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Effect of Hepatic Impairment on the Multiple-Dose Pharmacokinetics of Ranolazine Sustained-Release Tablets

From Clinical Pharmacology, CV Therapeutics, Inc, Palo Alto, California.

Address for reprints: Markus Jerling, MD, PhD, Stavgardsgatan 30, Bromma 16756, Sweden.

	ABSTRACT

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
The effect of hepatic impairment on the pharmacokinetics of a sustained-release formulation of ranolazine and 3 major metabolites was investigated in an open-label, parallel-group study. Ranolazine (875-mg loading dose followed by 500 mg every 12 hours for a total of 4 maintenance doses) was administered to subjects with mild (n = 8) or moderate (n = 8) hepatic impairment and a matched control group of healthy volunteers (n = 16). Moderate, but not mild, hepatic impairment significantly increased ranolazine steady-state area under the concentration-time curve (AUC_0-12) by 76% (P < .001) and maximum plasma concentration C_max by 51% (P < .01). The AUC_0-12 ratio (metabolite/ranolazine) decreased for all metabolites in parallel with the degree of hepatic impairment. AUC_0- for the CYP3A substrate midazolam administered as a single dose was significantly correlated with ranolazine AUC_0-12 at steady state (r² = .33, P < .001). Over the time interval studied, ranolazine was well tolerated in healthy subjects and hepatically impaired subjects.

Key Words: Ranolazine • hepatic impairment • pharmacokinetics

Ranolazine (Figure 1) is extensively metabolized in the liver by the cytochrome P450 (CYP) system, with less than 5% of the dose excreted unchanged by the kidneys.⁵ It has been calculated based on human-drug interaction studies that on average, 70% to 75% of total systemic clearance is mediated by CYP3A-dependent pathways and 10% to 15% by CYP2D6-dependent pathways. In a single-dose oral study with ¹⁴C-ranolazine in healthy male subjects,⁵ the area under the concentration-time curve (AUC) of the ranolazine metabolite CVT-2512, which is formed through the removal of the methoxyphenyl group, was 12% that of ranolazine. The AUC of the O-demethylated metabolite CVT-2514 was 37% that of ranolazine. The metabolite CVT-2738 is produced by N-dealkylation of ranolazine and reached an AUC that was approximately 40% that of ranolazine.⁵ The present study was designed to determine the effect of mild and moderate hepatic impairment on the pharmacokinetics of ranolazine SR and 3 of its major metabolites (CVT-2512, CVT-2514, and CVT-2738) following multiple oral dosing. These metabolites were selected for analysis by virtue of their significant contribution (>10%) to the overall systemic exposure following ranolazine administration.⁵

View larger version (9K): [in this window] [in a new window]   Figure 1. Chemical structure of ranolazine.

	METHODS

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

Key inclusion criteria dictated that participants aged 18 to 75 years, with a body weight between 40 kg and 120 kg that was within 25% of their ideal body weight, and who were nonsmokers or light smokers able to abstain for 24 hours, were eligible for study entry. A normal electrocardiogram (ECG), blood pressure, and heart rate at baseline were required along with the absence of clinically important physical or laboratory abnormalities, except those related to underlying hepatic dysfunction. Female subjects had to use an acceptable form of contraception and have a negative pregnancy test at screening and admission. Volunteers were excluded if they had received another investigational drug within 4 weeks of the study; suffered from any surgical or medical condition that might interfere with the absorption, distribution, metabolism, or excretion of the drug; or were positive for HIV or hepatitis B. In addition, subjects were excluded if ongoing treatment included drugs classified as significantly affecting CYP3A activity or if they had a hemoglobin level below 10 g/dL or encephalopathy higher than grade 2.

Subjects were screened by physical examination, medical history, vital signs, laboratory assessments, ECG, and testing for hepatitis B, hepatitis C, and HIV. Admission procedures included a medical history update, vital signs, ECG, and an alcohol breath test. Key exclusion criteria dictated that participants were not permitted methylxanthine-containing beverages or alcohol within 24 hours before the study start or grapefruit/grapefruit juice within 14 days before the study, neither of which could be consumed until after study completion. Strenuous exercise was not permitted during the study, nor was smoking during the first 24 hours or for 2 hours preceding ECG recordings.

Subjects received an initial loading dose of 875 mg ranolazine SR (500- + 375-mg tablets), followed by 4 maintenance doses of ranolazine 500 mg administered twice daily. All morning doses were administered under fasting conditions. This regimen was intended to result in steady state on day 3. Ranolazine SR tablets were supplied by CV Therapeutics, Inc (Palo Alto, Calif).

Safety Assessments
Safety assessments included blood pressure, heart rate, ECG, blood and clinical chemistry, urinalysis, and physical examination. Adverse events were recorded throughout the study until the final scheduled follow-up. A follow-up telephone call was made 14 days after discharge to complete any outstanding inquiries, including adverse events.

Bioanalytical and Pharmacokinetic Methods
Midazolam determinations were conducted by ACC GmbH, Leidersbach. Blood was sampled predose; 5, 15, 30, 45, and 60 minutes; and 2, 3, 4, 6, and 8 hours after dosing. The blood samples were collected into tubes containing lithium heparin, mixed, and stored on ice before centrifugation. The plasma was separated as soon as possible after collection by centrifugation at 3000 rpm for 10 minutes at 4°C, transferred to polypropylene tubes, and frozen. Midazolam was extracted with toluene, evaporated, and the residue reconstituted. Separation of the analyte from the remaining matrix components was accomplished by capillary column gas chromatography with selective nitrogen/phosphorous detection. The calibration range of the method for midazolam was 0.5 to 30 ng/mL, with a limit of quantification of 0.5 ng/mL. The following parameters were computed for midazolam by noncompartmental analysis using WinNonlin version 3.2 (Pharsight Corporation, Mountain View, Calif): terminal rate constant (ke), plasma half-life (t_1/2), area under the plasma concentration versus time curve to infinity (AUC_0-), total plasma clearance (CL), and volume of distribution (Vss).

Concentrations of ranolazine and 3 of its major metabolites (CVT-2512, CVT-2514, and CVT-2738) were determined from heparinized plasma. Blood samples were collected predose; at 1, 2, 3, 4, 5, 7, 9, and 12 hours after dose 1; before doses 3, 4, and 5; and at 1, 2, 3, 4, 5, 7, 9, 12, 16, 24, 28, 32, 36, and 48 hours after dose 5. Plasma was separated using a procedure similar to that for the midazolam samples and frozen. Proteins in plasma samples were precipitated with a mixture of acetonitrile and methanol followed by centrifugation at 2600g for 10 minutes. The assay for the quantification of ranolazine, CVT-2514, CVT-2512, and CVT-2738, involves precipitation of human plasma with acetonitrile and methanol, followed by analysis by LC/MS/MS using positive-ion ionspray ionization. The mass spectrometer was operated in the multiple-reaction monitoring mode. An internal standard, CVT-3023 (d₃-ranolazine) was used in the construction of standard calibration curves. The concentration range of the validated assay for ranolazine was from 50 to 10000 ng/mL and 10 to 2000 ng/mL for CVT-2514, CVT-2512, and CVT-2738 based on using a 0.1-mL sample volume. High-performance liquid chromatography was carried out on a Waters 2795 Alliance system using a Phenomenex Synergi Hydro-R (2 x 50 mm) column. The mobile phase consists of (1) water containing 0.1% formic acid, pH 3.0, and (2) acetonitrile containing 0.1% formic acid. Chromatography was carried out under gradient elution conditions under ambient temperature according to Table I.

The effluent was monitored using tandem mass spectrometry on a Micromass Quattro Ultima mass spectrometer (Beverly, Mass). The source temperature and the desolvation temperature were 120°C and 400°C, respectively. The ion transitions, cone voltage, and collision energy settings for the individual analytes are shown in Table II. Data were processed using the MassLynx Data system (version 3.4). Accuracy, as measured by percentage relative error of the quality control samples (QC) at 3 concentration levels (low, medium, and high) imbedded in the bioanalyses, was 1% for all QC for ranolazine, -3.50% to 1.00% for CVT-2514, -4.00% to 3.50% for CVT-2512, and -2.00% to 6.00% for CVT-2738. Precision, as measured by percentage coefficient of variation, ranged from 2.74% to 11.3% for ranolazine, 3.66% to 8.91% for CVT-2514, 4.21% to 9.17% for CVT-2512, and 3.64% to 10.5% for CVT-2738 across all QC concentrations. The accuracy and precision for all 4 analytes throughout the bioanalyses were well within the predefined specification (±15%) of the validated assay.

The pharmacokinetic parameters calculated for ranolazine and its metabolites were computed by noncompartmental analysis using WinNonlin version 3.2 (Pharsight Corporation, Mountain View, Calif). Parameters included the AUC between 0 and 12 hours postdose on days 1 and 3 (AUC_0-12), maximum observed concentration on days 1 and 3 (C_max), and terminal phase half-life on day 3 (t_1/2). The day 3 trough concentration was defined as C_trough =(C_predose +C₁₂)/2. The fluctuation ratio was calculated as C_max/C_trough on day 3, and accumulation ratios with respect to AUC_0-12, C_max, and C₁₂ were calculated as the ratios of each day 3 parameter value to the corresponding day 1 value. For ranolazine only, apparent oral clearance was computed from day 3 measurements as dose/AUC_0-12. The achievement of steady-state kinetics on day 3 was tested by comparing the plasma concentration predose 5 (C₄₈) to the 12-hour postdose (C₆₀) concentration.

Statistical Analyses
US Food and Drug Administration guidelines for pharmacokinetic studies in subjects with hepatic impairment were followed.⁷ The sample size of 32 subjects is appropriate for a study of this type. No formal sample size calculation was performed.

The effects of hepatic impairment on key ranolazine pharmacokinetic parameters were evaluated using analysis of variance (ANOVA) models. Potential covariates including age, body weight, degree of hepatic impairment (none, mild, and moderate), and sex were evaluated, and those that correlated significantly with each pharmacokinetic parameter were retained for the final analysis (body weight was the only covariate other than hepatic impairment that was significant). The association between ranolazine AUC and midazolam AUC was assessed using simple linear regression. Demographic variables (age, sex, race, height, and weight) were summarized by hepatic impairment. Vital signs, ECGs, and laboratory parameters were summarized at each time point, including changes from baseline by degree of hepatic impairment. Descriptive statistics were used to summarize adverse events. Analyses were performed using SAS statistical software version 6.12.

	RESULTS

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Subjects
Thirty-two subjects were enrolled and completed the study, 8 subjects in each of the 2 hepatic impairment groups (mild and moderate) and 16 healthy controls with normal hepatic function matched to each hepatically impaired subject by gender, age, and weight. Baseline characteristics are shown in Table III. No notable differences were observed between healthy controls and their respective subject groups by age, weight, or height. All subjects were white. The overall mean age was 52.3 years. Midazolam clearance was reduced in subjects with hepatic impairment, resulting in an increased AUC, as expected.

Pharmacokinetics of Ranolazine SR in Hepatic Impairment
The pharmacokinetic parameters of ranolazine and 3 of its metabolites in healthy and hepatically impaired subjects are summarized in Tables IV and V. Figure 2 depicts the plasma concentration versus time profiles for ranolazine, CVT-2512, CVT-2514, and CVT-2738. At steady state (day 3), the mean time to peak ranolazine plasma concentration (T_max) was between 6 and 8 hours (range, 1-9 hours), with no apparent difference among the groups. In subjects with normal liver function, the ranolazine steady-state C_max ranged from 453 to 2660 ng/mL and the AUC_0-12 ranged from 3896 to 16 201 ng•h/mL.

View larger version (66K): [in this window] [in a new window]   Figure 2. Mean plasma concentration-time profile for (A) ranolazine, (B) CVT-2512, (C) CVT-2514, and (D) CVT-2738 at steady state.

Only minor differences in concentrations predose and 12 hours postdose related to the last dose on day 3 were found for ranolazine and metabolites, indicating that steady state had been achieved (data not shown). At steady state, the AUC_0-12 of ranolazine was not significantly different between healthy volunteers and the group with mild impairment but was 76% higher in subjects with moderate impairment (P < .001; Table IV). There were no significant differences in AUC_0-12 of the ranolazine metabolites with respect to hepatic impairment (Table IV). A similar pattern was observed for C_max, with a 51% increase of ranolazine in the moderate hepatic impairment group compared with healthy subjects on day 3 (P < .01), with no significant differences among the metabolites (Table IV). Ranolazine C_trough was also 2.2-fold higher in subjects with moderate impairment compared with healthy subjects (P < .001; Table V).

Mild and moderate hepatic impairment was a factor in ranolazine-metabolite ratios, with mild impairment significantly decreasing the CVT-2738-ranolazine ratio (P < .05) and moderate hepatic impairment significantly decreasing the CVT-2514-ranolazine and CVT-2738-ranolazine ratios (P < .05 and P < .001, respectively; Table V). The C_trough accumulation ratio of CVT-2512 was also significantly decreased by hepatic impairment (P < .05).

Table VI shows the accumulation ratios and the fluctuation ratios. The ANOVA overall test for significance showed hepatic impairment (none, mild, moderate) to be a significant predictor of ranolazine AUC_0-12, C_max, C_trough, AUC accumulation ratio, and fluctuation ratio. CVT-2512 and CVT-2514 showed less dependence on hepatic impairment, but hepatic impairment was a significant predictor of t_1/2, accumulation ratios (AUC and C_max), and the fluctuation ratio.

Table III shows the midazolam AUC that was determined at study entry to characterize hepatic impairment. Subjects with moderate impairment had significantly higher values than did subjects with mild impairment and healthy controls (P <.05 and P < .01, respectively). Consistent with the increase in midazolam AUC with increasing degree of hepatic impairment, there was a significant correlation between ranolazine day 3 AUC_0-12 and midazolam AUC_0- (r² = 0.33, P < .01), as shown in Figure 3. Also significant was the negative correlation between the CVT-2738 metabolite to ranolazine AUC ratio and midazolam AUC (r² = 0.49, P < .0001).

View larger version (16K): [in this window] [in a new window]   Figure 3. Association between ranolazine AUC0-12 at steady state and midazolam AUC0- after a single dose. Linear regression function r2 = 0.33, P < .001.

Safety
There were no serious adverse events or early withdrawals due to adverse events. All adverse events were mild or moderate in severity. More all-cause adverse events were reported in subjects with hepatic impairment (mild, 4/8 subjects; moderate, 4/8 subjects) compared with healthy controls (3/16 subjects). Constipation, a possibly drug-related event, was noted in 1/8 subjects with mild hepatic impairment. Possibly drug-related adverse events in subjects with moderate hepatic impairment included constipation (1/8 subjects), headache (1/8 subjects), and prolonged QTc interval (1/8 subjects). In healthy controls, headache (2/16 subjects), asthenia (1/16 subjects), and nausea (1/16 subjects) were reported as possibly drug related. There were no clinically significant changes in hematology, urinalysis, or clinical chemistry.

	DISCUSSION

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Hepatic impairment can significantly alter the rate of drug metabolism. Altered hepatic blood flow and extraction as well as a reduced functional mass are the primary causes of these changes, and the effect of liver disease on pharmacokinetics is highly variable⁸; therefore, studies such as this in subjects with different degrees of hepatic impairment versus healthy volunteers can provide critical drug metabolism information specific to ranolazine administration.

In the present study, mild hepatic impairment did not significantly affect ranolazine pharmacokinetics. In contrast, moderate hepatic impairment caused significant changes; steady-state AUC_0-12 was increased by 76%, C_trough was more than doubled, and C_max increased by 51% compared with healthy subjects. The absolute bioavailability of ranolazine has, in other studies, been shown to be in the range of 35% to 50%, indicating that the increased concentrations in subjects with moderate impairment may be related to both increased bioavailability and reduced systemic clearance.

Although systemic exposure to the 3 ranolazine metabolites was largely unaffected by the level of hepatic impairment, the ratio of AUC of the metabolites to ranolazine was generally reduced in moderate hepatic impairment, indicating a compromise in the rate of formation of the metabolites. Because the functional mass of the liver is markedly reduced in subjects with liver cirrhosis, this compromise of ability would be expected considering the liver is the major metabolizing organ for ranolazine.

Previous studies have demonstrated that the CYP3A isoenzymes are primarily responsible for the metabolism of ranolazine and that CVT-2738 is a major CYP3A-mediated metabolite.⁹ For the purposes of comparing a known CYP3A substrate with ranolazine and its metabolites, we used midazolam to quantify the effect of hepatic impairment on this system. Midazolam AUC was increased in subjects with hepatic impairment and significantly correlated with ranolazine AUC. This correlation suggests that the metabolism of both compounds was altered by hepatic impairment through a common mechanism. The negative correlation between the CVT-2738 metabolite to ranolazine AUC ratio and midazolam AUC was consistent with CVT-2738 being a major CYP3A-mediated metabolite.

Conclusions
The systemic exposure to ranolazine at steady state, expressed as AUC_0-12, C_max, and C_trough, was significantly higher in subjects with moderate hepatic impairment, but not mild hepatic impairment, when compared with healthy subjects. Ranolazine and its metabolites did not appear to accumulate or fluctuate (peak to trough) to a much greater extent in subjects with hepatic impairment compared with healthy subjects. Over the time interval studied, multiple dosing with ranolazine SR was well tolerated in hepatically impaired subjects and in healthy subjects.

	ACKNOWLEDGEMENTS

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
This study was supported by CV Therapeutics, Inc.

	REFERENCES

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 

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