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DRUG INTERACTIONS |
From Merck Research Laboratories, Rahway, New Jersey, and West Point, Pennsylvania (Dr Bergman, Ms Burke, Mr Larson, Dr Johnson-Levonas, Dr Murphy, Dr Gottesdiener, Dr Paolini); Schering-Plough Research Institute, Kenilworth, New Jersey (Dr Reyderman, Dr Statkevich, Dr Kosoglou); and the Clinical Research Unit, Division of Clinical Pharmacology, Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania (Dr Greenberg, Dr Kraft, Dr Frick).
Address for reprints: Arthur J. Bergman, Clinical Drug Metabolism, Merck & Co, Inc, WP 75-100, Sumneytown Pike, PO Box 4, West Point, PA 19486.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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1.3 hours) was similar with and without EZE (P >.200). Mean CyA exposure slightly increased (15%) with multiple-dose EZE 20 mg; however, this value was contained within (0.80, 1.25). The implications for chronic EZE dosing within the usual clinical paradigm of chronic CyA dosing have not been established; caution is recommended when using these agents concomitantly. CyA concentrations should be monitored in patients receiving EZE and CyA.
Key Words: Ezetimibe • cyclosporine • interaction
To reduce overall cardiovascular risk, lipid-lowering medications, especially 3-hydroxy-3-methylglutarylcoenzyme A reductase inhibitors (statins), have become widely used in transplant patients.5,14,15 Statins block hepatic cholesterol biosynthesis and can result in plasma low density lipoprotein cholesterol (LDL-C) reductions of >50% depending on the statin dose and type.16 However, caution must be exercised when coadministering CyA with statins (lovastatin, simvastatin, atorvastatin, pravastatin, rosuvastatin, fluvastatin) since CyA is known to affect the pharmacokinetics of statins.17 The mechanism of these interactions is not clear; CyA may inhibit the cytochrome (CYP) 3A4-mediated metabolism of some statins (simvasatin, lovastatin, atorvastatin) or inhibit transporters responsible for the elimination of other statins (pravastatin, rosuvastatin).17,18 Increases in statin exposure following concomitant administration of CyA and statins can result in an increased risk of myopathy and other serious side effects.17,19 Thus, although statins will remain the mainstay of therapy for reduction of lipid-related cardiovascular risk, alternative therapies with improved safety or efficacy profiles that will allow the reduction of statin dose are being sought for the management of plasma lipid levels in transplant recipients.
Ezetimibe (EZE), a novel cholesterol-lowering agent that inhibits the intestinal absorption of dietary and biliary cholesterol, reduces plasma LDL-C concentrations by approximately 18% and further enhances the LDL-C-lowering efficacy of statins by 25% in hypercholesterolemic patients.20,21 Overall, EZE 10 mg is well tolerated with an adverse event profile similar to that of placebo. Previous studies have shown that multiple dosing of EZE up to 50 mg/d is generally well tolerated in healthy subjects without a greater incidence of total adverse experiences or evidence of dose-related toxicity.22 Furthermore, EZE is neither an inhibitor nor an inducer of common CYP drug-metabolizing enzymes (1A2, 2D6, 2C8, 2C9, and 3A4), thereby minimizing its potential interaction with medications frequently used in transplant recipients (eg, CyA).22,23
We previously reported the results of a study designed to examine the single-dose plasma pharmacokinetics of EZE 10 mg in the setting of steady-state CyA dosing.22,24 In that study of renal transplant patients with creatinine clearance >50 mL/min, a 3.4-fold increase in mean total EZE plasma area under the curve (AUC) was observed in CyA-treated patients compared with a healthy control population derived from 2 prior studies. Mean CyA trough concentrations remained within the therapeutic range up to 120 hours following single-dose EZE administration (92 µg/L and 114 µg/L at 0 and 120 hours postdose, respectively); however, that analysis was only an exploratory investigation of the potential effects of EZE on CyA, as CyA troughs, not full pharmacokinetic profiles, were measured, and EZE was not dosed to steady state.
Given the complex drug-interaction profile and the narrow therapeutic index of CyA, a more thorough examination of the potential effect of EZE on CyA pharmacokinetics was warranted. Thus, the current study was conducted to determine the effects of steady-state EZE dosing (20 mg) on the pharmacokinetics of a single oral dose of CyA (100 mg). Multiple doses of EZE 20 mg were administered in this study to simulate the increase in EZE exposure seen with steady-state CyA dosing while maintaining an acceptable safety margin for healthy subjects. The use of an open-label, 2-period, crossover design allowed for a comparison of CyA pharmacokinetics in the presence and absence of EZE within the same subject.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Key exclusion criteria were pregnant or nursing women; premenopausal women receiving hormonal contraception; postmenopausal women taking hormone replacement therapy; use of prescription or non-prescription drugs (including herbal remedies) on a regular basis that could not be discontinued for the duration of the study; diagnosis of glaucoma, dyslipidemia (types 1, 2, 4, 5 or homozygous familial hypercholesterolemia), endocrine or metabolic disease, chronic obstructive pulmonary disease, diabetes mellitus, hepatic or biliary tract disease, coagulopathy, or cardiac disease; and disorder of digestive system or previous gastrointestinal tract surgery.
Subjects could be withdrawn from the study for the following predefined reasons: positive pregnancy test, treatment with excluded concomitant medications (ie, immunosuppressants, corticosteroids, or potent inhibitors of cytochrome P450 3A4), or a significant adverse event or laboratory abnormality.
Study Design
Thirteen subjects were enrolled in this study between November 2003 and January 2004. The protocol for this single-center study was approved by the Thomas Jefferson University Institutional Review Board, and all subjects provided written informed consent prior to the initiation of study procedures. This was a 7-week open-label study in which subjects were randomized to receive 2 treatments (A and B) in a 2-period crossover design. In treatment A, subjects received a single oral dose of CyA alone (100 mg) on day 1. In treatment B, subjects received multiple once-daily oral doses of EZE 20 mg alone for 6 days (days 1 through 6), followed by coadministered oral doses of EZE 20 mg and CyA 100 mg on day 7 and a single oral dose of EZE 20 mg alone on day 8. In treatment periods A and B, CyA (Neoral; Novartis Pharmaceutical, East Hanover, NJ) was administered as a single 100-mg tablet. In treatment period B, EZE (Zetia; Merck/Schering-Plough Pharmaceuticals, North Wales, Pa) was administered as two 10-mg tablets. All doses of EZE and CyA were administered with 240 mL of water between 8:00 and 10:00 AM in the clinical research unit. The order in which each subject received the treatments was assigned according to a computer-generated allocation schedule with a 14-day washout between treatment periods. Blood samples (3 mL; collected in tubes with K3 EDTA and frozen at -20°C) for determination of plasma CyA concentrations in whole blood were collected predose (within 15 minutes prior to study drug administration) and at 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 4, 6, 9, 12, 16, 20, 24, 28, 32, 36, 40, and 48 hours after the administration of study drug.
Analytical Methods
CyA concentrations in whole-blood samples were determined using high-performance liquid chromatography with tandem mass spectrometric detection. Cyclosporine C was used as the internal standard. A Genesis C18 column (50 x 4.6 mm, 3 µm particle size) was used for liquid chromatography with a mobile phase containing acetonitrile:water:formic acid (85:15:0.1 by volume). The mass spectroscopy ion transitions monitored were 1202.8 
224.4 m/z and 1218.8 224.4 m/z for CyA and the internal standard (cyclosporine C), respectively. The lower limit of quantification for the blood assay was 5.00 ng/mL, with a linear calibration range of 5.00 to 2000 ng/mL. Analysis of blood CyA concentrations was conducted at Covance Laboratories Inc (Madison, Wis).
Pharmacokinetic Assessments
It was not clear prior to the conduct of the study whether apparent terminal t1/2 and AUC0-
could be computed reliably from study concentration data. Thus, AUC0-last was prespecified as the primary pharmacokinetic parameter for measuring CyA exposure because this parameter does not require computation of apparent terminal t1/2. Secondary pharmacokinetic parameters included maximum concentration at 12 hours (C12 hr) and time to maximum concentration (Tmax) of CyA alone and in the presence of steady-state EZE dosing. Upon examination of the blood concentration-time data, it was determined that apparent terminal t1/2 and AUC0- could be accurately computed and were therefore reported for completeness.
AUC0-last was defined by the area under the blood concentration-time curve to the last time when the blood sample collected had a CyA concentration above the lower limit of assay quantification. AUC0-last was calculated using the linear trapezoidal method for ascending concentrations and the log trapezoidal method for descending concentrations. The CyA apparent terminal rate constant (
) was estimated by regression of the terminal log-linear portion of the blood concentration-time profile; t1/2 was calculated as the quotient of ln(2) and . AUC0- was estimated as the sum of AUC0-last and the extrapolated area given by the quotient of the last measured concentration and . Cmax and Tmax were obtained by inspection of the blood concentration data. Provided that the actual observed time of Tmax did not differ in a meaningful way from the nominal blood-sampling time, nominal blood-sampling times were used to determine Tmax. C12 hr values were assessed from the blood concentrations determined for the nominal sampling time at 12 hours postdose.
Statistical Analysis
The effect of coadministration of multiple doses of EZE on the single-dose pharmacokinetics of CyA was analyzed using an analysis of variance (ANOVA) model appropriate for a 2-period, crossover study design. The ANOVA model contained factors for sequence, subject within sequence, period, and treatment. Appropriate transformations of pharmacokinetic parameters were used (ie, log transformation for AUC0-last, AUC0-, C12 hr, and Cmax values, and rank transformation for Tmax, inverse transformation for t1/2). Back-transformed summary statistics and results of inferential testing were reported. The assumptions of the ANOVA model were tested by the Shapiro-Wilk test for normality.
The 90% confidence interval (CI) for the geometric mean ratio (GMR; [CyA + EZE]/CyA) of CyA AUC0-last was constructed using estimates from the ANOVA model. To conclude that the coadministration of multiple doses of EZE does not alter single-dose pharmacokinetics of CyA in a clinically important manner, the 90% CI for the AUC0-last GMR was prespecified to be contained in the interval of [0.80, 1.25]. Similarly, the 90% CIs for the GMR ([CyA + EZE]/CyA alone) for C12 hr, AUC0-, and Cmax were computed using the same ANOVA model.
Safety and Tolerability Assessments
Data from all randomized subjects (N = 13) were included in safety and tolerability assessments. Evaluation of safety was accomplished through subject reported adverse signs and symptoms, investigator observations and assessments, and various laboratory tests including blood evaluations and electrocardiograms. Investigators determined the severity of adverse events (mild, moderate, severe, or life threatening) and the potential relationship to study drug (definitely not, probably not, possibly, probably, definitely). Safety and tolerability were evaluated by clinical review of all safety parameters, including adverse experiences (AEs), laboratory safety tests (blood chemistry and urinalysis), electrocardiograms, and vital signs. The number of subjects experiencing clinical AEs, treatment-related AEs (clinical and laboratory), serious clinical AEs, discontinuations due to AEs, and clinically significant laboratory abnormalities were tabulated by treatment group.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Pharmacokinetics
Mean plasma concentration-time profiles for single-dose CyA 100 mg in the absence and presence of multiple-dose EZE 20 mg are illustrated in Figure 1. These graphs show generally similar plasma concentration profiles following single doses of CyA and coadministration of CyA and EZE. Summary statistics for AUC0-last, AUC0-, C12 hr, apparent t1/2, Cmax, and Tmax, as well as the corresponding GMRs and 90% CIs for select pharmacokinetic parameters (AUC0-last, AUC0-, C12 hr, and Cmax), are provided in Table I. Individual whole-blood CyA AUC0-last values in the absence and presence of multiple-dose EZE 20 mg are provided in Figure 2.
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AUC0-last was the prespecified primary parameter of interest in the evaluation of CyA exposure. The least-squares mean AUC0-last following administration of CyA with and without multiple doses of EZE 20 mg was 2174 and 1885 ng•h/mL, respectively. Multiple doses of EZE increased the total CyA exposure by approximately 15% (AUC0-last GMR [CyA + EZE]/CyA = 1.15) with a 90% CI of (1.07, 1.25); the 90% CI for the AUC0-last GMR fell within the prespecified comparability interval of (0.80, 1.25). Consistent with the AUC0-last results, the AUC0-GMR ([CyA + EZE]/CyA alone) was 1.15, with a 90% CI of (1.06, 1.25).
Generally consistent with the AUC0-last results, the GMRs ([CyA + EZE]/CyA alone) of CyA C12 hr and Cmax were 1.15 with a 90% CI (1.04, 1.28) and 1.10 with a 90% CI (0.97, 1.26), respectively (Table I). The median blood CyA Tmax values were 1.3 hours for both treatments, and no statistically significant between-group difference was found (P > .200; Table I). The harmonic mean apparent terminal t1/2 values were 11.3 and 10.2 hours following the administration of CyA alone or coadministered CyA plus EZE, respectively; no statistically significant between-group difference was observed (P > .200; Table I).
Safety and Tolerability
Coadministration of a single dose of CyA 100 mg in the setting of steady-state EZE 20 mg was generally well tolerated in healthy adult subjects. There were no serious AEs reported in this study, and no subjects discontinued treatment prematurely due to AEs. Three of 13 subjects reported clinical AEs (nausea, headache, increased heart rate/upset stomach). All of these AEs were considered by the investigators to be mild in intensity and possibly or probably related to study medication except for the heart rate AE, which was considered probably not drug related. One subject had a decrease in hemoglobin of approximately 1.5 g/dL from prestudy to predose on day 1 in period 2. This laboratory AE was considered probably not drug related, and no clinical AEs were reported for this subject. The subject's hemoglobin levels rose over the course of follow-up poststudy visits. All clinical and laboratory AEs resolved by completion of the study.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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In a previous pharmacokinetic interaction study conducted in renal transplant patients with creatinine clearance >50 mL/min, CyA trough concentrations were measured for safety purposes every 12 hours following administration of a single oral dose of EZE 10 mg.22,24 Mean CyA trough concentrations remained stable and within the therapeutic range for up to 120 hours (92 µg/L and 114 µg/L at 0 and 120 hours postdose, respectively). However, the design of that study was not intended to thoroughly characterize the effect of EZE on CyA plasma pharmacokinetics for the following reasons: (1) full CyA pharmacokinetic profiles that would permit determination of plasma AUC and Cmax were not collected and (2) only a single oral dose of EZE 10 mg was administered; hence, plasma concentrations were less than those achieved when EZE is dosed to steady state.
In the previous study of post-renal transplant patients receiving CyA, mean total ezetimibe AUC was increased by 3.4-fold relative to a prespecified, historical, healthy control population.22,24 Since steady-state exposure to EZE 10 mg may be higher in transplant patients receiving chronic CyA dosing (target population), multiple doses of EZE 20 mg were used in the current study (instead of the EZE 10-mg doses typically used) to ensure EZE exposure is consistent with that observed when EZE was administered with steady-state CyA and to maintain an acceptable safety margin for the healthy subjects enrolled in this study. In addition, 48-hour CyA pharmacokinetic profiles were obtained in both study periods, thus allowing for a direct comparison of CyA exposure in the presence and absence of EZE.
The results of this study show that the GMR ([CyA + EZE]/CyA alone) of CyA AUC0-last was 1.15 with a 90% CI of (1.07, 1.25). The 90% CI fell within the prespecified bounds of (0.80, 1.25). Consistent with the AUC0-last results, the AUC0- GMR ([CyA + EZE]/CyA alone) for CyA was 1.15, with a 90% CI of (1.06, 1.25). The prespecified (0.8, 1.25) bounds for AUC were selected in this study because sustained alterations in CyA levels >25% would likely be managed by downward titration of the daily CyA dose. It is not clear whether compensatory titration of the CyA dose would be required for changes in CyA exposure 
25%. This study demonstrated a small but statistically significant effect of EZE 20 mg on plasma CyA exposure (P = .009); however, the upper bound of the 90% CI still fell within the prespecified similarity bounds.
The mechanism of the interaction between EZE and CyA is not known. CyA has been shown to be a substrate of P-glycoprotein, a protein that actively transports xenobiotics from the cytoplasm of enterocytes into the lumen of the gut, thereby limiting its systemic accumulation.25,26 A small fraction of CyA may undergo first-pass metabolism by CYP3A4 within the enteral mucosa; however, available data suggest that intestinal CYP3A4 plays a relatively minor role in determining CyA pharmacokinetics.27 After passing the enterocyte layer and entering the portal blood, subsequent metabolism of CyA appears to be dominated by hepatic CYP3A4.28,29 Many drug interactions involving CyA are thought to result from inhibition or induction of liver CYP3A4 (eg, ketoconazole, erythromycin, and corticosteroids) and/or intestinal P-glycoprotein (eg, grapefruit juice, St. Johns Wort), sometimes with severe consequences (ie, drug toxicity and graft rejection).30-32 Previous pharmacokinetic studies have shown that EZE is neither a substrate nor an inhibitor of common CYP drug-metabolizing isoenzymes (including hepatic and intestinal CYP3A4) or P-glycoprotein.22,23 Instead, EZE undergoes extensive glucuronidation in the wall of the small intestine and liver via uridine 5'-diphosphate-glucuronosyltransferase enzymes (UGT1A1, UGT1A3, and UGT2B15) to form the active metabolite EZE-glucuronide.22 Therefore, it is unlikely that the increased exposure to single-dose CyA (approximately 15%) seen in this study is caused by EZE-induced inhibition of CYP3A4 metabolism and/or P-glycoprotein-mediated transport. Additional studies would be required to elucidate the mechanism of action underlying the increased systemic exposure of CyA when coadministered with EZE and the potential clinical relevance of this interaction.
In summary, it is difficult to predict the magnitude and clinical significance of the pharmacokinetic effects of coadministered EZE and CyA in the clinical setting. The possible interdependent effects of both EZE on CyA and CyA on EZE at steady state are beyond the scope of this study. The implications of these findings for chronic EZE dosing within the usual clinical paradigm of chronic CyA dosing have not been established; therefore, caution is recommended when using these agents concomitantly. Physicians should monitor plasma concentrations of CyA in patients receiving EZE and CyA.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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