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PHARMACOKINETICS

Bioavailability of Amlodipine Besylate/Atorvastatin Calcium Combination Tablet

Menger Chung, PhD, FCP, Albert Calcagni, BS, Paul Glue, MD, PhD and Candace Bramson, MD

From Pfizer Inc, New York, New York (Dr Chung); Pfizer Inc, Groton, Connecticut (Mr Calcagni, Dr Glue); Pfizer Global Research and Development, Clinical Research Unit, Ann Arbor, Michigan (Dr Bramson).

Address for reprints: Candace Bramson, MD, Pfizer Global Research and Development, Ann Arbor Laboratories, 2800 Plymouth Road, Ann Arbor, MI 48105.


   ABSTRACT
TOP
 ABSTRACT
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
The bioequivalence of combination tablets containing amlodipine besylate/atorvastatin calcium with coadministered matching doses of amlodipine besylate and atorvastatin calcium tablets was investigated in randomized, 2-way crossover studies in healthy volunteers (N = 126). Subjects received a single dose of the amlodipine/atorvastatin tablet or coadministered matching doses of amlodipine and atorvastatin at the highest (10/80 mg; n = 62) and lowest (5/10 mg; n = 64) dose strengths. Atorvastatin geometric mean ratios for maximum plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC) for the highest and lowest dose strengths were 94.1 and 98.8, and 104.5 and 103.8, respectively. Amlodipine geometric mean ratios for Cmax and AUC for the highest and lowest dose strengths were 100.8 and 103.4, and 100 and 102.7, respectively. The 90% confidence intervals for all comparisons were within 80% to 125%, demonstrating bioequivalence for amlodipine and atorvastatin at both dose strengths. Use of amlodipine/atorvastatin combination tablets may provide a more integrated approach to treatment of cardiovascular risk.

Key Words: Amlodipine besylate • atorvastatin calcium • bioequivalence • combination tablet

Recent clinical guidelines have called for a more integrated approach to the treatment of patients with risk factors for cardiovascular disease (CVD).1-3 This is because risk factors for CVD frequently occur together, further increasing risk for coronary events.4-6 The benefits of using a multifactorial approach to the treatment of hypertensive patients with multiple risk factors has been demonstrated in recent clinical studies.7,8 However, the diagnosis and control of cardiovascular risk factors in general practice, while improving, are still far from optimal.9 Hence, a novel approach to the treatment of CVD is required. One such approach is combining an antihypertensive and lipid-lowering agent into a single tablet.

A combination tablet containing both amlodipine besylate and atorvastatin calcium has been approved for the treatment of hypertension and dyslipidemia in a growing number of countries including the United States.10 Amlodipine besylate is a long-acting dihydropyridine calcium channel blocker indicated for the treatment of hypertension and angina,11 and atorvastatin calcium is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor ("statin") indicated for the treatment of dyslipidemia and the prevention of CVD.12

To optimize treatment of patients requiring both antihypertensive and lipid-lowering therapy, it is important to know whether the pharmacokinetic properties of amlodipine/atorvastatin combination tablets are comparable to those of the coadministered matching doses of the component drugs. We investigated the highest dose strength (10/80 mg) and lowest dose strength (5/10 mg) of amlodipine/atorvastatin combination tablets from commercially available dosages to determine whether combining amlodipine and atorvastatin in a single tablet affects the bioavailability of these drugs.


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Formulation and Dose of Amlodipine/Atorvastatin Combination Tablets
Combination amlodipine/atorvastatin (Caduet) is available in 11 dose strengths (amlodipine/atorvastatin 2.5/10, 2.5/20, 2.5/40, 5/10, 5/20, 5/40, 5/80, 10/10, 10/20, 10/40, and 10/80 mg). All combinations contain the same standard excipients, with minor differences in the proportions of certain excipients to account for variable amounts of the active drug substance in the different dose strengths.10,13 Both amlodipine14 and atorvastatin15 show dose-pharmacokinetic linearity across the dose ranges tested in this study, when tested as monotherapies.

Subjects
Healthy male and female subjects aged 18 to 64 years (inclusive) with a body mass index between 18 and 30 kg/m2 (inclusive) were enrolled in the studies. Subjects had to be in good health to participate, as determined by a detailed medical history, full physical examination, 12-lead electrocardiogram, and clinical laboratory tests with values within the reference range or not judged abnormal by the investigator. Negative serum pregnancy test (female subjects) and urine drug screen also were required. Subjects were not permitted to consume grapefruit juice within 7 days prior to dosing or to use St John's Wort within 14 days prior to dosing.

Study Design
Two studies were conducted at Pfizer Global Research and Development, Clinical Research Unit, Ann Arbor, Michigan, to assess the bioequivalence of combination tablets containing amlodipine/atorvastatin with coadministered individual drugs. The first study assessed the bioequivalence of the lowest dose strength combination tablet (amlodipine/atorvastatin 5/10 mg) with matching coadministered doses of amlodipine besylate 5 mg and atorvastatin calcium 10 mg. The second study evaluated the bioequivalence of the highest dose strength combination tablet (amlodipine /atorvastatin 10/80 mg) with matching coadministered doses of amlodipine 10 mg and atorvastatin 80 mg. With the exception of use of different dose strengths, the design and procedural aspects of both studies were similar.

Both studies were open-label, single-dose, randomized, 2-treatment, 2-period, 2-sequence crossover trials with a minimum 14-day washout period between treatments. In each study, subjects had to complete both study periods and randomized, using a computer-generated randomization code, to first receive either the combination tablet or the coadministered amlodipine and atorvastatin tablets. On each dosing day, subjects fasted for 8 hours before receiving the medication with 240 mL water. Subjects fasted for 4 more hours, with meals provided approximately 4 and 10 hours after drug administration. After a 14-day washout period, subjects received the next study treatment in the sequence.

The protocols were approved by the Pfizer Research Clinic Institutional Review Board, Ann Arbor, Michigan, and the studies were conducted in accordance with the International Conference on Harmonisation Guidelines for Good Clinical Practice and in compliance with United States Food and Drug Administration (FDA) regulations. All subjects provided informed consent prior to participation.

Sample Collection and Analysis
Blood samples for pharmacokinetic analysis were taken just prior to dosing and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours after each dose. Samples (sufficient to provide 5 mL of plasma) were collected in heparinized tubes, which were immediately placed in an ice water bath and underwent centrifugation within 30 minutes of collection. After centrifugation, 1 mL of the plasma from samples obtained from 0 to 72 hours was transferred into polypropylene tubes, flash-frozen in an alcohol–dry ice bath, and stored at –70°C until atorvastatin analysis. The remainder of the plasma from these samples, as well as all plasma collected from 96 to 168 hours, was transferred into polypropylene tubes and stored frozen at –20°C until amlodipine analysis.

Plasma concentrations of amlodipine were determined at Pharmaceutical Product Development Inc, Richmond, Virginia, by gas chromatography with electron-capture detection. Amlodipine and UK-52,829-42 (internal standard) were extracted from human plasma (1 mL) with methyl-t-butyl ether and derivatized with trimethylacetyl chloride. Chromatographic separation was achieved on a J&W DB-17HT (15 m x 0.32 mm ID x 0.15 µm film thickness) capillary column. The assay demonstrated a linear range of 0.2 ng/mL to 50 ng/mL, with a lower limit of quantitation (LLOQ) of 0.2 ng/mL. Quality control sample accuracy and precision results during method validation had interassay coefficients of variation ranging from 4.60% to 4.98% and percentage differences within 4.48% of theoretical.

Plasma concentrations of atorvastatin were determined at Advion BioSciences Inc, Ithaca, New York. Atorvastatin and its deuterated internal standard (atorvastatin-d5) were extracted from human plasma (0.1 mL) by a 96-well solid-phase extraction (SPE) procedure. The SPE eluent was evaporated to dryness, and the residue was reconstituted in 100 µL of a 30:70 solution of acetonitrile: 0.1% acetic acid in water. The analytes were separated by reverse-phase chromatography on a 2.1 x 50 mm (4 µm) Genesis C18 column (Jones Chromatography, Lakewood, Colo) with a flow rate of 200 µL/min. Plasma concentrations of atorvastatin were determined using turbo ion spray, liquid chromatography/tandem mass spectrometry in the positive ion mode, using a PE SCIEX API 3000 mass spectrometer. Multiple reaction monitoring transitions were mass-to-charge ratio (m/z) = 559.3 -> 440.2 and m/z = 564.3 -> 445.3 for atorvastatin and atorvastatin-d5, respectively. The assay demonstrated a linear range of 0.25 ng/mL to 100 ng/mL, with a LLOQ of 0.25 ng/mL. Quality control sample accuracy and precision results during method validation had interassay coefficients of variation ranging from 1.87% to 7.35% and percentage differences within 6.25% of theoretical. Assay methods for the detection of amlodipine and atorvastatin in human plasma were validated prior to sample analysis.

Safety Assessments
All observed or volunteered adverse events and any suspected causal relationship to study drug were recorded. Subjects with clinically important abnormal laboratory test results had the tests repeated at appropriate intervals until values returned to baseline or to levels deemed acceptable by the investigator and a medical monitor or until a diagnosis was made that explained them.

Pharmacokinetic and Statistical Analyses
Noncompartmental pharmacokinetic analysis was performed on the plasma concentration–time profiles of individual subjects using WinNonlin Pro version 2.1 (Pharsight Corp, Mountain View, Calif). The primary parameters for assessing bioequivalence were the log-transformed maximum plasma concentration (Cmax) and area under the plasma concentration–time curve from time 0 to infinity (AUC0-{infty}); secondary parameters included in the analysis were time to Cmax (tmax) and terminal disposition half-life (t1/2). The AUC for the last quantifiable concentration (Ct) AUC0-t, was calculated by the linear trapezoid rule. The total AUC0-{infty} was estimated from AUC0-t + Ct/kel, where kel was determined by regression analysis of the terminal log linear phase of the plasma concentration–time data. The t1/2 was calculated from 0.693/kel.

Data were evaluated by analysis of variance (ANOVA) using a model incorporating sequence, group, subject within sequence, and group, period, and treatment effects. Statistical tests were performed using the type III sum of squares following the Proc GLM procedure of SAS (version 6.12, SAS Institute, Cary, NC). Least square treatment mean values were determined for each parameter. Confidence intervals (CIs) were calculated using SASPK version 4.0.

Per bioequivalence criteria,16 the amlodipine/atorvastatin combination tablet would be considered bioequivalent with coadministered commercially available amlodipine and atorvastatin tablets if the 90% CI for the treatment ratios of the geometric means of Cmax and AUC0-{infty} values for both amlodipine and atorvastatin were entirely within the bioequivalence limit of 80% to 125%.

It was calculated that 62 participants per study would provide at least 80% power to demonstrate bioequivalence if the true difference between test (combination tablet) and reference (coadministered individual tablet) treatments was no more than 5% and the within-subject standard deviation (SD) of log-transformed AUC0-{infty} and Cmax was no more than 0.37. This calculation assumed that bioequivalence was assessed using a 90% CI on the geometric mean ratio of test/reference with a bioequivalence limit of 80% to 125%.


   RESULTS
TOP
 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Subjects
In total, 64 healthy subjects (17 male, 47 female; age [mean ± SD], 38.9 ± 9.9 years; body mass index, 24.8 ± 2.7 kg/m2) were enrolled in the lowest dose strength (5/10 mg) study and 62 subjects (29 male, 33 female; age [mean ± SD], 39.5 ± 12.9 years; body mass index, 25.2 ± 2.9 kg/m2) were enrolled in the highest dose strength (10/80 mg) study.


Figure 1
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  		Figure 1. Mean plasma concentrations of amlodipine (A) and atorvastatin (B) after the administration of 5/10-mg combination tablets versus the coadministration of amlodipine 5-mg and atorvastatin 10-mg tablets.

 
In the lowest dose strength study, 2 subjects withdrew after receiving only 1 of the 2 treatments for reasons not considered to be related to the study drugs. One male subject, who received coadministered amlodipine 5 mg and atorvastatin 10 mg on day 1, developed influenza on day 12 and withdrew from the study on day 15. One female subject, who received the low-dose combination tablet on day 1, developed dysmenorrhea on day 14 and withdrew from the study on day 15. As a result, 63 subjects each completed a single period, and 62 subjects completed both periods of the study of the lowest dose strength study. For the highest dose strength study, all 62 subjects completed both periods of the study.

Pharmacokinetics
Lowest Dose Strength Study (amlodipine/atorvastatin 5/10 mg)
Amlodipine. Mean amlodipine concentration–time profiles were virtually identical after dosing with the combination 5/10-mg tablet and coadministration of amlodipine 5-mg and atorvastatin 10-mg tablets (Figure 1A). Amlodipine bioavailability was similar for the 2 treatments based on tmax, Cmax, and AUC0-{infty} (Table I), and the 90% CIs for the ratios of the geometric mean Cmax and AUC0-{infty} for the combination tablet/coadministered tablets were within the bioequivalence limit of 80% to 125% (Cmax, 99.6-107.7; AUC0-{infty}, 98.9-105.4). In addition, the mean half-life of amlodipine was also similar for the 2 treatments.


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  		Table I Mean (N = 63) Pharmacokinetic Parameters for Amlodipine and Atorvastatin After Administration of 5/10-mg Combination Tablets Versus Coadministration of Amlodipine 5-mg and Atorvastatin 10-mg Tablets

 


Figure 2
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  		Figure 2. Mean plasma concentrations of amlodipine (A) and atorvastatin (B) after the administration of 10/80-mg combination tablets versus the coadministration of amlodipine 10-mg and atorvastatin 80-mg tablets.

 

Atorvastatin. Mean atorvastatin concentration–time profiles were similar after dosing with the combination 5/10-mg tablet and coadministration of amlodipine 5-mg and atorvastatin 10-mg tablets (Figure 1B). Atorvastatin bioavailability was also similar for the 2 treatments based on tmax, Cmax, and AUC0-{infty} (Table I). The 90% CIs for the ratios of the geometric mean Cmax and AUC0-{infty} for the combination tablet/coadministered tablets were within the bioequivalence limit of 80% to 125% (Cmax, 88.3-110.6; AUC0-{infty}, 96.4-111.8), and the mean half-life of atorvastatin was similar in both treatment groups.

Highest Dose Strength Study (amlodipine/atorvastatin 10/80 mg)
Amlodipine. Mean amlodipine concentration–time profiles were virtually identical after dosing with the combination tablet and coadministration of amlodipine 10-mg and atorvastatin 80-mg tablets (Figure 2A). Amlodipine bioavailability was not different for the 2 treatments based on tmax, Cmax, and AUC0-{infty} (Table II). The 90% CIs for the ratios of the geometric mean Cmax and AUC0-{infty} for the combination tablet/coadministered tablets were within the 80% to 125% bioequivalence limit (Cmax, 97.6-103.9; AUC0-{infty}, 97.2-102.9). In addition, the mean half-life of amlodipine was also similar for the 2 treatments.


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  		Table II Mean (N = 62) Pharmacokinetic Parameters for Amlodipine and Atorvastatin After Administration of 10/80-mg Combination Tablets Versus Coadministration of Amlodipine 10-mg and Atorvastatin 80-mg Tablets

 

Atorvastatin. Mean atorvastatin concentration–time profiles were similar after dosing with the combination tablet and coadministration of amlodipine 10-mg and atorvastatin 80-mg tablets (Figure 2B). Atorvastatin bioavailability was similar for the 2 treatments based on tmax, Cmax, and AUC0-{infty} (Table II). The 90% CIs for the ratios of the mean Cmax and AUC0-{infty} for the combination tablet/coadministered tablets were within the bioequivalence limit of 80% to 125% (Cmax, 84.6-104.4; AUC0-{infty}, 98.8-110.8), and the mean half-life of atorvastatin was similar for the 2 treatments.

Safety
The amlodipine/atorvastatin combination tablets were well tolerated, and the incidence of adverse events was virtually the same as those observed with coadministration of the 2 drugs at both the lowest and highest dose strengths (Table III). The most common adverse events across the 2 studies were headache and somnolence. Most adverse events were mild to moderate in nature, and all resolved spontaneously. There were no serious adverse events or deaths associated with the administration of amlodipine (5 mg or 10 mg) or atorvastatin (10 mg or 80 mg), either as a combination tablet or after the coadministration of the 2 drugs.


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  		Table III Most Common Treatment-Emergent Adverse Events (AEs)a in Subjects Taking Amlodipine/Atorvastatin Combination Tablets or Coadministered Doses

 


   DISCUSSION
TOP
 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
ACKNOWLEDGEMENTS
 REFERENCES
 
Pharmacokinetic parameters of the combination tablet containing amlodipine/atorvastatin observed in these studies are similar to those reported in the current product label of commercially available amlodipine besylate11 and atorvastatin calcium12 tablets. The rate and extent of both amlodipine and atorvastatin absorption were similar after administration of the combination tablet and coadministration of the component drugs, and the 90% CIs for the ratios of the atorvastatin and amlodipine treatment geometric mean Cmax and AUC0-{infty} values were within the 80% to 125% bioequivalence limits. Thus, combining amlodipine and atorvastatin in a single tablet does not affect the bioavailability of these drugs at both the highest (10/80 mg) and lowest (5/10 mg) dose strengths.

Both the lowest and highest dose strengths of the combination amlodipine/atorvastatin tablet were well tolerated, and the incidence of adverse events was similar to that observed with coadministration of the component drugs. There were no new or unexpected adverse events compared with previous studies of these agents alone or in combination.17-19 Although headaches are a known side effect of amlodipine,11 the higher incidence of headaches reported in the current trials may have been due in part to caffeine withdrawal, as caffeine intake was not permitted before dosing and for a number of hours afterward. In support of this, a recent study of the efficacy of the combination amlodipine/atorvastatin tablet that did not impose a similar caffeine restriction showed a substantially lower incidence of headaches (5.4%).17

Amlodipine19-23 and atorvastatin18,24-28 are approved for use in the treatment of hypertension and dyslipidemia, respectively, and recent clinical studies support coprescription of these drugs in a broadening range of patients at risk for CVD (including those with hypertension and multiple risk factors, regardless of baseline lipid levels). For example, atorvastatin significantly reduces the occurrence of CVD events in treated patients with hypertension who have mildly elevated or normal lipid levels,8 and both drugs can reduce progression of atherosclerosis in patients with coronary artery disease.21,26 Unfortunately, adherence to multidrug treatment regimens is low,29,30 but adherence to antihypertensive medications can be improved by prescribing combination tablets.31 Treating patients with a single amlodipine/atorvastatin tablet should lead to improved adherence and greater reductions in CVD risk. A recent study has shown that this combination tablet is effective in helping patients reach their blood pressure and lipid goals.17

The results presented here demonstrate that combination tablets of amlodipine/atorvastatin are bioequivalent to coadministered amlodipine and atorvastatin tablets. Combination tablets containing amlodipine/atorvastatin are well tolerated, and the safety profile is similar to that observed with coadministration of the component drugs. These results are therefore encouraging for the potential use of the amlodipine/atorvastatin combination tablet for integrated cardiovascular risk management.


   ACKNOWLEDGEMENTS
TOP
 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
REFERENCES
 
The authors thank Dr Edward Randinitis for assistance in performing this study.

Financial support for this study was provided by Pfizer Inc.

This study was conducted at Pfizer Global Research and Development, Clinical Research Unit, Ann Arbor, Michigan, and it was approved by Pfizer Research Clinic Institutional Review Board, Ann Arbor, Michigan. All authors were or are currently employees of Pfizer Inc.

The data derived herein were presented in part at the XIII International Symposium on Atherosclerosis, September 28, 2003, Kyoto, Japan.

DOI: 10.1177/0091270006291031


   REFERENCES
TOP
 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 

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19. Viskoper RJ, Bernink PJ, Schelling A, et al. A randomised, double-blind trial comparing mibefradil and amlodipine: two long-acting calcium antagonists with similar efficacy but different tolerability profiles. Mibefradil International Study Group. J Hum Hypertens. 1997;11: 387-393.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

20. Phillips RA, Kloner RA, Grimm RH Jr, Weinberger M. The effects of amlodipine compared to losartan in patients with mild to moderately severe hypertension. J Clin Hypertens (Greenwich). 2003;5: 17-23.

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22. Julius S, Kjeldsen SE, Weber M, et al. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet. 2004;363: 2022-2031.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

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24. Jones P, Kafonek S, Laurora I, Hunninghake D. Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study). Am J Cardiol. 1998;81: 582-587.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

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