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Pharmacokinetic and pharmacodynamic characteristics of aranidipine sustained-release, enteric-coated tablets in healthy chinese men: A phase I, randomized, open-label, single- and multiple-dose study
Clinical Therapeutics/Volume 30, Number 7, 2008
Pharmacokinetic and Pharmacodynamic Characteristics of Aranidipine Sustained-Release, Enteric-Coated Tablets in Healthy Chinese Men: A Phase I, Randomized, Open-Label, Single- and Multiple-Dose Study Juanjuan Jiang, MS; Lei Tian, MS; Yiling Huang, BS; Yishi Li, MD; and Li Xu, MD The Key Laboratory of Clinical Trial Research on Cardiovascular Drugs, Fu Wai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China ABSTRACT Objective: The aim of this study was to explore the pharmacokinetic (PK) and pharmacodynamic (PD) properties and safety profiles of aranidipine and its active M-1 metabolite in healthy Chinese men. Methods: This Phase I, randomized, open-label, single- and multiple-dose study included healthy, nonsmoking male volunteers aged 18 to 45 years. In the single-dose study, subjects were randomly assigned to receive oral sustained-release, enteric-coated aranidipine tablets 5, 10, or 20 mg. In the multiple-dose study, volunteers who had been assigned to the aranidipine 10-mg group in the single-dose study received this dose for 7 days. In the single-dose study, blood samples for the PK analyses were obtained immediately before dosing and at regular intervals up to 36 hours after dosing. In the multiple-dose study, predose blood samples were collected on days 4 through 7; on the last day of treatment, blood samples were drawn at the same times as in the single-dose study. Plasma concentrations of aranidipine and M-1 were determined using a highperformance liquid chromatography method with tandem mass-spectrometric detection. For the PD analyses, blood pressure (BP) and heart rate were measured before dosing, at regular intervals up to 24 hours after dosing, and after the final dose during repeated administration. Tolerability was assessed throughout the study, based on adverse events, physical examinations, electrocardiography, vital signs, and laboratory tests. Results: The study enrolled 30 healthy Chinese men (mean [SD] age, 23 [2] years; mean body weight, 66 [7] kg; mean height, 174 [6] cm). In the single-dose study, the mean tl/2 for aranidipine 5, 10, and 20 mg was 3.0 (2.7), 2.7 (1.1), and 3.1 (2.2) hours, respectively; mean Tm~x was 4.9 (0.4), 4.4 (1.0), and 4.3 (0.9) hours; mean Cm~x was 1.1 (0.6), 2.4 (0.8), and 1290
4.0 (2.0) pg/L; and mean AUClast was 4.1 (1.4), 10.3 (2.3), and 20.9 (4.2) pg • h/L. There were no significant differences in any PK parameter between dose groups. For M-l, the corresponding values were 4.6 (1.0), 4.1 (0.5), and 4.1 (0.3) hours for tl/2; 5.6 (2.0), 5.0 (1.6), and 5.0 (0.8) hours for Tmax; 18.4 (0.6), 40.5 (10.0), and 39.2 (11.3) pg/L for Cm~x;and 143.5 (39.1), 304.5 (108.2), and 403.9 (73.5) pg • h/L for AUC~st. Only dose-normalized Cm~x and AUC~t differed significantly between dose groups (P < 0.001 and P = 0.018, respectively). After multiple doses, the mean values for tl/2, T . . . . C. . . . and AUC0_~ for aranidipine 10 mg were 2.3 (0.9) hours, 5.0 (1.2) hours, 3.1 (1.1) pg/L, and 13.8 (3.6) pg • h/L, respectively. Repeated oral administration of aranidipine 10 mg was associated with a significant increase in AUClast (P = 0.027). The corresponding values for M-1 were 4.8 (0.9) hours, 5.7 (1.3) hours, 40.0 (11.3) pg/L, and 381.8 (161.2) pg • h/L. There were no significant differences between dose groups in any PK parameter for M-1 after single or multiple doses. In the PD analyses, the mean change from baseline in diastolic BP was statistically significant in all groups (P < 0.01) except the aranidipine 10-mg group in the single-dose study. Three volunteers (10%) reported adverse events after administration of a single dose: headache (10-mg group), palpitations (20-mg group), and dizziness (20-mg group). The headache and palpitations were considered possibly related to study drug. Conclusions: The results of this small study in healthy Chinese men suggest that the PK properties of Accepted forpubfication April 22, 2008. doi:10.1016/j.clinthe ra.2008.07.014 0149-2918/$32.00 © 2008 Excerpta Medica Inc. All rights reserved.
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aranidipine were linear with respect to dose, whereas the PK properties of the active M-1 metabolite were not fully linear. There was no apparent accumulation of aranidipine or M-1 with administration of single and multiple doses. Aranidipine was generally well tolerated. (C/in Ther. 2008;30:1290-1299) © 2008 Excerpta Medica Inc. Key words: aranidipine, active metabolite, pharmacokinetics, pharmacodynamics.
INTRODUCTION Calcium channel blockers have been found to be effective and well tolerated in the treatment of essential hypertension. 1,2 Their mechanism of blood pressure (BP) reduction is direct dilatation of vascular smooth muscle, 3-5 which distinguishes them from other vasodilating agents (eg, hydralazine, minoxidil) that affect sodium and water retention. 5-8 Aranidipine (MPC-1304; [_+]-methyl-2-oxopropyl1,4-dihydro-2,6-dimethyl-4- [2-nitrophenyl]-3,5pyridinedicarboxylate) is a dihydropyridine-type calcium channel blocker used for the treatment of essential hypertension. 7 Unlike the metabolites of other dihydropyridines, aranidipine's major metabolite in humans, M- 1 ([_+]-methyl-2-hydroxopropyl- 1,4-dihydro-2,6dimethyl-4-[2-nitrophenyl]-3,5-pyridinedicarboxylate), also has vasodilatory and antihypertensive activity. 8,9 In fact, M-1 is thought to contribute to the antihypertensive effect of aranidipine. 8,9 Aranidipine has been reported to be effective in the treatment of hypertension in clinical studies. 7,1° However, few such studies have been published, and aranidipine is not approved for use in China. The present study was conducted to explore the pharmacokinetic (PK) and pharmacodynamic (PD) properties and safety profiles of aranidipine and M-1 in healthy Chinese men. SUBJECTS A N D M E T H O D S Inclusion and Exclusion Criteria Eligible volunteers were healthy nonsmoking men aged between 18 and 45 years who were within 15% of their ideal height/weight range and had a body mass index between 19 and 24 kg/m 2. They were required to have normal results on chest radiography and electrocardiography, normal BP (based on 2005 Chinese guidelines for the prevention and control of hypertension) and heart rate (HR), normal results on routine July 2008
laboratory tests (hematology, biochemistry, hepatic function, and urinalysis), and negative results on testing for HIV and hepatitis B and C virus. All routine laboratory tests were performed in the clinical laboratory of Fu Wai Hospital using an automated test system. Volunteers were excluded if they had any disease or disorder of the cardiac, hepatic, renal, respiratory, immune, or nervous system; had used prescription or over-the-counter medications, including herbal products, within 2 weeks before the start of the study; had donated blood or participated in another clinical trial within 3 months of study enrollment; had a history of alcohol or drug abuse; had clinically significant allergies to drugs or foods; had a sitting BP <100/ 60 mm Hg; or had a ventricular HR <60 beats/min at rest. All volunteers were required to abstain from drinking alcoholic beverages for at least i week before enrollment.
Study Design This was a Phase I, randomized, open-label, singleand multiple-dose study conducted at the Clinical Pharmacology Center, Fu Wai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College in Beijing, People's Republic of China. The study protocol and informed-consent form were approved by the ethics and research committees at Fu Wai Hospital. The study was conducted in accordance with the Declaration of Helsinki and its amendments 11 and the Guideline for Good Clinical Practice. 12 The purpose of the study, study procedures, and potential risks were described to the volunteers in nontechnical terms. Each volunteer provided written informed consent before any study-related procedure was conducted.
Single-Dose Study A computer-generated randomization scheme was used to assign eligible volunteers to receive single oral doses of sustained-release, enteric-coated aranidipine tablets 5, 10, or 20 mg. These doses were selected to encompass the anticipated therapeutic dose range. The volunteers were admitted to the Phase I ward of the Clinical Pharmacology Center on the day before drug administration. After a 10-hour overnight fast, they received a single oral dose at -8 AM with 200 mL of water. Standardized meals (consisting of 75 g rice, 50 g pork, 200 g vegetables, and 200 mL milk, supply1291
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ing -650 kcal) were provided at 4, 8, and 24 hours after the morning dose. Smoking and consumption of alcohol or caffeine-containing beverages were prohibited throughout the study. For the determination of plasma aranidipine and M-1 concentrations, venous blood samples (5 mL) were collected into heparinized tubes (Becton, Dickinson and Company, Franklin Lakes, New Jersey) before dosing and at 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 32, and 36 hours after administration of study drug from an indwelling catheter (0.7-mm internal diameter x 19-mm long) inserted into a forearm vein. Plasma was separated by centrifugation at 2500g for 10 minutes at 4°C and stored at -20°C until analyzed. Samples were collected and processed under conditions of minimal light exposure.
Multiple-Dose Study Volunteers who had been assigned to the aranidipine 10-mg group in the single-dose study continued to receive this dose for 7 days. This dose was chosen for the multiple-dose study because it is likely to be the most commonly used dose in clinical practice. Volunteers were confined to the clinic for the duration of the study. Blood samples were collected before dosing on days 4, 5, 6, and 7. On the last day of treatment, blood samples were drawn at the same times as in the single-dose study. All other experimental conditions were the same as in the single-dose study.
Pharmacokinetic Assessments Plasma concentrations of aranidipine and M-1 were determined using a high-performance liquid chromatography method (Agilent 1100, Agilent Technologies, Wilmington, Delaware) with tandem mass-spectrometric detection that had been validated in our laboratory. 13 Briefly, aranidipine and M-1 were extracted from plasma samples by liquid-liquid extraction and separated on a C18 column (150 mm x 3.9 mm, 5 lam; Waters Corporation, Milford, Massachusetts) using acetonitrile-water (65:35 v/v) as the mobile phase. The column temperature was maintained at 35°C. Detection was performed on a triple-quadrupole tandem mass spectrometer (API 3200 Q TRAP, Applied Biosystems/MDS Sciex, Concord, Ontario, Canada) in multiple reactions monitoring mode via TurboIonSpray ionization. Linear calibration curves were obtained in the concentration range from 0.02 to 10 ng/mL for aranidipine and 0.2 to 100 ng/mL for 1292
M-l, with lower limits of quantitation of 0.02 and 0.2 ng/mL, respectively. Intraday and interday precision (percent coefficient of variation) were within 10% for aranidipine and 15% for M-1. The PK parameters of aranidipine and M-1 were estimated by noncompartmental methods using WinNonlin version 4.1 (Pharsight Corporation, Mountain View, California). Cmax and Tma x w e r e estimated directly from observed plasma concentration-time data. The AUC from time 0 to the last available measurement (AUC~ast) was calculated using the linear trapezoidal rule. The AUC from time 0 to infinity (AUC0~) was calculated using the following formula: AUC0_~ = AUClast + Ct/ke, where Ct is the last measured plasma concentration and k e is the elimination rate constant, determined using linear regression analysis of the linear portion of the log plasma concentration-time curve. The apparent terminal elimination half-life (tl/2) was calculated using the formula tl/2 = ln2/k e. The systemic clearance (CL) of aranidipine and M-1 was calculated as CL = dose/AUC0_~, and the volume of distribution (Vd) was based on the terminal elimination phase as follows: Vd = dose/(k x AUC0_~). For the multiple-dose portion of the study, the average plasma concentration was calculated as AUC0_24/24. Other PK parameters were the AUC0_24 at steady state (AUCs~) and the ratio of the AUG0_24in the single-dose study to the AUC~ (Re) in the same volunteer.
Pharmacodynamic Assessments Systolic and diastolic BP (SBP and DBP, respectively) and HR were measured before and at 2, 4, 8, 12, and 24 hours after administration of single doses and the last dose during repeated administration. Measurements were obtained after the volunteers had rested in a supine position for at least 10 minutes. Duplicate BP measurements were obtained 5 minutes apart in the left arm using an electronic device (Omron HEM-746C, Omron Corporation, Dalian, China), and the mean of the 2 measurements was recorded. Tolerability Assessments Adverse events (AEs) were monitored throughout the study based on spontaneous reports by volunteers, questioning by investigators, physical examinations, electrocardiograms, vital signs, and routine laboratory tests. AEs were classified according to their intensity (mild, moderate, or severe), and their duration, outcome, and relationship to study drug (related, not reVolume 30 Number 7
J. Jiang et al. lated, or possibly related) were recorded. Volunteers were observed closely until resolution of AEs. Physical examinations and routine laboratory tests (ie, clinical chemistry, hematology, and urinalysis) were performed before and 24 hours after administration of study drug. Electrocardiography was performed before and 2 and 24 hours after administration of study drug. Volunteers were instructed to return to the clinic for a safety evaluation (physical examination, vital signs) 1 week after the final blood sample was collected.
Statistical Analysis The number of subjects per group met the guidelines for Phase I clinical trials issued by the State Food and Drug Administration (SFDA) of the People's Republic of China. Therefore, no power analysis was performed for the purposes of calculating the sample size. All analyses were performed according to the SFDA guidelines. All volunteers who received study drug were included in the PK/PD assessments. Analysis of variance (ANOVA) with dose-normalized values was used to evaluate the dose linearity of Cm~x and AUC for aranidipine and M-1. ANOVA was also used to evaluate any differences in tl/2 between dose groups. The resuits for Tm~x were evaluated using Wilcoxon rank sum analysis. For the PD assessments, interdose comparisons of the change from baseline in each variable were performed using ANOVA with adjustment for multiple comparisons; repeated-measures ANOVA and paired t tests were used for comparisons of the PD data within volunteers and between dose groups. The relationship between individual PK parameters (AUC, C . . . . and tl/2 for aranidipine and M-l) and individual maximum changes in PD parameters was assessed by linear correlation analysis. P < 0.05 was considered statistically significant. All analyses were performed using SAS version 8.2 (SAS Institute Inc., Cary, North Carolina).
RESULTS Study Population Thirty healthy Chinese men (mean [SD] age, 23 [2] years [range, 19-27 years[; mean body weight, 66 [7] kg [range, 57-75 kg]; mean height, 174 [6] cm [range, 165-182 cm]) were enrolled in and completed the study. There were no significant differences in baseline characteristics between dose groups.
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Pharmacokinetic Properties The plasma concentration-time profiles of aranidipine and M-1 at the doses studied in the single- and multiple-dose studies are depicted in Figure 1.
Single-Dose Study In the single-dose study, the mean (SD) tl/2 for aranidipine 5, 10, and 20 mg was 3.0 (2.7), 2.7 (1.1), and 3.1 (2.2) hours, respectively; the mean Tmax was 4.9 (0.4), 4.4 (1.0), and 4.3 (0.9) hours; the mean Cmax was 1.1 (0.6), 2.4 (0.8), and 4.0 (2.0) pg/L; and the mean AUClast was 4.1 (1.4), 10.3 (2.3), and 20.9 (4.2) pg • h/L (Table I). There were no statistically significant differences in aranidipine Tmax or tl/2 over the dose range studied. Results of ANOVA indicated no difference between groups in terms of the dosenormalized AUC or Cm~x of aranidipine. There was 1.8- to 3.1-fold variation in individual aranidipine AUC values and 3.0- to 7.8-fold variation in individual aranidipine Cm~x values. For M-l, the mean (SD) tl/2 for the 5-, 10-, and 20-mg doses was 4.6 (1.0), 4.1 (0.5), and 4.1 (0.3) hours, respectively; the mean Tmax was 5.6 (2.0), 5.0 (1.6), and 5.0 (0.8) hours; the mean Cmax was 18.4 (0.6), 40.5 (10.0), and 39.2 (11.3) pg/L; and the mean AUClast was 143.5 (39.1), 304.5 (108.2), and 403.9 (73.5) pg • h/L (Table I). There was no significant difference in the Tmax and tl/2 between dose groups. Results of ANOVA indicated a significant difference in dose-normalized Cm~x and AUClast for M-1 (P < 0.001 and P = 0.018, respectively). Pairwise comparisons of the degree of nonlinearity for each dose level suggested that the 20-mg dose was associated with the greatest nonlinearity. Between volunteers in the individual dose groups, there was 1.7- to 3.0-fold variation in AUC values for M-1 and 2.1- to 3.6-fold variation in Cmax values.
Multiple-Dose Study In the multiple-dose study, the mean tl/2, T . . . . C . . . . and AUC0_~ for aranidipine 10 mg were 2.3 (0.9) hours, 5.0 (1.2) hours, 3.1 (1.1) pg/L, and 13.8 (3.6) pg • h/L, respectively (Table II). There were no significant changes relative to the single-dose study in tl/2, Tmax, or Cmax; however, there was a statistically significant increase in AUC0~ (P = 0.027). For M-l, the mean values for tl/2, T . . . . C . . . . and AUC0_~ were 4.8 (0.9) hours, 5.7 (1.3) hours, 40.0 (11.3) pg/L, and 381.8 (161.2) pg • h/L. There were no significant
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-O- Single S-mg dose (n = 10) -~- Single 10-mg dose (n = 10) -dk- Single 20-mg dose (n = 10) -0- Multiple 10-mgdoses (n = 10)
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Figure 1. Mean (SD) plasma concentrations of(A) aranidipine and (B) its active M-1 metabolite before and after oral administration of single and multiple doses ofaranidipine.
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Table I. Pharmacokinetic properties of aranidipine and its active M-1 metabolite in 30 healthy volunteers
after administration of single oral doses. Values are mean (SD). Aranidipine
M-1
Parameter
5 mg (n = 10)
10 mg (n = 10)
20 mg (n = 10)
5 mg (n = 10)
10 mg (n = 10)
20 mg (n = 10)
[1/2, h
3.0 (2.7)
2.7 (1.1)
3.1 (2.2)
4.6 (1.0)
4.1 (0.5)
4.1 (0.3)
Tm~x, h
4.9 (0.4)
4.4 (I .0)
4.3 (0.9)
5.6 (2.0)
5.0 (1.6)
5.0 (0.8)
CL, L/h x 103
1.3 (0.6)
1.0 (0.2)
1.0 (0.2)
37.0 (11.2)*
36.3 (12.3)*
50.7 (9.3)*
Cmax
Unadjusted, IJg/L Dose-adjusted, ng/mL per mg/kg
1.1 (0.6)
2.4 (0.8)
4.0 (2.0)
18.4 (0.6)*
40.5 (10.0)*
39.2 (11.3)*
14.2 (7.2)
15.4 (6.2)
13.5 (7.1)
233.7 (84.0)*
257.1 (63.9)*
127.3 (39.6)*
AUClast Unadjusted, lag" h/L Dose-adjusted, ng. h/mE per mg/kg
4.1 (1.4) 52.3 (16.9)
10.3 (2.3) 64.6 (11.4)
20.9 (4.2) 70.1 (18.9)
143.5 (39.1)* 1826.4 (532.7)*
304.5 (108.2)* 1899.7 (552.4)*
403.9 (73.5)* 1306.1 (288.8)*
4.3 (1.4) 54.8 (16.6)
10.5 (2.4) 66.1 (11.9)
21.4 (4.3) 71.8 (19.5)
145.2 (39.3) 1848.7* (537.3)*
306.9 (109.5) 1914.5* (559.2)*
406.2 (73.9) 1313.8* (291.0)*
AUC0
Unadjusted, , g .
h/L Dose-adjusted, ng. h/mL per mg/kg
tl/2 = apparent terminal elimination half-life; CL = systemic clearance; AUClast = AUC From time 0 to the last available
measurement; AUC 0 ~ = AUC From time 0 to infinity. *P < 0.05 between dose groups.
Table II. Pharmacokinetic properties of aranidipine and its active M-1 metabolite in 10 healthy volunteers after administration of single and multiple doses ofaranidipine 10 rag. Values are mean (SD). Aranidipine
Parameter
tl/2, h T~ax, h CL, L/h x 103 C ......pg/L AUC 0 ~, lag" h/L R c
Single l0-mg Dose (n= 10)
2.7 (1.1) 4.4 (1.0) 1.0 (0.2) 2.4 (0.8) 10.5 (2.4)
M-1
Multiple l0-mg Doses (n= 10)
2.3 5.0 0.8 3.1 13.8 1.4
(0.9) (1.2) (0.2)* (I.I) (3.6)* (0.3)
Single l0-mg Dose (n=10)
4.1 5.0 36.3 40.5 307.1
(0.5) (1.6) (12.3) (I0.0) (110.2)
Multiple 10-mg Doses (n = 10)
4.8 5.7 29.9 40.0 381.8 1.3
(0.9) (1.3) (10.6) (11.3) (161.2) (0.3)
q/2 = apparent terminal elimination halglife; CL = systemic clearance; AUC 0 ~ = AUC From time 0 to infinity; Rac = ratio oFthe AUC 0 24 From the single-dose study to the AUC at steady state. *P < 0.05 versus single-dose study.
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changes in these parameters compared with the singledose study.
Pharmacodynamic Properties After administration of single aranidipine doses, a decrease in BP was observed in 27 of the 30 volunteers (90%), and an increase in HR was observed in 28 volunteers (93%). The changes in HR, SBP, and DBP are depicted in Figure 2. With both single and multiple doses of aranidipine, the mean (SD) change from baseline in HR ranged from 0.3 (3.2) to 4.3 (6.8) beats/min (P = NS vs baseline) (Table III). Among all volunteers, the maximum change in HR was 16 beats/min; 14 volunteers had a maximum increase of >10 beats/min. The mean change from baseline in SBP ranged from -0.7 to -4.7 mm Hg (P = NS vs baseline). The maximum decrease in SBP was 21 mm Hg; 15 volunteers had a maximum decrease of >10 mm Hg. The mean change from baseline in DBP ranged from 0.9 to -6.6 mm Hg; the changes from baseline were statistically significant in all groups (P < 0.01) except the aranidipine 10-mg group in the single-dose study. The maximum decrease in DBP was 18 mm Hg; 12 volunteers had a decrease of >10 mm Hg. No relationship was found between dose and the mean change in BP or HR, or between individual PK parameters (AUC, C . . . . and tl/2 of aranidipine and M-l) and individual changes in BP and HR.
Tolerability In the single- and multiple-dose studies combined, 1 volunteer in the 10-mg group reported mild headache 5 hours after dosing that resolved without intervention within 19 hours of its onset. One volunteer in the 20-mg group reported palpitations 5 hours after dosing, and another volunteer complained of dizziness 3 hours after dosing. Both of these AEs were considered mild and resolved without intervention within 3 and 9 hours of onset, respectively, with no residual effects. The headache and palpitations were considered by the investigator to be possibly related to study drug. Vital signs and electrocardiographic findings were within normal ranges throughout the study. No volunteers were withdrawn from the study because of AEs. No abnormalities in physical, biochemical, hematologic, or urinalysis variables that were considered clinically meaningful occurred during the study. 1296
DISCUSSION In 28 of the volunteers, AUClast accounted for >95% of the total AUC0_~ for both aranidipine and M-l, indicating that the plasma concentration-time profile had been well characterized. In the remaining 2 volunteers, in whom the tl/2 was particularly long, AUClast accounted for 88% of the total aranidipine AUC0~. Cmax and Tmax were determined based on both the rate of absorption and the rate of elimination. Given that the aranidipine Tmax and dose-normalized Cm~x were similar in the 3 groups in the single-dose study, the rate and extent of absorption of aranidipine did not appear to be affected by higher doses, suggesting that there was no saturation in aranidipine absorption. The ratio of the Cm~x of M-1 to that of aranidipine was >10 and the ratio of the AUC of M-1 to that of aranidipine was >20, indicating a first-pass effect after oral administration. The departure from linearity of M-1 at the 20-mg dose may be explained by the metabolite saturation of aranidipine. After administration of single doses, the mean Tmax of M-1 occurred -0.7 hour later than that of the parent compound. Individual Tmax values for M-1 varied from 1 hour earlier relative to aranidipine in 2 volunteers to 5 hours later in 1 volunteer. The Tmax for aranidipine and M-1 was identical in 12 volunteers; in another 8 volunteers, the Tmax of M-1 occurred 1 hour later that that of aranidipine. The results of the PK analyses of single and multiple oral doses of aranidipine indicated a mean (SD) R~c of 1.4 (0.3) for the 10-mg dose, which was inconsistent with the accumulation factor of -1.0 derived from the dosing interval and tl/2. This discrepancy may be explained by an alteration in the extent of absorption (bioavailability) or by a first-pass effect on the rate of absorption or CL after administration of multiple doses. Two peaks in the concentration-time profile of aranidipine and M-1 were observed in 16 and 10 volunteers, respectively. The first peak occurred 4 to 5 hours after dosing, and the second occurred 8 to 12 hours after dosing. Hepatoenteral circulation may have been responsible for this finding. Although the maximum mean change in HR differed significantly from baseline (P < 0.01) (Table III), the mean changes from baseline were not statistically significant between dose groups. The time of the maximum decreases in SBP and DBP ranged from 2 to 12 hours after dosing. Analysis of BP changes in individual volunteers indicated significant decreases in the Volume 30 Number 7
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-@- Single 5-mg dose (n = 10) -D- Single 10-mg dose (n = 10) Single 20-mg dose (n = 10) -O- Multiple 10-mg doses (n = 10)
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Time (h) Figure 2. Mean (SD) values for (A) heart rate, (B) systolic blood pressure (SBP), and (C) diastolic blood pressure (DBP) before and after oral administration o f single and multiple doses ofaranidipine.
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Table III. Pharmacodynamic properties ofaranidipine in healthy volunteers in the single- and multiple-dose studies. Values are mean (SD). Single Dose
Parameter
5 mg (n= 10)
10 mg (n= 10)
20 mg (n=10)
Heart rate, beats/min Baseline Maximum mean change Mean change
57.7 (4.4) 5.6 (2.1)* 1.8 (2.7)
58.7 (5.0) 5.3 (6.8)* 1.9 (4.6)
57.1 (7.0) 9.8 (6.1)* 4.3 (6.8)
59.0 (5.1) 5.1 (6.7)* 0.3 (3.2)
108.7 (7.6) -7.6 (6.0)* -4.7 (7.2)
106.6 (9.6) -3.0 (8.08) -1.6 (4.3)
10Z2 (12.0) -3.0 (5.3) -0.7 (5.9)
64.1 (5.6) -1.8 (5.9) 0.9 (4.7)
71.3 (4.9) -7.8 (6.3)* -6.6 (2.9)*
6Z5 (4.6) -5.9 (4.5)* -3.1 (2.1)*
Systolic blood pressure, mm Hg Baseline Maximum mean change Mean change Diastolic blood pressure, mm Hg Baseline Maximum mean change Mean change
109.7 (5.5) -4.3 (Z1) -2.7 (5.0) 69.7 (4.0) -6.9 (6.3)* -4.8 (4.2)*
Multiple 10-mg Doses (n= 10)
< 0.01 versus baseline. fP < 0.05 versus baseline.
*P
mean change in BP at 2, 4, and 12 hours after dosing (P < 0.05) and significant decreases in HR from 4 to 12 hours after administration (P < 0.05). Aranidipine was generally well tolerated. No serious AEs or deaths were reported during the study. Given that the C. . . . T . . . . and AUC in volunteers who experienced AEs were similar to the mean value for their dose groups, there was no apparent direct relationship between PK values and the incidence of AEs. There were no clinically meaningful changes from baseline to the final assessment in vital signs, serum biochemistry or hematology variables, electrocardiographic parameters, or findings on physical examination. This study had several limitations. First, because there were no published reports on the tolerability of aranidipine in Chinese men, a single- and multipledose design was used rather than a crossover design. Thus, it was not possible to apply a linear mixedeffects model, which would have been more appropriate and accurate for assessing dose proportionality. 14 Instead, ANOVA of the dose-normalized Cmax and AUC was used to evaluate the linearity of aranidipine and M-1 over the dose range studied. Second, this
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study was performed in healthy volunteers, which limits the generalizability of the results to other populations. Third, because of the possible bias introduced by the absence of a placebo group, the results for the PK/PD relationship may not be sufficiently reliable. Finally, the sample size was small and the power of the study may not have been adequate. CONCLUSIONS
The results of this small study in healthy Chinese men suggest that the PK properties of aranidipine were linear with respect to dose, whereas the active M-1 metabolite was not fully linear with respect to dose. The PK analyses of single and multiple oral doses indicated no apparent accumulation of aranidipine or M-1 with the 10-mg dose. No significant difference between dose groups was observed with respect to mean changes from baseline in BP and HR. Aranidipine appeared to be well tolerated in the population studied. ACKNOWLEDGM ENT
The authors thank the nurses in Ward IV, Fu Wai Hospital, Beijing, for their medical and nursing support.
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J. Jiang et REFERENCES 1. Epstein BJ, Vogel K, Palmer BF. Dihydropyridine calcium channel antagonists in the management of hypertension. Drugs. 2007;67:13091327. 2. Weber MA. Calcium channel antagonists in the treatment of hypertension. AmJ CardiovascDrugs. 2002; 2:415-43 I. 3. Grossman E, Messerli FH. Calcium antagonists. Prog Cardiovasc Dis. 2004;47:34-57. 4. Van Zwieten PA, Pfaffendorf M. Similarities and differences between calcium antagonists: Pharmacological aspects. J Hypertens Suppl. 1993; 11:$3-$11. 5. Struyker-Boudier HA, Smits JF, De Mey JG. The pharmacology of calcium antagonists: A review.J Cardiovasc PharmacoL 1990;15(SuppI 4): $1-$10. 6. Leonetti G. The effects of calcium antagonists on electrolytes and water balance in hypertensive patients. J CardiovascPharmacol. 1994;24(Suppl A):$25-$29. 7. Ohashi K, Ebihara A. Aranidipine (MPC-1304): A new dihydropyridine calcium antagonist: A review of its antihypertensive action. CardiovascDrug Rev. 1996; 14: I - I 6. 8. Ichihara K, Okumura K, Kamei H, et al. Renal effects of the calcium channel blocker aranidipine and its active metabolite in anesthetized dogs and conscious spontaneously hypertensive rats. J Cardiovasc Pkarmacol. 1998;31:277-285. 9. Miyoshi K, Miyake H, Ichihara K, et al. Contribution of aranidipine metabolites with slow binding kinetics to the vasodilating activity of aranidipine. Naunyn Schmiedebergs Arch Pharmacol. 1997;355:119-125. 10. ShimosawaT, Ando K, Takahashi K. Effect of aranidipine, a long-acting Ca antagonist, on circadian variation of blood pressure in essential hypertension patients [in Japanese]. J Clin Ther Med. 2001;17:13071313.
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11. World Medical Association Declaration of Helsinki. Ethical Principles for Medical Research Involving Human Subjects. As amended by the 52nd WMA General Assembly; Edinburgh, Scotland; October 2000. 12. European Medicines Agency. ICH Topic E 6 (RI). Guideline for Good Clinical Practice [EMEA Web Site]. http://www.emea.eu ropa.eu/pd fs/ human/ich/O13595en.pdf. Accessed May 28, 2008.
al.
13. Tian L, JiangJ, HuangY, et al. Determination of aranidipine and its active metabolite in human plasma by liquid chromatography/negative electrospray ionization tandem mass spectrometry. Rapid Commun Mass Spectrom. 2006;20:2871-2877. 14. Smith BP, Vandenhende FR, DeSante KA, et al. Confidence interval criteria for assessment of dose proportionality. Pharm Res. 2000;17: 1278-1 283.
Address correspondence to: Prof. Li Yishi, Clinical Pharmacology Center,
Fu Wai Hospital, 167 Beilishi Road, Beijing 100037, People's Republic of China. E-maih [email protected] 1299
Pharmacokinetic and Pharmacodynamic Characteristics of Aranidipine Sustained-Release, Enteric-Coated Tablets in Healthy Chinese Men: A Phase I, Randomized, Open-Label, Single- and Multiple-Dose Study Juanjuan Jiang, MS; Lei Tian, MS; Yiling Huang, BS; Yishi Li, MD; and Li Xu, MD The Key Laboratory of Clinical Trial Research on Cardiovascular Drugs, Fu Wai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China ABSTRACT Objective: The aim of this study was to explore the pharmacokinetic (PK) and pharmacodynamic (PD) properties and safety profiles of aranidipine and its active M-1 metabolite in healthy Chinese men. Methods: This Phase I, randomized, open-label, single- and multiple-dose study included healthy, nonsmoking male volunteers aged 18 to 45 years. In the single-dose study, subjects were randomly assigned to receive oral sustained-release, enteric-coated aranidipine tablets 5, 10, or 20 mg. In the multiple-dose study, volunteers who had been assigned to the aranidipine 10-mg group in the single-dose study received this dose for 7 days. In the single-dose study, blood samples for the PK analyses were obtained immediately before dosing and at regular intervals up to 36 hours after dosing. In the multiple-dose study, predose blood samples were collected on days 4 through 7; on the last day of treatment, blood samples were drawn at the same times as in the single-dose study. Plasma concentrations of aranidipine and M-1 were determined using a highperformance liquid chromatography method with tandem mass-spectrometric detection. For the PD analyses, blood pressure (BP) and heart rate were measured before dosing, at regular intervals up to 24 hours after dosing, and after the final dose during repeated administration. Tolerability was assessed throughout the study, based on adverse events, physical examinations, electrocardiography, vital signs, and laboratory tests. Results: The study enrolled 30 healthy Chinese men (mean [SD] age, 23 [2] years; mean body weight, 66 [7] kg; mean height, 174 [6] cm). In the single-dose study, the mean tl/2 for aranidipine 5, 10, and 20 mg was 3.0 (2.7), 2.7 (1.1), and 3.1 (2.2) hours, respectively; mean Tm~x was 4.9 (0.4), 4.4 (1.0), and 4.3 (0.9) hours; mean Cm~x was 1.1 (0.6), 2.4 (0.8), and 1290
4.0 (2.0) pg/L; and mean AUClast was 4.1 (1.4), 10.3 (2.3), and 20.9 (4.2) pg • h/L. There were no significant differences in any PK parameter between dose groups. For M-l, the corresponding values were 4.6 (1.0), 4.1 (0.5), and 4.1 (0.3) hours for tl/2; 5.6 (2.0), 5.0 (1.6), and 5.0 (0.8) hours for Tmax; 18.4 (0.6), 40.5 (10.0), and 39.2 (11.3) pg/L for Cm~x;and 143.5 (39.1), 304.5 (108.2), and 403.9 (73.5) pg • h/L for AUC~st. Only dose-normalized Cm~x and AUC~t differed significantly between dose groups (P < 0.001 and P = 0.018, respectively). After multiple doses, the mean values for tl/2, T . . . . C. . . . and AUC0_~ for aranidipine 10 mg were 2.3 (0.9) hours, 5.0 (1.2) hours, 3.1 (1.1) pg/L, and 13.8 (3.6) pg • h/L, respectively. Repeated oral administration of aranidipine 10 mg was associated with a significant increase in AUClast (P = 0.027). The corresponding values for M-1 were 4.8 (0.9) hours, 5.7 (1.3) hours, 40.0 (11.3) pg/L, and 381.8 (161.2) pg • h/L. There were no significant differences between dose groups in any PK parameter for M-1 after single or multiple doses. In the PD analyses, the mean change from baseline in diastolic BP was statistically significant in all groups (P < 0.01) except the aranidipine 10-mg group in the single-dose study. Three volunteers (10%) reported adverse events after administration of a single dose: headache (10-mg group), palpitations (20-mg group), and dizziness (20-mg group). The headache and palpitations were considered possibly related to study drug. Conclusions: The results of this small study in healthy Chinese men suggest that the PK properties of Accepted forpubfication April 22, 2008. doi:10.1016/j.clinthe ra.2008.07.014 0149-2918/$32.00 © 2008 Excerpta Medica Inc. All rights reserved.
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aranidipine were linear with respect to dose, whereas the PK properties of the active M-1 metabolite were not fully linear. There was no apparent accumulation of aranidipine or M-1 with administration of single and multiple doses. Aranidipine was generally well tolerated. (C/in Ther. 2008;30:1290-1299) © 2008 Excerpta Medica Inc. Key words: aranidipine, active metabolite, pharmacokinetics, pharmacodynamics.
INTRODUCTION Calcium channel blockers have been found to be effective and well tolerated in the treatment of essential hypertension. 1,2 Their mechanism of blood pressure (BP) reduction is direct dilatation of vascular smooth muscle, 3-5 which distinguishes them from other vasodilating agents (eg, hydralazine, minoxidil) that affect sodium and water retention. 5-8 Aranidipine (MPC-1304; [_+]-methyl-2-oxopropyl1,4-dihydro-2,6-dimethyl-4- [2-nitrophenyl]-3,5pyridinedicarboxylate) is a dihydropyridine-type calcium channel blocker used for the treatment of essential hypertension. 7 Unlike the metabolites of other dihydropyridines, aranidipine's major metabolite in humans, M- 1 ([_+]-methyl-2-hydroxopropyl- 1,4-dihydro-2,6dimethyl-4-[2-nitrophenyl]-3,5-pyridinedicarboxylate), also has vasodilatory and antihypertensive activity. 8,9 In fact, M-1 is thought to contribute to the antihypertensive effect of aranidipine. 8,9 Aranidipine has been reported to be effective in the treatment of hypertension in clinical studies. 7,1° However, few such studies have been published, and aranidipine is not approved for use in China. The present study was conducted to explore the pharmacokinetic (PK) and pharmacodynamic (PD) properties and safety profiles of aranidipine and M-1 in healthy Chinese men. SUBJECTS A N D M E T H O D S Inclusion and Exclusion Criteria Eligible volunteers were healthy nonsmoking men aged between 18 and 45 years who were within 15% of their ideal height/weight range and had a body mass index between 19 and 24 kg/m 2. They were required to have normal results on chest radiography and electrocardiography, normal BP (based on 2005 Chinese guidelines for the prevention and control of hypertension) and heart rate (HR), normal results on routine July 2008
laboratory tests (hematology, biochemistry, hepatic function, and urinalysis), and negative results on testing for HIV and hepatitis B and C virus. All routine laboratory tests were performed in the clinical laboratory of Fu Wai Hospital using an automated test system. Volunteers were excluded if they had any disease or disorder of the cardiac, hepatic, renal, respiratory, immune, or nervous system; had used prescription or over-the-counter medications, including herbal products, within 2 weeks before the start of the study; had donated blood or participated in another clinical trial within 3 months of study enrollment; had a history of alcohol or drug abuse; had clinically significant allergies to drugs or foods; had a sitting BP <100/ 60 mm Hg; or had a ventricular HR <60 beats/min at rest. All volunteers were required to abstain from drinking alcoholic beverages for at least i week before enrollment.
Study Design This was a Phase I, randomized, open-label, singleand multiple-dose study conducted at the Clinical Pharmacology Center, Fu Wai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College in Beijing, People's Republic of China. The study protocol and informed-consent form were approved by the ethics and research committees at Fu Wai Hospital. The study was conducted in accordance with the Declaration of Helsinki and its amendments 11 and the Guideline for Good Clinical Practice. 12 The purpose of the study, study procedures, and potential risks were described to the volunteers in nontechnical terms. Each volunteer provided written informed consent before any study-related procedure was conducted.
Single-Dose Study A computer-generated randomization scheme was used to assign eligible volunteers to receive single oral doses of sustained-release, enteric-coated aranidipine tablets 5, 10, or 20 mg. These doses were selected to encompass the anticipated therapeutic dose range. The volunteers were admitted to the Phase I ward of the Clinical Pharmacology Center on the day before drug administration. After a 10-hour overnight fast, they received a single oral dose at -8 AM with 200 mL of water. Standardized meals (consisting of 75 g rice, 50 g pork, 200 g vegetables, and 200 mL milk, supply1291
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ing -650 kcal) were provided at 4, 8, and 24 hours after the morning dose. Smoking and consumption of alcohol or caffeine-containing beverages were prohibited throughout the study. For the determination of plasma aranidipine and M-1 concentrations, venous blood samples (5 mL) were collected into heparinized tubes (Becton, Dickinson and Company, Franklin Lakes, New Jersey) before dosing and at 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 32, and 36 hours after administration of study drug from an indwelling catheter (0.7-mm internal diameter x 19-mm long) inserted into a forearm vein. Plasma was separated by centrifugation at 2500g for 10 minutes at 4°C and stored at -20°C until analyzed. Samples were collected and processed under conditions of minimal light exposure.
Multiple-Dose Study Volunteers who had been assigned to the aranidipine 10-mg group in the single-dose study continued to receive this dose for 7 days. This dose was chosen for the multiple-dose study because it is likely to be the most commonly used dose in clinical practice. Volunteers were confined to the clinic for the duration of the study. Blood samples were collected before dosing on days 4, 5, 6, and 7. On the last day of treatment, blood samples were drawn at the same times as in the single-dose study. All other experimental conditions were the same as in the single-dose study.
Pharmacokinetic Assessments Plasma concentrations of aranidipine and M-1 were determined using a high-performance liquid chromatography method (Agilent 1100, Agilent Technologies, Wilmington, Delaware) with tandem mass-spectrometric detection that had been validated in our laboratory. 13 Briefly, aranidipine and M-1 were extracted from plasma samples by liquid-liquid extraction and separated on a C18 column (150 mm x 3.9 mm, 5 lam; Waters Corporation, Milford, Massachusetts) using acetonitrile-water (65:35 v/v) as the mobile phase. The column temperature was maintained at 35°C. Detection was performed on a triple-quadrupole tandem mass spectrometer (API 3200 Q TRAP, Applied Biosystems/MDS Sciex, Concord, Ontario, Canada) in multiple reactions monitoring mode via TurboIonSpray ionization. Linear calibration curves were obtained in the concentration range from 0.02 to 10 ng/mL for aranidipine and 0.2 to 100 ng/mL for 1292
M-l, with lower limits of quantitation of 0.02 and 0.2 ng/mL, respectively. Intraday and interday precision (percent coefficient of variation) were within 10% for aranidipine and 15% for M-1. The PK parameters of aranidipine and M-1 were estimated by noncompartmental methods using WinNonlin version 4.1 (Pharsight Corporation, Mountain View, California). Cmax and Tma x w e r e estimated directly from observed plasma concentration-time data. The AUC from time 0 to the last available measurement (AUC~ast) was calculated using the linear trapezoidal rule. The AUC from time 0 to infinity (AUC0~) was calculated using the following formula: AUC0_~ = AUClast + Ct/ke, where Ct is the last measured plasma concentration and k e is the elimination rate constant, determined using linear regression analysis of the linear portion of the log plasma concentration-time curve. The apparent terminal elimination half-life (tl/2) was calculated using the formula tl/2 = ln2/k e. The systemic clearance (CL) of aranidipine and M-1 was calculated as CL = dose/AUC0_~, and the volume of distribution (Vd) was based on the terminal elimination phase as follows: Vd = dose/(k x AUC0_~). For the multiple-dose portion of the study, the average plasma concentration was calculated as AUC0_24/24. Other PK parameters were the AUC0_24 at steady state (AUCs~) and the ratio of the AUG0_24in the single-dose study to the AUC~ (Re) in the same volunteer.
Pharmacodynamic Assessments Systolic and diastolic BP (SBP and DBP, respectively) and HR were measured before and at 2, 4, 8, 12, and 24 hours after administration of single doses and the last dose during repeated administration. Measurements were obtained after the volunteers had rested in a supine position for at least 10 minutes. Duplicate BP measurements were obtained 5 minutes apart in the left arm using an electronic device (Omron HEM-746C, Omron Corporation, Dalian, China), and the mean of the 2 measurements was recorded. Tolerability Assessments Adverse events (AEs) were monitored throughout the study based on spontaneous reports by volunteers, questioning by investigators, physical examinations, electrocardiograms, vital signs, and routine laboratory tests. AEs were classified according to their intensity (mild, moderate, or severe), and their duration, outcome, and relationship to study drug (related, not reVolume 30 Number 7
J. Jiang et al. lated, or possibly related) were recorded. Volunteers were observed closely until resolution of AEs. Physical examinations and routine laboratory tests (ie, clinical chemistry, hematology, and urinalysis) were performed before and 24 hours after administration of study drug. Electrocardiography was performed before and 2 and 24 hours after administration of study drug. Volunteers were instructed to return to the clinic for a safety evaluation (physical examination, vital signs) 1 week after the final blood sample was collected.
Statistical Analysis The number of subjects per group met the guidelines for Phase I clinical trials issued by the State Food and Drug Administration (SFDA) of the People's Republic of China. Therefore, no power analysis was performed for the purposes of calculating the sample size. All analyses were performed according to the SFDA guidelines. All volunteers who received study drug were included in the PK/PD assessments. Analysis of variance (ANOVA) with dose-normalized values was used to evaluate the dose linearity of Cm~x and AUC for aranidipine and M-1. ANOVA was also used to evaluate any differences in tl/2 between dose groups. The resuits for Tm~x were evaluated using Wilcoxon rank sum analysis. For the PD assessments, interdose comparisons of the change from baseline in each variable were performed using ANOVA with adjustment for multiple comparisons; repeated-measures ANOVA and paired t tests were used for comparisons of the PD data within volunteers and between dose groups. The relationship between individual PK parameters (AUC, C . . . . and tl/2 for aranidipine and M-l) and individual maximum changes in PD parameters was assessed by linear correlation analysis. P < 0.05 was considered statistically significant. All analyses were performed using SAS version 8.2 (SAS Institute Inc., Cary, North Carolina).
RESULTS Study Population Thirty healthy Chinese men (mean [SD] age, 23 [2] years [range, 19-27 years[; mean body weight, 66 [7] kg [range, 57-75 kg]; mean height, 174 [6] cm [range, 165-182 cm]) were enrolled in and completed the study. There were no significant differences in baseline characteristics between dose groups.
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Pharmacokinetic Properties The plasma concentration-time profiles of aranidipine and M-1 at the doses studied in the single- and multiple-dose studies are depicted in Figure 1.
Single-Dose Study In the single-dose study, the mean (SD) tl/2 for aranidipine 5, 10, and 20 mg was 3.0 (2.7), 2.7 (1.1), and 3.1 (2.2) hours, respectively; the mean Tmax was 4.9 (0.4), 4.4 (1.0), and 4.3 (0.9) hours; the mean Cmax was 1.1 (0.6), 2.4 (0.8), and 4.0 (2.0) pg/L; and the mean AUClast was 4.1 (1.4), 10.3 (2.3), and 20.9 (4.2) pg • h/L (Table I). There were no statistically significant differences in aranidipine Tmax or tl/2 over the dose range studied. Results of ANOVA indicated no difference between groups in terms of the dosenormalized AUC or Cm~x of aranidipine. There was 1.8- to 3.1-fold variation in individual aranidipine AUC values and 3.0- to 7.8-fold variation in individual aranidipine Cm~x values. For M-l, the mean (SD) tl/2 for the 5-, 10-, and 20-mg doses was 4.6 (1.0), 4.1 (0.5), and 4.1 (0.3) hours, respectively; the mean Tmax was 5.6 (2.0), 5.0 (1.6), and 5.0 (0.8) hours; the mean Cmax was 18.4 (0.6), 40.5 (10.0), and 39.2 (11.3) pg/L; and the mean AUClast was 143.5 (39.1), 304.5 (108.2), and 403.9 (73.5) pg • h/L (Table I). There was no significant difference in the Tmax and tl/2 between dose groups. Results of ANOVA indicated a significant difference in dose-normalized Cm~x and AUClast for M-1 (P < 0.001 and P = 0.018, respectively). Pairwise comparisons of the degree of nonlinearity for each dose level suggested that the 20-mg dose was associated with the greatest nonlinearity. Between volunteers in the individual dose groups, there was 1.7- to 3.0-fold variation in AUC values for M-1 and 2.1- to 3.6-fold variation in Cmax values.
Multiple-Dose Study In the multiple-dose study, the mean tl/2, T . . . . C . . . . and AUC0_~ for aranidipine 10 mg were 2.3 (0.9) hours, 5.0 (1.2) hours, 3.1 (1.1) pg/L, and 13.8 (3.6) pg • h/L, respectively (Table II). There were no significant changes relative to the single-dose study in tl/2, Tmax, or Cmax; however, there was a statistically significant increase in AUC0~ (P = 0.027). For M-l, the mean values for tl/2, T . . . . C . . . . and AUC0_~ were 4.8 (0.9) hours, 5.7 (1.3) hours, 40.0 (11.3) pg/L, and 381.8 (161.2) pg • h/L. There were no significant
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-O- Single S-mg dose (n = 10) -~- Single 10-mg dose (n = 10) -dk- Single 20-mg dose (n = 10) -0- Multiple 10-mgdoses (n = 10)
A 5-
E
4-
¢v ¢0
3-
¢¢0
L) E
1
0 I
I
I
I
I
I
I
I
I
0
5
10
15
20
25
30
35
40
T i m e (h)
60-
400
L~
20-
O0
I
I
I
I
I
I
I
5
10
15
20
25
30
35
I
40
T i m e (h)
Figure 1. Mean (SD) plasma concentrations of(A) aranidipine and (B) its active M-1 metabolite before and after oral administration of single and multiple doses ofaranidipine.
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J. Jiang et al.
Table I. Pharmacokinetic properties of aranidipine and its active M-1 metabolite in 30 healthy volunteers
after administration of single oral doses. Values are mean (SD). Aranidipine
M-1
Parameter
5 mg (n = 10)
10 mg (n = 10)
20 mg (n = 10)
5 mg (n = 10)
10 mg (n = 10)
20 mg (n = 10)
[1/2, h
3.0 (2.7)
2.7 (1.1)
3.1 (2.2)
4.6 (1.0)
4.1 (0.5)
4.1 (0.3)
Tm~x, h
4.9 (0.4)
4.4 (I .0)
4.3 (0.9)
5.6 (2.0)
5.0 (1.6)
5.0 (0.8)
CL, L/h x 103
1.3 (0.6)
1.0 (0.2)
1.0 (0.2)
37.0 (11.2)*
36.3 (12.3)*
50.7 (9.3)*
Cmax
Unadjusted, IJg/L Dose-adjusted, ng/mL per mg/kg
1.1 (0.6)
2.4 (0.8)
4.0 (2.0)
18.4 (0.6)*
40.5 (10.0)*
39.2 (11.3)*
14.2 (7.2)
15.4 (6.2)
13.5 (7.1)
233.7 (84.0)*
257.1 (63.9)*
127.3 (39.6)*
AUClast Unadjusted, lag" h/L Dose-adjusted, ng. h/mE per mg/kg
4.1 (1.4) 52.3 (16.9)
10.3 (2.3) 64.6 (11.4)
20.9 (4.2) 70.1 (18.9)
143.5 (39.1)* 1826.4 (532.7)*
304.5 (108.2)* 1899.7 (552.4)*
403.9 (73.5)* 1306.1 (288.8)*
4.3 (1.4) 54.8 (16.6)
10.5 (2.4) 66.1 (11.9)
21.4 (4.3) 71.8 (19.5)
145.2 (39.3) 1848.7* (537.3)*
306.9 (109.5) 1914.5* (559.2)*
406.2 (73.9) 1313.8* (291.0)*
AUC0
Unadjusted, , g .
h/L Dose-adjusted, ng. h/mL per mg/kg
tl/2 = apparent terminal elimination half-life; CL = systemic clearance; AUClast = AUC From time 0 to the last available
measurement; AUC 0 ~ = AUC From time 0 to infinity. *P < 0.05 between dose groups.
Table II. Pharmacokinetic properties of aranidipine and its active M-1 metabolite in 10 healthy volunteers after administration of single and multiple doses ofaranidipine 10 rag. Values are mean (SD). Aranidipine
Parameter
tl/2, h T~ax, h CL, L/h x 103 C ......pg/L AUC 0 ~, lag" h/L R c
Single l0-mg Dose (n= 10)
2.7 (1.1) 4.4 (1.0) 1.0 (0.2) 2.4 (0.8) 10.5 (2.4)
M-1
Multiple l0-mg Doses (n= 10)
2.3 5.0 0.8 3.1 13.8 1.4
(0.9) (1.2) (0.2)* (I.I) (3.6)* (0.3)
Single l0-mg Dose (n=10)
4.1 5.0 36.3 40.5 307.1
(0.5) (1.6) (12.3) (I0.0) (110.2)
Multiple 10-mg Doses (n = 10)
4.8 5.7 29.9 40.0 381.8 1.3
(0.9) (1.3) (10.6) (11.3) (161.2) (0.3)
q/2 = apparent terminal elimination halglife; CL = systemic clearance; AUC 0 ~ = AUC From time 0 to infinity; Rac = ratio oFthe AUC 0 24 From the single-dose study to the AUC at steady state. *P < 0.05 versus single-dose study.
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changes in these parameters compared with the singledose study.
Pharmacodynamic Properties After administration of single aranidipine doses, a decrease in BP was observed in 27 of the 30 volunteers (90%), and an increase in HR was observed in 28 volunteers (93%). The changes in HR, SBP, and DBP are depicted in Figure 2. With both single and multiple doses of aranidipine, the mean (SD) change from baseline in HR ranged from 0.3 (3.2) to 4.3 (6.8) beats/min (P = NS vs baseline) (Table III). Among all volunteers, the maximum change in HR was 16 beats/min; 14 volunteers had a maximum increase of >10 beats/min. The mean change from baseline in SBP ranged from -0.7 to -4.7 mm Hg (P = NS vs baseline). The maximum decrease in SBP was 21 mm Hg; 15 volunteers had a maximum decrease of >10 mm Hg. The mean change from baseline in DBP ranged from 0.9 to -6.6 mm Hg; the changes from baseline were statistically significant in all groups (P < 0.01) except the aranidipine 10-mg group in the single-dose study. The maximum decrease in DBP was 18 mm Hg; 12 volunteers had a decrease of >10 mm Hg. No relationship was found between dose and the mean change in BP or HR, or between individual PK parameters (AUC, C . . . . and tl/2 of aranidipine and M-l) and individual changes in BP and HR.
Tolerability In the single- and multiple-dose studies combined, 1 volunteer in the 10-mg group reported mild headache 5 hours after dosing that resolved without intervention within 19 hours of its onset. One volunteer in the 20-mg group reported palpitations 5 hours after dosing, and another volunteer complained of dizziness 3 hours after dosing. Both of these AEs were considered mild and resolved without intervention within 3 and 9 hours of onset, respectively, with no residual effects. The headache and palpitations were considered by the investigator to be possibly related to study drug. Vital signs and electrocardiographic findings were within normal ranges throughout the study. No volunteers were withdrawn from the study because of AEs. No abnormalities in physical, biochemical, hematologic, or urinalysis variables that were considered clinically meaningful occurred during the study. 1296
DISCUSSION In 28 of the volunteers, AUClast accounted for >95% of the total AUC0_~ for both aranidipine and M-l, indicating that the plasma concentration-time profile had been well characterized. In the remaining 2 volunteers, in whom the tl/2 was particularly long, AUClast accounted for 88% of the total aranidipine AUC0~. Cmax and Tmax were determined based on both the rate of absorption and the rate of elimination. Given that the aranidipine Tmax and dose-normalized Cm~x were similar in the 3 groups in the single-dose study, the rate and extent of absorption of aranidipine did not appear to be affected by higher doses, suggesting that there was no saturation in aranidipine absorption. The ratio of the Cm~x of M-1 to that of aranidipine was >10 and the ratio of the AUC of M-1 to that of aranidipine was >20, indicating a first-pass effect after oral administration. The departure from linearity of M-1 at the 20-mg dose may be explained by the metabolite saturation of aranidipine. After administration of single doses, the mean Tmax of M-1 occurred -0.7 hour later than that of the parent compound. Individual Tmax values for M-1 varied from 1 hour earlier relative to aranidipine in 2 volunteers to 5 hours later in 1 volunteer. The Tmax for aranidipine and M-1 was identical in 12 volunteers; in another 8 volunteers, the Tmax of M-1 occurred 1 hour later that that of aranidipine. The results of the PK analyses of single and multiple oral doses of aranidipine indicated a mean (SD) R~c of 1.4 (0.3) for the 10-mg dose, which was inconsistent with the accumulation factor of -1.0 derived from the dosing interval and tl/2. This discrepancy may be explained by an alteration in the extent of absorption (bioavailability) or by a first-pass effect on the rate of absorption or CL after administration of multiple doses. Two peaks in the concentration-time profile of aranidipine and M-1 were observed in 16 and 10 volunteers, respectively. The first peak occurred 4 to 5 hours after dosing, and the second occurred 8 to 12 hours after dosing. Hepatoenteral circulation may have been responsible for this finding. Although the maximum mean change in HR differed significantly from baseline (P < 0.01) (Table III), the mean changes from baseline were not statistically significant between dose groups. The time of the maximum decreases in SBP and DBP ranged from 2 to 12 hours after dosing. Analysis of BP changes in individual volunteers indicated significant decreases in the Volume 30 Number 7
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-@- Single 5-mg dose (n = 10) -D- Single 10-mg dose (n = 10) Single 20-mg dose (n = 10) -O- Multiple 10-mg doses (n = 10)
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Time (h) Figure 2. Mean (SD) values for (A) heart rate, (B) systolic blood pressure (SBP), and (C) diastolic blood pressure (DBP) before and after oral administration o f single and multiple doses ofaranidipine.
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Clinical Therapeutics
Table III. Pharmacodynamic properties ofaranidipine in healthy volunteers in the single- and multiple-dose studies. Values are mean (SD). Single Dose
Parameter
5 mg (n= 10)
10 mg (n= 10)
20 mg (n=10)
Heart rate, beats/min Baseline Maximum mean change Mean change
57.7 (4.4) 5.6 (2.1)* 1.8 (2.7)
58.7 (5.0) 5.3 (6.8)* 1.9 (4.6)
57.1 (7.0) 9.8 (6.1)* 4.3 (6.8)
59.0 (5.1) 5.1 (6.7)* 0.3 (3.2)
108.7 (7.6) -7.6 (6.0)* -4.7 (7.2)
106.6 (9.6) -3.0 (8.08) -1.6 (4.3)
10Z2 (12.0) -3.0 (5.3) -0.7 (5.9)
64.1 (5.6) -1.8 (5.9) 0.9 (4.7)
71.3 (4.9) -7.8 (6.3)* -6.6 (2.9)*
6Z5 (4.6) -5.9 (4.5)* -3.1 (2.1)*
Systolic blood pressure, mm Hg Baseline Maximum mean change Mean change Diastolic blood pressure, mm Hg Baseline Maximum mean change Mean change
109.7 (5.5) -4.3 (Z1) -2.7 (5.0) 69.7 (4.0) -6.9 (6.3)* -4.8 (4.2)*
Multiple 10-mg Doses (n= 10)
< 0.01 versus baseline. fP < 0.05 versus baseline.
*P
mean change in BP at 2, 4, and 12 hours after dosing (P < 0.05) and significant decreases in HR from 4 to 12 hours after administration (P < 0.05). Aranidipine was generally well tolerated. No serious AEs or deaths were reported during the study. Given that the C. . . . T . . . . and AUC in volunteers who experienced AEs were similar to the mean value for their dose groups, there was no apparent direct relationship between PK values and the incidence of AEs. There were no clinically meaningful changes from baseline to the final assessment in vital signs, serum biochemistry or hematology variables, electrocardiographic parameters, or findings on physical examination. This study had several limitations. First, because there were no published reports on the tolerability of aranidipine in Chinese men, a single- and multipledose design was used rather than a crossover design. Thus, it was not possible to apply a linear mixedeffects model, which would have been more appropriate and accurate for assessing dose proportionality. 14 Instead, ANOVA of the dose-normalized Cmax and AUC was used to evaluate the linearity of aranidipine and M-1 over the dose range studied. Second, this
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study was performed in healthy volunteers, which limits the generalizability of the results to other populations. Third, because of the possible bias introduced by the absence of a placebo group, the results for the PK/PD relationship may not be sufficiently reliable. Finally, the sample size was small and the power of the study may not have been adequate. CONCLUSIONS
The results of this small study in healthy Chinese men suggest that the PK properties of aranidipine were linear with respect to dose, whereas the active M-1 metabolite was not fully linear with respect to dose. The PK analyses of single and multiple oral doses indicated no apparent accumulation of aranidipine or M-1 with the 10-mg dose. No significant difference between dose groups was observed with respect to mean changes from baseline in BP and HR. Aranidipine appeared to be well tolerated in the population studied. ACKNOWLEDGM ENT
The authors thank the nurses in Ward IV, Fu Wai Hospital, Beijing, for their medical and nursing support.
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J. Jiang et REFERENCES 1. Epstein BJ, Vogel K, Palmer BF. Dihydropyridine calcium channel antagonists in the management of hypertension. Drugs. 2007;67:13091327. 2. Weber MA. Calcium channel antagonists in the treatment of hypertension. AmJ CardiovascDrugs. 2002; 2:415-43 I. 3. Grossman E, Messerli FH. Calcium antagonists. Prog Cardiovasc Dis. 2004;47:34-57. 4. Van Zwieten PA, Pfaffendorf M. Similarities and differences between calcium antagonists: Pharmacological aspects. J Hypertens Suppl. 1993; 11:$3-$11. 5. Struyker-Boudier HA, Smits JF, De Mey JG. The pharmacology of calcium antagonists: A review.J Cardiovasc PharmacoL 1990;15(SuppI 4): $1-$10. 6. Leonetti G. The effects of calcium antagonists on electrolytes and water balance in hypertensive patients. J CardiovascPharmacol. 1994;24(Suppl A):$25-$29. 7. Ohashi K, Ebihara A. Aranidipine (MPC-1304): A new dihydropyridine calcium antagonist: A review of its antihypertensive action. CardiovascDrug Rev. 1996; 14: I - I 6. 8. Ichihara K, Okumura K, Kamei H, et al. Renal effects of the calcium channel blocker aranidipine and its active metabolite in anesthetized dogs and conscious spontaneously hypertensive rats. J Cardiovasc Pkarmacol. 1998;31:277-285. 9. Miyoshi K, Miyake H, Ichihara K, et al. Contribution of aranidipine metabolites with slow binding kinetics to the vasodilating activity of aranidipine. Naunyn Schmiedebergs Arch Pharmacol. 1997;355:119-125. 10. ShimosawaT, Ando K, Takahashi K. Effect of aranidipine, a long-acting Ca antagonist, on circadian variation of blood pressure in essential hypertension patients [in Japanese]. J Clin Ther Med. 2001;17:13071313.
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11. World Medical Association Declaration of Helsinki. Ethical Principles for Medical Research Involving Human Subjects. As amended by the 52nd WMA General Assembly; Edinburgh, Scotland; October 2000. 12. European Medicines Agency. ICH Topic E 6 (RI). Guideline for Good Clinical Practice [EMEA Web Site]. http://www.emea.eu ropa.eu/pd fs/ human/ich/O13595en.pdf. Accessed May 28, 2008.
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Address correspondence to: Prof. Li Yishi, Clinical Pharmacology Center,
Fu Wai Hospital, 167 Beilishi Road, Beijing 100037, People's Republic of China. E-maih [email protected] 1299