Conversion of Functional Assessment of Chronic Illness Therapy-Fatigue to Patient-Reported Outcomes Measurement Information System Fatigue Scores in Two Phase III Baricitinib Rheumatoid Arthritis Trials.

OBJECTIVE: The Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) is validated for measuring fatigue in rheumatoid arthritis (RA). However, 10 of 13 FACIT-F items are identified as relevant to patients with RA. The Patient-Reported Outcomes Measurement Information System (PROMIS) uses an item response theory-calibrated T score metric. The PROMIS Fatigue item bank includes the FACIT-F items, enabling score conversion. The performance of converted PROMIS Fatigue scores has not been evaluated in RA populations or clinical trials. Our objective was to assess the performance of converted PROMIS Fatigue scores in 2 RA clinical trials of baricitinib. METHODS: Crosswalk tables and pattern-scoring methods converted FACIT-F scores to PROMIS Fatigue for both the 13-item FACIT-F and the 10-item RA-optimized FACIT-F instrument, in 2 RA clinical trials evaluating baricitinib, RA-BEAM, and RA-BEACON. RA-BEAM patients had an inadequate response to methotrexate. RA-BEACON patients had an inadequate response or intolerance to ≥1 tumor necrosis factor inhibitor. Baricitinib was compared to all treatment arms via analysis of covariance on PROMIS Fatigue score conversions. RESULTS: Baseline FACIT-F-derived PROMIS Fatigue scores reflected severe fatigue across treatment groups and were similar using different scoring methods. At week 24 in both studies, baricitinib was associated with clinically meaningful improvements in PROMIS Fatigue scores. PROMIS Fatigue scores were consistent for conversion methods and for the 13-item or 10-item FACIT-F. CONCLUSION: All 4 conversion methods showed differentiation of active treatment compared with placebo from week 12, supporting the use of the PROMIS Fatigue and converting the 10-item FACIT-F to assess fatigue and demonstrate treatment benefit in RA clinical trials on a standardized metric.

Assessment of acute kidney injury related to small-molecule protein kinase inhibitors using the FDA adverse event reporting system.

PURPOSE: Small-molecule protein kinase inhibitors (PKIs) have substantially improved clinical outcomes of various diseases. However, some studies suggested these agents might induce acute kidney injury (AKI). This study was designed to comprehensively assess the adverse events of AKI in real-world patients receiving small-molecule PKIs using the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). METHODS: The FAERS data between 2004 and 2019 were extracted to describe the characteristics of AKI cases after the use of small-molecule PKIs approved by the FDA. The reporting odds ratio (ROR) with 95% confidence interval (CI) for AKI was calculated for each small-molecule PKI agent. A disproportionality signal was defined when the lower limit of 95% CI > 1. RESULTS: Among the 462,020 adverse event reports for small-molecule PKIs, 9970 (2.16%) were identified as AKI cases. The median AKI onset time was 32 (interquartile range 11-124) days after the initiation of small-molecule PKI treatment. A total of 61.38% and 26.04% of AKI cases resulted in hospitalization and death, respectively. Based on RORs, 14 of 52 small-molecule PKIs yielded disproportionality signals for AKI, including six VEGFR inhibitors, three mTOR inhibitors and five small-molecule PKIs with other targets. The agents with the highest AKI RORs were entrectinib (ROR 6.40, 95% CI 2.23, 18.34), sirolimus (ROR 3.76, 95% CI 3.45, 4.09), and cobimetinib (ROR 3.40, 95% CI 2.69, 4.28). CONCLUSION: Analysis of the FAERS data helped identify the small-molecule PKIs that were most frequently reported for AKI. Further investigations are needed to confirm these potential risks.

Critical Assessment of Pharmacokinetic Drug-Drug Interaction Potential of Tofacitinib, Baricitinib and Upadacitinib, the Three Approved Janus Kinase Inhibitors for Rheumatoid Arthritis Treatment.

The introduction of novel, small-molecule Janus kinase inhibitors namely tofacitinib, baricitinib and upadacitinib has provided an alternative treatment option for patients with rheumatoid arthritis outside of traditional drugs and expensive biologics. This review aimed to critically assess the drug-drug interaction potential of tofacitinib, baricitinib and upadacitinib and provide a balanced perspective for choosing the most appropriate Janus kinase inhibitor based on the needs of patients with rheumatoid arthritis including co-medications and renal/hepatic impairment status. Based on the critical assessment, all three approved Janus kinase inhibitors generally provide a favourable opportunity for co-prescription with a plethora of drugs. While cytochrome P450 3A4-related inhibition or induction altered the exposures (area under the curve) of tofacitinib and upadacitinib, it did not impact the exposure of baricitinib. Transporter drug-drug interaction studies revealed that the disposition of baricitinib was altered with certain transporter inhibitors as compared with either tofacitinib or upadacitinib. Adjustment of tofacitinib or baricitinib dosages but not that of upadacitinib is required with the progression of renal impairment from a mild to a severe condition. While the dosage of tofacitinib needs to be adjusted for patients with moderate hepatic impairment status, it is not the case for either baricitinib or upadacitinib. Assessment of the drug-drug interaction potential suggests that tofacitinib, baricitinib and upadacitinib generally show a favourable disposition with no perpetrator activity; however, as victim drugs, they show subtle pharmacokinetic differences that may be considered during polypharmacy. Moreover, careful choice of the three drugs could be made in patients with rheumatoid arthritis with varying degrees of renal/hepatic impairments.

Carcinogenicity assessment of baricitinib in Tg.rasH2 mice and Sprague-Dawley (Crl:CD) rats.

Baricitinib is a potent and selective Janus kinase (JAK)1 and JAK2 inhibitor, and is approved for the treatment of moderately to severely active RA in adults in Europe, Japan, and other countries. This study evaluated the carcinogenic potential of baricitinib in Tg. rasH2 mice and Sprague-Dawley (Crl:CD) rats. Baricitinib was administered daily by oral gavage to Crl:CD rats for up to 94 weeks (dose levels of 0, 1, 3, or 8 mg/kg for males and 0, 3, 8, or 25 mg/kg for females) and to Tg. rasH2 mice for 26 weeks (dose levels of 0, 15, 40, or 300 mg/kg for males and 0, 10, 30, or 150 mg/kg for females). Baricitinib was well tolerated with no incidence of compound-related neoplasms at any dose levels in rats and mice. In mice, non-neoplastic events observed were bone marrow hypocellularity and increased adipocytes. In rats, baricitinib administration was associated with a dose-dependent increase in survival, with a decreased incidence of neoplasm (hematopoietic and mammary), potentially secondary to drug-related decreased weight gain. The incidence of proliferative changes such as neoplastic and hyperplastic lesions in the mammary glands of females and in the livers of males and females also decreased. In conclusion, baricitinib is not considered to be carcinogenic.

Incidence, course, and management of toxicities associated with cobimetinib in combination with vemurafenib in the coBRIM study.

Background: In the coBRIM phase III trial, the addition of cobimetinib, an MEK inhibitor, to vemurafenib, a BRAF inhibitor, significantly improved progression-free survival [hazard ratio (HR), 0.58; P < 0.0001] and overall survival (HR, 0.70; P = 0.005) in advanced BRAF-mutated melanoma. Here, we report on the incidence, course, and management of key adverse events (AEs) in the coBRIM study. Patients and methods: Patients were randomly assigned 1:1 to receive vemurafenib (960 mg twice a day) and either cobimetinib (60 mg once a day, 21 days on/7 days off) or placebo. In addition to standard safety evaluations, patients underwent regular ophthalmic, cardiac, and dermatologic surveillance examinations. Results: Of 495 patients recruited to the study, 493 patients received treatment and constituted the safety population (cobimetinib combined with vemurafenib, 247; vemurafenib, 246). At data cut-off (30 September 2015), median follow-up was 18.5 months. Nearly every patient experienced an AE. In patients who received cobimetinib combined with vemurafenib, the frequency of grade ≥3 AEs was higher than in patients who received vemurafenib alone (75% versus 61%). Most AEs, including grade ≥3 AEs, occurred within the first treatment cycle. After the first cycle (28 days), the incidence of common AEs (rash, diarrhoea, photosensitivity, elevated creatine phosphokinase, serous retinopathy, pyrexia, and liver laboratory abnormalities) decreased substantially over time. Most AEs were managed conservatively by supportive care measures, dose modifications of study treatment, and, occasionally, permanent treatment discontinuation. Conclusions: These data indicate that most AEs arising from treatment with cobimetinib combined with vemurafenib generally occur early in the treatment course, are mild or moderate and are manageable by patient monitoring, dose modification and supportive care. ClinicalTrials.gov: NCT01689519.

Cholesterol treatment patterns and cardiovascular clinical outcomes associated with colesevelam HCl and ezetimibe.

INTRODUCTION: Pharmaceuticals are commonly used to help at-risk patients reduce low-density lipoprotein cholesterol (LDL-C) levels in an effort to prevent atherosclerotic coronary artery disease. Although both the cholesterol inhibitor ezetimibe and the newer generation bile acid sequestrant colesevelam hydrochloride (HCl) effectively reduce LDL-C levels in patients with hypercholesterolemia, real-world evidence based on clinical outcomes is lacking. METHODS: A retrospective analysis of healthcare insurance claims data from a large national healthcare payer was conducted to evaluate outcomes within 12 months among 2,067 patients with hypercholesterolemia after the initiation of treatment with colesevelam HCl (679 patients) as compared with ezetimibe (1,388 patients). Outcomes evaluated were (1) composite cardiovascular event which included myocardial infarction, stroke, angina, or revascularization and (2) macrovascular complication event which was a wider-encompassing measure that included all composite cardiovascular outcomes along with atherosclerosis, aneurysm, embolism, and peripheral vascular disease. RESULTS: An adjusted logistic regression model found lower odds of a composite cardiovascular event (odds ratio [OR] 0.54, 95 % confidence interval [CI] 0.30-0.97) within 12 months for subjects initiating treatment with colesevelam HCl compared with subjects initiating treatment with ezetimibe. The unadjusted OR was slightly lower (OR 0.52, 95 % CI 0.30-0.90). The odds ratio for the wider-encompassing macrovascular complication event occurring within 12 months of initiating treatment with colesevelam HCl or ezetimibe was not statistically significant (OR 0.821, 95 % CI 0.49-1.35). DISCUSSION: The evidence of lower risk for composite cardiovascular event rates for subjects treated with colesevelam HCl compared with those treated with ezetimibe suggests the potential need to consider risk of clinical outcomes, in addition to LDL-C levels, in real-world practice when choosing a pharmaceutical treatment.

Changes in LDL-C levels and goal attainment associated with addition of ezetimibe to simvastatin, atorvastatin, or rosuvastatin compared with titrating statin monotherapy.

BACKGROUND: Many high-risk coronary heart disease (CHD) patients on statin monotherapy do not achieve guideline-recommended low-density lipoprotein cholesterol (LDL-C) goals, and combination lipid-lowering therapy may be considered for these individuals. The effect of adding ezetimibe to simvastatin, atorvastatin, or rosuvastatin therapy versus titrating these statins on LDL-C changes and goal attainment in CHD or CHD risk-equivalent patients was assessed in a large, managed-care database in the US. METHODS: Eligible patients (n=17,830), initially on statin monotherapy who were ≥18 years with baseline and follow-up LDL-C values, no concomitant use of other lipid-lowering therapy, and on lipid-lowering therapy for ≥42 days, were identified between November 1, 2002 and September 30, 2009. The percent change from baseline in LDL-C levels and the odds ratios for attainment of LDL-C<1.8 and <2.6 mmol/L (70 and 100 mg/dL) were estimated using an analysis of covariance and logistic regression, respectively, adjusted for various baseline factors. RESULTS: LDL-C reductions from baseline and goal attainment improved substantially in patients treated with ezetimibe added onto simvastatin, atorvastatin, or rosuvastatin therapy (n=2,312) versus those (n=13,053) who titrated these statins. In multivariable models, percent change from baseline in LDL-C was -13.1% to -14.8% greater for those who added ezetimibe onto simvastatin, atorvastatin, or rosuvastatin versus those who titrated. The odds of attaining LDL-C<1.8 and <2.6 mmol/L (70 and 100 mg/dL) increased by 2.6-3.2-fold and 2.5-3.1-fold, respectively, in patients who added ezetimibe onto simvastatin, atorvastatin, or rosuvastatin versus titrating statins. CONCLUSION: CHD/CHD risk-equivalent patients in a large US managed-care database, who added ezetimibe onto simvastatin, atorvastatin, or rosuvastatin, had greater LDL-C reductions and goal attainment than those who uptitrated these statin therapies. Our study suggests that high-risk CHD patients in need of more intensive LDL-C lowering therapy may benefit by adding ezetimibe onto statin therapy.

Warnings without guidance: patient responses to an FDA warning about ezetimibe.

BACKGROUND: In January 2008, the Food and Drug Administration (FDA) communicated concerns about the efficacy of ezetimibe, but did not provide clear clinical guidance, and substantial media attention ensued. We investigated the proportion of patients who discontinued therapy and switched to a clinically appropriate alternative after the FDA communication. METHODS: Using claims data from a national pharmacy benefits manager, we created a rolling cohort of new users of ezetimibe between January 2006 and August 2008 and created a supply diary for each patient in the year after cohort entry. A patient was identified as nonpersistent if a gap of 90 days was seen in the diary. Using segmented linear regression, we compared rates of nonpersistence before and after the FDA communication and assessed patient-level characteristics associated with discontinuation. Among nonpersistent patients, we determined whether a patient made a clinically appropriate switch in the subsequent 90 days by adding a new cholesterol-lowering medication or by increasing the dose of an existing one. We used a weighted t test to compare the rates of appropriate switching before and after the communication. RESULTS: Among 867,027 new ezetimibe users, 407,006 (46.9%) were nonpersistent in the first year. After the FDA communication, the monthly level of ezetimibe nonpersistence increased by 5.7 percentage points (P<0.0001). Younger patients, those who lived in low-income zip codes, and female patients were less likely to discontinue therapy (P<0.0001 for all). Among nonpersistent patients, rates of clinically appropriate switching increased from 10.8% before to 16.5% after the FDA warning (P = 0.004). CONCLUSIONS: A substantial increase in ezetimibe nonpersistence rates was seen after an FDA communication regarding its efficacy and following associated media attention, and a small proportion of patients made a clinically appropriate switch after discontinuation. Further consideration is needed to deliver messages that promote appropriate use of chronic therapy rather than simply reduce use.

Assessment of potential pharmacokinetic interactions of ezetimibe/simvastatin and extended-release niacin tablets in healthy subjects.

BACKGROUND: Efforts to lower plasma lipid levels sometimes require multiple agents with different mechanisms of action to achieve results specified by national treatment guidelines. METHODS: This was an open-label, randomized, three-period, multiple-dose crossover study that assessed the potential for pharmacokinetic interaction between extended-release niacin and ezetimibe/simvastatin and their major metabolites. Eighteen adults received three randomized treatments: (A) extended-release (ER) niacin 1000 mg/day for 2 days, followed by 2000 mg/day for 5 days; (B) ezetimibe/simvastatin 10 mg/20 mg/day; (C) coadministration of Treatments A and B. Treatments were given once a day after a low fat breakfast for a total of 7 days, with a 7-day inter-dose period. RESULTS: There were small (mean ≤35%) increases in drug exposure for all analytes after coadministration of ER niacin and ezetimibe/simvastatin 10 mg/20 mg. The least-square mean between treatment C(max) (maximum plasma concentration) ratios (×100) were 97, 98, and 109% for ezetimibe, simvastatin and niacin, respectively. The corresponding ratios for total ezetimibe, simvastatin acid, and nicotinuric acid were 99, 118, and 110%. The AUC((0-24)) (area under the plasma concentration-time curve from time zero to 24 h after dosing) ratios for ezetimibe, simvastatin, and niacin were 109, 120, and 122%, respectively, and the corresponding ratios for total ezetimibe, simvastatin acid, and nicotinuric acid were 126, 135 and 119%. CONCLUSION: There is a small pharmacokinetic drug interaction between ER niacin and ezetimibe/simvastatin and although this is not considered to be clinically significant, the concomitant use of these drugs should be appropriately monitored, especially during the niacin titration period.

Safety assessment of new antithrombotic agents: lessons from the EXTEND study on ximelagatran.

BACKGROUND: Ximelagatran, the first oral direct thrombin inhibitor, was shown to be an effective antithrombotic agent but was associated with potential liver toxicity after prolonged administration. OBJECTIVES AND METHODS: The aim of the EXTEND study was to assess safety and efficacy of extended administration (35 days) of ximelagatran or enoxaparin for the prevention of venous thromboembolism after elective hip replacement and hip fracture surgery. A follow-up period, including assessment of liver enzymes (in particular alanine aminotransferase; ALAT), until post-operative day 180 was planned, with visits at days 56 and 180. RESULTS: Randomization and administration of study drugs were stopped following a report of serious liver injury occurring 3 weeks after completion of ximelagatran treatment. At the time of study termination, 1158 patients had been randomized and 641 had completed the 35-day treatment; with 303 ximelagatran and 265 enoxaparin patients remaining in the study through to the day 56 follow-up visit. Overall, 58 patients showed an ALAT increase to >2x upper limit of normal: 31 treated with enoxaparin, 27 with ximelagatran. Three ximelagatran patients also showed symptoms potentially related to liver toxicity. Eleven ximelagatran patients showed an ALAT increase after study treatment ended. The clinical development of ximelagatran was terminated and the drug withdrawn from the market. Evaluation of the relative efficacy of the two treatments as specified in the protocol was impossible due to the premature termination of the study. CONCLUSIONS: Prolonged administration of ximelagatran was associated with an increased risk of liver toxicity. In a substantial proportion of patients, ALAT increase occurred after treatment withdrawal. The findings seen with ximelagatran should be considered when designing studies with new antithrombotic agents.

Utility of the Roussel Uclaf Causality Assessment Method (RUCAM) to analyze the hepatic findings in a clinical trial program: evaluation of the direct thrombin inhibitor ximelagatran.

AIMS: Causality assessment in drug-induced liver injury is often based on circumstantial evidence rather than a formal, systematic review. The Roussel Uclaf Causality Assessment Method (RUCAM) provides a more objective means of assessing causality of a suspected hepatotoxin but, to our knowledge, has never been used in the assessment of a single drug with unknown hepatotoxic potential in a clinical trial setting. METHODS: We studied the utility of RUCAM in assessing the hepatic events during the long-term clinical trials of the oral direct thrombin inhibitor ximelagatran, which has been associated with an increased incidence of alanine aminotransferase (ALT) elevations. A total of 233 subjects with elevated ALT values signalling possibly severe hepatic injury were eligible for RUCAM analysis (198 ximelagatran and 35 comparator anticoagulants). RESULTS: RUCAM scores, calculated independently by the assessors, using the existing numerical criteria provided in its methodology, suggested a possible or probable causal relationship between ALT and ximelagatran in 37 and 27% of cases, respectively. Causality was excluded or unlikely in the remaining 36% of cases. However, in the course of utilizing RUCAM, several limitations to the methodology came to light, including awarding additional points for age > 55 years, an unspecified use of alcohol, and a latency period of < 90 days, which may have had the unintentional effect of raising the overall score. Moreover, rechallenge is highly rewarded by RUCAM but is seldom done in clinical practice or in clinical trials. We also found ambiguities in the extent to which other causes of liver injury were excluded, what constitutes a significant hepatotoxic concomitant medication, and whether a clinical trial drug should be considered as having an unknown hepatotoxic potential for purposes of RUCAM scoring. Increasing familiarity with the RUCAM over the course of the study allowed for only a slight improvement in concordance between and among the assessors regarding the scoring. CONCLUSIONS: While the results indicate that RUCAM can provide for an objective assessment of causality of the hepatotoxicity of a drug under development in the clinical trial setting, this study highlights a number of problems with the current scoring system that should be addressed by future enhancements of the methodology.

The direct thrombin inhibitor ximelagatran/melagatran: a systematic review on clinical applications and an evidence based assessment of risk benefit profile.

The direct thrombin inhibitor, ximelagatran, and its active form, melagatran (X/M), have been compared against conventional anticoagulant therapy (CAT) in many clinical settings. Their risk-benefit profile drove large debate until withdrawal by the manufacturer. A systematic review of all published randomized trials has been performed and a meta-analysis of randomised controlled trial (RCT) of X/M versus CAT. Major medical databases were searched for RCTs. Major adverse events (MAE: all cause death, nonfatal myocardial infarction, nonfatal thromboembolic stroke, pulmonary embolism), major bleeds (MB), minor bleeds and the rate of hepatotoxicity (HT) were compared. In terms of efficacy, X/M was at least as effective as, or even superior to, CAT. In terms of safety, the overall risk of MAE, MB, minor bleeds and HT was not significantly different for X/M compared with CAT. According to individual clinical settings, X/M was associated with a lower risk of MB but a prohibitive higher risk of HT in those clinical settings requiring prolonged treatment.

Ximelagatran: a new type of oral anticoagulant.

OBJECTIVES: This assessment sought to evaluate the comparative benefit and adverse effect profile of ximelagatran, as well as the clinical issues surrounding its potential use. METHODS: We performed a Dialog OneSearch across BIOSIS Previews, EMBASE, MEDLINE, PASCAL, and ToxFile to identify published literature. PubMed and The Cochrane Library were also searched. Gray literature was identified by searching a variety of Web sites of health technology assessment and related agencies and their associated databases. The manufacturer's Canadian office, AstraZeneca, was invited to submit information. RESULTS: Ximelagatran is the first oral agent from a new class of anticoagulants called direct thrombin inhibitors. Other oral anticoagulants require routine blood monitoring; ximelagatran does not. Ximelagatran has been evaluated in the areas of venous thromboembolism management, particularly after orthopedic surgery, and stroke prevention in patients with atrial fibrillation. Overall, ximelagatran's efficacy appears comparable to other anticoagulants in these clinical settings. Also, bleeding rates were generally similar between ximelagatran and comparators but, as for warfarin, bleeding risk increases with higher ximelagatran doses. In addition, there is no specific antidote to help manage ximelagatran-induced bleeding. Finally, significantly more patients exposed to long-term ximelagatran developed elevated liver enzymes more than three times the upper normal limit, compared with patients on comparator anticoagulants. CONCLUSIONS: Given its apparent simplicity of use, ximelagatran carries the potential to replace, at least in part, anticoagulants currently used in the management of venous thromboembolism or for preventing stroke in atrial fibrillation patients. However, the safety of ximelagatran will not be fully known without further evaluation and surveillance for potential liver toxicity. There is also a need to evaluate its use in special populations such as patients with renal failure and patients using several concurrent medications.

A preliminary assessment of the critical differences between novel oral anticoagulants currently in development.

Chronic anticoagulation represents a clinical conundrum for the health care community that balances unquestionable morbidity and mortality benefits against interindividual variability, leading to drug interactions, adverse events, and thromoembolic events related to underdosing. Despite the growing data regarding the appropriate use and dosing of agents used for chronic anticoagulation, use in clinical practice remains low, thus leading to a theoretical reduction in the risk-to-benefit ratio in the clinical setting relative to that reported in the literature. Oral anticoagulants currently in development represent a heterogeneous group of compounds that are specific for the final common pathway in the coagulation cascade and show indications toward a reduced drug interaction profile, reduced interpatient variation in pharmacokinetic parameters, and morbidity and mortality benefits that might be similar to currently available treatment modalities. This review highlights the critical differences among oral anticoagulants in development and places their role in the context of the benefits and limitations of currently available anticoagulants.

Changing the guard in long-term anticoagulation: clinical and economic implications.

The topic of anticoagulant prescription in patients with nonvalvular atrial fibrillation, for the primary and secondary prevention of stroke, provides a forum for discussion of current challenges in anticoagulation management and ways in which the introduction of ximelagatran will provide an opportunity to overcome many of them. Anticoagulation with warfarin has been shown to reduce stroke rates by 68%, providing significant net monetary savings. However, physician fear of hemorrhagic side effects, the need for regular INR monitoring, food and drug interactions, and patient noncompliance have all played a part in either suboptimal utilization or complete avoidance of anticoagulant therapy, even in patients at high risk for stroke. Ximelagatran, a new oral direct thrombin inhibitor, circumvents most of these problems and provides a more physician- and patient-friendly method of stroke prophylaxis. With the utilization of this new anticoagulation method, the incidence of stroke in high risk groups, and the corresponding quality-of-life and economic impact, can potentially be greatly reduced.

Assessment of a multiple-dose drug interaction between ezetimibe, a novel selective cholesterol absorption inhibitor and gemfibrozil.

OBJECTIVE: Ezetimibe is a novel lipid-lowering drug that prevents intestinal absorption of dietary and biliary cholesterol leading to significant reduction in total-C, LDL-C, Apo B, and TG and increases in HDL-C in patients with hypercholesterolemia. Gemfibrozil, a fibric acid derivative, is an effective lipid-modulating agent that increases serum high-density lipoprotein cholesterol and decreases serum TG. The objective of this study was to evaluate the potential for a pharmacokinetic (PK) interaction between ezetimibe and gemfibrozil. METHODS: This was a randomized, open-label, 3-way crossover, multiple-dose study in 12 healthy adult male volunteers. All subjects received the following 3 treatments orally for 7 days: ezetimibe 10 mg once daily, gemfibrozil 600 mg every 12 hours, and ezetimibe 10 mg once daily plus gemfibrozil 600 mg every 12 hours. A washout period of > or = 7 days separated the 3 treatments. In each treatment, blood samples were collected on day 7 to assess the steady-state PK of ezetimibe and gemfibrozil. The oral bioavailability of ezetimibe coadministered with gemfibrozil relative to each drug administered alone was evaluated with an analysis-of-variance model. RESULTS: Ezetimibe was rapidly absorbed and extensively conjugated to its glucuronide metabolite. Ezetimibe did not alter the bioavailability (based on AUC) of gemfibrozil. The mean AUC0-12 of gemfibrozil was 74.7 and 74.1 microg h/ml with and without ezetimibe coadministration, respectively (log-transformed geometric mean ratio (GMR) = 99.2; 90% confidence interval (CI) = 92 - 107%). Conversely, gemfibrozil significantly (p < 0.05) increased the plasma concentrations of ezetimibe and total ezetimibe (i.e. ezetimibe plus ezetimibe-glucuronide). Exposure to ezetimibe and total ezetimibe was increased approximately 1.4-fold and 1.7-fold, respectively (CI = 109 - 173% for ezetimibe and 142 - 190% for total ezetimibe), however, this increase was not considered to be clinically relevant. Ezetimibe and gemfibrozil administered alone or concomitantly for 7 days was well tolerated. CONCLUSIONS: The coadministration of ezetimibe and gemfibrozil in patients is unlikely to cause a clinically significant drug interaction. The coadministration of these agents is a promising approach for patients with mixed dyslipidemia. Additional clinical studies are warranted.