, 8, 10, 12, 16, 24 and 36 hours after the first (single) administration. Second, samples were drawn before and at 2,12, 24, 26, 36, 38, 48, 60, 96, 144,156, 204, 206, 216, 218, 228 and 240 hours after the first dose of repeated administration. Samples were also obtained at 0.5,1, 1.5, 2, 2.5, 3, 4, 6, 8,10,12,16, 24, 36 and 48 hours after the final (twenty-first) dose. Urine was collected before dosing, then during the following periods: 0 to 12, 12 to 24, 24 to 48 and 48 to 72 hours after the single administration and 240 to 252 hours after the first dose of repeated administration. Pharmacokinetic parameters were calculated after single administration and at steady state after the twenty-first administration. Comparison of parameters obtained after single and repeated administration (parameters calculated in the interval 240 to 252 hours) were performed by analysis of variance. Analytic methods: Because of the low dosage administered (1 mg per dose) and taking into account the first results after radiolabeled studies, it was necessary to use a sensitive and specific analytic technique. For these reasons, a quantitative analysis of rilmenidine by combined gas chromatography-negative ion chemical ionization-mass spectrometry was used. The assay of rilmenidine was performed either as a bistrifluomethyl benzoyl derivativegJO or as a trifluoroacetyl derivative.ll Outlines of the latter assay are as follows: alkalinized samples were extracted by a mixture of diethyl ether/hexane (40/60) followed by a back extraction in HCl 0.5 N. A second extraction was performed after alkalinization of the acidic phase by the same diethyl ether/hexane mixture. The organic layer was then evaporated to dryness under nitrogen. The dry residue was then derivatized by trifluoroacetic acid in ethyl acetate (80’ C/W min) before injection onto the gas chromatography column. Negative ions from trifluoroacetic derivatives of rilmenidine (m/z 276) and the deuterated rilmenidine internal standard (m/z2801 are monitored simultaneously by selected ion monitoring. The calibration curves were linear from the limit of detection (0.2 ngml-l) to 5 ng-ml-l. The assay precision [coefficient of variation), was 9.6% at the limit of detection and 2.9% at 5 ngm-l, whereas the accuracy (percent of error] was 6.5 and 2.3%, respectively. Calculation of pharmacokinetic parameters: All results are expressed as mean f standard error of the mean. From plasma data: C,,, and t,,, were obtained from experimental concentrations. The following pharmacokinetic parameters were calculated12J3: tlag time of absorption; AUC-area under the curve of plasma concentration vs time, extrapolated to infinity assessed by AUC = AUCt + C/Xz, where AUCt is calculated in the time interval 0 to t using the trapezoidal method [experimental concentrations), Ct the last concentration at or above the detection limit of the assay and Xz the rate-constant relative to the terminal
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elimination phase; the slope of this phase was estimated by regression analysis of the terminal phase of the plasma concentration curve vs time (log/decimal); F, Fr-absolute (Fj or relative (Fr) bioavailability factors calculated from AUC; V-volume of distribution calculated using V = D/AUC.Xz, where D is the dose administered; Vs,--volume of distribution at steady state using V,, = MRT.CL after i.v. administration or V,,/F = CL (MRT - l/ka) after oral administration,14 where MRT is the mean residence time, CL the total plasma clearance and ka the rate constant relative to the absorption phase; W&z-terminal half-life, estimated by tl%,z = LnYXz; and CL-total plasma clearance calculated using CL = D/AUC. After oral administration, volume of distribution as well as plasma clearance were calculated assuming F = 1. Accumulation ratio after repeated administration: RI is theoretical accumulation ratio calculated after single administration using, Rl = AUC/AU&; Rz is the observed accumulation ratio calculated from R2 = AUCX-& AU& [single administration). From urinary data: The following parameters were calculated from urinary data: Act--the cumulative amount of unchanged compound, excreted from 0 to t; fe-fraction of the dose administered excreted in the urine in unchanged form, calculated using fe = A,/ F.D; and-F, Fr-the absolute (F) or relative (Fr) bioavailability factors calculated using Ae.
Results 1Grilmenidine pharmacokinetics (total radioactivity): The results were expressed as total radioactivity, which was assumed to represent the parent drug (rilmenidine) or metabolites, or both. Study I: Renal elimination was the main process, because after 7 days of recovery, 88.08 f 5.09% and 86.65 f 3.46% of the total radioactivity were excreted in urine after oral or i.v. administration, respectively. Fecal elimination was weak; no more than 1% was excreted after 7 days. 14C-rilmenidine appeared to be rapidly (tmax= 1.25 f 0.15 hours) and completely absorbed (absolute bioavailability from urinary data: 102 f 7%). Total radioactivity distribution was characterized by a volume of distribution of 7.3 f 1.2 l-kg-l. Elimination was characterized by biexponential decay curves. Due to the weak plasma concentrations, the 2 elimination half-lives (distribution and elimination) were calculated from total radioactivity in urine: 6.50 f 1.05 hours and 28.18 f 4.31 hours, respectively. Study II: After 7 days of recovery, 93.04 f 2.94% of the total radioactivity was excreted in urine after oral administration, 84.58 f 2.22% of which was found 24 hours after dosing. Fecal elimination was weak: 0.99 f 0.07% was excreted after 7 days. Metabolism results showed that unchanged 14Grilmenidine was the main product identified in all the urine samples. Other minor products were found, which represented no more than 5% of the total radioactivity. Among them, N-dicyclopropylmethylurea (S 114591,N-(hydroxyethyl)-N’-dicyclopropylurea (S 11460) and &(dicyclopropylmethyl] amino-2-oxazoline-4-one (S 11316) were identified and 2 other products remained unknown. In the blood, rilmenidine was the only product identified,
50D
A SYMPOSIUM:
RILMENIDINE-A
NOVEL
ALPHA?
AGONIST
ANTIHYPERTENSIVE
AGENT
ng.ml-1
--
0
6
12
18
24
.
IV
.
TABLET
30
FIGURE 2. Mean * standard error of the mean plasma concentrations of rilmenidine after single 1 mg dose via intravenous (IV) (0.01% solution) and oral (tablet) routes in healthy subjects (n = 12).
1MG
36
1 MG
42
48 hours
TABLE I Pharmacokinetic Parameters of Rilmenidine in Healthy Subjects (n = 12) After Intravenous and Oral Administration of 1 mg Intravenous tl,, (hours) C,, (ngm-I) t, (hours) F(%) AUC (nphours.ml-l) V (liters) t’/z, z (hours) MRT (hours) CL (mlemin-I) CLR (mlamin-‘) fe (%)
Route
38.61 314.44 8.31 11.77 463.58 296.81 63.74
f f f f f f f
3.31 18.31 0.77 1.11 35.05 33.56 5.14
Oral Route 0.25 3.49 1.79 100.1 38.33 324.68 8.51 12.28 475.17 330.13 71.18
f f f f f f f f f f f
0.07 1.79 0.21 5.3 3.55 20.67 0.86 0.99 41.32 27.42 4.49
Values are expressed as mean jr standard error of the mean. AUC = area under the plasma concentration curve; CL = total plasma clearance: CLR = renal clearance; C,, = maximal plasma concentration; F = bioavailability factor; fe = fraction of the unchanged drug excreted in urine; MRT = mean residence time; t,, = lag time of absorption; t,, = time to reach the maximal plasma concentration; t%, z = terminal half-life; V = volume of distribution. For oral route, total plasma clearance and volume of distribution were calculated assuming bioavailability factor = 1.
and no trace of metabolite was detectable by any analytical method used. Absolute bioavailability study: The study involving single oral and i.v. administration of rilmenidine in healthy subjects was described to evaluate the reference pharmacokinetic parameters of rilmenidine. The plasma concentration curves after oral and i.v. administration are displayed in Figure 2. After i.v. administration or beyond the plasma peak (oral route], the plasma concentrations decreased according to a mono- or biphasic profile. Table I summarizes the main parameters of both routes. Plasma concentration time profiles were quite similar whatever the administration route. Digestive absorption of rilmenidine (tablet) was rapid Urnaxrange-l.0 to 3.0 hours] with C,,, of ap-
proximately 3.5 ngml-l [range 2.7 to 4.3 ngml-l). Rilmenidine was not subject to presystemic metabolism and its absolute bioavailability was total [from plasma data-F = 100.1 f 5.3%; from urinary data-F = 116.8 f 9.54701. The reference pharmacokinetic parameters of distribution and elimination were those calculated from plasmatic and urinary data after iv. administration. Distribution was large, with a volume of distribution of about 315 liters, i.e. 5.13 l-kg-l (range 3.6 to 7.2 l-kg-l). Elimination was characterized by a total plasma body clearance of about 460 ml-min-l (range 281 to 679 ml-min-l), an elimination half-life of 8 hours (range 4.7 to 13.6 hours) and a mean residence time of 12 hours [range 7.3 to 17.8 hours). From urinary data, about 64% of the dose injected was found as unchanged compound; the renal clearance (CLR, range 149 to 466 mlamin-l) represented the two-thirds of the total body clearance, indicating renal excretion as the major elimination process. No difference between men and women was observed. Interindividual variability of the pharmacokinetic parameters was moderate; for instance, the coefficient of variation (standard deviation divided by mean] of elimination half-life was 32.1% (iv. route) and 35.0% (oral route). Relative bioavailability studies: Tablet versus solution: The time course of mean plasma levels of rilmenidine obtained after tablet and solution administration is shown in Figure 3. Statistical comparison of pharmacokinetic parameters failed to reveal any significant difference between the tablet and solution forms; the Wilcoxon test showed no significant difference between t,,, (1.46 f 0.14 hours and 1.83 f 0.24 hours after solution and tablet, respectively]. The relative bioavailability factor of tablet in comparison with solution was 94.08 f 6.37%. Parameters characterizing bioavailability, C,,, and AUC, were compared by the Westlake test showing differences of 9.3 and 21.3%, respectively, in respect to the reference form (solu-
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Influence of food intake: The time course of mean plasma levels of rilmenidine obtained with and without food intake is shown in Figure 5. Absorption was slowed when the tablet was administered after a standard meal. C,,, (approximately 2.8 ng-ml-l with and without food] was reached (tmax]2.90 f 0.32 and 1.68 f 0.31 hours after dosing, with and without food, respectively (p
tion]. These differences between the forms were less than 25% (for p <0.05); therefore both forms were bioequivalent. Capsule versus tablet: The time profile of mean plasma levels of rilmenidine obtained after capsule and tablet administration is shown in Figure 4. Statistical comparison of pharmacokinetic parameters did not show any significant difference between the capsule and tablet forms; the Wilcoxon test showed no differences between t,,, (1.63 f 0.21 and 1.38 f 0.13 hours after tablet and solution, respectively]. The relative bioavailability factor of capsule compared with tablet was 92.36 f 5.42% from plasma data and 101.26 f 15.41% from urinary data. The Westlake test applied to Cmax,AUC and A,cJ8) showed respective differences of 10.5,24.4 and 12.3%, in respect to the reference form (tablet). These differences between the forms were less than 25% (for p <0.05); therefore both forms were equivalent.
T I
FIGURE 3. Mean f standard error of the mean plasma concentrations of rilmenidine after single 1 mg oral dose (oral 0.02% solution and tablet) in healthy subjects (n = 12).
6
12
18
.
SOLUTION
0
TABLET
24
I 36
30 hours
n CAPSULE
FIGURE 4. Mean f standard error of the mean plasma concentrations of rilmenidine after single 1 mg oral dose (capsule and tablet) in healthy subjects (n = 16).
0 TABLET
5 2 d a
‘. 04
0
6
12
18
hours
24
52D
A SYMPOSIUM:
RILMENIDINE-A
NOVEL
ALPHA*
AGONIST
ANTIHYPERTENSIVE
0
WITH FOOD
.
WITHOUTFOOD
AGENT
FIGURE 5. Mean f standard error of the mean plasma concentrations of rilmenidine after single 1 mg oral dose (tablet) with and without food in healthy subjects (n = 12).
D
0
6
12
18
24
30
36 hours
TABLE II Pharmacokinetic Parameters of Rilmenidine Single Administration of 0.5, 1, 2 and 3 mg 0.5 mg
Cm.,(nwml-‘1 t,, (hours) V/F (liters) AUC (ng-houwml-‘) t’/s, z (hours) MRT (hours) CL/F (mkmin-‘)
1.40 2.00 443.35 14.28 7.74 11.64 725.91
f f f f f f f
0.18 0.34 57.35 3.58 1.06 1.46 87.87
in Healthy Subjects (n = 8) After Oral
1 mg 3.25 1.94 332.98 29.95 6.99 10.46 570.79
f f f f f f f
0.26 0.64 32.49 1.79 0.86 1.22 39.92
5.41 2.00 408.63 59.64 8.15 12.05 598.09
Values are expressed as mean f standard error of the mean. CL/F = apparent plasma clearance; V/F = apparent volume of distribution;
are summarized in Table II. The absorption of rilmenidine was rapid at all doses. The C,,, followed a significant linear relation within the 0.5 to 2 mg range and tmaxwas independent of the dose. Distribution was independent of the dose in the 0.5 to 2 mg dose range and was decreased at 3 mg. AUC followed a significant linear relation within the 0.5 to 2 mg range. At 3 mg, a slight deviation from linearity was observed. Elimination of rilmenidine was characterized by a terminal half-life of 7 to 8 hours and a mean residence time of 11 to 12 hours, both independent of the dose administered. Total apparent clearance was independent of the dose administered in the 0.5 to 2 mg range (600 to 700 ml-min-l] and reached 400 mlamin-l at 3 mg. Steady-state study: A graphic simulation corresponding to the theoretical profile of plasma concentrations during a repeated administration was drawn on the basis of concentrations obtained after single administration. Plasma concentrations actually found were juxtaposed with this simulation (Fig. 6). This simulation gave theoretical maximal and minimal concentrations at steady state. Statistical comparison of different plasma and urinary pharmacokinetic parameters
3 mg
2mg f f f f f f f
0.33 0.61 49.95 6.28 0.98 1.42 53.97
other abbreviations
10.79 1.75 262.95 130.00 7.69 11.35 397.34
f f f f f f f
0.94 0.40 19.14 9.23 0.43 0.54 26.05
as in Table I.
,obtained after single administration and at steady state revealed no significant difference. In accordance with terminal half-life of approximately 8 hours, plasma levels of rilmenidine reached steady state during the third day after repeated administration. Plasma concentrations [after the last tablet) at steady state gave values of C,,, and Cminof 4.44 f 0.30 ngml-l (range2.4 to 6.4 ngml-l] and 1.73 f 0.19 ngml-l [range-O.8 to 3.0 ngml-l), respectively. The observed accumulation ratio (RX= 1.48 f 0.08) was similar to the theoretical ratio (R1= 1.48 f 0.05). Half-lives found after single (7.63 f 0.78 hours) or repeated (7.10 f 0.58 hours] administration were in accordance.
Discussion The results of these studies in healthy subjects, after single and repeated administration, have allowed the determination of the main pharmacokinetic parameters of rilmenidine. From radiolabeled studies and bioavailability studies, rilmenidine was rapidly and extensively absorbed with a bioavailability factor close to 1. The relative bioavailability factors of various pharmaceutical forms were calculated, showing their bioequivalence. More-
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ng.ml-1
FIGURE 6. Mean plasma concentrations of rilmenidine after single 1 mg dose and repeated administration every 12 hours for 10 days. Theoretical simulation curve was extrapolated from data after the single administration. Plasma concentrations after repeated administration were drawn to give an appreciation of the correlation between the theoretical simulation curve and real plasma concentrations after repeated administration.
g4 5 F E3 Y s 4
s2
s 2 iI z ha
0
1
2
4
5
6
7
8
9
10
11
12
13
14
15
days
over, it was demonstrated that food intake had no significant effect on the bioavailability of rilmenidine, although absorption appeared delayed. The increasing t,,, and ttag time had no influence on the C,,, and AUC values. Distribution was characterized by a large volume of distribution reflecting the good tissular affinity of rilmenidine. The binding of rilmenidine on the human free fatty-acid serum albumin fraction (equilibrium dialysis) is approximately 7.5% and on the a1 glycoprotein acid approximately 3.5% (data not shown). Therefore, the large free fraction explains, at least partially, the large distribution. The weak involvement of protein binding minimizes the risk of pharmacokinetic interactions with other drugs, which are frequently coadministered with such antihypertensive agents. Elimination was characterized mainly by renal excretion of rilmenidine as the unchanged compound. The large free fraction and the value of the renal clearance indicate that rilmenidine undergoes not only a glomerular filtration but also an active secretion process far superior to that of an eventual reabsorption. However, owing to the pKa of this weak base (pKa = 91,it is likely that such a reabsorption is pH-dependent. Metabolism was poorly involved in the elimination process. This allows the assumption that no hepatic first-pass effect occurs after oral administration, as confirmed by the absolute bioavailability. The linearity of the pharmacokinetics was demonstrated within the 0.5 to 2 mg range after single dose administration. For the 3 mg dose, the significant differences observed were slight. The usual prescriptions of rilmenidine (1 mg once or twice daily] are in the range 0.5 to 2 mg and repeated administration in healthy subjects and long-term clinical studies (Beau et al., this issue, pages 95D-102Dj have never shown
any accumulation or modifications of the main pharmacokinetic parameters.
References 1. Guicheney P, Dausse JP, Meyer P. Affinites respectives du S 3341 et de la clonidine pour les r.&pteurs adrenergiques alpha 1 et alpha 2 du cerveau du Rat. J Pharmacol (Paris) 1981;12(3):255-262. 2. Weerasuriya K, Shaw E, Turner P. Preliminary clinical pharmacological studies of S 3341 a new hypotensive agent, and comparison with clonidine in normal males. Eur J Clin Pharmacol 1984;27:281-286. 3. Fillastre JP, Godin M, Moulin B, Schwartz J, A double blind comparative study of S 3341 and clonidine in 333 hypertensive patients. Third European Meeting on Hypertension 1987;Milan:abstr. no. 174. 4. Laubie M, Poignant JC, Scuv&-Moreau J, Dabire H, Dresse A, Schmitt H. Pharmacological properties of (N-dicyclopropylmethyI]amino-2-oxazoline S 3341, an alpha 2 adrenoreceptor agonist. J Phormacol (Paris) 1985;16(3):259278. 5. Van Zwieten PA, Thoolen MJMC, Jonkman FAM, Wilffert B, De Jong A, Timmermans PBMWM. Central and peripheral effects of S 3341 (N-dicyclopropyImethyI)-amino-2-oxazoline in animal models. Arch Int Pharmacodyn Ther 1986;279(1]:130-149. 6. Westlake WJ. Symmetrical confidence intervals for bioequivalence trials. Biometrics 1976;32:741-744. 7. Spriet A, Beiler D. Table to facilitate determination of symmetrical confidence intervals in bioavailability trials with Westlake’s method. Eur J Drug Metab Pharmacokinet 1978;2:129-132. 8. Melander A. Influence of food on the bioavailability of drugs. Clin Pharmacokinet 1978;3:337-351. 9. Ehrhardt JD. Gas chromatography negative ion massspectrometric assay of 2-dicyclopropylmethy1 amino-2-oxazoline [S 3341), a new antihypertensive drug. Biomed Mass Spectrom 1985;12(10]:593-595. 10. Murray S, Watson D, Davies DS. Bistrifluoromethyfaryl derivatives for drug analysis by gas chromatography electron capture negative ion chemical ionization massspectrometry. Application to the measurement of (N-dicyclopropylmethyl]amino-2-oxazoline in plasma. Biomed Mass Spectrom 1985;12: -230-237. 11. Ung HL, Girault J, Lefebvre MA, Mignot A, Fourtillan JB. Quantitative analysis of S 3341 in human plasma and urine by combined gas chromatography-negative ion chemical ionization mass spectrometry: 15 month inter-day precision and accuracy validation. Biomed Mass Spectrom 1987;14:289-293. 12. Gibaldi M. Biopharmaceutics and Clinical Pharmacokinetics. Philadelphia: Lea 8 Febiger, 1984. 13. Rowland M, Tozer TN. Clinical Pharmacokinetics: Concepts and Applications. Philadelphia: Lea 8 Febiger, 1980. 14. Perrier D, Mayersohn M. Noncompartmental determination of the steady state volume of distribution for any mode of administration. J Pharm Sci 1982;71(3):372-373.
Rilmenidine is a novel a*-adrenoceptor agonist, used in the treatment of mild or moderate hypertension at the oral dose of 1 mg once or twice daily. The pharmacokinetic parameters were investigated after single or repeated administration in healthy subjects, using labeled and unlabeled compounds. Rilmenidine was rapidly and extensively absorbed, with an absolute bioavailability factor close to 1 and a maximal plasma concentration achieved within 2 hours. Rilmenidine was not subject to presystemic metabolism. Distribution was independent of the free fraction because rilmenidine was weakly bound to plasma proteins (< 10 % ). The volume of distrlbution was approximately 5 hkg-’ (315 liters).
Elimination was rapid with a total body plasma clearance of approximately 450 ml*min-’ and an elimination half-life of approximately 8 hours. Renal excretion was the major elimination process (twothirds of the total clearance). Metabolism was very poor, with a renal elimination of rilmenidine as the parent drug (urinary fraction of rilmenidine was about 65% and no metabolite plasma levels were detected). Linear pharmacokinetics were demonstrated for rilmenidine from 0.5 to 2 mg but, at 3 mg, a slight deviation from linearity was observed. In repeated administration, the linear disposition of rilmenidine with dose was confirmed. (Am J Cardiol 1988;61:47D-53D)
R
ilmenidine or 2-(dicyclopropylmethyl] amino-Z-oxazoline is a novel a2-adrenoceptor agonist1 effective in the treatment of mild and moderate hypertension at the oral dose of 1 mg once or twice daily.2*s Various pharmacologic studies 4,5have revealed a dissociation between the potent hemodynamic properties of rilmenidine, and the adverse effects usually attributed to this therapeutic class. Rilmenidine (Fig. 1) is a weak base of molecular weight of 180.25 with a pKa of approximately 9; at a physiologic pH of 7.4, only 1% exists as the unionized form. However it is mildly lipid soluble, with a true partition coefficient between octanol and water of about 20. Rilmenidine in clinical administration is used as the phosphate salt that is freely soluble in water. Radioactive material was available for human and animal studies, by labeling rilmenidine with carbon 14 on position 2 of the oxazoline ring. The human pharmacokinetics of rilmenidine were studied in 65 healthy subjects, but the various studies
in fact included 173 pharmacokinetic profiles because many of them were performed using a crossover design. The purpose of this report is to present the main pharmacokinetic results found after single and repeated administrations in healthy subjects.
Methods For all studies, drug dosage administered was 1 mg of rilmenidine expressed as base form (1.54 mg rilmenidine phosphate], except for the radiolabeled studies (14Crilmenidine) in which the dosage is indicated later. All subjects underwent full clinical examination including blood pressure, electrocardiography, medical history, blood chemistry and hematology. Each subject gave written informed consent and institutional review board approval was obtained. 14Grilmenidine pharmacokinetics (total radioactivity): Study I: To study the absorption, bioavailability and elimination of 14C-rilmenidine, 4 healthy subjects were given (in crossover design) 14Grilmenidine intravenously (i.v.) (29 &i, which represent 1.1 mg] and orally (26 &i, which represent 0.9 mg of rilmenidine). Blood samples were obtained immediately before dosing and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 24, 36, 48 and 72 hours after administration, Total voided urine was collected over 0 to 0.5, 0.5 to 1, 1 to 2, 2 to 3, 3 to 4, 4 to 6, 6 to 8, 8 to 12,lZ to 24, 24 to 48 and 48 to 72 hours and
From the Institut de Recherche Internationales Servier, Neuilly-sur-Seine, Cephac, Poitiers, and Laboratoire de Pharmacologie, Universiti: de Bordeaux II, Bordeaux, France. Address for reprints: Patrick Genissel, PhD, Institut de Recherches Internationales Servier, 27, rue du Pont, 92202 Neuilly-sur-Seine, France. 47D
48D
A SYMPOSIUM:
RILMENIDINE-A
NOVEL ALPHA2
AGONIST
ANTIHYPERTENSIVE
N‘i’
‘k-N-CH 0’ FIGURE 1. Rilmenidine
formula.
daily until the radioactivity levels decreased to twice background. In the same manner, total feces were collected daily until the radioactivity decreased to twice background. Study II: To study the metabolism and elimination routes of rilmenidine, 4 other healthy subjects were given oral 14Grilmenidine (39 &i, which represent 0.8 mg). Blood samples were obtained immediately before dosing and at 2, 6 and10 hours. Total voided urine was collected over 0 to l,.l to 2,2 to 3,3 to 4,4 to 6, 6 to 8,8 to 12,12 to 24,24 to 32,32 to%,, 48 to 72, 72 to96, 96 to 120, 120 to 144 and 144 to 168 &ours. Total feces were collected daily until 160 hours. Metabolism pathway was studied from blood [Z, 6 and 10 hours) and urinary samples (0 to 48 hours) by using a combination of various analytic methods: thin layer chromatography, liquid chromatography linked with ultraviolet or radioactive detection and further gas chromatography with mass spectrometry for structural analysis. For each study, clinical acceptability was evaluated by gathering adverse effects rey?orted by the subject. Each plasma, urine and fecal sample was analyzed for total radioactivity using liquid scintillation counting after appropriate sample preparation. Absolute bioavailability study: Study of the pharmacokinetics and absolute bioavailability of rilmenidine was undertaken in 12 subjects (6 men and 6 women). Rilmenidine was administered using a crossover design at the single iv. dose of 1 mg (0.01% aqueous solution) and oral (tablet] routes, the order of administration being defined at random and separated by an interval of 2 weeks. Blood samples were obtained before, then 5, 10, 20, 30 and 45 minutes, 1, 2, 3,4, 6, 8, 10, 12, 16, 24, 36, 48 and 60 hours after i.v. administration; and before, then 0.5,1,1.5,2, 2.5, 3,4,6,8,10,12, 16, 24, 36, 48 and 60 hours after oral administration. Urine was collected before, then during the following periods: 0 to 6,6 to 12,12 to 24,24 to 36,36 to 48,48 to 96 and 96 to 144 hours after both administrations. To measure the influence of gender on the pharmacokinetics of rilmenidine, the parameters from men and women were compared by Student t test for nonpaired series; for time to reach the maximal plasma concentration (t,,,], a Mann-Whitney test was performed. Relative bioavailability studies: Tablet versus solution: Relative bioavailability between tablet and oral solution was studied in 12 healthy men. Each subject received an oral dose of 1 mg as a tablet and a single 1 mg dose as 0.2% oral aqueous solution. The washout period between each administration was at least 1 week. Blood samples were obtained before dosing,
AGENT
then 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 16, 24 and 36 hours after dosing. Capsule versus tablet: Relative bioavailability between capsule and tablet was studied in 16 healthy men. Rilmenidine was administered using a crossover design at the single oral dose of 1 mg (capsule or tablet). The order of administration was defined at random and separated by a minimum interval of 1 week. Blood samples were obtained before dosing, then 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24 and 48 hours after dosing. Urine was collected before, then during the following periods: 0 to 24 and 24 to 48 hours after both administrations. Statistical analysis: The comparisons between the pharmacokinetic parameters obtained after tablet vs solution and capsule vs tablet administrations were performed by analysis of variance; for tmax,a Wilcoxon test was performed. Bioequivalence between 2 formulations was tested by total areas under the curve (AUC] and maximal plasma concentrations (C,,,) by the symmetrical confidence interval according to Westlake and Spriet and Beilers7 A less than 25% difference between both formulations (p <0.05) implies bioequivalence between the 2 forms. Influence of food intake: Influence of food intake on rilmenidine pharmacokinetics was studied in 12 healthy subjects. Rilmenidine was administered using a crossover design with the single oral (tablet] dose of 1 mg fasting or 30 minutes after food intake (standardized meal],* the order of administration being defined at random and separated by an interval of 1 week. Blood samples were obtained before dosing then 0.25, 0.5,0.75,1,1.5,2,2.5,3,4,6,10,16,24 and 36 hoursafter dosing. Urine was collected before, then during the following periods: 0 to 12, 12 to 24 and 24 to 48 hours after both administrations. Statistical analysis of pharmacokinetic parameters obtained after rilmenidine administration with or without food was performed by crossover analysis of variance; fort,,,, a Wilcoxon test was performed. Linearity study: Linearity of the pharmacokinetics of rilmenidine was studied after dose ranging administration in 8 healthy men. Rilmenidine was administered orally (capsule] in a double-blind random order at doses of 0.5, 1, 2 or 3 mg. The washout period between each dose was 1 week. Blood samples were obtained before dosing, then 0.5,1,1.5,2,2.5,3,3.5,4,5, 6, 8,10,12, 24 and 48 hours after dosing. A dose-effect relation was sought between C,,, and AUC. This relation was tested by a linear regression analysis: the dose effect was first verified if the significance level was reached (p 10.05] and the difference from linearity was tested. Second, if the difference from linearity was nonsignificant, a probability associated with the regression 50.05 led to the conclusion of a significant dose-effect relation. Finally, in order to conclude the linearity of the pharmacokinetics (AUC = Kdose), the slope of the line of regression was tested with respect to unity and the intercept of the line was tested with respect to zero. The t,,, was compared with a Friedman test. Steady-state study: The pharmacokinetics of rilmenidine were studied at steady state in 12 healthy
February 24, 1988
men. The subjects first received rilmenidine as a single oral dose (one l-mg tablet), then 72 hours after this first administration as repeated doses of 1 tablet every 12 hours for 10 days (2 mg/day). Blood samples were obtained first before dosing, then 0.5, 1,1.5, 2, 2.5, 3,4, 6, 8, 10, 12, 16, 24 and 36 hours after the first (single) administration. Second, samples were drawn before and at 2,12, 24, 26, 36, 38, 48, 60, 96, 144,156, 204, 206, 216, 218, 228 and 240 hours after the first dose of repeated administration. Samples were also obtained at 0.5,1, 1.5, 2, 2.5, 3, 4, 6, 8,10,12,16, 24, 36 and 48 hours after the final (twenty-first) dose. Urine was collected before dosing, then during the following periods: 0 to 12, 12 to 24, 24 to 48 and 48 to 72 hours after the single administration and 240 to 252 hours after the first dose of repeated administration. Pharmacokinetic parameters were calculated after single administration and at steady state after the twenty-first administration. Comparison of parameters obtained after single and repeated administration (parameters calculated in the interval 240 to 252 hours) were performed by analysis of variance. Analytic methods: Because of the low dosage administered (1 mg per dose) and taking into account the first results after radiolabeled studies, it was necessary to use a sensitive and specific analytic technique. For these reasons, a quantitative analysis of rilmenidine by combined gas chromatography-negative ion chemical ionization-mass spectrometry was used. The assay of rilmenidine was performed either as a bistrifluomethyl benzoyl derivativegJO or as a trifluoroacetyl derivative.ll Outlines of the latter assay are as follows: alkalinized samples were extracted by a mixture of diethyl ether/hexane (40/60) followed by a back extraction in HCl 0.5 N. A second extraction was performed after alkalinization of the acidic phase by the same diethyl ether/hexane mixture. The organic layer was then evaporated to dryness under nitrogen. The dry residue was then derivatized by trifluoroacetic acid in ethyl acetate (80’ C/W min) before injection onto the gas chromatography column. Negative ions from trifluoroacetic derivatives of rilmenidine (m/z 276) and the deuterated rilmenidine internal standard (m/z2801 are monitored simultaneously by selected ion monitoring. The calibration curves were linear from the limit of detection (0.2 ngml-l) to 5 ng-ml-l. The assay precision [coefficient of variation), was 9.6% at the limit of detection and 2.9% at 5 ngm-l, whereas the accuracy (percent of error] was 6.5 and 2.3%, respectively. Calculation of pharmacokinetic parameters: All results are expressed as mean f standard error of the mean. From plasma data: C,,, and t,,, were obtained from experimental concentrations. The following pharmacokinetic parameters were calculated12J3: tlag time of absorption; AUC-area under the curve of plasma concentration vs time, extrapolated to infinity assessed by AUC = AUCt + C/Xz, where AUCt is calculated in the time interval 0 to t using the trapezoidal method [experimental concentrations), Ct the last concentration at or above the detection limit of the assay and Xz the rate-constant relative to the terminal
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elimination phase; the slope of this phase was estimated by regression analysis of the terminal phase of the plasma concentration curve vs time (log/decimal); F, Fr-absolute (Fj or relative (Fr) bioavailability factors calculated from AUC; V-volume of distribution calculated using V = D/AUC.Xz, where D is the dose administered; Vs,--volume of distribution at steady state using V,, = MRT.CL after i.v. administration or V,,/F = CL (MRT - l/ka) after oral administration,14 where MRT is the mean residence time, CL the total plasma clearance and ka the rate constant relative to the absorption phase; W&z-terminal half-life, estimated by tl%,z = LnYXz; and CL-total plasma clearance calculated using CL = D/AUC. After oral administration, volume of distribution as well as plasma clearance were calculated assuming F = 1. Accumulation ratio after repeated administration: RI is theoretical accumulation ratio calculated after single administration using, Rl = AUC/AU&; Rz is the observed accumulation ratio calculated from R2 = AUCX-& AU& [single administration). From urinary data: The following parameters were calculated from urinary data: Act--the cumulative amount of unchanged compound, excreted from 0 to t; fe-fraction of the dose administered excreted in the urine in unchanged form, calculated using fe = A,/ F.D; and-F, Fr-the absolute (F) or relative (Fr) bioavailability factors calculated using Ae.
Results 1Grilmenidine pharmacokinetics (total radioactivity): The results were expressed as total radioactivity, which was assumed to represent the parent drug (rilmenidine) or metabolites, or both. Study I: Renal elimination was the main process, because after 7 days of recovery, 88.08 f 5.09% and 86.65 f 3.46% of the total radioactivity were excreted in urine after oral or i.v. administration, respectively. Fecal elimination was weak; no more than 1% was excreted after 7 days. 14C-rilmenidine appeared to be rapidly (tmax= 1.25 f 0.15 hours) and completely absorbed (absolute bioavailability from urinary data: 102 f 7%). Total radioactivity distribution was characterized by a volume of distribution of 7.3 f 1.2 l-kg-l. Elimination was characterized by biexponential decay curves. Due to the weak plasma concentrations, the 2 elimination half-lives (distribution and elimination) were calculated from total radioactivity in urine: 6.50 f 1.05 hours and 28.18 f 4.31 hours, respectively. Study II: After 7 days of recovery, 93.04 f 2.94% of the total radioactivity was excreted in urine after oral administration, 84.58 f 2.22% of which was found 24 hours after dosing. Fecal elimination was weak: 0.99 f 0.07% was excreted after 7 days. Metabolism results showed that unchanged 14Grilmenidine was the main product identified in all the urine samples. Other minor products were found, which represented no more than 5% of the total radioactivity. Among them, N-dicyclopropylmethylurea (S 114591,N-(hydroxyethyl)-N’-dicyclopropylurea (S 11460) and &(dicyclopropylmethyl] amino-2-oxazoline-4-one (S 11316) were identified and 2 other products remained unknown. In the blood, rilmenidine was the only product identified,
50D
A SYMPOSIUM:
RILMENIDINE-A
NOVEL
ALPHA?
AGONIST
ANTIHYPERTENSIVE
AGENT
ng.ml-1
--
0
6
12
18
24
.
IV
.
TABLET
30
FIGURE 2. Mean * standard error of the mean plasma concentrations of rilmenidine after single 1 mg dose via intravenous (IV) (0.01% solution) and oral (tablet) routes in healthy subjects (n = 12).
1MG
36
1 MG
42
48 hours
TABLE I Pharmacokinetic Parameters of Rilmenidine in Healthy Subjects (n = 12) After Intravenous and Oral Administration of 1 mg Intravenous tl,, (hours) C,, (ngm-I) t, (hours) F(%) AUC (nphours.ml-l) V (liters) t’/z, z (hours) MRT (hours) CL (mlemin-I) CLR (mlamin-‘) fe (%)
Route
38.61 314.44 8.31 11.77 463.58 296.81 63.74
f f f f f f f
3.31 18.31 0.77 1.11 35.05 33.56 5.14
Oral Route 0.25 3.49 1.79 100.1 38.33 324.68 8.51 12.28 475.17 330.13 71.18
f f f f f f f f f f f
0.07 1.79 0.21 5.3 3.55 20.67 0.86 0.99 41.32 27.42 4.49
Values are expressed as mean jr standard error of the mean. AUC = area under the plasma concentration curve; CL = total plasma clearance: CLR = renal clearance; C,, = maximal plasma concentration; F = bioavailability factor; fe = fraction of the unchanged drug excreted in urine; MRT = mean residence time; t,, = lag time of absorption; t,, = time to reach the maximal plasma concentration; t%, z = terminal half-life; V = volume of distribution. For oral route, total plasma clearance and volume of distribution were calculated assuming bioavailability factor = 1.
and no trace of metabolite was detectable by any analytical method used. Absolute bioavailability study: The study involving single oral and i.v. administration of rilmenidine in healthy subjects was described to evaluate the reference pharmacokinetic parameters of rilmenidine. The plasma concentration curves after oral and i.v. administration are displayed in Figure 2. After i.v. administration or beyond the plasma peak (oral route], the plasma concentrations decreased according to a mono- or biphasic profile. Table I summarizes the main parameters of both routes. Plasma concentration time profiles were quite similar whatever the administration route. Digestive absorption of rilmenidine (tablet) was rapid Urnaxrange-l.0 to 3.0 hours] with C,,, of ap-
proximately 3.5 ngml-l [range 2.7 to 4.3 ngml-l). Rilmenidine was not subject to presystemic metabolism and its absolute bioavailability was total [from plasma data-F = 100.1 f 5.3%; from urinary data-F = 116.8 f 9.54701. The reference pharmacokinetic parameters of distribution and elimination were those calculated from plasmatic and urinary data after iv. administration. Distribution was large, with a volume of distribution of about 315 liters, i.e. 5.13 l-kg-l (range 3.6 to 7.2 l-kg-l). Elimination was characterized by a total plasma body clearance of about 460 ml-min-l (range 281 to 679 ml-min-l), an elimination half-life of 8 hours (range 4.7 to 13.6 hours) and a mean residence time of 12 hours [range 7.3 to 17.8 hours). From urinary data, about 64% of the dose injected was found as unchanged compound; the renal clearance (CLR, range 149 to 466 mlamin-l) represented the two-thirds of the total body clearance, indicating renal excretion as the major elimination process. No difference between men and women was observed. Interindividual variability of the pharmacokinetic parameters was moderate; for instance, the coefficient of variation (standard deviation divided by mean] of elimination half-life was 32.1% (iv. route) and 35.0% (oral route). Relative bioavailability studies: Tablet versus solution: The time course of mean plasma levels of rilmenidine obtained after tablet and solution administration is shown in Figure 3. Statistical comparison of pharmacokinetic parameters failed to reveal any significant difference between the tablet and solution forms; the Wilcoxon test showed no significant difference between t,,, (1.46 f 0.14 hours and 1.83 f 0.24 hours after solution and tablet, respectively]. The relative bioavailability factor of tablet in comparison with solution was 94.08 f 6.37%. Parameters characterizing bioavailability, C,,, and AUC, were compared by the Westlake test showing differences of 9.3 and 21.3%, respectively, in respect to the reference form (solu-
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Influence of food intake: The time course of mean plasma levels of rilmenidine obtained with and without food intake is shown in Figure 5. Absorption was slowed when the tablet was administered after a standard meal. C,,, (approximately 2.8 ng-ml-l with and without food] was reached (tmax]2.90 f 0.32 and 1.68 f 0.31 hours after dosing, with and without food, respectively (p
tion]. These differences between the forms were less than 25% (for p <0.05); therefore both forms were bioequivalent. Capsule versus tablet: The time profile of mean plasma levels of rilmenidine obtained after capsule and tablet administration is shown in Figure 4. Statistical comparison of pharmacokinetic parameters did not show any significant difference between the capsule and tablet forms; the Wilcoxon test showed no differences between t,,, (1.63 f 0.21 and 1.38 f 0.13 hours after tablet and solution, respectively]. The relative bioavailability factor of capsule compared with tablet was 92.36 f 5.42% from plasma data and 101.26 f 15.41% from urinary data. The Westlake test applied to Cmax,AUC and A,cJ8) showed respective differences of 10.5,24.4 and 12.3%, in respect to the reference form (tablet). These differences between the forms were less than 25% (for p <0.05); therefore both forms were equivalent.
T I
FIGURE 3. Mean f standard error of the mean plasma concentrations of rilmenidine after single 1 mg oral dose (oral 0.02% solution and tablet) in healthy subjects (n = 12).
6
12
18
.
SOLUTION
0
TABLET
24
I 36
30 hours
n CAPSULE
FIGURE 4. Mean f standard error of the mean plasma concentrations of rilmenidine after single 1 mg oral dose (capsule and tablet) in healthy subjects (n = 16).
0 TABLET
5 2 d a
‘. 04
0
6
12
18
hours
24
52D
A SYMPOSIUM:
RILMENIDINE-A
NOVEL
ALPHA*
AGONIST
ANTIHYPERTENSIVE
0
WITH FOOD
.
WITHOUTFOOD
AGENT
FIGURE 5. Mean f standard error of the mean plasma concentrations of rilmenidine after single 1 mg oral dose (tablet) with and without food in healthy subjects (n = 12).
D
0
6
12
18
24
30
36 hours
TABLE II Pharmacokinetic Parameters of Rilmenidine Single Administration of 0.5, 1, 2 and 3 mg 0.5 mg
Cm.,(nwml-‘1 t,, (hours) V/F (liters) AUC (ng-houwml-‘) t’/s, z (hours) MRT (hours) CL/F (mkmin-‘)
1.40 2.00 443.35 14.28 7.74 11.64 725.91
f f f f f f f
0.18 0.34 57.35 3.58 1.06 1.46 87.87
in Healthy Subjects (n = 8) After Oral
1 mg 3.25 1.94 332.98 29.95 6.99 10.46 570.79
f f f f f f f
0.26 0.64 32.49 1.79 0.86 1.22 39.92
5.41 2.00 408.63 59.64 8.15 12.05 598.09
Values are expressed as mean f standard error of the mean. CL/F = apparent plasma clearance; V/F = apparent volume of distribution;
are summarized in Table II. The absorption of rilmenidine was rapid at all doses. The C,,, followed a significant linear relation within the 0.5 to 2 mg range and tmaxwas independent of the dose. Distribution was independent of the dose in the 0.5 to 2 mg dose range and was decreased at 3 mg. AUC followed a significant linear relation within the 0.5 to 2 mg range. At 3 mg, a slight deviation from linearity was observed. Elimination of rilmenidine was characterized by a terminal half-life of 7 to 8 hours and a mean residence time of 11 to 12 hours, both independent of the dose administered. Total apparent clearance was independent of the dose administered in the 0.5 to 2 mg range (600 to 700 ml-min-l] and reached 400 mlamin-l at 3 mg. Steady-state study: A graphic simulation corresponding to the theoretical profile of plasma concentrations during a repeated administration was drawn on the basis of concentrations obtained after single administration. Plasma concentrations actually found were juxtaposed with this simulation (Fig. 6). This simulation gave theoretical maximal and minimal concentrations at steady state. Statistical comparison of different plasma and urinary pharmacokinetic parameters
3 mg
2mg f f f f f f f
0.33 0.61 49.95 6.28 0.98 1.42 53.97
other abbreviations
10.79 1.75 262.95 130.00 7.69 11.35 397.34
f f f f f f f
0.94 0.40 19.14 9.23 0.43 0.54 26.05
as in Table I.
,obtained after single administration and at steady state revealed no significant difference. In accordance with terminal half-life of approximately 8 hours, plasma levels of rilmenidine reached steady state during the third day after repeated administration. Plasma concentrations [after the last tablet) at steady state gave values of C,,, and Cminof 4.44 f 0.30 ngml-l (range2.4 to 6.4 ngml-l] and 1.73 f 0.19 ngml-l [range-O.8 to 3.0 ngml-l), respectively. The observed accumulation ratio (RX= 1.48 f 0.08) was similar to the theoretical ratio (R1= 1.48 f 0.05). Half-lives found after single (7.63 f 0.78 hours) or repeated (7.10 f 0.58 hours] administration were in accordance.
Discussion The results of these studies in healthy subjects, after single and repeated administration, have allowed the determination of the main pharmacokinetic parameters of rilmenidine. From radiolabeled studies and bioavailability studies, rilmenidine was rapidly and extensively absorbed with a bioavailability factor close to 1. The relative bioavailability factors of various pharmaceutical forms were calculated, showing their bioequivalence. More-
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ng.ml-1
FIGURE 6. Mean plasma concentrations of rilmenidine after single 1 mg dose and repeated administration every 12 hours for 10 days. Theoretical simulation curve was extrapolated from data after the single administration. Plasma concentrations after repeated administration were drawn to give an appreciation of the correlation between the theoretical simulation curve and real plasma concentrations after repeated administration.
g4 5 F E3 Y s 4
s2
s 2 iI z ha
0
1
2
4
5
6
7
8
9
10
11
12
13
14
15
days
over, it was demonstrated that food intake had no significant effect on the bioavailability of rilmenidine, although absorption appeared delayed. The increasing t,,, and ttag time had no influence on the C,,, and AUC values. Distribution was characterized by a large volume of distribution reflecting the good tissular affinity of rilmenidine. The binding of rilmenidine on the human free fatty-acid serum albumin fraction (equilibrium dialysis) is approximately 7.5% and on the a1 glycoprotein acid approximately 3.5% (data not shown). Therefore, the large free fraction explains, at least partially, the large distribution. The weak involvement of protein binding minimizes the risk of pharmacokinetic interactions with other drugs, which are frequently coadministered with such antihypertensive agents. Elimination was characterized mainly by renal excretion of rilmenidine as the unchanged compound. The large free fraction and the value of the renal clearance indicate that rilmenidine undergoes not only a glomerular filtration but also an active secretion process far superior to that of an eventual reabsorption. However, owing to the pKa of this weak base (pKa = 91,it is likely that such a reabsorption is pH-dependent. Metabolism was poorly involved in the elimination process. This allows the assumption that no hepatic first-pass effect occurs after oral administration, as confirmed by the absolute bioavailability. The linearity of the pharmacokinetics was demonstrated within the 0.5 to 2 mg range after single dose administration. For the 3 mg dose, the significant differences observed were slight. The usual prescriptions of rilmenidine (1 mg once or twice daily] are in the range 0.5 to 2 mg and repeated administration in healthy subjects and long-term clinical studies (Beau et al., this issue, pages 95D-102Dj have never shown
any accumulation or modifications of the main pharmacokinetic parameters.
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