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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 Maxwell, Dr Kosoglu); and Christchurch Clinical Studies Trust, Christchurch, New Zealand (Dr Robson).
Address for reprints: Arthur J. Bergman, Clinical Drug Metabolism, Merck Research Laboratories, 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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Key Words: Ezetimibe • cyclosporine • interaction • renal • transplant
Upon oral administration, EZE (unconjugated, parent drug) is rapidly absorbed and extensively metabolized in the intestine and liver to form a phenolic glucuronide metabolite (EZE-glucuronide).10 Both EZE and EZE-glucuronide have been shown to be pharmacologically active, and the sum of these 2 species in plasma is termed total EZE (EZE-total).2 Typically, EZE represents approximately 15% of EZE-total concentrations, while EZE-glucuronide represents close to 85%.11 Secondary peaks in the plasma concentrationtime profiles suggest that both EZE and EZE-glucuronide are subject to significant entero-hepatic recirculation, which may be important in establishing the therapeutic efficacy of ezetimibe as this process repeatedly delivers active species to their site of action (intestinal lumen).12 There is relatively little release of EZE and EZE-glucuronide into the peripheral circulation. The effective half-life of EZE is approximately 22 hours, thus enabling once-daily dosing.10 Cyclosporine (CyA) is a potent immunosuppressive agent that is used to prolong the survival of allogenic transplants by suppressing both cell-mediated and humoral immunity.13 The effective half-life of CyA is approximately 8.4 hours, requiring this agent to be administered twice daily. CyA has been implicated as the cause of several pharmacokinetic drug-drug interactions with coadministered oral agents. The mechanisms of action underlying some of these interactions are not fully understood. CyA is extensively metabolized by the cytochrome P-450 3A4 enzyme system in the liver and to a lesser degree in the gastrointestinal tract and the kidney.13,14 Consequently, many drugs that have been reported to interact with CyA are inducers, inhibitors, or substrates of these same enzymes (eg, azole antifungal drugs, macrolide antibiotics).14,15 Furthermore, in vitro assays have shown that CyA inhibits several drug transporters including multidrug resistance protein 1 (P-glycoprotein/MDR1), multidrug resistance-associated protein 2, and the bile salt export pump.16,17
Hyperlipidemia is undertreated in transplant patients receiving CyA therapy because of drug-drug interactions and safety concerns with statin coadministration. EZE may represent an important alternative treatment of transplant recipients with hyperlipidemia if coadministration with CyA can be shown to be safe and efficacious. In a previous study, EZE-total exposure was increased 12-fold in a single renal transplant patient on CyA therapy (150 mg/d; Neoral) who had severe renal impairment (creatinine clearance 13.2 mL/min) compared to healthy control subjects following a single 10-mg dose of EZE.1,10 Of note, adverse events were not observed in this patient who was receiving several other medications for the treatment of coexisting conditions. Although this patient was taking numerous concomitant medications, a pharmacokinetic interaction with CyA was considered reasonable, given the number of drug reactions known to be ascribed to CyA. The present study was undertaken to evaluate the single-dose pharmacokinetics of EZE 10 mg in renal transplant patients receiving ongoing CyA therapy relative to a group of historical control subjects not on CyA therapy.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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6 months prior to randomization), between 30 and 70 years of age, with relatively normal renal clearance (mean calculated creatinine clearance >50 mL/min). Creatinine clearance was estimated at the prestudy visit using the Cockcroft-Gault formula. Patients had to be on a stable dose of CyA (either Gengraf, Abbott Laboratories, Chicago, Ill, or Neoral, Novartis Pharmaceutical, East Hanover, NJ) for at least 3 months prior to study initiation. Patients were required to have a stable level of whole-blood CyA (morning fasting trough CyA concentrations measured at 2 different times within 1 week prior to start of study had to be within ±15%). Concomitant medications were carefully reviewed throughout the course of the study. Subjects agreed to refrain from consuming grapefruit juice (shown to inhibit cytochrome P450 3A4 activity) from at least 2 weeks prior to the start of the study until study completion. Premenopausal women were eligible for participation if they had negative pregnancy test results and were either surgically sterilized or agreed to use an appropriate double-barrier method of contraception. Key exclusion criteria were pregnant or nursing women, premenopausal women receiving hormonal contraception, postmenopausal women taking hormone replacement therapy, use of nonprescription drugs (including herbal remedies) on a regular basis that could not be discontinued for the duration of the study, use of prescription drugs known to influence CyA metabolism, and diagnosis of glaucoma or endocrine or metabolic disease (except for diabetes and repleted hypothyroid condition), chronic obstructive pulmonary disease, hepatic or biliary tract disease, coagulopathy, or cardiac disease.
Patients could be withdrawn from the study for the following predefined reasons: positive or borderline pregnancy test, treatment with excluded concomitant medications, or a significant adverse event or laboratory abnormality.
Study Design
The protocol for this single-center study was approved by the Canterbury Ethics Committee, and all patients provided written informed consent prior to the initiation of study procedures. This was an open-label, single-period study to determine plasma pharmacokinetics of EZE after single oral dosing of EZE 10 mg in post-renal transplant patients on steady-state CyA therapy. The plasma pharmacokinetics of EZE in these patients was compared to data obtained in a prespecified, historical, healthy control population not on CyA therapy. For 1 week prior to study initiation, all patients continued taking their usual prescribed dosage of CyA (ranging from 75 to 150 mg) but were instructed to take these doses on a more rigorously timed schedule (ie, at exact 12-hour intervals, preferably at approximately 8 AM and approximately 8 PM). Concomitant medications were carefully restricted to avoid potential drug interactions. After an overnight fast, a single oral 10-mg dose of EZE was coadministered with the morning prescribed dose of CyA. Plasma samples were collected predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96, and 120 hours post-EZE dosing. Patients continued to receive individualized doses of CyA at the 12-hour scheduled intervals throughout the study. Blood was also collected for serial CyA trough measurements at 12, 24, 36, 48, 60, 72, and 120 hours post-EZE administration for safety monitoring throughout the study.
Analytical Methods
Plasma concentrations of EZE-total and EZE were determined by MDS Pharma Services Inc using validated high-performance liquid chromatographic-tandem mass spectrometric methods using 13C-ezetimibe as an internal standard. A Zorbax SB-C18 column (7.5 cm x 4.6 mm, 3.5 µm particle size) was used for liquid chromatography with a methanol mobile phase containing 0.025M ammonium acetate at a flow rate of 1.0 mL/min. The mass spectroscopy ion transitions monitored were 392 
133 m/z and 398 139 m/z for ezetimibe and the internal standard, respectively. The plasma samples were analyzed before and after enzymatic cleavage of the glucuronide conjugate with ß-glucuronidase (50 µL of Sigma G7017 at 100000 U/mL) at 50°C for 60 minutes to yield concentrations of EZE and EZE-total, respectively. The lower limit of quantification for EZE and EZE-total were 0.200 and 1.0 ng/mL, respectively. The analytical ranges of quantitation were 0.200 to 20.0 ng/mL and 1.0 to 250 ng/mL for EZE and EZE-total, respectively. Plasma EZE-glucuronide concentration, reported as EZE equivalents, was calculated by subtracting the EZE concentration from the corresponding EZE-total concentration for each sample. Prior to the study, it was confirmed that the presence of CyA did not interfere with EZE assays. Monoclonal whole-blood assays with fluorescence polarization methodology (Abbott Laboratories, Ill, and Dade Behring Limited, UK) were used to quantify CyA concentrations in whole-blood samples. The lower limit of quantification for CyA was 20 µg/L.
Prior to the conduct of this study, a competitive binding immunoassay was performed to evaluate the potential interference of EZE and EZE-glucuronide on CyA whole blood measured by fluorescence polarization. A 1-µg/mL stock solution of EZE and a 50-µg/mL stock solution of EZE-glucuronide were diluted in a saline solution. CyA whole-blood calibrators (Dade Behring Diagnostics, New Zealand) with known concentrations (80 and 500 µg/L) were spiked with either 53.5 µL of EZE (EZE and EZE-glucuronide) or an equal volume of saline. These samples were analyzed in triplicate for whole-blood CyA concentrations by Canterbury Health Laboratories. The 80-µg/L calibrator spiked with EZE yielded a mean CyA concentration of 88.2 µg/L (110% recovery), while the same calibrator spiked with an equal volume of saline yielded a mean CyA concentration of 83.7 µg/L (105% recovery). A 500-µg/L calibrator spiked with EZE yielded a mean CyA concentration of 462.5 µg/L (93% recovery), while the same calibrator spiked with an equal volume of saline yielded a mean CyA concentration of 476.4 µg/L (95% recovery). The preceding results confirmed the lack of interference of EZE on CyA concentrations when measured using this fluorescence polarization immunoassay.
Pharmacokinetic Assessments
Plasma concentrations and actual sampling times were used to determine pharmacokinetic parameters for EZE-total (primary analyte) and EZE (supplemental analyte). The primary pharmacokinetic parameter (AUC0-last) was defined by the area under the blood concentration-time curve to the last time when the blood sample collected had an EZE-total or EZE concentration above the lower limit of assay quantification. AUC0-last was calculated using the linear trapezoidal method. Secondary pharmacokinetic parameters included maximum plasma concentration (Cmax) and time to maximum concentration (Tmax) of EZE-total and EZE and trough CyA concentrations. Cmax and Tmax were obtained by inspection of the plasma concentrationtime data. The apparent terminal rate constant (
;secondary pharmacokinetic parameter) was determined for EZE and EZE-glucuronide (supplemental analytes) by regression of the terminal log-linear portion of the plasma concentration-time profile. Since EZE-total is an analyte that represents 2 species with different kinetics, an apparent terminal rate constant was not determined for this parameter. For EZE and EZE-glucuronide, the apparent elimination t1/2 was calculated as the quotient of ln(2) and .
Statistical Analysis
Based on an estimated between-subject standard deviation of 0.365 for EZE-total AUC0-last, a sample size of 8 renal transplant patients and 17 healthy reference subjects was required to provide 99% probability of observing a 90% confidence interval (CI) for the geometric mean ratio (GMR) AUC0-last contained within (0.50, 2.00). The prespecified, historical, control data set was obtained from 2 prespecified studies (single-dose renal and liver studies) of normal healthy subjects who received single doses of EZE 10 mg in the absence of CyA.
The AUC0-last and Cmax of EZE-total and EZE following a single 10-mg dose of EZE in the presence of steady-state CyA were compared to data derived from the healthy control population using an analysis of covariance (ANCOVA) model. The ANCOVA model contained factors for treatment group (study vs reference population), age, weight, and height. Race and gender terms were not included in the final model because these subgroups were underrepresented in the sample patient population. Appropriate transformations of pharmacokinetic parameters were employed (ie, log-transformation of AUC0-last and Cmax and rank transformation of Tmax). Back-transformation from the log scale was applied to the present results in the original scale. The ANCOVA model was adjusted for prespecified covariates, and least-squares (LS) means were reported.
The assumptions of the ANCOVA model were tested by the Shapiro-Wilk test for normality. The homogeneity of variance assumption was evaluated using Levene's test on the absolute value of residuals from the ANCOVA model. Because the homogeneity of variance assumption was not satisfied in the analysis of EZE-total Cmax, a rank transformation was used, and the P value of the treatment effect from the ANCOVA model was compared to that obtained using log transformation. A weighted LS ANCOVA model was used to compare the 2 populations in the same manner described above. Covariate-by-treatment interaction was performed to validate the parallelism assumption to include age, weight, and height terms in the model. The between-group results from these models yielded generally consistent results; thus, only the parametric results are presented.
The 90% CIs for the GMRs (post-renal transplant patients/historical healthy reference population) of AUC0-last and Cmax for EZE-total and EZE were constructed using LS mean estimates derived from the ANCOVA model. The conclusion that steady-state CyA does not alter single-dose pharmacokinetics of EZE in a clinically important manner was supported if the 90% CI for EZE-total AUC0-last GMR was contained in the interval of (0.50, 2.00).
The LS mean apparent elimination t1/2 of EZE was determined using the ANCOVA model described above. The jacknife technique was used to estimate the standard deviation associated with back inverse-transformed LS mean of 1/t1/2. The principle of this method is to estimate the variability of half-life values by dropping 1 data point at a time from the data set and estimating the parameter of interest. An inverse transformation was applied to the apparent elimination t1/2 to normalize the distribution. Summary statistics for CyA trough concentrations also were calculated.
Safety and Tolerability Assessments
Data from all randomized patients (N = 8) were included in safety and tolerability assessments. Evaluation of safety was accomplished through patient-reported adverse signs and symptoms, investigator observations and assessments, and various laboratory tests including blood evaluations (hematology, blood chemistry, urinalysis, and serum/urine ß-human chorionic gonadotropin) 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). Trough CyA concentrations were monitored by twice-daily laboratory testing over the course of the entire study.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Pharmacokinetics
Mean plasma concentration-time profiles of total EZE following a single dose of EZE 10 mg administered in the presence and absence of steady-state CyA are illustrated in Figure 1. Mean plasma concentrations of EZE-total were higher in post-renal transplant patients compared to healthy control subjects. Summary statistics for EZE-total AUC0-last, Cmax, and Tmax, as well as the corresponding GMRs and 90% CIs for select pharmacokinetic parameters (AUC0-last, Cmax) are provided in Table I.
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EZE-total AUC0-last was the primary parameter of interest in the evaluation of EZE exposure. The geometric LS mean AUC0-last of EZE-total following a single oral dose of EZE 10 mg was 2867 ng•h/mL in post-renal transplant patients receiving steady-state CyA therapy and 840 ng•h/mL in the healthy reference population. The GMR of EZE-total AUC0-last (post-renal transplant patients on CyA/historical healthy reference population) was 3.41 with a 90% CI of (2.55, 4.56). The 90% CI for the AUC0-last GMR exceeded the prespecified comparability interval of (0.50, 2.00). The difference in AUC0-last values between the study and reference populations was statistically significant (P < .001).
The geometric LS mean Cmax of EZE-total following a single oral dose of EZE 10 mg was 363 ng/mL for post-renal transplant patients receiving steady-state CyA therapy and 93 ng/mL for the healthy reference population. Consistent with the AUC0-last results, the GMR (post-renal patients on CyA/historical healthy reference population) of EZE-total Cmax (secondary pharmacokinetic parameter) was 3.91 with a 90% CI (3.13, 4.89; Table I). The between-group difference in Cmax was statistically significant (P < .001). The median Tmax values (secondary pharmacokinetic parameter) were 1.5 hours in the setting of steady-state CyA dosing and 1.0 hour without CyA pretreatment. The small difference in Tmax values between the 2 patient populations was statistically significant (P = .010).
EZE was a supplementary analyte in the evaluation of EZE exposure. Mean plasma EZE concentration-time profiles following a single dose of EZE 10 mg administered in the presence and absence of steady-state CyA are illustrated in Figure 2. Mean plasma concentrations of EZE were higher in post-renal transplant patients compared to healthy control subjects. As expected, the plasma profile of EZE demonstrated multiple peaks consistent with its enterohepatic recirculation. Summary statistics for EZE AUC0-last, Cmax, Tmax, and apparent elimination t1/2, as well as the corresponding GMRs and 90% CIs for select pharmacokinetic parameters (AUC0-last, Cmax), are provided in Table II.
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The geometric LS mean AUC0-last of EZE following a single oral dose of EZE 10 mg was 106.8 ng•h/mL in post-renal transplant patients receiving steady-state CyA therapy and 66.8 ng•h/mL in the healthy reference population. The GMR of EZE AUC0-last (post-renal transplant patients on CyA/historical healthy reference population) was 1.60 with a 90% CI of (1.12, 2.27). The difference in AUC0-last values between the study and reference populations was statistically significant (P = .033). The geometric means of EZE Cmax were 10.2 ng/mL in the setting of steady-state CyA and 3.8 ng/mL without CyA pretreatment. The GMR of EZE Cmax (post-renal transplant patients on CyA/historical healthy reference population) was 2.71 with a 90% CI of (1.72, 4.25). The difference in Cmax values between the study and reference populations was statistically significant (P = .001). The median EZE Tmax values (secondary pharmacokinetic parameter) were 1.0 hour in the setting of steady-state CyA dosing and 6.0 hours without CyA pretreatment. The difference in median Tmax values between the 2 populations was statistically significant (P < .001).
EZE-total apparent elimination t1/2 was not determined because EZE-total is composed of 2 species (EZE and EZE-glucuronide) that have different plasma elimination characteristics. For this reason, apparent elimination t1/2 values were determined for EZE and EZE-glucuronide (Table II). The LS mean t1/2 values of EZE following a single dose of EZE 10 mg were 22.2 and 19.9 hours with and without CyA pretreatment, respectively; no statistically significant between-group difference was observed (P = .508). Similarly, there was not a significant difference (P = .187) in LS mean t1/2 values of EZE-glucuronide in the presence (24.0 hours) and absence (19.2 hours) of steady-state CyA dosing.
Dosing of CyA continued at 12-hour intervals throughout the entire study, and whole-blood CyA was monitored for safety purposes. The mean CyA trough concentrations remained stable for up to 120 hours following administration of EZE 10 mg in post-renal transplant patients (Figure 3).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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The index case was a 51-year-old black male post-renal transplant patient with multiple but stable medical conditions including hypertension, asthma, gout, and coronary artery disease. This individual had severe renal dysfunction, with a creatinine clearance of 13.2 mL/min/1.73m2. He was taking 150 mg/d CyA (Neoral formulation) as part of his posttransplant immunosuppressive regimen as well as multiple other medications to treat various medical conditions. The CyA dose was administered 4 hours after EZE administration. Although the index patient was taking numerous concomitant medications, a pharmacokinetic interaction study with CyA was considered reasonable, given the number of drug interactions known for CyA. There was no a priori reason to expect a metabolism-based pharmacokinetic interaction between CyA itself and EZE, as the main pathway of EZE metabolism is glucuronidation, which CyA is not known to affect.
Consequently, the present study was undertaken to evaluate the single-dose pharmacokinetics of EZE 10 mg in post-renal transplant patients receiving ongoing CyA therapy relative to a group of historical control subjects with relatively normal renal function who were not on CyA therapy. Ethical concerns precluded a study design in which healthy patients would be dosed to steady state with CyA. The most appropriate population, therefore, was renal transplant patients who were receiving stable doses of CyA as a part of their immunosuppression regimen. A crossover study design comparing the pharmacokinetic profile of CyA in the absence and presence of EZE was deemed not appropriate because transplant patients require constant dosing with CyA to prevent graft rejection. Since transplant patients could not have their CyA dose withheld for the period necessary to assess a pharmacokinetic profile of EZE in the absence of CyA, a prespecified database consisting of healthy control subjects from 2 previous studies was selected for comparison.1,10,18 The reference population was carefully selected to match the demographics and creatinine clearance level of the study population.
In this study, coadministration of a single dose of EZE 10 mg in renal transplant patients receiving ongoing CyA treatment was generally well tolerated. The pharmacokinetic results demonstrate that EZE-total AUC0-last and Cmax were 3.4- and 3.9-fold higher (P 
.001 for both comparisons), respectively, in transplant patients on CyA versus a prespecified, historical healthy control population. The effect of CyA on EZE pharmacokinetics was more modest; AUC0-last and Cmax were 1.6- and 2.7-fold higher, respectively, in transplant patients on CyA versus historical healthy controls. EZE-total represents all active and potentially active EZE-related material in plasma; therefore, EZE-total was predefined as the primary analyte in this study, and EZE was a secondary end point. The increased plasma concentrations of EZE-total and EZE may be in part due to an increase in ezetimibe bioavailability, although the precise mechanism of this effect is unknown. Of note, the mean EZE-total exposure observed in this study was substantially lower than the exposure level in the index case. Thus, the level of EZE exposure seen in this study may be more representative of the magnitude of interaction, which would be expected with concomitant use of EZE and CyA in transplant patients with relatively preserved renal function.
The mean EZE-total exposures observed in the present study were similar to those observed in a phase 1 multiple-dose study (n = 9) in which EZE 50 mg was administered daily for 14 days and was generally well tolerated in healthy volunteers (data on file, Schering-Plough Pharmaceuticals, 2002).10 In a separate 8-week parallel-group, multiple-dose safety and pharmacodynamic study of 124 patients in which doses of up to 40 mg/d EZE were administered (18 subjects received 40 mg/d), an analysis of EZE trough levels for that study suggests that similar mean EZE exposures were attained compared to those in patients on chronic CyA. In both of these studies, the highest EZE exposures were well tolerated without an increased frequency of total adverse experiences or evidence of dose-related toxicity.
The mechanism underlying the interaction between EZE and CyA is not known. One potential mechanism is an alteration in the glucuronidation of EZE induced by CyA in human gastrointestinal tissue, leading to changes in the pharmacokinetics of EZE and its metabolites. A series of in vitro experiments led to the identification of uridine 5'-diphosphate (UDP)-glucuronosyltransferase (UGT) enzymes responsible for the glucuronidation of EZE.19 The formation EZE-glucuronide is mediated primarily by UGT1A1, UGT1A3, and UGT2B15. In addition, the formation of a trace benzylic glucuronide of EZE is dependent on UGT2B7. CyA also has been shown to undergo hepatic and extrahepatic glucuronidation mainly by UGT2B7.20 The glucuronidation of CyA in the gastrointestinal epithelia may compete with EZE and affect mucosal first-pass metabolism and enterohepatic circulation. Additional studies would be required to fully evaluate the mechanism of action underlying the increased systemic exposure of EZE when coadministered with CyA and the potential clinical relevance of this interaction.
This study was not designed to quantitatively examine the effect of EZE on CyA pharmacokinetics, as only a single dose of EZE was administered. Trough levels of CyA were drawn for safety monitoring within the study. In this exploratory analysis, the mean CyA trough concentrations measured every 12 hours following a single 10-mg dose of EZE remained within the therapeutic range for up to 120 hours. It is not possible to extrapolate these findings to the clinical setting. A more rigorous evaluation of the effects of EZE on CyA pharmacokinetics in transplant recipients is needed because of the variable pharmacokinetics and narrow therapeutic index of CyA, which make graft rejection and/or renal toxicity possible outcomes of sustained deviations in steady-state CyA concentrations.
In summary, this study demonstrates that steady-state CyA dosing significantly increases EZE exposure in renal transplant patients with creatinine clearance >50 mL/min. The mechanism of this interaction is unclear. The EZE exposure seen in this study was similar to levels observed in previous studies of healthy subjects receiving EZE at doses up to 50 mg, which were generally well tolerated. Because the long-term clinical safety implications of both the higher EZE exposures and undetermined effect on CyA are not yet understood, the clinical significance of this pharmacokinetic interaction is unknown.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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REFERENCES |
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