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DRUG INTERACTIONS |
From the Departments of Clinical Research Operations (Dr Burstein), Medical and Developmental Sciences (Dr Clark), Biostatistics (Dr Willavize), Clinical Pharmacology (Ms Gorman, Dr Faessel), and Pharmacokinetics, Dynamics, and Drug Metabolism (Mr Brayman, Mr Grover, Mr Walsky, Dr Obach), Pfizer Global Research & Development, Groton, Connecticut, and Ann Arbor, Michigan.
Address for correspondence: Aaron H. Burstein, PharmD, Pfizer Global Research and Development, Groton/New London Labs, Eastern Point Road. MS8260-2505, Groton, CT 06340.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSPharmacokinetic ResultsDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Key Words: Varenicline • warfarin • coadministration • pharmacokinetics • pharmacodynamics • cytochrome P450
4ß2 receptors that has been approved in more than 50 countries worldwide as an aid to smoking cessation. Preclinical studies have demonstrated that varenicline has a high binding selectivity for the 4ß2 receptor.1 In vitro and in vivo studies have shown that varenicline is effective at blocking nicotine-induced dopamine release in the nucleus accumbens while also eliciting approximately 35% to 60% of the maximal nicotine effect at the 4ß2 receptor.1 Therefore, through its action as a partial agonist, varenicline can block nicotine binding to the receptor, thereby having the potential to minimize the rewarding effect of nicotine, and because it possesses some of the agonist activity associated with nicotine, varenicline is believed to limit craving and withdrawal symptoms during abstinence.
In humans, varenicline exhibits linear kinetics.2,3 Maximum plasma concentration of varenicline typically occurs within 3 to 4 hours after oral administration. Varenicline is a small, organic base, which, based on absorption, distribution, metabolism, and elimination information, is primarily excreted as parent molecule in the urine.4 Consistent with a terminal elimination half-life of approximately 24 hours, steady-state conditions of varenicline are reached within 4 days.2,3 Plasma protein binding of varenicline is low (
20%) and independent of age or renal function.4,5
Warfarin, a coumarin derivative, is an oral anticoagulant that is widely used in the clinical settings of atrial fibrillation, stroke, and thrombotic disease.6-8 Warfarin exists as a racemic mixture of 2 optically active isomers in approximately equal proportions. The (S)-enantiomer is 3 to 5 times more potent as an anticoagulant than the (R)-enantiomer.10 Both enantiomers are eliminated extensively via hepatic metabolism, and CYP2C9 is almost exclusively responsible for the metabolism of the pharmacologically more active (S)-enantiomer.15 Also, both warfarin enantiomers are extensively bound (99%) to plasma proteins.16,17 Warfarin is subject to numerous pharmacokinetic and pharmacodynamic drug interactions resulting from induction or inhibition of the metabolism of both its (R)- and (S)-enantiomers or its displacement from plasma proteins, which can lead to transient changes in anticoagulation.9 Drug interactions with warfarin are particularly important because of its widespread use, the greater than 10-fold interpatient variability in the doses required to attain therapeutic responses, and its narrow therapeutic index.9-14
The relationship between smoking and cardiovascular disease increases the prospect of patients receiving smoking cessation therapy and warfarin concomitantly in clinical practice. The likelihood of a clinically relevant pharmacokinetic interaction between varenicline and warfarin was considered to be low; nevertheless, the possibility of a pharmacodynamic interaction between these 2 drugs could not be ruled out. Hence, the present study was undertaken to investigate the effects of steady-state varenicline on the pharmacokinetics and pharmacodynamics of a single dose of warfarin in adult smokers who were otherwise healthy.
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METHODS |
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TOPABSTRACTMETHODSRESULTSPharmacokinetic ResultsDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Participants
Healthy male or female smokers were eligible for this study if they were aged 18 to 55 years and had smoked an average of at least 10 cigarettes per day during the previous year (confirmed by urine cotinine measurements >200 ng/mL), with no period of abstinence of more than 3 months. Platelet counts, prothrombin times (reported as international normalized ratios [INRs]), and partial thromboplastin times (PTTs) were required to be within normal ranges. The INR represents the ratio of prothrombin time to the control prothrombin time raised to the power of the International Sensitivity Index (ISI). The ISI is the index of the reference thromboplastin used for the study compared with the World Health Organization reference reagent.18
Screening for eligibility was performed within 28 days before the first dose of study medication. Volunteers with a history or evidence of clinically significant disease or conditions potentially affecting drug absorption were excluded, as were those with protein C or protein S deficiency, a creatinine clearance less than 80 mL/min as estimated by the method of Cockcroft and Gault,19 sensitivity to oral anticoagulants or heparin, or a history of heparin-induced thrombocytopenia. Also excluded were subjects with electrocardiogram (ECG) abnormalities, a history of regular alcohol consumption exceeding predefined limits, or a positive drug screen and those who had received another investigational drug within 30 days or 5 half-lives (whichever was longer). Women of childbearing potential were required to use acceptable methods of contraception during the study.
Protocol
The study consisted of 2 periods of 14 days (inpatient confinement to research unit), separated by a washout period sufficient to allow at least 3 weeks between warfarin doses, because previous studies9,20 had indicated that this was a sufficient period to allow the INR and the activity of clotting factors to return to baseline levels after warfarin treatment. During the first study period, eligible participants were randomized to receive placebo or varenicline 1 mg twice daily for 13 days. A single dose of warfarin, 25 mg, was given at 8 AM on day 8. During the second study period, participants were switched to receive the other treatment for 13 days, with a second dose of warfarin being given on day 8. All study medication (varenicline or placebo) was administered with 240 mL of water, immediately following a meal, at approximately 8 AM and 6 PM. Meals with a standardized nutritional composition (maximum daily caloric intake 2800 kcal) were provided during each study period. Grapefruit-containing products were not permitted during the study. Participants were required to abstain from drinking alcohol from 24 hours before the first dose until the collection of the final pharmacokinetic blood sample in each study period. Subjects were permitted to smoke without restriction (except during the time of conduct of specific study procedures) during their inpatient confinement.
Pharmacokinetic Sampling and Analytical Methods
Warfarin. Blood samples (5 mL) for measurement of plasma warfarin concentrations were obtained on day 8 before dosing with warfarin and at 0.5, 1, 2, 4, 8, 12, 24, 36, 48, 72, 96, 120, and 144 hours after dosing. Samples were collected into heparinized tubes and centrifuged at approximately 1700g for 10 minutes at 4°C. Plasma was stored at -20°C within 1 hour of collection. Concentrations of (R)- and (S)-warfarin enantiomers were measured using a validated stereospecific high-performance liquid chromatography with tandem mass spectrometric detection. Warfarin-d6 was used as an internal standard (IS). The assay had a dynamic range of 5.00 to 1000 ng/mL for each enantiomer using a 250-µL human plasma aliquot containing sodium heparin. After acidification of plasma, warfarin and internal standard were isolated from human plasma via liquid-liquid extraction with dichloromethane/hexane (1:5, vol:vol). The organic phase was evaporated to dryness and reconstituted in 500 µL of a mixture of 1.0 mM ammonium acetate and acetonitrile (70:30 by volume). Reconstituted extracts were injected (25 µL) onto a Chirobiotic V column (4.6 x 100 mm, 5 µm; Advanced Separation Technologies Inc, Whippany, NJ) protected with a Chirobiotic V guard column (4.0 x 20 mm, 5 µm; Advanced Separation Technologies Inc) and equilibrated in 1.0 mM ammonium acetate in 31% acetonitrile at a flow of 0.4 mL/min. Elution was isocratic, and the retention times for (R)- and (S)-warfarin and their IS were 5.7 and 6.4 minutes, respectively. The effluent was introduced into an atmospheric pressure-electrospray ionization source on a Micromass Quattro microTM triple quadrupole mass spectrometer (Waters Corporation, Milford, Mass) used in the negative ion mode with the following tuning conditions: capillary voltage 2.2 kV, cone 40 V, extractor 2 V, Rf lens 0.2 V, source temperature 120°C, desolvation temperature 350°C, cone gas flow 100 L/h, desolvation gas flow 600 L/h, entrance lens -5, exit lens 1, collision energy 35 V. Analysis was performed by multiple reaction monitoring with an acquisition dwell time of 200 milliseconds per transition. The mass spectrometer was adjusted to monitor parent to product ion transitions of m/z 307.2 to 161.1 for (R)- and (S)-warfarin and m/z 313.2 to 161.1 for (R)- and (S)-warfarin-d6. For both enantiomers and independently prepared quality control samples, interassay variability was less than 10%, and the assay was accurate to within 8% of the nominal concentration over the range of 5 to 800 ng/mL. Varenicline did not interfere with the measurement of the warfarin enantiomers in plasma. Samples were analyzed by the local laboratory for determination of INR.
Varenicline. Blood samples (7 mL) for measurement of plasma varenicline concentrations were obtained before the morning dose of varenicline on days 6, 7, 8, and 9 of each study period. Plasma was separated and stored as described above. Plasma concentrations of varenicline were determined using a validated high-performance liquid chromatography-atmospheric pressure ionization/tandem mass spectrometry assay following liquid-liquid extraction, as described previously2 with the following modifications: a guard column (BDS Hypersil Cyano 10 x 2 mm) was added to the analytical column; and a method modification validation was conducted to change from the internal standard CP-533 633 to the stable isotope labeled internal standard PF-142,282. The assay had a dynamic range of 0.100 to 50.0 ng/mL. Quality control samples prepared in human plasma were extracted and analyzed. Intra-assay mean accuracy and precision values were within 85% to 115% and ±15%, respectively. The mean accuracy at the LLOQ was within 80% to 120%, and precision was within ±20%.
Analysis and Calculation of Pharmacokinetic Parameters
Plasma concentration-time data for (R)- and (S)-warfarin were analyzed by noncompartmental techniques with WinNonlin Enterprise (version 3.2, Pharsight Corporation, Mountain View, Calif) software. Peak plasma concentrations (Cmax) and the time to peak concentrations (Tmax) were derived directly from the observed data. The apparent terminal phase rate constant (Kel) was calculated by least squares regression analysis of the plasma concentration-time data obtained during the terminal log-linear phase. The apparent terminal phase half-life (t1/2) was calculated as ln 2/Kel. The area under the plasma concentration-time curve from zero to the last time with a measurable concentration (AUC0-tlast) was measured by linear-log trapezoidal approximation. The AUC from the last time with a measurable concentration to infinity (AUCtlast-
) was estimated as Cpest/Kel, where Cpest was the estimated concentration at tlast, derived by regression analysis. AUC0- was calculated as the sum of AUC0-tlast and AUCtlast-. The attainment of steady-state conditions for varenicline was confirmed by visual inspection of varenicline predose concentration-time profiles on days 6, 7, 8, and 9.
Pharmacodynamic Analysis
Blood samples were obtained for measurement of prothrombin time, reported as the INR, on day 8 before dosing with warfarin and at 4, 12, 24, 36, 48, 60, 72, 96, 120, and 144 hours after dosing. Maximum INR values (INRmax) and Tmax were determined by direct observation; the area under the INR-time curve (AUCINR) was calculated using the linear trapezoidal method.
Safety Assessments
Clinical laboratory testing was performed at screening and on days 0 and 14, and PTT was measured at screening and on day 14 of each study period. Vital signs were measured, and a 12-lead ECG was obtained on day 1 (prior to morning varenicline dosing) and day 14 (approximately 144 hours after dosing with warfarin [day 8]) of each study period. Physical examinations were performed during the course of the study and any untoward findings recorded as adverse events (AEs).
Sample Size Determination and Statistical Analysis
Sample size was determined to provide 90% power to demonstrate equivalence of AUC and Cmax for both warfarin enantiomers administered alone or in combination with varenicline, using the established equivalence range of 80% to 125%. This was based on an assumed coefficient of variation (CV) for warfarin Cmax of 17%.9 For pharmacodynamic parameters, a maximum CV of 4% was assumed for INRmax. Sample size calculations were performed using the approximate formulas for the multiplicative model and were implemented using an in-house SAS program, CBET.
Warfarin coadministered with varenicline (test) was compared with warfarin coadministered with placebo (reference) for AUC0- and Cmax for both the (R)- and (S)-warfarin enantiomers. AUC0- and Cmax were natural log-transformed and analyzed by a mixed effects model, with sequence, treatment, and period effects considered fixed and subjects (within sequence) considered random. Compound symmetry was assumed, and restricted maximum likelihood estimates were used. Least-squares means and their associated standard errors were calculated to estimate the adjusted treatment mean difference and the associated log-transformed standard errors. The 90% confidence intervals (CIs) for these differences were calculated and back-transformed to yield the corresponding CIs for the ratio of AUC0- or Cmax in the presence and absence of varenicline. This analysis was performed for both (R)- and (S)-enantiomers of warfarin. It was concluded that there is no effect of varenicline on the pharmacokinetics of warfarin if the 90% CIs for the ratios for both primary end points, AUC and Cmax, for both (R)-warfarin and (S)-warfarin, fell entirely within the 80% to 125% equivalence range.
A similar analysis was performed for the secondary pharmacodynamic end points, AUCINR and INRmax. A lack of effect of varenicline on the pharmacodynamics of warfarin was concluded if the 90% CI for the ratios of these parameters in the presence and absence of varenicline was within the 80% to 125% range. All statistical analyses were performed using the SAS software program version 8.2 (SAS Institute, Cary, NC).
In Vitro Methods
Varenicline was tested as a potential inhibitor of human cytochrome P450 enzyme activities in pooled liver microsomes using previously described methods.21 Varenicline was examined up to a concentration of 30 µmol/L (6330 ng/mL) for an effect on CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A. Each incubation was performed in duplicate.
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RESULTS |
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Visual inspection of mean and individual plasma trough concentration-time profiles showed that all subjects attained steady-state conditions for varenicline by day 7. Plasma varenicline concentrations on days 6 to 9 ranged from 4.3 ± 1.6 ng/mL to 4.9 ± 1.5 ng/mL.
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Pharmacokinetic Results |
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and Cmax of both (R)- and (S)-enantiomers were approximately 100%, and the bounds of the 90% CI were completely contained within the predefined limits for equivalence (80% to 125%). As shown in Figure 1, the plasma concentration-time profiles for both (R)- and (S)-warfarin enantiomers in the presence and absence of varenicline are virtually superimposable. In both cases, peak concentrations of approximately 1 mg/L were achieved approximately 4 hours after dosing.
The pharmacokinetic parameters of (R)- and (S)-warfarin in the presence and absence of varenicline are summarized in Table I. The plasma half-life and AUC0- were slightly greater for (R)-warfarin than for (S)-warfarin. When warfarin was administered alone, (R)-warfarin exhibited, on average, a longer t
than (S)-warfarin as well as a greater systemic exposure, as assessed by AUC0-. Mean Cmax values were, however, similar for both enantiomers. The terminal elimination phase was well characterized, with the percent extrapolated for AUC0- not exceeding greater than 18% in all 24 subjects. Individual elimination half-life estimates for (R)-warfarin ranged from 26.0 to 59.4 hours in the absence of varenicline and 27.2 to 50.8 hours in the presence of varenicline and for (S)-warfarin 23.8 to 55.1 hours and 22.8 to 52.4 hours in the absence and presence of varenicline, respectively.
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and Cmax, were nearly identical between the varenicline and placebo treatments. The AUC0- geometric mean ratios for (R)- and (S)-warfarin in the presence and absence of varenicline were 102% (90% CI 98.0-106) and 101% (90% CI 97.1-105), respectively. Similarly, the (R)- and (S)-warfarin Cmax geometric mean ratios in the presence and absence of varenicline were 101% (90% CI 97.3-104) and 100% (90% CI 96.8-104), respectively. The bounds of the 90% CIs were all completely contained within the predefined limits for equivalence (80% to 125%). Overall, within-subject CVs for the primary pharmacokinetic parameters, AUC0- and Cmax, of both warfarin enantiomers were below 10%.
Warfarin Pharmacodynamics
The INR time curves for warfarin alone and coadministered with varenicline 1 mg twice daily are practically superimposable, as shown in Figure 2. Mean INRmax and AUCINR values for warfarin in the presence (1.39 and 161 hours, respectively) and absence (1.40 and 162 hours, respectively) of varenicline were measured over 144 hours on day 8. No statistically significant effects on prothrombin time were detected in the presence and absence of varenicline. Both the geometric mean ratios for INRmax and AUCINR in the presence and absence of varenicline were 99.4% with an associated 90% CI of 95.4% to 104% for INRmax and 97.6% to 101% for AUCINR. Both these 90% CIs fell entirely within the 80% to 125% equivalence range. In addition, there was no marked change in Tmax (INR) between both treatment periods.
Safety and Tolerability
Concomitant administration of varenicline and warfarin was well tolerated, and the incidence of AEs was relatively low. Six subjects experienced 6 adverse events (3 subjects with headache, 1 subject with nausea, 1 subject with urticaria, 1 subject with dizziness) during varenicline + warfarin, whereas 5 subjects experienced 5 adverse events (5 subjects with headache) during placebo + warfarin. The majority of adverse events (90%) were considered by the investigators to be treatment-related. No serious AEs or deaths were reported. With the exception of 3 cases of moderate headache, all AEs were mild in intensity. No clinically significant changes in clinical laboratory tests, vital signs, or ECG were recorded during the study.
In Vitro Results
Varenicline was shown not to inhibit or induce human cytochrome P450 activities. At a concentration of 30 µmol/L, no effect was seen on CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 2E1. A very mild effect was seen on CYP3A catalyzed felodipine dehydrogenase activity (25% inhibition at 30 µmol/L) but not the other CYP3A activities (Table II). In the assessment of induction of CYP1A and 3A4, varenicline showed no appreciable effect (1.08- to 1.58-fold increase), whereas the positive control compounds lansoprazole and rifampin markedly induced CYP1A2 (36-fold) and CYP3A4 (6-fold) activities, respectively (Table III).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSPharmacokinetic ResultsDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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and Cmax, the 90% CIs of the ratios of values obtained in the presence and absence of varenicline were within the predefined equivalence range. This stable pharmacokinetic profile was reflected in almost identical prothrombin time profiles and pharmacodynamic parameters in the presence and absence of varenicline. The pharmacokinetics of warfarin are complex. The drug exists as a racemic mixture of (R)- and (S)-enantiomers, both of which have anticoagulant activity, have high protein binding, and are subject to stereospecific elimination.15,17,24 Moreover, warfarin is widely used but has a narrow therapeutic index, and there is considerable interindividual and intraindividual variability in therapeutic doses.10-14 In this study, the pharmacokinetic parameters estimated for both the (R)- and (S)-enantiomers of warfarin were consistent with data previously reported in the literature.9,24 The steady-state plasma concentrations of varenicline observed in this study were similar to those seen in previous studies.2,3
Recent data on the pharmacogenetics of warfarin suggest that there are differences in allele frequencies for CYP2C9*2 and *3 between Caucasians, African Americans, and Asians that could result in a significant reduction in clearance of (S)-warfarin10; however, the effects of this polymorphism are not fully understood. The majority (79%) of participants in this study were African American; however, this does not affect the validity of these results because of the crossover design of the study.
Lack of a drug interaction between warfarin and varenicline is consistent with the known pharmacokinetic properties of varenicline. In humans, varenicline is primarily excreted unchanged in the urine.4 In human liver microsomes, varenicline had very little or no inhibitory effect (IC50 >30 µM, 6.3 µg/mL) on cytochrome P450 enzymes, including those responsible for warfarin metabolism (ie, CYP2C9, 1A2), and hence potentiation of warfarin's anticoagulant effect would be unlikely to occur during varenicline treatment. Varenicline concentrations at the recommended dose of 1 mg twice daily typically achieve maximum values of about 10 ng/mL in plasma (
0.05 µmol/L), which is well below the highest concentration that was tested for inhibition of P450 enzymes. Thus, the in vivo and in vitro findings are in concordance. Furthermore, varenicline did not show an induction effect in vitro at concentrations in 10-fold excess of typical in vivo concentrations, which is consistent with the observation of no decrease in warfarin exposure. Similarly, varenicline shows low binding to plasma proteins and hence is unlikely to displace protein-bound warfarin, which can lead to an increase in unbound, biologically active levels of warfarin. Moreover, even if such displacement did occur, it normally produces only transient increases in unbound drug concentrations and so is seldom associated with clinically relevant interactions.9
The combination of warfarin and varenicline was well tolerated, and no safety issues were identified during the study. In clinical practice, the coadministration of varenicline and warfarin is anticipated because of the comorbidities associated with a smoking population and the potential use of warfarin in the clinical setting of atrial fibrillation, prosthetic heart valves, stroke, and deep arterial and venous thromboembolic disorders. Although interactions between warfarin and several other drugs have been identified,20,24-29 this study suggests that warfarin and varenicline can be safely coadministered without a need for dose adjustment. Furthermore, given the in vitro data and the fact that varenicline did not affect the pharmacokinetics of warfarin in vivo, it can be predicted that varenicline will not affect the pharmacokinetics of other drugs that are primarily cleared by cytochrome P450 enzymes.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSPharmacokinetic ResultsDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Financial disclosure: Supported by Pfizer Inc: Aaron H. Burstein, David J. Clark, Melissa O'Gorman, Susan A. Willavize, Timothy G. Brayman, G. Scott Grover, Robert L. Walsky, R. Scott Obach, and Hélène M. Faessel are employees of Pfizer Global Research and Development.
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REFERENCES |
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