Influence of Renal and Hepatic Impairment on the Pharmacokinetics of Anacetrapib
Abstract
Two open-label, parallel-group studies evaluated the influence of renal and hepatic insufficiency on the pharmacokinetics of a single-dose anacetrapib 100 mg. Eligible participants included adult men and women with moderate hepatic impairment, assessed by Child-Pugh criteria, or severe renal impairment, characterized by a creatinine clearance of less than 30 mL/min/1.73 m². In both studies, patients were matched with healthy control subjects based on race, age, sex, and body mass index (BMI). Each study randomized 24 subjects, consisting of 12 individuals with either moderate hepatic or severe renal impairment and 12 matched healthy controls. In the hepatic insufficiency study, the geometric mean ratio for the area under the concentration-time curve from time zero to infinity and the maximum concentration of drug in plasma were 1.16 and 1.02, respectively. In the renal insufficiency study, the geometric mean ratios for the same parameters were 1.14 and 1.31, respectively. Anacetrapib was generally well tolerated, and there was no clinically meaningful effect of moderate hepatic or severe renal insufficiency on its pharmacokinetics.
Keywords: anacetrapib, hepatic, renal, insufficiency, pharmacokinetics
Introduction
Cholesteryl ester transfer protein (CETP) is a hydrophobic plasma protein that facilitates the bidirectional transfer of cholesteryl esters and triglycerides between high-density lipoprotein particles and atherogenic apolipoprotein B-containing lipoprotein particles. Anacetrapib is an orally active, potent, and selective CETP inhibitor currently in Phase III clinical development for treating patients with cardiovascular disease or primary hypercholesterolemia/mixed dyslipidemia at risk for atherosclerotic cardiovascular disease. Liver and renal dysfunctions can alter drug exposure by affecting drug absorption, plasma protein binding, metabolism, and biliary/renal excretion. Results from the human ADME study with anacetrapib show that most of the radioactive dose is recovered as unchanged parent drug in the feces. In humans, anacetrapib is negligibly excreted, with less than 0.1% of the radioactive dose recovered as unchanged parent drug in the urine. Thus, renal impairment is not expected to significantly affect anacetrapib pharmacokinetics. In preclinical experiments, cytochrome P450 (CYP3A) isoenzyme-mediated oxidation is the primary pathway for anacetrapib clearance. Prior studies in humans indicated that anacetrapib does not alter the pharmacokinetics of the sensitive CYP3A probe midazolam when administered at the anticipated clinical dose of 100 mg, and is unlikely to induce or inhibit CYP3A isozymes. However, anacetrapib is a moderately sensitive CYP3A substrate, as shown by a significant increase in exposure when coadministered with the strong CYP3A inhibitor, ketoconazole. These data suggest that hepatic impairment may have a clinically relevant effect on anacetrapib pharmacokinetics.
The present Phase I clinical studies aimed to investigate the safety, tolerability, and pharmacokinetics of anacetrapib 100 mg in patients with varying degrees of hepatic and renal impairment. The first study included individuals with moderate hepatic insufficiency, while the second study focused on individuals with severe renal insufficiency.
Methods
Study Designs and Populations
All subjects and patients provided written informed consent before the initiation of study procedures. The protocols received approval from the institutional review boards of the respective study centers. Both studies adhered to Good Clinical Practice Guidelines and other regulations regarding the protection of the rights and welfare of human subjects participating in biomedical research.
Study 1 was a multi-center, open-label, single-dose study conducted in patients with moderate hepatic insufficiency between June 3, 2010, and July 8, 2011. Twelve patients and 12 matched healthy control subjects each received a single 100-mg dose of anacetrapib in a fed state following a low-fat meal. Eligible patients included male and female subjects aged 18 to 70 years with a body mass index (BMI) of 37 kg/m² or less and no significant electrocardiogram abnormalities. A diagnosis of chronic, stable, moderate hepatic impairment, as defined by a Child-Pugh score of 7 to 9, was required for the subset of patients with hepatic impairment. Healthy subjects were matched to each patient by race, sex, age, and BMI. Patients with unstable disease or a history of renal disease were excluded from the study.
Study 2 was a multi-center, open-label, single-dose study conducted in patients with severe renal insufficiency, defined as a creatinine clearance of less than 30 mL/min/1.73 m², confirmed by two 24-hour urine collections. This study took place between June 8, 2010, and June 15, 2011. Eligible patients included male and female subjects aged 18 to 75 years with a BMI of 35 kg/m² or less and no significant ECG abnormalities. Twelve patients with renal insufficiency and 12 matched healthy control subjects each received a single 100-mg dose of anacetrapib in a fed state after a low-fat meal. Healthy subjects were matched to each patient by race, sex, age, and BMI. According to the study protocol, patients with mild and moderate disease would be enrolled if a meaningful effect was observed in patients with severe disease. Patients with unstable disease or a history of active hepatic disease were excluded, as were dialysis patients and healthy control subjects with chronic renal disease.
In both studies, women of child-bearing potential were enrolled if they were determined to be in a non-gravid state based on serum b-human chorionic gonadotropin measurements and were required to remain abstinent or use a double barrier method of birth control throughout the study. All subjects agreed to refrain from consuming grapefruit and grapefruit juice. Healthy volunteer control subjects also agreed to refrain from using any medications for at least two weeks prior to the start of the study and throughout the study. Generally, subjects with hepatic or renal impairment were allowed to continue medications needed to stabilize their condition. Diuretics were not to be used within four hours of dosing. The use of strong inducers or inhibitors of drug-metabolizing enzymes was prohibited. Subjects were excluded from both studies if they were infected with HIV, had recently donated blood, had experienced significant blood loss, had a significant clinical history of concern, or had an anticipated need for any prescription or non-prescription drugs during the study.
Analytical and Pharmacokinetic Assessments
Plasma samples were collected at various time points after dosing to measure anacetrapib concentrations. Following collection, blood samples were placed on ice and then centrifuged. The resulting plasma samples were frozen until they were sent to the analytical facility for quantification. The concentrations of plasma anacetrapib were determined using a liquid-liquid extraction method followed by liquid chromatographic tandem mass spectrometric detection, ensuring accurate measurement of drug levels.
Pharmacokinetic Endpoints
The plasma concentrations of anacetrapib were converted into molar units (mM) using a molecular weight of 637.508 g/mol. Important pharmacokinetic parameters calculated included the area under the concentration-time curve from time zero to infinity (AUC0–∞ [mM h]) and the peak plasma concentration (Cmax [mM]). Any values that were below the quantification limit for the plasma assay, which was set at 1.569 nM, were addressed by replacing pre-dose values with zero. A non-compartmental analysis was performed to calculate pharmacokinetic parameters using WinNonlin software (Version 5.2). The AUC0–∞ was calculated using the linear trapezoidal method for ascending concentrations and the log trapezoidal method for descending concentrations. The AUC0–∞ was determined by adding AUC0–last to Cest,last divided by lz, where Cest,last represents the estimated plasma concentration at the last measured time and lz is the apparent terminal elimination rate constant. lz was derived from the terminal log-linear portion of the plasma concentration-time profile. The apparent terminal half-life (t1/2) was calculated by dividing the natural logarithm of 2 (ln[2]) by lz, with a requirement of at least three data points in the terminal phase for lz calculations.
Statistical Analysis
The sample sizes for the studies were determined based on variance estimates from prior pharmacokinetic data on anacetrapib. For both studies, individual AUC0–∞ values for anacetrapib were analyzed using an analysis of covariance model after transforming the data to the natural log scale. This was done to compare the pharmacokinetics of anacetrapib in patients with hepatic or renal insufficiency against healthy matched control subjects. In the renal study, the analysis of covariance model included a categorical factor for population, a categorical covariate for sex, and continuous covariates for age and body mass index (BMI). The assumption of common variance was tested and not supported by the data, necessitating the use of estimated variance by population in the ANCOVA. In the hepatic study, the model also included a categorical factor for population, with sex as a categorical covariate and age and weight as continuous covariates. A 90% confidence interval was calculated for the geometric mean ratios of AUC0–∞ and Cmax within each study. Additionally, a 95% confidence interval was calculated for the geometric means of AUC0–∞ and Cmax for each population. Median, minimum, and maximum values were computed for Tmax, while geometric mean and percent coefficient of variation (CV) were computed for apparent terminal t1/2. Descriptive statistics were provided for all pharmacokinetic parameters by population.
According to the clinical protocols, the primary study hypotheses were considered met if the 90% confidence interval for the AUC0–∞ ratio of the geometric mean ratios was entirely contained within the interval (0.50, 2.00). This applied to comparisons between subjects with moderate hepatic insufficiency and healthy matched control subjects in Study 1, as well as between subjects with severe renal insufficiency and healthy matched control subjects in Study 2. Cmax was analyzed similarly to AUC0–∞. If advanced organ disease did not significantly affect anacetrapib plasma pharmacokinetics, it was assumed that lesser degrees of organ impairment would also not affect the pharmacokinetic profile of anacetrapib.
The comparability bounds were selected based on Phase II studies that demonstrated similar safety profiles with doses ranging from 10 to 300 mg, although the 50 mg dose showed slightly less lipid efficacy compared to the anticipated marketed dose of 100 mg. A pharmacokinetic dose/exposure reduction of greater than two-fold could potentially lead to clinically meaningful changes in lipid efficacy. Given the wide safety margins associated with this drug, any change in exposure of less than two-fold was not anticipated to be clinically meaningful. Thus, with safety considerations as the primary determinant for the upper bound and efficacy considerations for the lower bound, comparability bounds of (0.50, 2.00) were established for use in both studies.
All subjects in Study 1 were included in the pharmacokinetic and safety/tolerability analyses. One subject in Study 2, a renal insufficiency patient, was excluded from pharmacokinetic analyses due to a very low but non-zero plasma concentration value at the pre-dose visit. Consequently, a total of 23 subjects were included in the pharmacokinetic analysis for the renal study. There were no missing pharmacokinetic data among the 23 subjects who contributed to the pharmacokinetic analyses. All 24 subjects were included in the analysis of safety and tolerability. Statistical analysis was performed using SAS software.
Safety and Tolerability Assessments
The safety and tolerability of the study medication were assessed through clinical evaluations of adverse events, as well as the examination of other safety parameters. These included physical examinations, vital signs, and routine laboratory safety measurements such as hematology, blood chemistry, and urinalysis. Additionally, serum beta-human chorionic gonadotropin tests and 12-lead electrocardiograms were performed. Adverse events were monitored throughout the study and assessed based on their intensity, which was categorized as mild, moderate, or severe, along with their duration, severity, outcome, and relationship to the study drug. All patients who received at least one dose of the study medication were included in the safety and tolerability analyses.
Results
Demographics and Baseline Characteristics
In Study 1, a total of 12 patients with hepatic insufficiency and 12 matched healthy control subjects were enrolled. The combined groups consisted of 16 males and 8 females. All patients and subjects met the inclusion criteria. Individual Child–Pugh classification scores and associated laboratory values were collected. Among the patients with moderate hepatic insufficiency, 17% had a score of 9, 42% had a score of 8, and the remaining 42% had a score of 7 on the Child–Pugh scale. According to the protocol, 50% of the patients had a score of 2 or higher on at least one of the laboratory parameters included in the Child–Pugh score. The matched healthy control subjects exhibited unremarkable medical histories, physical examinations, ECGs, and clinical chemistry tests. All 24 enrolled individuals completed the study as per the protocol and were included in the primary pharmacokinetic and safety analyses.
In Study 2, 12 patients with renal insufficiency and 12 matched healthy control subjects were enrolled. The combined patient and healthy control groups included 14 males and 10 females. All patients and subjects met the inclusion criteria. According to the protocol, 50% of the subjects had severe renal insufficiency, defined by a creatinine clearance value of less than 30 mL/min/1.73 m², confirmed by two 24-hour urine collections. The matched healthy control subjects had unremarkable medical histories, physical examinations, ECGs, clinical chemistry tests, hematology tests, and urinalyses. A total of 24 enrolled individuals completed the study per protocol and were included in the safety analyses. One patient with severe renal insufficiency was excluded from the pharmacokinetic analyses due to a non-zero plasma concentration value at the pre-dose visit, resulting in a total of 23 subjects included in the pharmacokinetic analysis for the renal study.
Pharmacokinetic Results
The plasma concentration-time profiles of anacetrapib following the administration of 100 mg oral doses in patients with moderate hepatic insufficiency or severe renal insufficiency were generally similar to those of the corresponding healthy matched control subjects. Consistent with prior observations, anacetrapib exhibited slow absorption, with a median Tmax of 4 to 5 hours, and a slow elimination, characterized by a mean terminal half-life of 45 to 60 hours. While there was some variability in the pharmacokinetic parameters AUC0–∞, Cmax, Tmax, and apparent half-life, there were no clinically significant differences between the populations with organ dysfunction and their respective healthy matched control subjects.
The AUC0–∞ values, which served as the primary endpoint, and the Cmax values, the secondary endpoint, were utilized to formally assess the effects of organ dysfunction on the pharmacokinetics of a single 100 mg dose of anacetrapib. In Study 1, the estimated geometric mean AUC0–∞ values for anacetrapib in patients with hepatic insufficiency and healthy matched control subjects were 21.8 and 18.8 mM h, respectively. The estimated geometric mean Cmax values for anacetrapib in hepatic insufficiency patients and healthy matched control subjects were 1.8 and 1.7 mM, respectively. In Study 2, the estimated geometric mean AUC0–∞ values for anacetrapib in renal insufficiency patients and healthy matched control subjects were 28.4 and 24.9 mM h, respectively. The estimated geometric mean Cmax values for anacetrapib in renal insufficiency patients and healthy matched control subjects were 3.1 and 2.3 mM, respectively.
In Study 1, the estimated AUC0–∞ geometric mean ratio for anacetrapib in moderate hepatic insufficiency patients compared to healthy matched control subjects was 1.16, with a 90% confidence interval of 0.84 to 1.60. The upper and lower bounds of this confidence interval were entirely contained within the prespecified comparability bounds of 0.50 to 2.00, indicating no clinically relevant effect of moderate hepatic insufficiency on anacetrapib exposure. The estimated Cmax geometric mean ratio for anacetrapib in moderate hepatic insufficiency patients compared to healthy matched control subjects was 1.02, with a 90% confidence interval of 0.71 to 1.49. In Study 2, the estimated AUC0–∞ geometric mean ratio for anacetrapib in severe renal insufficiency patients compared to healthy matched control subjects was 1.14, with a 90% confidence interval of 0.80 to 1.63. The upper and lower bounds of this confidence interval were also contained within the prespecified comparability bounds of 0.50 to 2.00, indicating no clinically relevant effect of severe renal insufficiency on anacetrapib exposure. The estimated Cmax geometric mean ratio for anacetrapib in severe renal insufficiency patients compared to healthy matched control subjects was 1.31, with a 90% confidence interval of 0.93 to 1.83.
In accordance with FDA guidance, baseline creatinine clearance for the subjects was provided based on the Cockcroft–Gault and baseline estimated glomerular filtration rate values based on the Modification of Diet in Renal Disease formulas. Under any of the methods used to estimate renal function, all subjects qualified as severely impaired. The creatinine clearance values measured by 24-hour urine collections normalized for body surface area were utilized to select subjects for this study.
Safety and Tolerability
The administration of a single 100 mg dose of anacetrapib was generally well tolerated among individuals with moderate hepatic insufficiency and severe renal insufficiency. In Study 1, there were no clinical or laboratory adverse events reported at any time during the study. In Study 2, only one on-treatment clinical adverse event was noted, which was a tension headache experienced by a healthy control subject. No laboratory adverse events were recorded. The tension headache was classified as mild in severity, transient in duration, and the investigator deemed it to be “possibly” related to the administration of the study drug. Additionally, one subject was hospitalized due to a serious clinical adverse event of major depression with psychotic features; however, this incident occurred during the initial screening period before the administration of the study drug, resulting in the exclusion of this patient from the study. Importantly, no patients in either study discontinued treatment due to clinical or laboratory adverse events. Throughout both studies, there were no clinically significant abnormalities observed in any safety parameters analyzed, including laboratory tests, vital sign measurements, and electrocardiogram parameters across any patient group.
Discussion
Two studies were conducted to investigate the potential effects of moderate hepatic insufficiency and severe renal insufficiency on the pharmacokinetics of anacetrapib. The clearance of anacetrapib from human plasma is primarily driven by CYP3A isozyme-mediated metabolism, with negligible elimination occurring through renal excretion. The target population for anacetrapib includes patients with cardiovascular disease and dyslipidemia who may also have co-existing hepatic or renal insufficiency. Therefore, it was essential to characterize the pharmacokinetics of anacetrapib in these patient populations to determine if plasma levels would be altered due to hepatic or renal organ impairment.
Given that the clearance of anacetrapib primarily relies on metabolic oxidation involving CYP3A isoenzymes, and considering the liver is a major site of activity for these enzymes, an important clinical goal was to establish a recommendation for dose adjustment. This was especially pertinent should it be found that liver impairment increases drug exposure due to drug accumulation. The investigation into the pharmacokinetics of anacetrapib in patients with moderate hepatic insufficiency revealed no clinically relevant effects from this condition on the pharmacokinetics of a single 100 mg dose of anacetrapib. The geometric mean ratio for the area under the concentration-time curve (AUC) of patients compared to matched healthy control subjects was 1.16, and the confidence interval was (0.84, 1.60). Furthermore, for maximum concentration (Cmax), the geometric mean ratio for patients compared to matched healthy control subjects was 1.02, with a confidence interval of (0.71, 1.49). These findings indicate a low risk of reduced efficacy and a low risk of decreased tolerability in patients with moderate hepatic insufficiency. The conclusions drawn from this study can also be safely extrapolated to patients with mild hepatic insufficiency.
Previous studies have indicated that anacetrapib is negligibly excreted, with less than 0.1% of the radioactive dose recovered as unchanged parent drug in urine. However, regulatory guidance specifies that patients with severe renal impairment should also be studied when assessing the pharmacokinetics of compounds predominantly metabolized through hepatic mechanisms. This is because renal impairment can potentially inhibit some pathways of hepatic metabolism, leading to increased drug concentrations. The investigation into the pharmacokinetics of anacetrapib in patients with severe renal insufficiency revealed no clinically relevant effects of this condition on the pharmacokinetics of a single 100 mg dose of anacetrapib. Nonetheless, there was some evidence of pharmacokinetic variability in patients with renal impairment when compared to healthy matched control subjects. The geometric mean ratio for AUC of patients to matched healthy control subjects was 1.14, with a confidence interval of (0.80, 1.63). For Cmax, the geometric mean ratio for patients to matched healthy control subjects was 1.31, with a confidence interval of (0.93, 1.83). These results suggest a low risk of reduced efficacy and a low risk of decreased tolerability in patients with severe renal insufficiency. Furthermore, the conclusions of this study can be safely extrapolated to patients with mild and moderate renal insufficiency.
The FDA’s guidance on pharmacokinetics in patients with impaired renal function notes that either the Cockcroft-Gault or the Modification of Diet in Renal Disease formula is suitable for measuring glomerular filtration rate in studies assessing the impact of renal impairment on pharmacokinetics. The guidance also acknowledges that 24-hour urine creatinine measurements can be more challenging to implement in practice but may be more appropriate in certain types of subjects where formula-based assessments may prove inaccurate. The data obtained from this study showed that the impact on subject selection and the results would likely have been negligible had other methods for determining glomerular filtration rate been used.
Both liver and kidney diseases have the potential to affect processes such as absorption, plasma protein binding, and tissue distribution, which are crucial in determining drug disposition. Due to the high plasma protein binding of anacetrapib, which exceeds 99% in both studies, and the relatively low circulating levels following single-dose administration, it was not feasible to evaluate protein binding of anacetrapib in ex vivo samples from these studies. The observed values for AUC and Cmax in the hepatic study were lower than the corresponding values in the renal study. Differences in sex balance, age, and weight among subjects in the two studies may partially explain these observed differences. Additionally, the small sample sizes and inherent variability in anacetrapib pharmacokinetics are likely contributing factors. Although formal cross-study comparisons cannot be made, it is worth noting that the confidence intervals for AUC between the control groups in the two studies do overlap.
In summary, the administration of a single 100 mg dose of anacetrapib was generally well tolerated in these studies involving patients with moderate hepatic insufficiency or severe renal insufficiency. There were no clinically significant effects of moderate hepatic insufficiency or severe renal insufficiency on the pharmacokinetic profile of anacetrapib. Collectively, these findings indicate that no dose adjustment of anacetrapib is necessary for patients with mild or moderate hepatic insufficiency or for those with mild, moderate, or severe renal insufficiency. However, due to the extensive role of the liver and CYP3A isoenzymes in the clearance of anacetrapib, the administration of anacetrapib is not recommended for patients with severe hepatic impairment.
Author Contributions
B. Lauring, X. Li, Y. Liu, C. Corr, N. Lazarus, J. Cote, P. Larson, A.O. Johnson Levonas, K.C. Lasseter, R.A. Preston, W.B. Smith, E. Lai, and J.A. Wagner contributed to the work described in this paper and were involved in at least one of the following activities: conception, design, acquisition, analysis, statistical analysis, interpretation of data, and drafting or revising the manuscript for important intellectual content. All authors provided final approval of the version to be published.
Declaration of Conflicting Interests
B. Lauring, X. Li, Y. Liu, C. Corr, N. Lazarus, J. Cote, P. Larson, A.O. Johnson Levonas, E. Lai, and J.A. Wagner are current or former employees of Merck & Co., Inc., located in Whitehouse Station, NJ, and may own stock or hold stock options in the company. R.A. Preston received a grant from Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., and has received grants from Abbvie, Celerion, Celgene, Chiasma, Forest, Novartis, Pfizer, Fujifilm, Watson, Takeda, Apopharma, and Exelexis for work outside the scope of this paper. He is also a consultant for Ferring. W.B. Smith received a grant from Merck & Co., Inc., to the New Orleans Center for Clinical Research for participation in this study but has no other conflicts of interest to report. K.C. Lasseter served as a clinical investigator with a grant from Merck & Co., Inc. but has no other conflicts of interest to report.
Funding
This study was supported by Merck & Co., Inc., located in Whitehouse Station, NJ, USA.
References
1. Tall AR. Plasma cholesteryl ester transfer protein. J Lipid Res. 1993;34(8):1255–1274.
2. Gutstein DE, Krishna R, Johns D, et al. Anacetrapib, a novel CETP inhibitor: pursuing a new approach to cardiovascular risk reduction. Clin Pharmacol Ther. 2012;91(1):109–122.
3. Kumar S, Tan EY, Hartmann G, et al. Metabolism and excretion of anacetrapib, a novel inhibitor of the cholesteryl ester transfer protein, in humans. Drug Metab Dispos. 2010;38(3):474–483.
4. Krishna R, Bergman AJ, Jin B, et al. Assessment of the CYP3A-mediated drug interaction potential of anacetrapib, a potent cholesteryl ester transfer protein (CETP) inhibitor, in healthy volunteers. J Clin Pharmacol. 2009;49(1):80–87.
5. Pugh JI, Stringer P. Glove-powder granuloma of the testis after surgery. Br J Surg. 1973;60(3):240–242.
6. Child CG, Turcotte JG. Surgery and portal hypertension. Major Probl Clin Surg. 1964;1:1–85.
7. US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER). Guidance for Industry: Pharmacokinetics in Patients with Impaired Hepatic Function: Study Design, Data Analysis, and Impact on Dosing and Labeling. Available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072123.pdf.
8. Krishna R, Bergman AJ, Jin B, et al. Multiple-dose pharmacodynamics and pharmacokinetics of anacetrapib (MK-0859), a potent cholesteryl ester transfer protein (CETP) inhibitor, in healthy subjects. Clin Pharmacol Ther. 2008;84(6):679–683.
9. Bloomfield D, Carlson GL, Sapre A, et al. Efficacy and safety of the cholesteryl ester transfer protein inhibitor anacetrapib as monotherapy and coadministered with atorvastatin in dyslipidemic patients. Am Heart J. 2009;157(2):352–360.
10. US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Guidance for Industry: Pharmacokinetics in Patients with Impaired Renal Function-Study Design, Data Analysis, and Impact on Dosing and Labeling. Available at: http://www.fda.gov/downloads/Drugs//Guidances/UCM204959.pdf.
Supporting Information
Additional supporting information, including the summarized protocols for this study, may be found in the online version of this article at the publisher’s website.