| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
DRUG INTERACTIONS |
From Abbott, Abbott Park, Illinois (Dr Zhu, Dr Awni, Dr Kelly, Dr Sleep, Dr Stolzenbach, Dr Wan, Mr Chira, Dr Pradhan) and Northern Illinois University, DeKalb, Illinois (Dr Hosmane).
Address for reprints: Tong Zhu, PhD, 100 Abbott Park Road, Dept R4PK, Bldg AP13A-3, Abbott Park, IL 60064-6104; e-mail: Tong.Zhu{at}abbott.com.
 |
ABSTRACT |
|---|
 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONACKNOWLEDGEMENTSREFERENCES |
|---|
Key Words: fenofibric acid • fibrate • rosuvastatin • dyslipidemia
Current guidelines from the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Cholesterol in Adults consider LDL-C the primary target of cholesterol-lowering therapy, but also highlight high triglycerides (TG) and low high-density lipoprotein cholesterol (HDL-C) as 2 additional risk factors for CHD.3 Mixed dyslipidemia (atherogenic dyslipidemia) is a common lipid abnormality characterized by elevated TG (
150 mg/dL), low HDL-C (<40 mg/dL men, <50 mg/dL women), and moderately elevated LDL-C with high numbers of small LDL particles. Patients with mixed dyslipidemia are at increased risk for CHD by virtue of this abnormal lipid triad, as well as the association of mixed dyslipidemia with abdominal obesity, impaired fasting glucose, and hypertension.4,5
Management of cardiovascular risk profiles in patients with the mixed dyslipidemia represents a substantial clinical challenge and requires aggressive lipid-altering therapy. However, single-agent therapy, including potent statins, frequently is unable to simultaneously normalize the elevated levels of LDL-C and TG and raise low levels of HDL-C to desired levels. Therefore, combination therapy, specifically fibric acid derivatives in combination with a statin, has become more prevalent in clinical practice.
Fibric acid derivatives (fibrates) and statins affect lipids through different mechanisms. Fibrates alter lipid levels through a complex mechanism involving activation of peroxisome proliferator-activated receptors (PPARs), which regulate gene transcription. Statins affect lipid levels by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that mediates the rate-limiting step of conversion of HMG-CoA to mevalonate in the biosynthesis of cholesterol.
ABT-335 is the choline salt of fenofibric acid, the active metabolite of fenofibrate. ABT-335 is currently in development for use as monotherapy or in combination with statins for the treatment of lipid abnormalities. In vivo, ABT-335 dissociates to release free fenofibric acid in the gastrointestinal tract. Fenofibric acid does not undergo oxidative metabolism (eg, cytochrome P450) to a significant extent and is primarily conjugated with glucuronic acid and excreted in urine. The elimination half-life is approximately 20 hours in participants with normal renal functions. The recommended daily dosage of ABT-335 is expected to be 135 mg fenofibric acid equivalent once daily.
Rosuvastatin is a selective, potent HMG-CoA reductase inhibitor. It is indicated as an adjunct to diet to reduce elevated total-C, LDL-C, apoB, non-HDL-C, and TG levels and to increase HDL-C in patients with primary hypercholesterolemia and mixed dyslipidemia, as well as reduce LDL-C, total-C, and apoB in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering treatments or if such treatments are unavailable.6 Rosuvastatin is not extensively metabolized; approximately 10% of a radiolabeled dose is recovered as metabolite. The major metabolite is N-desmethyl rosuvastatin, which is formed principally by cytochrome P450 (CYP) 2C9, and in vitro studies have demonstrated that N-desmethyl rosuvastatin has approximately one sixth to one half the HMG-CoA reductase inhibitory activity of rosuvastatin. Overall, greater than 90% of active plasma HMG-CoA reductase inhibitory activity is accounted for by rosuvastatin. Rosuvastatin and its metabolites are primarily excreted in the feces (90%). The elimination half-life (t
) of rosuvastatin is approximately 19 hours.6 Active transporters such as organic anion-transporting polypeptide 1B1 (OATP1B1, OATP-C, OATP-2, gene SLCO1B1),7-9 organic anion transporter 3 (OAT3),10 and breast cancer resistance protein (BCRP)11,12 are involved in the distribution and elimination of rosuvastatin.
A concern with administering fibrates and statins in combination has been the potential for a pharmacokinetic interaction resulting in increased systemic levels of either drug, accompanied by toxic effects such as myopathy. Schneck et al9 reported that the coadministration of gemfibrozil, a fibrate, approximately doubled rosuvastatin plasma concentrations. Similar effects of gemfibrozil on pravastatin, simvastatin acid, and lovastatin acid were reported.13-15 Gemfibrozil coadministration was also shown to increase exposure to atorvastatin and its metabolites by 24% to 82% and to increase cerivastatin exposure by 559%.16,17 In contrast to gemfibrozil, a multiple-dose study conducted by Martin et al18 indicated that the coadministration of rosuvastatin and fenofibrate produced minimal changes in rosuvastatin and fenofibric acid exposure. Other studies also showed that fenofibrate coadministration has resulted in little to no increase in systemic exposure of pravastatin, simvastatin, simvastatin acid, or atorvastatin.19-22
The current study was designed to evaluate the potential pharmacokinetic interactions between ABT-335 and rosuvastatin. The highest dose approved for rosuvastatin, 40 mg, and the full clinical dose of ABT-335, 135 mg, were coadministered once daily for 10 days. The pharmacokinetic interactions were evaluated under steady-state conditions.
|
METHODS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONACKNOWLEDGEMENTSREFERENCES |
|---|
Randomizing 18 participants was expected to provide at least 99% power to detect a 25% higher fenofibric acid AUC central value with the combination regimen than with ABT-335 alone and at least 95% power to detect a 43% higher fenofibric acid Cmax central value with the combination regimen than with ABT-335 alone. The power for rosuvastatin AUC and Cmax was expected to be higher than the power for fenofibric acid AUC. The study was conducted in accordance with the protocol, good clinical practice (GCP) guidelines, applicable regulations, and guidelines governing clinical study conduct and ethical principles that have their origin in the Declaration of Helsinki. The Victory Memorial Hospital Institutional Review Board approved the protocol, informed consent, and other information as relevant (eg, advertising, written information provided to participants) prior to any volunteer participating in the study. All participants voluntarily provided written informed consent prior to participating in the study.
Participants were randomly assigned to 1 of 6 sequences to receive 1 of the 3 treatments on study days 1 through 10 of each period: one 135-mg ABT-335 capsule, one rosuvastatin 40-mg tablet (Crestor, AstraZeneca, Wilmington, Delaware), or a 135-mg ABT-335 capsule plus a rosuvastatin 40-mg tablet (coadministration regimen). Each dose was taken orally with approximately 240 mL of water 30 minutes after the start of a low-fat breakfast. A washout interval of at least 14 days separated the last dose of one treatment period and the first day of the next period.
Participants were confined to the study site for approximately 16 days in each treatment period. Meals during confinement were standardized; included no caffeine, alcohol, grapefruit, or grape-fruit juice; and provided approximately 30% of the daily calories from fat. The breakfast content was identical on the intensive pharmacokinetic sampling days (study day 10) in each period.
For the assay of fenofibric acid plasma concentrations, blood samples were collected into 2-mL evacuated collection tubes containing potassium oxalate plus sodium fluoride within 5 minutes prior to dosing (0 hours) on study days 1, 5, 7, 8, 9, and 10 and at 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 18, 24, 48, 72, 96, and 120 hours after the dosing on study day 10 of ABT-335 alone and coadministration regimens. For the assay of rosuvastatin plasma concentrations, blood samples were collected into 6-mL evacuated collection tubes containing edetic acid (EDTA) within 5 minutes prior to dosing (0 hours) on study days 1, 5, 7, 8, 9, and 10 and 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 30, 48, 72, 96, and 120 hours after the dosing on study day 10 of rosuvastatin alone and coadministration regimens. Sufficient blood was collected to provide approximately 1 mL plasma for the fenofibric acid assay and approximately 3 mL plasma for the rosuvastatin assay. Each blood sample was centrifuged within 1 hour of collection in a refrigerated centrifuge, and the plasma was frozen at -20°C or colder within 3 hours after collection. Plasma samples remained frozen until analysis.
Analytical Methods
Plasma concentrations of fenofibric acid were determined at Abbott (Abbott Park, Illinois) using a validated liquid chromatography method with tandem mass spectrometric detection (LC/MS/MS). In brief, plasma samples (0.05 mL) were mixed with internal standard 2-(2, 4, 5-trichlorophenoxy)-propionic acid (Pestanal; 0.05 mL), extracted by adding 0.15 mL of organic extraction solvent (2 mM acetate acid), and vortexed for 1 minute. After extraction, the organic layer was transferred to a clean 96-well plate, and the solvent was evaporated under nitrogen at room temperature (approximately 24°C). The dry residue was reconstituted with 50 mL of mobile phase and 50 mL of water, and then 40 mL was injected into the high-performance LC system. Separation was achieved by using a Waters Symmetry Shield RP18, 5 mm (2.1 x 50 mm), at room temperature. The mobile phase was 1:2 acetonitrile (ACN)/H2O (4.7 mM ammonium, 6 mM acetate). The flow rate was 0.3 mL/min. Quantitation was determined by a mass spectrometer (PE Sciex API-3000, Applied Biosystems/MDS Sciex) using the (Turbo IonSpray) electrospray ion source and monitoring the precursor-to-product ion reaction channels: m/z 317 
231 for ABT-335 and m/z 267 195 for the internal standard (2-(2, 4, 5-trichlorophenoxy)-propionic acid [Pestanal]). The concentrations of ABT-335 in unknown samples were calculated by interpolation, using the regression parameters of the calibration curve. The lower limit of quantitation (LLOQ) for fenofibric acid was established at 0.019 µg/mL using a 0.05-mL plasma sample. The in-study calibration contained 10 standards ranging from approximately 0.019 to 5.3 µg/mL. All calibration curves had correlation coefficient (r2) values greater than or equal to 0.9948. Samples quantified above the highest standard were diluted and assayed with a set of quality control (QC) samples with the same dilution factor. Samples quantified below the lowest standard were reported as zero. In-study QC samples, supplemented with concentrations of 0.05, 0.3, 1.3, and 4.2 µg/mL of fenofibric acid, were analyzed with the unknowns. The coefficient of variation (CV) values ranged from 2.7% to 5.8%; the mean bias values ranged from -1.2% to 4.9%.
Plasma concentrations of rosuvastatin were determined by PPD, Inc (Richmond, Virginia) using a validated LC/MS/MS method. The internal standard was rosuvastatin-d3 methylamine salt. The LLOQ for rosuvastatin was established at 0.100 ng/mL using a 200-µL plasma sample. The in-study calibration contained 8 standards ranging from approximately 0.100 to 100 ng/mL. All calibration curves had r2 values greater than or equal to 0.9991. Samples quantified above the highest standard were diluted and assayed with a set of QC samples with the same dilution factor. Samples quantified below the lowest standard were reported as <0.1. In-study QC samples, supplemented with concentrations of 0.300, 0.750, 3.00, 12.5, and 75.0 ng/mL of rosuvastatin, were analyzed with the unknowns. The CV values ranged from 2.86% to 7.68%; the mean bias values ranged from -7.11% to -4.39%.
All samples were analyzed within a timeframe for which frozen sample stability was documented.
Pharmacokinetic Parameters
Values of pharmacokinetic parameters for fenofibric acid and rosuvastatin were calculated by noncompartmental methods (WinNonlin-Professional, Version 4.1, Pharsight Corporation, Mountain View, California). Parameters estimated for each analyte included the maximum plasma concentration (Cmax), time of peak plasma concentration (tmax), minimum plasma concentration (Cmin), area under the plasma concentration versus time curve from time 0 to 24 hours (AUC0-24), apparent terminal elimination rate constant (
z), terminal phase elimination half-life (t), and apparent oral clearance (CL/F, where F is the bioavailability).
Statistical Methods
Only participants with data from the coadministration regimen and at least one other regimen were included in the statistical analyses for pharmacokinetic interactions. The data for all participants who received at least one dose of the study drug were included in the safety analyses.
The primary analysis was conducted to assess the pharmacokinetic interaction between fenofibric acid and rosuvastatin. An analysis of variance (ANOVA) was performed for tmax, z, and the natural logarithms of Cmax, Cmin, and AUC24 of fenofibric acid and rosuvastatin. Ninety percent confidence intervals for comparing pharmacokinetic parameters, Cmax, Cmin, and AUC24, between the coadministration regimen and ABT-335 or rosuvastatin-alone regimen were provided. The confidence intervals were obtained by exponentiating the endpoints of confidence intervals for the difference of mean logarithms obtained within the framework of the ANOVA model. No pharmacokinetic interaction was concluded if the 90% confidence intervals were contained within the equivalence range of 0.80 to 1.25.
A secondary analysis was conducted to assess the attainment of steady state for rosuvastatin and fenofibric acid concentrations. A linear mixed-effects model was used to analyze the predose concentrations of study days 5, 7, 8, 9, and 10. Within the framework of the model, the pairwise comparison between study day 10 and study days 5, 7, 8, and 9 using t tests was performed. All statistical tests were two-tailed and were performed at a significance level of 0.05. Computation for the statistical tests was performed with the SAS Version 8.2 (SAS Institute, Cary, North Carolina) using the Unix operating system. SAS procedure PROC MIXED with type III test was used for the analysis. SAS procedures PROC UNIVARIATE and PROC MEANS were used to obtain summary statistics.
The number and percentage of participants reporting treatment-emergent adverse events were tabulated by the Medical Dictionary for Regulatory Activities' (MedDRA's)23 preferred term and primary system organ class with a breakdown by regimen. Laboratory test values and vital signs measurements that were outside the predefined ranges were identified and evaluated for clinical significance.
|
RESULTS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONACKNOWLEDGEMENTSREFERENCES |
|---|
|
Effect of Rosuvastatin Coadministration on Fenofibric Acid Pharmacokinetics
Pairwise comparison of fenofibric acid predose concentrations between study days 5 and 10, 7 and 10, 8 and 10, and 9 and 10 showed that fenofibric acid predose concentrations were not statistically significantly different between study days 8 and 10 or between study days 9 and 10 (P = .3995 and .9977, respectively). The result indicates that steady state was reached by study day 8.
The mean (SD) plasma concentration-time profiles of fenofibric acid after the administration of ABT-335 alone and in combination with rosuvastatin are shown in Figure 1. Steady-state pharmacokinetic parameters of fenofibric acid from the 2 regimens are presented in Table II. The mean tmax, Cmax, Cmin, and AUC24 for fenofibric acid after the coadministration regimen were not statistically significantly different from those after the administration of ABT-335 alone (P .5687). The 90% confidence intervals for comparing fenofibric acid Cmax, Cmin, and AUC0-24 between the 2 regimens were within the range of 0.80 to 1.25 for establishing equivalence (Table III). These results indicate that rosuvastatin coadministration had no effect on fenofibric acid pharmacokinetics.
|
|
|
|
.1095). The 90% confidence intervals for comparing rosuvastatin Cmin and AUC0-24 between the 2 regimens were within the range of 0.80 to 1.25 for establishing equivalence (Table V).
|
|
|
|
DISCUSSION |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONACKNOWLEDGEMENTSREFERENCES |
|---|
The current study used the highest dose approved for rosuvastatin, 40 mg, and the expected full clinical dose of ABT-335, 135 mg. The results demonstrated no effect of rosuvastatin on the steady-state pharmacokinetics of fenofibric acid. Coadministering ABT-335 had no effect on the Cmin and AUC0-24 of rosuvastatin but increased rosuvastatin mean Cmax by 20%, and the upper bound of the 90% confidence interval for the ratio of the combined-regimen central value to the rosuvastatin-alone central value extended slightly above the upper limit of the range for establishing equivalence, 1.25 to 1.278. The magnitude of increase in rosuvastatin Cmax observed in the current study is similar to that reported by Martin et al.18 The slight increase in rosuvastatin Cmax when coadministered with ABT-335 is not clinically significant and would not require rosuvastatin dose adjustment not only because the absolute magnitude of the increase is small but because phase III clinical trials have shown that the use of rosuvastatin in combination with ABT-335 did not demonstrate new safety findings or adverse event rates above those expected based on the known safety profiles of the monotherapies.24
The results from the current study were in sharp contrast to those demonstrated when gemfibrozil (another fibrate) was combined with rosuvastatin. In a randomized, double-blind, 2-period crossover trial reported by Schneck et al,9 20 healthy volunteers were given oral doses of gemfibrozil 600 mg or placebo bid for 7 days. On the fourth morning of each dosing period, a single oral dose of rosuvastatin, 80 mg, was coadministered. Gemfibrozil increased rosuvastatin AUC by 88% (90% confidence interval: 1.60-2.21) and Cmax by 121% (90% confidence interval: 1.81-2.69) compared with placebo. The increases in rosuvastatin exposure are clinically significant.6
Rosuvastatin is not extensively metabolized. CYP2C9 is primarily responsible for the metabolism of rosuvastatin to form the major metabolite, N-desmethyl rosuvastatin, which has approximately one sixth to one half the HMG-CoA reductase inhibitory activity of rosuvastatin. Rosuvastatin accounts for >90% of active HMG-CoA reductase inhibitory activity in plasma.6 After oral administration, rosuvastatin is rapidly and selectively taken up from blood into the liver by OATP1B17-9 and is mainly excreted into the bile unchanged by BCRP.11,12 Gemfibrozil inhibits OATP1B1 at therapeutic concentrations.7 An in vitro study indicated that gemfibrozil inhibited the OATP1B1-mediated hepatic uptake of rosuvastatin by a maximum of 50%, which is likely the cause of the drug-drug interaction observed in vivo.9 By similar mechanism (ie, inhibition of OATP1B1), gemfibrozil significantly increases the exposure of active moieties of other statins, including simvastatin acid (185%), lovastatin acid (280%), pravastatin (202%), and atorvastatin and its metabolite (24%-82%).7,13-16 Gemfibrozil also potently inhibits CYP2C8 but does not appear to inhibit CYP3A4.7 As a result of dual inhibition of OATP1B1 and CYP2C8, gemfibrozil increases cerivastatin exposure by 559%.7,17 Literature data also suggest that the β-hydroxy acid forms of statins, which are pharmacologically active and include simvastatin acid, lovastatin acid, cerivastatin, atorvastatin, cerivastatin, and rosuvastatin, undergo glucuronidation mediated by uridine diphosphate glucuronosyltransferase (UGT) 1A1 and 1A3. Gemfibrozil inhibits UGTs, which may contribute to the observed increase in plasma exposures of simvastatin acid, lovastatin acid, cerivastatin, atorvastatin, and rosuvastatin in vivo.25,26
Following oral administration, ABT-335 disassociates to form fenofibric acid in the gastrointestinal tract. Fenofibric acid is primarily eliminated via urinary excretion of the glucuronide conjugate. There is no evidence to suggest that fenofibric acid inhibits OAPT1B1. Drug interaction studies in humans demonstrated that fenofibric acid following oral dosing of fenofibrate, the ester form of fenofibric acid, causes little to no increase in systemic exposure of pravastatin, simvastatin, simvastatin acid, or atorvastatin.19-22 In vitro studies showed that fenofibric acid is not an inhibitor of CYP3A, CYP2D6, CYP2E1, or CYP1A2, UGT 1A1 and 1A3.22,25 It is a weak inhibitor of CYP2C19 and CYP2A6 and a mild to moderate inhibitor of CYP2C9 at therapeutic concentrations.22 The inhibition of CYP2C9 may contribute to the slight increase in rosuvastatin Cmax by ABT-335 observed in the current study.
Systemic exposure of rosuvastatin in study participants of Japanese, Chinese, Malay, and Asian-Indian ancestry is about 2-fold of that for Caucasian participants in the same studies.27-30 Therefore, individuals self-identified as of Asian ancestry were excluded from this study for their safety and to reduce rosuvastatin pharmacokinetic variability.
Participants in our study received drug in the morning, under nonfasted conditions, to mimic the manner in which many patients take their medications. Neither rosuvastatin6 nor ABT-335 has a food effect, and thus fasting conditions were not required for this study. Consistent with anticipated therapeutic use for both ABT-335 and rosuvastatin, a low-fat menu was used that provided approximately 30% of the daily calories from fat. Unlike many other statins, rosuvastatin is equally effective after morning or evening administration.31 Fibrates including ABT-335 are not known to have a circadian effect.
|
CONCLUSION |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONACKNOWLEDGEMENTSREFERENCES |
|---|
|
ACKNOWLEDGEMENTS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONACKNOWLEDGEMENTSREFERENCES |
|---|
Financial disclosure: All authors are employed by Abbott except Balakrishna Hosmane, who is a statistical consultant for Abbott and employed by Northern Illinois University.
Walid Awni, PhD, is a Fellow of the American College of Clinical Pharmacology.
|
REFERENCES |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONACKNOWLEDGEMENTSREFERENCES |
|---|
1. McGovern ME. Taking aim at HDL-C. Postgraduate Med. 2005;117: 29-44.[Medline] [Order article via Infotrieve]
2. Wilt TJ, Bloomfield HE, MacDonald R, et al. Effectiveness of statin therapy in adults with coronary heart disease. Arch Intern Med. 2004;164: 1427-1436.
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 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. Sattar N, Gaw A, Scherbakova O, et al. Metabolic syndrome with and without C-reactive protein as a predictor of coronary heart disease and diabetes in the West of Scotland Coronary Prevention Study. Circulation. 2003;108: 414-419.
5. Ford E, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among U.S. adults, findings from the Third National Health and Nutrition Examination Survey. JAMA. 2002;287: 356-359.
6. Crestor (rosuvastatin calcium) [prescribing information]. Wilmington, DE: AstraZeneca; 2007.
7. Neuvonen PJ, Niemi M, Backman JT. Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance. Clin Pharmacol Ther. 2006;80: 565-581.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
8. Brown CDA, Windass A, Bleasby K, Lauffart B. Rosuvastatin is a high affinity substrate of hepatic organic anion transporter OATP-C [abstract]. Atherosclerosis. 2001;2: 90.
9. Schneck DW, Birmingham BK, Zalikowski JA, et al. The effect of gemfibrozil on the pharmacokinetics of rosuvastatin. Clin Pharmacol Ther. 2004;75: 455-463.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
10. Windass AS, Lowes S, Wang Y, Brown CDA. The contribution of organic anion transporters OAT1 and OAT3 to the renal uptake of rosuvastatin. J Pharmacol Exp Ther. 2007;322: 1221-1227.
11. Zhang W, Yu BN, He YJ, et al. Role of BCRP 421C>A polymorphism on rosuvastatin pharmacokinetics in healthy Chinese males. Clin Chim Acta. 2006;373: 99-103.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
12. Huang LY, Wang Y, Grimm S. ATP-dependent transport of rosuvastatin in membrane vesicles expressing breast cancer resistant protein. Drug Metab Dispos. 2006;34: 738-742.
13. Kyrklund C, Backman JT, Neuvonen M, Neuvonen PJ. Gemfibrozil increases plasma pravastatin concentrations and reduces pravastatin renal clearance. Clin Pharmacol Ther. 2003;73: 538-544.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
14. Backman JT, Kyrklund C, Kivistö KT, Wang J-S, Neuvonen PJ. Plasma concentrations of active simvastatin acid are increased by gemfibrozil. Clin Pharmacol Ther. 2000;68: 122-129.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
15. Kyrklund C, Backman JT, Kivistö KT, Neuvonen M, Laitila J, Neuvonen PJ. Plasma concentrations of active lovastatin acid are markedly increased by gemfibrozil but not by bezafibrate. Clin Pharmacol Ther. 2001;69: 340-345.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
16. Backman JT, Luurila H, Neuvonen M, Neuvonen PJ. Rifampin markedly decreases and gemfibrozil increases the plasma concentrations of atorvastatin and its metabolites. Clin Pharmacol Ther. 2005;78: 154-167.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
17. Backman JT, Kyrklund C, Neuvonen M, Neuvonen PJ. Gemfibrozil greatly increases plasma concentrations of cerivastatin. Clin Pharmacol Ther. 2002;72: 685-691.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
18. Martin PD, Dane AL, Schneck DW, Warwick MJ. An open-label, randomized, three-way crossover trial of the effects of coadministration of rosuvastatin and fenofibrate on the pharmacokinetic properties of rosuvastatin and fenofibric acid in healthy male volunteers. Clin Ther. 2003;25: 459-471.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
19. Gustavson LE, Schweitzer SM, Koehne-Voss S, et al. The effects of multiple doses of fenofibrate on the pharmacokinetics of pravastatin and its 3
-hydroxy isomeric metabolite. J Clin Pharmacol. 2005;45: 947-953.
20. Pan W-J, Gustavson LE, Achari R, et al. Lack of a clinically significant pharmacokinetic interaction between fenofibrate and pravastatin in healthy volunteers. J Clin Pharmacol. 2000;40: 316-323.[Abstract]
21. Bergman AJ, Murphy G, Burke J, et al. Simvastatin does not have a clinically significant pharmacokinetic interaction with fenofibrate in humans. J Clin Pharmacol. 2004;44: 1054-1062.
22. TriCor tablets [US prescribing information]. Abbott Park, IL: Abbott Laboratories; 2005.
23. Medical Dictionary for Regulatory Activities. Reston, VA: MedDRA MSSO VAR1/8A/MSSO.
24. Jones PH, Davidson MH, Kashyap ML, et al. Efficacy and safety of ABT-335 (fenofibric acid) in combination with rosuvastatin in patients with mixed dyslipidemia: a phase 3 study. National Lipid Association (NLA) Abstract 214. J Clin Lipidol. 2008;2: 218.
25. Prueksaritanont T, Tang C, Qiu Y, Mu L, Subramanian R, Lin JH. Effects of fibrates on metabolism of statins in human hepatocytes. Drug Metab Dispos. 2002;30: 1280-1287.
26. Prueksaritanont T, Zhao JJ, Ma B, et al. Mechanistic studies in metabolic interactions between gemfibrozil and statins. J Clin Pharmco Exp Ther. 2002;301: 1042-1051.[CrossRef]
27. Lee E, Ryan S, Birmingham B, et al. Rosuvastatin pharmacokinetcs and pharmacogenetics in white and Asian subjects residing in the same environment. Clin Pharmacol Ther. 2005;78: 330-341.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
28. Tzeng T, Mitchell P, Zhang H, Kung L, Schneck D, Birmingham B. Population pharmacokinetics of rosuvastatin in normal subjects and subjects with dyslipidemia [abstract]. Clin Pharmacol Ther. 2004;75: 56.
29. Sekino H, Onishi T. Phase I study of ZD4522 (rosuvastatin), a new HMG-CoA reductase inhibitor evaluation of tolerance and pharmacokinetics in healthy adult male volunteers after single and repeated oral administration. J Clin Ther Med. 2005;21: 187-203.
30. Warwick MJ, Dane AL, Raza A, Schneck DW. Single- and multiple-dose pharmacokinetics and safety of the new HMG-CoA reductase inhibitor ZD4522 [abstract]. Atherosclerosis. 2000;151: 39.
31. Martin PD, Mitchell PD, Schneck DW. Pharmacodynamic effects and pharmacokinetics of a new HMG-CoA reductase inhibitor, rosuvastatin, after morning or evening administration in healthy volunteers. Br J Clin Pharmacol. 2002;54: 472-477.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
CiteULike 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  M. Miller Dyslipidemia and cardiovascular risk: the importance of early prevention QJM, June 4, 2009; (2009) hcp065v1. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
