Clinical Therapeutics/Volume ], Number ], 2014
Comparison of Pharmacokinetics of Two Fenofibrate Tablet Formulations in Healthy Human Subjects Siddharth S. Chachad1; Milind Gole1; Geena Malhotra1; and Raghu Naidu2 1
Department of Clinical and Bioequivalence Research, Cipla Limited, Mumbai, India; and 2Contract Research Organisation, Sitec Labs Pvt Ltd, Mumbai, India
ABSTRACT Background: Fenofibrate is a serum lipid-lowering agent used as an adjunct to diet in patients with hypercholesterolemia and hypertriglyceridemia. The new fenofibrate tablet formulation was developed as a pharmaceutical equivalent to the marketed tablet formulation containing 145 mg. Objective: The objective of this study was to compare the pharmacokinetics and safety of 2 tablet formulations containing 145 mg of fenofibrate (CAS number 49562-28-9) in healthy human subjects. Methods: The study was a randomized, 2-treatment, 3-period, 3-sequence, single-dose, 3-way crossover, partial replicate bioequivalence study in healthy human subjects under fasting conditions. Eligible subjects received each treatment in a crossover manner according to the randomization schedule. Replicate dosing was conducted for the reference formulation to determine its intrasubject variability. The predose blood sample was taken within 1 hour before dosing, and serial blood sampling was performed up to 72.0 hours’ postdose. The analysis of plasma samples for concentrations of fenofibric acid, the active metabolite of fenofibrate, was conducted by using a validated LCMS/MS method. Bioequivalence was to be concluded if the 90% CIs as constructed were within the range of 80% to 125% for Cmax, AUC0–t, and AUC0–1 for fenofibric acid. Subjects were monitored for safety and tolerability throughout the study. Results: 15 healthy human subjects between 18 and 45 years of age and having body mass index between 18.5 and 30 kg/m2 were recruited into the study. The 90% CIs for the test/reference mean ratios of the lntransformed pharmacokinetic variables Cmax, AUC0–t, and AUC0–1 were within the conventional bioequivalence range of 80% to 125%. Both formulations were well tolerated after a single oral dose in these healthy male subjects. Conclusions: Both fenofibrate tablet formulations demonstrated equivalent rates and extent of systemic
] 2014
absorption, and hence were considered bioequivalent. (Clin Ther. 2014;]:]]]–]]]) & 2014 Elsevier HS Journals, Inc. All rights reserved. Key words: bioequivalence, fenofibrate, pharmacokinetics.
INTRODUCTION According to the World Health Organization fact sheet No. 317 (updated March 2013), cardiovascular diseases are the number one cause of death globally: more people die annually of cardiovascular diseases than of any other cause.1 Most cardiovascular diseases can be prevented by addressing risk factors such as tobacco use, unhealthy diet and obesity, physical inactivity, high blood pressure, diabetes, and increased lipid levels. Elevated serum cholesterol is a modifiable risk factor that is associated with an estimated 4.4 million deaths each year and accounts for a considerable proportion of ischemic strokes and heart disease worldwide.2 Therapeutic lifestyle changes (reduced dietary intake of saturated fats and cholesterol, weight control, and increased physical activity) form the core of all cholesterol-lowering initiatives. Supplemental therapy with lipid-lowering medications has been shown to safely reduce the longterm incidence of major cardiovascular events in secondary prevention trials and in high-risk primary prevention trials, and this therapy is universally recommended in patients with established or at high predicted risk of cardiovascular disease.3,4 Fenofibrate is marketed in 86 countries and is one of the most commonly used fibrates worldwide, with 46 million patient-years of experience.5 More than Accepted for publication April 14, 2014. http://dx.doi.org/10.1016/j.clinthera.2014.04.017 0149-2918/$ - see front matter & 2014 Elsevier HS Journals, Inc. All rights reserved.
1
Clinical Therapeutics 80 clinical trials of fenofibrate have been conducted, involving 49000 patients and 431,000 patient-years of drug exposure.6,7 Fenofibrate’s indications include hypercholesterolemia, combined dyslipidemia, remnant hyperlipidemia, endogenous hyperlipemia (hypertriglyceridemia), and mixed hyperlipemia (Fredrickson types IIa, IIb, III, IV, and V dyslipidemia, respectively).8 Fenofibrate is a prodrug of the active chemical moiety fenofibric acid. Fenofibrate is converted by ester hydrolysis in the liver to fenofibric acid, which is the active constituent measurable in the circulation. After oral administration in healthy volunteers, peak plasma levels of fenofibric acid occur within 6 to 8 hours after administration. After absorption, 60% of a single dose of radiolabeled fenofibrate is excreted in the urine, primarily as fenofibric acid and its glucuronate conjugate, and 25% is excreted in the feces.9 Several reformulations of fenofibrate dominate the market, although generic fenofibrate has been available for almost a decade. This continued use of branded formulations, which cost twice as much as generic versions of fenofibrate, imposes a high cost on the health care system. It is hence essential that lowcost yet equally effective and safe drug formulations are made available. In anticipation of the patent expiry, a pharmaceutical equivalent to the marketed fenofibrate 145-mg tablets was developed (by Cipla Limited, Mumbai, India). The objective of the present study was to compare the pharmacokinetics and safety of 2 tablet formulations containing 145 mg of fenofibrate (CAS number 49562-28-9) in healthy human subjects.
SUBJECTS AND METHODS This study was conducted at Sitec Labs Pvt Ltd (Mumbai, India) in accordance with the ethical standards presented in the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. Before the start of the study, written informed consent was obtained from all patients, and the protocol was approved by the local ethical review boards.
Subjects This research was conducted as a pilot study with a minimum number of 12 evaluable subjects. Thus, to obtain data in at least 12 subjects completing the study and considering dropout and discontinued
2
subjects, 15 subjects were recruited. Healthy human subjects between 18 and 45 years of age and having a body mass index between 18.5 and 30 kg/m2 were included. Eligible subjects were considered healthy, as demonstrated by no medical history of significant diseases and no clinically significant abnormal findings during the prestudy screening, physical examination, and laboratory evaluations. Results of a breath alcohol test, test for drugs of abuse, and a urine pregnancy test (for female subjects) were negative at the time of screening. Hepatitis A, B, and C and antibodies to HIV I and II, Venereal Disease Research Laboratory test were negative or nonreactive. Subjects were excluded if they were allergic to fenofibrate; had a history of or current cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal, metabolic, immunologic, dermatologic, neurologic, or psychiatric disease; had participated in any other clinical investigation using an investigational product; or had donated 4350 mL of blood within 90 days before the first dose of study drug. Subjects were excluded from the study if they had taken any prescription medication (eg, coumarin anticoagulant, cyclosporine, tacrolimus, bile acid resins), over-the-counter products (eg, vitamins, products of natural origin [including St. John’s wort]), or topical medications meant for systemic absorption within 7 days before administration of the investigational product. All subjects were instructed to abstain from consuming grapefruit or its products and alcohol/ alcoholic products for at least 48 hours before dosing until the last blood sampling in each study period. They were also instructed to abstain from consuming citrus fruits or their products and xanthine-containing products (chocolate, tea, coffee, or cola drink); they were prohibited from smoking and consuming tobacco or tobacco-containing products for at least 24 hours before dosing.
Study Design The pharmacokinetics of 2 fenofibrate tablet formulations were compared in this randomized, 2-treatment, 3-period, 3-sequence, single-dose, 3-way crossover, partial replicate bioequivalence study. All 15 recruited subjects were administered treatment in a crossover manner under fasting conditions according to the randomization schedule. Replicate dosing was conducted for the reference formulation to determine its intrasubject variability. Because this was a
Volume ] Number ]
S.S. Chachad et al. crossover study, each subject acted as his own control when taking the investigational product on each occasion. The 3 periods of the study were separated by a 9-day washout period, which is 410 times the reported t½ of fenofibric acid (ie, 20 hours).9 The study procedure was repeated in each period with the administration of the investigational product as per randomization details. On the prestudy day, before admission of subjects into the clinical pharmacology unit (CPU) prior to the first dose, the subjects were given full details of the study, both in writing and verbally, by the principal investigator or designated staff. Check-in was followed by catering, vital sign examination, and wellbeing assessment. There was a supervised overnight fasting period of at least 10 hours before dosing. A baseline blood sample was taken within 1 hour before dosing, and while the subject was seated upright, either the test or reference product was administered orally with 240 mL of water. Thereafter, a series of blood samples were taken over the following 24 hours’ postdose with the subject remaining in the CPU. Subjects were allowed to leave the CPU after their vital sign examinations were conducted, their well-being was assessed, and the 24 hours’ postdose blood sample was collected. The subjects returned to the CPU for 48- and 72-hour postdose blood sampling. Breath alcohol test, test for drugs of abuse, vital sign examination, and well-being assessments were performed during the ambulatory visit before blood sampling.
Pharmacokinetic Sampling In the morning of the dosing day, an intravenous cannula was inserted into a forearm vein to facilitate the withdrawal of the blood samples. Blood samples of 5 mL were collected into labeled vacuum tubes containing K2-EDTA as anticoagulant. The samples were kept in an ice water bath until they were centrifuged. The baseline predose sample was taken within 1 hour before dosing. After dosing, samples were taken at 1, 2, 3, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 12, 16, 24, 48, and 72 hours’ postdose. The cannula was withdrawn after the 16-hour postdose blood sample, and 24-, 48-, and 72-hour samples were obtained by direct venipuncture. The choice of the blood sampling time schedule was intended to cover the expected time of the peak plasma concentrations of fenofibric acid, which is at
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6 to 8 hours. It was also extended for sufficient time to be able to obtain a reliable estimate of AUC0–1. The last sample collection was at 72 hours’ postdose, which is 43 times the maximum reported t½ of fenofibric acid (ie, 20 hours), which is sufficient to cover at least 80% of the AUC0–1.9 The blood samples were centrifuged at 10 (2)1C and at 2500 to 3000 rpm for 10 minutes. Each plasma sample was divided into 2 aliquots stored in separate, stoppered, and suitably labeled tubes. All plasma samples were kept upright in dry ice below –201C until delivery to the analytical center for assay. They were stored upright in a deep freezer at a temperature of –70 (10)1C until the completion of analysis.
Analytical Assay The concentrations of fenofibric acid in the plasma of study subjects were measured by using a validated LC-MS/MS method in accordance with the principles of Good Laboratory Practice. The bioanalytical method was developed and validated at Sitec Labs Pvt Ltd. Fenofibric acid was extracted from human plasma by using a liquid–liquid extraction procedure and injected into the liquid chromatograph coupled with a tandem MS/MS detector. The analyte (fenofibric acid) and internal standard (fenofibric D6 acid) were extracted from 100 mL of plasma sample by using tert-Butyl methyl ether, which was then evaporated and the residue was reconstituted in the mobile phase. The liquid chromatograph and mass spectrometer used for this analysis was Agilent 1100 series HPLC (Agilent, Germany) and PE Sciex API 2000 mass spectrometer (MDS Sciex, Toronto, Canada). The mobile phase consisted of acetonitrile and 0.2% formic acid in the proportion of 80:20 and column used was ACE 3 C18, 100 mm 3.0 mm, 3µ (Advanced Chromatography Technologies, Scotland). The flow rate of the mobile phase was 500 mL/min, and the injection volume was 10 mL. The retention time of the analyte and internal standard was 1.46 minutes, and the chromatographic run time was 2.5 minutes. Quantitation was performed by using the internal standard method. Fenofibric D6 acid was used as the internal standard. Fenofibric acid and the internal standard were detected by LC-MS/MS in multiple reaction monitoring with negative polarity mode using the mass transitions 317.00/231.00 amu and 323.00/230.90 amu, respectively. A weighted linear regression using weighting 1/concentration2
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Clinical Therapeutics was prepared to determine the concentration of fenofibric acid in human plasma. The bioanalytical method validation parameters were system suitability, carryover test, specificity and selectivity, matrix effect, sensitivity, linearity (calibration curve), precision and accuracy, ruggedness, hemolysis effect, recovery, stability under different conditions, plasma dilution integrity, and re-injection reproducibility. The lower limit of quantitation (LLOQ) of this method for the measurement of fenofibric acid concentrations in plasma was 99.6 ng/mL. The linearity range was 99.6 to 19,928.1 ng/ mL for fenofibric acid. Four precision and accuracy sets were analyzed during method validation, and each set consisted of 7 quality control (QC) samples each at 5 different concentration levels (low QC, midQC–A, mid-QC–B, and high QC). The within-batch precision (%CV) ranged from 0.99% to 4.91% and the within-batch accuracy (%nominal) ranged from 88.96% to 106.93%. The between-batch precision (% CV) ranged from 1.77% to 6.04% and the betweenbatch accuracy (%nominal) ranged from 92.20% to 99.60%. During study sample analysis, QC samples were distributed throughout each batch. To avoid bias, the analyst did not have access to the randomization code. Samples for any given subject for all time points were assayed under similar chromatographic conditions that were validated for the analysis of fenofibric acid in human plasma. The between-batch precision (%CV) of QC samples ranged from 2.39% to 3.60% and the between-batch accuracy ranged from 97.02% to 100.01%. Concentrations below the LLOQ were set to zero for pharmacokinetic and statistical calculations.
Study Outcomes The primary objective of the present study was to compare the rate and extent of absorption of fenofibric acid after administration of test or reference fenofibrate tablet formulations in healthy adult human subjects. The secondary objective of the study was to monitor the safety and tolerability of a single dose of fenofibrate 145 mg when administered to these subjects under fasting conditions. The safety profile was evaluated by monitoring all the subjects for adverse events throughout the course of the study. An adverse event was defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product, which need
4
not necessarily have a causal relationship with the treatment. Recording of the vital signs at predetermined intervals and the comparison of prestudy and poststudy laboratory parameters formed the basis of the safety evaluation.
Pharmacokinetic Assessment The pharmacokinetic parameters evaluated for fenofibric acid were Cmax, AUC0–t, AUC0–1, Tmax, ke, and t½. Cmax and Tmax were taken directly from the plasma concentration–time profiles of individual subjects. AUC0–t was estimated by using the linear trapezoidal rule, and AUC0–1 was obtained as (AUC0–t þ Clast)/ke, where Clast was the last quantifiable concentration and ke was the terminal rate constant. For the estimation of ke, time points after Tmax in the elimination phase were used to fit a linear regression on the log concentration data with a base 10 using the least squares methods. The t½ was estimated (in hours) from the slope (ke) of the terminal phase of the semi-logarithmic plot of the plasma concentration curve (t½ ¼ ln 2/ke). All pharmacokinetic parameters were calculated by using the noncompartmental method using WinNonlin version 6.3 (Pharsight Corporation, Sunnyvale, California).
Statistical Analysis Statistical analysis of fenofibric acid plasma concentration data and pharmacokinetic parameters was performed by using WinNonlin version 6.3 and SAS version 9.3 (SAS Institute, Inc, Cary, North Carolina). ANOVA was performed (α ¼ 0.05) on the untransformed and ln-transformed pharmacokinetic parameters Cmax, AUC0–t, and AUC0–1. The ANOVA model included sequence, patients nested within sequence, period, and treatment as factors. Each ANOVA model also included calculation of least squares mean (LSM) values, adjusted differences between formulation means, and the SE associated with these differences. The significance of the sequence effect was tested by using the subjects nested within the sequence as the error term. Geometric LSM values were reported for lntransformed Cmax, AUC0–t, and AUC0–1. Ratios of means were calculated by using the LSM for untransformed and ln-transformed Cmax, AUC0–t, and AUC0–1. Ratios of means were expressed as a Volume ] Number ]
Concentration (ng/mL)
S.S. Chachad et al. formula: intrasubject CV ¼ sqrt(exp[residual_variance] – 1), where residual_variance (ie, mean square error) was obtained from the ANOVA model, in which factors such as sequence, period, formulation, and subject(sequence) were used on the log-transformed data.
1000
100
RESULTS
10
Reference Product Test Product
1 0
12
24
36 Time (h)
48
60
72
Figure. Mean plasma concentration–time profile of fenofibrate.
percentage of the LSM for the reference treatment (marketed formulation). Consistent with the 2 one-sided tests for bioequivalence, 90% CIs for the difference between treatments, LSM were calculated for both untransformed and ln-transformed C max, AUC0–t, and AUC 0–1. The test product was to be considered bioequivalent to the reference product if the 90% CIs of Cmax, AUC0–t, and AUC0–1 of fenofibric acid were within the acceptance range of 80% to 125%. If the within-subject SD was Z0.294 (ie, intrasubject variability) for the reference product, then a reference-scaled average bioequivalence procedure was to be used to determine bioequivalence for the individual pharmacokinetic parameters. Intrasubject variability was estimated by using the
15 healthy human subjects between 18 and 45 years of age and having body mass index between 18.5 and 30 kg/m2 were recruited into the study. The mean plasma concentration–time profile obtained after single oral administration of fenofibrate 145 mg in the form of test and reference formulations is shown in the Figure. For fenofibric acid, the mean ratios (for test/reference) and 90% CIs for the ln-transformed parameters of Cmax, AUC0–t, and AUC0–1 are listed in the Table. Because the 90% CIs for the lntransformed test and reference treatment averages were within the bioequivalence acceptance range of 80% to 125%, the test and reference treatments were considered to be bioequivalent. The observed intrasubject variability for the reference product lntransformed parameters of Cmax, AUC0–t, and AUC0–1 were 13.59%, 7.25%, and 7.51%, respectively. Both formulations of fenofibrate 145 mg were reasonably tolerated after a single oral dose in these healthy male subjects. Mild to moderate adverse events, including abdominal pain, nausea, diarrhea, headache, and fever, were observed in some subjects during the study. However, these events resolved after counseling or medical treatment, and there was no definite causal relationship established with either of
Table. Pharmacokinetic parameters and the 90% CIs after a single oral dose of fenofibrate 145 mg. Geometric LSM
Test
Reference
Test/Reference Ratio of Geometric LSM (%)
10,781.18 17,6920.61 19,5084.26
11,015.99 17,9269.01 19,5363.89
97.87 98.69 99.86
Parameter Cmax, ng/mL AUC0–t, h ng/mL AUC0–1, h ng/mL
90% CI
Intrasubject %CV
91.04–105.21 93.96–103.65 94.78–105.21
11.69 7.92 8.43
LSM ¼ least squares mean.
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Clinical Therapeutics the 2 administered products. No serious adverse events or deaths were reported during the conduct of the study. During examination of vital signs, there were no significant deviations observed from the baseline values, and no clinically significant changes were noted in poststudy laboratory data or results of physical examinations.
DISCUSSION Fibrates (especially fenofibrate) are the principal agents recommended for add-on therapy to treat elevated triglyceride levels or low HDL-C levels. Currently, there is strong evidence regarding the benefit of adding fenofibrate to statin treatment in high-risk patients with type 2 diabetes and dyslipidemia.10 An alternative approach is the addition of agents to reduce LDL-C beyond the levels attainable with statin monotherapy.11 Combination therapy with a statin and fibrate offers significant therapeutic advantages for the treatment of severe or refractory mixed hyperlipidemia. Although such a combination increases the risk of myopathy, with an incidence of 0.12%, this small risk rarely outweighs the established morbidity and mortality benefits of achieving lipid goals.12 The present study evaluated the comparative pharmacokinetics of a fenofibrate tablet formulation compared with an already marketed fenofibrate formulation in healthy human subjects under fasting conditions. Fifteen healthy adult subjects were planned for and recruited. The plasma samples of all subjects were analyzed for fenofibric acid. Three subjects did not arrive in subsequent periods due to personal reasons. Therefore, the final pharmacokinetic and statistical analyses included data from 12 subjects. The mean plasma concentrations of fenofibric acid for both formulations were similar and yielded overlapping curves. This observation was supported by the 90% CIs for the test/reference mean ratios of the ln-transformed pharmacokinetic variables Cmax, AUC 0–t , and AUC 0-1, which fell within the conventional bioequivalence range of 80% to 125%. The formulation effects for the pharmacokinetic variables Cmax, AUC 0–t, and AUC 0–1were statistically insignificant. Intrasubject variability observed for the reference formulation was low (o30%) for all 3 pharmacokinetic variables. It was concluded that both fenofibrate
6
formulations were equivalent to each other in terms of pharmacokinetics. Fibrates are known to interact with other drugs that share a high degree of binding to albumin or are metabolized by cytochrome P-450 (CYP)2C9. Clinically, the most important and most commonly reported drug interactions are with hydroxymethylglutaryl-coenzyme A reductase inhibitors.13,14 Because stringent inclusion/exclusion criteria were used in the present study, subjects were not included if they had taken these medications. Some limitations of the study design warrant mention. First, although the marketed drug product is used for both male and female patients, all the volunteers in the study were healthy male subjects. However, this choice can be justified because no literature could be identified demonstrating that there is a gender effect for this drug related to pharmacokinetics. Second, although there is literature supporting modulation of fenofibrate response by CYP7A1 polymorphisms,15 no such prescreening for subjects was conducted in this study. Pharmacokinetic variabilities can be reduced to a certain degree by selecting a genetically homogenous study population. In the United States, fibrate prescriptions increased from 336 prescriptions/100,000 population in January 2002 to 730 prescriptions/100,000 population in December 2009; crude fenofibrate expenditures increased from $11,535/100,000 population per month in 2002 to $44,975/100,000 population per month in 2009.16 High treatment costs of marketed fenofibrate formulations may compromise the medical management of patients. In such a case, therapeutically equivalent formulations at an affordable cost may enhance patient compliance to the treatment regimen.
CONCLUSIONS In these healthy male volunteers, both fenofibrate tablet formulations demonstrated equivalent rates and extent of systemic absorption, and hence were considered bioequivalent.
ACKNOWLEDGEMENT This study was sponsored by Cipla Limited. All authors contributed equally to the literature search, data interpretation, and writing of the manuscript.
CONFLICTS OF INTEREST The authors have indicated that they have no conflicts of interest regarding the content of this article.
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S.S. Chachad et al.
REFERENCES 1. World Health Organization. Cardiovascular diseases. Fact sheet N1317, updated March 2013. http://www. who.int/mediacentre/factsheets/ fs317/en/. Accessed September 11, 2013. 2. World Health Organization. The World Health Report 2002: reducing risks, promoting healthy life. Geneva, Switzerland: World Health Organization; 2002. http://www.who.int/ whr/2002/en/. Accessed September 11, 2013. 3. National Cholesterol Education Program (NCEP) Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002;106:3143–3421. 4. De Backer G, Ambrosioni E, BorchJohnsen K, et al. European guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J. 2003;24:1601–1610. 5. Brown WV. Focus on fenofibrate. Hosp Pract (Off Ed). 1988;23(Suppl 1): 31–40. 6. Blane GF. Review of European clinical experience with fenofibrate. Cardiology. 1989;76(Suppl 1):1–13. 7. Keech A, Simes RJ, Barter P, et al. FIELD study investigators. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): a randomised controlled trial. Lancet. 2005;366:1849– 1861. 8. Keating GM, Ormrod D. Micronised fenofibrate: an updated review of its clinical efficacy in the management of dyslipidaemia. Drugs. 2002;62: 1909–1944. 9. US Food and Drug Administration. TRICORs 48 mg and 145 mg (fenofibrate tablets). Prescribing Information from Abbott Laboratories,
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10.
11.
12.
13.
14.
15.
16.
USA. Label approved on 02/05/ 2013. http://www.accessdata.fda.gov. Accessed September 19, 2013. Bays HE, Jones PH, Mohiuddin SM, et al. Long-term safety and efficacy of fenofibric acid in combination with statin therapy for the treatment of patients with mixed dyslipidemia. J Clin Lipidol. 2008;2:426–435. Reiner Z. Managing the residual cardiovascular disease risk associated with HDL-cholesterol and triglycerides in statin-treated patients: a clinical update. Nutr Metab Cardiovasc Dis. 2013;23:799–807. Kota SK, Meher LK, Rao ES, et al. Efficacy and safety of statin and fibrate combination therapy in lipid management. Diabetes Metab Syndr. 2012;6:173–174. Miller DB, Spence JD. Clinical pharmacokinetics of fibric acid derivatives (fibrates). Clin Pharmacokinet. 1998;34:155–162. Kim KY, Mancano MA. Fenofibrate potentiates warfarin effects. Ann Pharmacother. 2003;37:212–215. Shen J, Arnett DK, Parnell LD, et al. The effect of CYP7A1 polymorphisms on lipid responses to fenofibrate. J Cardiovasc Pharmacol. 2012; 59:254–259. Jackevicius CA, Tu JV, Ross JS, et al. Use of fibrates in the United States and Canada. JAMA. 2011;305:1217– 1224.
Address correspondence to: Siddharth S. Chachad, Department of Clinical and Bioequivalence Research, Cipla Limited, 3rd Floor C Wing, Raj Plaza, L.B.S. Marg Vikhroli (W) 400083, Mumbai, India. E-mail: siddharth. [email protected]
7
Comparison of Pharmacokinetics of Two Fenofibrate Tablet Formulations in Healthy Human Subjects Siddharth S. Chachad1; Milind Gole1; Geena Malhotra1; and Raghu Naidu2 1
Department of Clinical and Bioequivalence Research, Cipla Limited, Mumbai, India; and 2Contract Research Organisation, Sitec Labs Pvt Ltd, Mumbai, India
ABSTRACT Background: Fenofibrate is a serum lipid-lowering agent used as an adjunct to diet in patients with hypercholesterolemia and hypertriglyceridemia. The new fenofibrate tablet formulation was developed as a pharmaceutical equivalent to the marketed tablet formulation containing 145 mg. Objective: The objective of this study was to compare the pharmacokinetics and safety of 2 tablet formulations containing 145 mg of fenofibrate (CAS number 49562-28-9) in healthy human subjects. Methods: The study was a randomized, 2-treatment, 3-period, 3-sequence, single-dose, 3-way crossover, partial replicate bioequivalence study in healthy human subjects under fasting conditions. Eligible subjects received each treatment in a crossover manner according to the randomization schedule. Replicate dosing was conducted for the reference formulation to determine its intrasubject variability. The predose blood sample was taken within 1 hour before dosing, and serial blood sampling was performed up to 72.0 hours’ postdose. The analysis of plasma samples for concentrations of fenofibric acid, the active metabolite of fenofibrate, was conducted by using a validated LCMS/MS method. Bioequivalence was to be concluded if the 90% CIs as constructed were within the range of 80% to 125% for Cmax, AUC0–t, and AUC0–1 for fenofibric acid. Subjects were monitored for safety and tolerability throughout the study. Results: 15 healthy human subjects between 18 and 45 years of age and having body mass index between 18.5 and 30 kg/m2 were recruited into the study. The 90% CIs for the test/reference mean ratios of the lntransformed pharmacokinetic variables Cmax, AUC0–t, and AUC0–1 were within the conventional bioequivalence range of 80% to 125%. Both formulations were well tolerated after a single oral dose in these healthy male subjects. Conclusions: Both fenofibrate tablet formulations demonstrated equivalent rates and extent of systemic
] 2014
absorption, and hence were considered bioequivalent. (Clin Ther. 2014;]:]]]–]]]) & 2014 Elsevier HS Journals, Inc. All rights reserved. Key words: bioequivalence, fenofibrate, pharmacokinetics.
INTRODUCTION According to the World Health Organization fact sheet No. 317 (updated March 2013), cardiovascular diseases are the number one cause of death globally: more people die annually of cardiovascular diseases than of any other cause.1 Most cardiovascular diseases can be prevented by addressing risk factors such as tobacco use, unhealthy diet and obesity, physical inactivity, high blood pressure, diabetes, and increased lipid levels. Elevated serum cholesterol is a modifiable risk factor that is associated with an estimated 4.4 million deaths each year and accounts for a considerable proportion of ischemic strokes and heart disease worldwide.2 Therapeutic lifestyle changes (reduced dietary intake of saturated fats and cholesterol, weight control, and increased physical activity) form the core of all cholesterol-lowering initiatives. Supplemental therapy with lipid-lowering medications has been shown to safely reduce the longterm incidence of major cardiovascular events in secondary prevention trials and in high-risk primary prevention trials, and this therapy is universally recommended in patients with established or at high predicted risk of cardiovascular disease.3,4 Fenofibrate is marketed in 86 countries and is one of the most commonly used fibrates worldwide, with 46 million patient-years of experience.5 More than Accepted for publication April 14, 2014. http://dx.doi.org/10.1016/j.clinthera.2014.04.017 0149-2918/$ - see front matter & 2014 Elsevier HS Journals, Inc. All rights reserved.
1
Clinical Therapeutics 80 clinical trials of fenofibrate have been conducted, involving 49000 patients and 431,000 patient-years of drug exposure.6,7 Fenofibrate’s indications include hypercholesterolemia, combined dyslipidemia, remnant hyperlipidemia, endogenous hyperlipemia (hypertriglyceridemia), and mixed hyperlipemia (Fredrickson types IIa, IIb, III, IV, and V dyslipidemia, respectively).8 Fenofibrate is a prodrug of the active chemical moiety fenofibric acid. Fenofibrate is converted by ester hydrolysis in the liver to fenofibric acid, which is the active constituent measurable in the circulation. After oral administration in healthy volunteers, peak plasma levels of fenofibric acid occur within 6 to 8 hours after administration. After absorption, 60% of a single dose of radiolabeled fenofibrate is excreted in the urine, primarily as fenofibric acid and its glucuronate conjugate, and 25% is excreted in the feces.9 Several reformulations of fenofibrate dominate the market, although generic fenofibrate has been available for almost a decade. This continued use of branded formulations, which cost twice as much as generic versions of fenofibrate, imposes a high cost on the health care system. It is hence essential that lowcost yet equally effective and safe drug formulations are made available. In anticipation of the patent expiry, a pharmaceutical equivalent to the marketed fenofibrate 145-mg tablets was developed (by Cipla Limited, Mumbai, India). The objective of the present study was to compare the pharmacokinetics and safety of 2 tablet formulations containing 145 mg of fenofibrate (CAS number 49562-28-9) in healthy human subjects.
SUBJECTS AND METHODS This study was conducted at Sitec Labs Pvt Ltd (Mumbai, India) in accordance with the ethical standards presented in the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. Before the start of the study, written informed consent was obtained from all patients, and the protocol was approved by the local ethical review boards.
Subjects This research was conducted as a pilot study with a minimum number of 12 evaluable subjects. Thus, to obtain data in at least 12 subjects completing the study and considering dropout and discontinued
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subjects, 15 subjects were recruited. Healthy human subjects between 18 and 45 years of age and having a body mass index between 18.5 and 30 kg/m2 were included. Eligible subjects were considered healthy, as demonstrated by no medical history of significant diseases and no clinically significant abnormal findings during the prestudy screening, physical examination, and laboratory evaluations. Results of a breath alcohol test, test for drugs of abuse, and a urine pregnancy test (for female subjects) were negative at the time of screening. Hepatitis A, B, and C and antibodies to HIV I and II, Venereal Disease Research Laboratory test were negative or nonreactive. Subjects were excluded if they were allergic to fenofibrate; had a history of or current cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal, metabolic, immunologic, dermatologic, neurologic, or psychiatric disease; had participated in any other clinical investigation using an investigational product; or had donated 4350 mL of blood within 90 days before the first dose of study drug. Subjects were excluded from the study if they had taken any prescription medication (eg, coumarin anticoagulant, cyclosporine, tacrolimus, bile acid resins), over-the-counter products (eg, vitamins, products of natural origin [including St. John’s wort]), or topical medications meant for systemic absorption within 7 days before administration of the investigational product. All subjects were instructed to abstain from consuming grapefruit or its products and alcohol/ alcoholic products for at least 48 hours before dosing until the last blood sampling in each study period. They were also instructed to abstain from consuming citrus fruits or their products and xanthine-containing products (chocolate, tea, coffee, or cola drink); they were prohibited from smoking and consuming tobacco or tobacco-containing products for at least 24 hours before dosing.
Study Design The pharmacokinetics of 2 fenofibrate tablet formulations were compared in this randomized, 2-treatment, 3-period, 3-sequence, single-dose, 3-way crossover, partial replicate bioequivalence study. All 15 recruited subjects were administered treatment in a crossover manner under fasting conditions according to the randomization schedule. Replicate dosing was conducted for the reference formulation to determine its intrasubject variability. Because this was a
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S.S. Chachad et al. crossover study, each subject acted as his own control when taking the investigational product on each occasion. The 3 periods of the study were separated by a 9-day washout period, which is 410 times the reported t½ of fenofibric acid (ie, 20 hours).9 The study procedure was repeated in each period with the administration of the investigational product as per randomization details. On the prestudy day, before admission of subjects into the clinical pharmacology unit (CPU) prior to the first dose, the subjects were given full details of the study, both in writing and verbally, by the principal investigator or designated staff. Check-in was followed by catering, vital sign examination, and wellbeing assessment. There was a supervised overnight fasting period of at least 10 hours before dosing. A baseline blood sample was taken within 1 hour before dosing, and while the subject was seated upright, either the test or reference product was administered orally with 240 mL of water. Thereafter, a series of blood samples were taken over the following 24 hours’ postdose with the subject remaining in the CPU. Subjects were allowed to leave the CPU after their vital sign examinations were conducted, their well-being was assessed, and the 24 hours’ postdose blood sample was collected. The subjects returned to the CPU for 48- and 72-hour postdose blood sampling. Breath alcohol test, test for drugs of abuse, vital sign examination, and well-being assessments were performed during the ambulatory visit before blood sampling.
Pharmacokinetic Sampling In the morning of the dosing day, an intravenous cannula was inserted into a forearm vein to facilitate the withdrawal of the blood samples. Blood samples of 5 mL were collected into labeled vacuum tubes containing K2-EDTA as anticoagulant. The samples were kept in an ice water bath until they were centrifuged. The baseline predose sample was taken within 1 hour before dosing. After dosing, samples were taken at 1, 2, 3, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 12, 16, 24, 48, and 72 hours’ postdose. The cannula was withdrawn after the 16-hour postdose blood sample, and 24-, 48-, and 72-hour samples were obtained by direct venipuncture. The choice of the blood sampling time schedule was intended to cover the expected time of the peak plasma concentrations of fenofibric acid, which is at
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6 to 8 hours. It was also extended for sufficient time to be able to obtain a reliable estimate of AUC0–1. The last sample collection was at 72 hours’ postdose, which is 43 times the maximum reported t½ of fenofibric acid (ie, 20 hours), which is sufficient to cover at least 80% of the AUC0–1.9 The blood samples were centrifuged at 10 (2)1C and at 2500 to 3000 rpm for 10 minutes. Each plasma sample was divided into 2 aliquots stored in separate, stoppered, and suitably labeled tubes. All plasma samples were kept upright in dry ice below –201C until delivery to the analytical center for assay. They were stored upright in a deep freezer at a temperature of –70 (10)1C until the completion of analysis.
Analytical Assay The concentrations of fenofibric acid in the plasma of study subjects were measured by using a validated LC-MS/MS method in accordance with the principles of Good Laboratory Practice. The bioanalytical method was developed and validated at Sitec Labs Pvt Ltd. Fenofibric acid was extracted from human plasma by using a liquid–liquid extraction procedure and injected into the liquid chromatograph coupled with a tandem MS/MS detector. The analyte (fenofibric acid) and internal standard (fenofibric D6 acid) were extracted from 100 mL of plasma sample by using tert-Butyl methyl ether, which was then evaporated and the residue was reconstituted in the mobile phase. The liquid chromatograph and mass spectrometer used for this analysis was Agilent 1100 series HPLC (Agilent, Germany) and PE Sciex API 2000 mass spectrometer (MDS Sciex, Toronto, Canada). The mobile phase consisted of acetonitrile and 0.2% formic acid in the proportion of 80:20 and column used was ACE 3 C18, 100 mm 3.0 mm, 3µ (Advanced Chromatography Technologies, Scotland). The flow rate of the mobile phase was 500 mL/min, and the injection volume was 10 mL. The retention time of the analyte and internal standard was 1.46 minutes, and the chromatographic run time was 2.5 minutes. Quantitation was performed by using the internal standard method. Fenofibric D6 acid was used as the internal standard. Fenofibric acid and the internal standard were detected by LC-MS/MS in multiple reaction monitoring with negative polarity mode using the mass transitions 317.00/231.00 amu and 323.00/230.90 amu, respectively. A weighted linear regression using weighting 1/concentration2
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Clinical Therapeutics was prepared to determine the concentration of fenofibric acid in human plasma. The bioanalytical method validation parameters were system suitability, carryover test, specificity and selectivity, matrix effect, sensitivity, linearity (calibration curve), precision and accuracy, ruggedness, hemolysis effect, recovery, stability under different conditions, plasma dilution integrity, and re-injection reproducibility. The lower limit of quantitation (LLOQ) of this method for the measurement of fenofibric acid concentrations in plasma was 99.6 ng/mL. The linearity range was 99.6 to 19,928.1 ng/ mL for fenofibric acid. Four precision and accuracy sets were analyzed during method validation, and each set consisted of 7 quality control (QC) samples each at 5 different concentration levels (low QC, midQC–A, mid-QC–B, and high QC). The within-batch precision (%CV) ranged from 0.99% to 4.91% and the within-batch accuracy (%nominal) ranged from 88.96% to 106.93%. The between-batch precision (% CV) ranged from 1.77% to 6.04% and the betweenbatch accuracy (%nominal) ranged from 92.20% to 99.60%. During study sample analysis, QC samples were distributed throughout each batch. To avoid bias, the analyst did not have access to the randomization code. Samples for any given subject for all time points were assayed under similar chromatographic conditions that were validated for the analysis of fenofibric acid in human plasma. The between-batch precision (%CV) of QC samples ranged from 2.39% to 3.60% and the between-batch accuracy ranged from 97.02% to 100.01%. Concentrations below the LLOQ were set to zero for pharmacokinetic and statistical calculations.
Study Outcomes The primary objective of the present study was to compare the rate and extent of absorption of fenofibric acid after administration of test or reference fenofibrate tablet formulations in healthy adult human subjects. The secondary objective of the study was to monitor the safety and tolerability of a single dose of fenofibrate 145 mg when administered to these subjects under fasting conditions. The safety profile was evaluated by monitoring all the subjects for adverse events throughout the course of the study. An adverse event was defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product, which need
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not necessarily have a causal relationship with the treatment. Recording of the vital signs at predetermined intervals and the comparison of prestudy and poststudy laboratory parameters formed the basis of the safety evaluation.
Pharmacokinetic Assessment The pharmacokinetic parameters evaluated for fenofibric acid were Cmax, AUC0–t, AUC0–1, Tmax, ke, and t½. Cmax and Tmax were taken directly from the plasma concentration–time profiles of individual subjects. AUC0–t was estimated by using the linear trapezoidal rule, and AUC0–1 was obtained as (AUC0–t þ Clast)/ke, where Clast was the last quantifiable concentration and ke was the terminal rate constant. For the estimation of ke, time points after Tmax in the elimination phase were used to fit a linear regression on the log concentration data with a base 10 using the least squares methods. The t½ was estimated (in hours) from the slope (ke) of the terminal phase of the semi-logarithmic plot of the plasma concentration curve (t½ ¼ ln 2/ke). All pharmacokinetic parameters were calculated by using the noncompartmental method using WinNonlin version 6.3 (Pharsight Corporation, Sunnyvale, California).
Statistical Analysis Statistical analysis of fenofibric acid plasma concentration data and pharmacokinetic parameters was performed by using WinNonlin version 6.3 and SAS version 9.3 (SAS Institute, Inc, Cary, North Carolina). ANOVA was performed (α ¼ 0.05) on the untransformed and ln-transformed pharmacokinetic parameters Cmax, AUC0–t, and AUC0–1. The ANOVA model included sequence, patients nested within sequence, period, and treatment as factors. Each ANOVA model also included calculation of least squares mean (LSM) values, adjusted differences between formulation means, and the SE associated with these differences. The significance of the sequence effect was tested by using the subjects nested within the sequence as the error term. Geometric LSM values were reported for lntransformed Cmax, AUC0–t, and AUC0–1. Ratios of means were calculated by using the LSM for untransformed and ln-transformed Cmax, AUC0–t, and AUC0–1. Ratios of means were expressed as a Volume ] Number ]
Concentration (ng/mL)
S.S. Chachad et al. formula: intrasubject CV ¼ sqrt(exp[residual_variance] – 1), where residual_variance (ie, mean square error) was obtained from the ANOVA model, in which factors such as sequence, period, formulation, and subject(sequence) were used on the log-transformed data.
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Reference Product Test Product
1 0
12
24
36 Time (h)
48
60
72
Figure. Mean plasma concentration–time profile of fenofibrate.
percentage of the LSM for the reference treatment (marketed formulation). Consistent with the 2 one-sided tests for bioequivalence, 90% CIs for the difference between treatments, LSM were calculated for both untransformed and ln-transformed C max, AUC0–t, and AUC 0–1. The test product was to be considered bioequivalent to the reference product if the 90% CIs of Cmax, AUC0–t, and AUC0–1 of fenofibric acid were within the acceptance range of 80% to 125%. If the within-subject SD was Z0.294 (ie, intrasubject variability) for the reference product, then a reference-scaled average bioequivalence procedure was to be used to determine bioequivalence for the individual pharmacokinetic parameters. Intrasubject variability was estimated by using the
15 healthy human subjects between 18 and 45 years of age and having body mass index between 18.5 and 30 kg/m2 were recruited into the study. The mean plasma concentration–time profile obtained after single oral administration of fenofibrate 145 mg in the form of test and reference formulations is shown in the Figure. For fenofibric acid, the mean ratios (for test/reference) and 90% CIs for the ln-transformed parameters of Cmax, AUC0–t, and AUC0–1 are listed in the Table. Because the 90% CIs for the lntransformed test and reference treatment averages were within the bioequivalence acceptance range of 80% to 125%, the test and reference treatments were considered to be bioequivalent. The observed intrasubject variability for the reference product lntransformed parameters of Cmax, AUC0–t, and AUC0–1 were 13.59%, 7.25%, and 7.51%, respectively. Both formulations of fenofibrate 145 mg were reasonably tolerated after a single oral dose in these healthy male subjects. Mild to moderate adverse events, including abdominal pain, nausea, diarrhea, headache, and fever, were observed in some subjects during the study. However, these events resolved after counseling or medical treatment, and there was no definite causal relationship established with either of
Table. Pharmacokinetic parameters and the 90% CIs after a single oral dose of fenofibrate 145 mg. Geometric LSM
Test
Reference
Test/Reference Ratio of Geometric LSM (%)
10,781.18 17,6920.61 19,5084.26
11,015.99 17,9269.01 19,5363.89
97.87 98.69 99.86
Parameter Cmax, ng/mL AUC0–t, h ng/mL AUC0–1, h ng/mL
90% CI
Intrasubject %CV
91.04–105.21 93.96–103.65 94.78–105.21
11.69 7.92 8.43
LSM ¼ least squares mean.
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Clinical Therapeutics the 2 administered products. No serious adverse events or deaths were reported during the conduct of the study. During examination of vital signs, there were no significant deviations observed from the baseline values, and no clinically significant changes were noted in poststudy laboratory data or results of physical examinations.
DISCUSSION Fibrates (especially fenofibrate) are the principal agents recommended for add-on therapy to treat elevated triglyceride levels or low HDL-C levels. Currently, there is strong evidence regarding the benefit of adding fenofibrate to statin treatment in high-risk patients with type 2 diabetes and dyslipidemia.10 An alternative approach is the addition of agents to reduce LDL-C beyond the levels attainable with statin monotherapy.11 Combination therapy with a statin and fibrate offers significant therapeutic advantages for the treatment of severe or refractory mixed hyperlipidemia. Although such a combination increases the risk of myopathy, with an incidence of 0.12%, this small risk rarely outweighs the established morbidity and mortality benefits of achieving lipid goals.12 The present study evaluated the comparative pharmacokinetics of a fenofibrate tablet formulation compared with an already marketed fenofibrate formulation in healthy human subjects under fasting conditions. Fifteen healthy adult subjects were planned for and recruited. The plasma samples of all subjects were analyzed for fenofibric acid. Three subjects did not arrive in subsequent periods due to personal reasons. Therefore, the final pharmacokinetic and statistical analyses included data from 12 subjects. The mean plasma concentrations of fenofibric acid for both formulations were similar and yielded overlapping curves. This observation was supported by the 90% CIs for the test/reference mean ratios of the ln-transformed pharmacokinetic variables Cmax, AUC 0–t , and AUC 0-1, which fell within the conventional bioequivalence range of 80% to 125%. The formulation effects for the pharmacokinetic variables Cmax, AUC 0–t, and AUC 0–1were statistically insignificant. Intrasubject variability observed for the reference formulation was low (o30%) for all 3 pharmacokinetic variables. It was concluded that both fenofibrate
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formulations were equivalent to each other in terms of pharmacokinetics. Fibrates are known to interact with other drugs that share a high degree of binding to albumin or are metabolized by cytochrome P-450 (CYP)2C9. Clinically, the most important and most commonly reported drug interactions are with hydroxymethylglutaryl-coenzyme A reductase inhibitors.13,14 Because stringent inclusion/exclusion criteria were used in the present study, subjects were not included if they had taken these medications. Some limitations of the study design warrant mention. First, although the marketed drug product is used for both male and female patients, all the volunteers in the study were healthy male subjects. However, this choice can be justified because no literature could be identified demonstrating that there is a gender effect for this drug related to pharmacokinetics. Second, although there is literature supporting modulation of fenofibrate response by CYP7A1 polymorphisms,15 no such prescreening for subjects was conducted in this study. Pharmacokinetic variabilities can be reduced to a certain degree by selecting a genetically homogenous study population. In the United States, fibrate prescriptions increased from 336 prescriptions/100,000 population in January 2002 to 730 prescriptions/100,000 population in December 2009; crude fenofibrate expenditures increased from $11,535/100,000 population per month in 2002 to $44,975/100,000 population per month in 2009.16 High treatment costs of marketed fenofibrate formulations may compromise the medical management of patients. In such a case, therapeutically equivalent formulations at an affordable cost may enhance patient compliance to the treatment regimen.
CONCLUSIONS In these healthy male volunteers, both fenofibrate tablet formulations demonstrated equivalent rates and extent of systemic absorption, and hence were considered bioequivalent.
ACKNOWLEDGEMENT This study was sponsored by Cipla Limited. All authors contributed equally to the literature search, data interpretation, and writing of the manuscript.
CONFLICTS OF INTEREST The authors have indicated that they have no conflicts of interest regarding the content of this article.
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REFERENCES 1. World Health Organization. Cardiovascular diseases. Fact sheet N1317, updated March 2013. http://www. who.int/mediacentre/factsheets/ fs317/en/. Accessed September 11, 2013. 2. World Health Organization. The World Health Report 2002: reducing risks, promoting healthy life. Geneva, Switzerland: World Health Organization; 2002. http://www.who.int/ whr/2002/en/. Accessed September 11, 2013. 3. National Cholesterol Education Program (NCEP) Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002;106:3143–3421. 4. De Backer G, Ambrosioni E, BorchJohnsen K, et al. European guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J. 2003;24:1601–1610. 5. Brown WV. Focus on fenofibrate. Hosp Pract (Off Ed). 1988;23(Suppl 1): 31–40. 6. Blane GF. Review of European clinical experience with fenofibrate. Cardiology. 1989;76(Suppl 1):1–13. 7. Keech A, Simes RJ, Barter P, et al. FIELD study investigators. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): a randomised controlled trial. Lancet. 2005;366:1849– 1861. 8. Keating GM, Ormrod D. Micronised fenofibrate: an updated review of its clinical efficacy in the management of dyslipidaemia. Drugs. 2002;62: 1909–1944. 9. US Food and Drug Administration. TRICORs 48 mg and 145 mg (fenofibrate tablets). Prescribing Information from Abbott Laboratories,
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USA. Label approved on 02/05/ 2013. http://www.accessdata.fda.gov. Accessed September 19, 2013. Bays HE, Jones PH, Mohiuddin SM, et al. Long-term safety and efficacy of fenofibric acid in combination with statin therapy for the treatment of patients with mixed dyslipidemia. J Clin Lipidol. 2008;2:426–435. Reiner Z. Managing the residual cardiovascular disease risk associated with HDL-cholesterol and triglycerides in statin-treated patients: a clinical update. Nutr Metab Cardiovasc Dis. 2013;23:799–807. Kota SK, Meher LK, Rao ES, et al. Efficacy and safety of statin and fibrate combination therapy in lipid management. Diabetes Metab Syndr. 2012;6:173–174. Miller DB, Spence JD. Clinical pharmacokinetics of fibric acid derivatives (fibrates). Clin Pharmacokinet. 1998;34:155–162. Kim KY, Mancano MA. Fenofibrate potentiates warfarin effects. Ann Pharmacother. 2003;37:212–215. Shen J, Arnett DK, Parnell LD, et al. The effect of CYP7A1 polymorphisms on lipid responses to fenofibrate. J Cardiovasc Pharmacol. 2012; 59:254–259. Jackevicius CA, Tu JV, Ross JS, et al. Use of fibrates in the United States and Canada. JAMA. 2011;305:1217– 1224.
Address correspondence to: Siddharth S. Chachad, Department of Clinical and Bioequivalence Research, Cipla Limited, 3rd Floor C Wing, Raj Plaza, L.B.S. Marg Vikhroli (W) 400083, Mumbai, India. E-mail: siddharth. [email protected]
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