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Journal of Clinical Pharmacology, 2004; 44:570-576
© 2004 the American College of Clinical Pharmacology

METHODS

Limited Sampling Strategy of S-Warfarin Concentrations, but Not Warfarin S/R Ratios, Accurately Predicts S-Warfarin AUC during Baseline and Inhibition in CYP2C9 Extensive Metabolizers

Joseph D. Ma, PharmD, Anne N. Nafziger, MD, MHS, Angela D. M. Kashuba, PharmD, Myong-Jin Kim, PharmD, Andrea Gaedigk, PhD, Elizabeth Rowland, BS, Jooran S. Kim, PharmD and Joseph S. Bertino, Jr., PharmD, FCP

From the Clinical Pharmacology Research Center (Dr. Ma, Dr. Nafziger, Dr. J. S. Kim, Dr. Bertino), Department of Medicine (Dr. Nafziger, Dr. Bertino), and Department of Pharmacy Services (Dr. Bertino), Bassett Healthcare, Cooperstown, New York; School of Pharmacy, University of North Carolina, Chapel Hill (Dr. Kashuba, Ms. Rowland); Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, Maryland (Dr. M.-J. Kim); and the Division of Pediatric Clinical Pharmacology and Experimental Therapeutics, Children's Mercy Hospital and Clinics, Kansas City, Missouri (Dr. Gaedigk).

Address for reprints: Joseph S. Bertino Jr., PharmD, FCP, Clinical Pharmacology Research Center, Bassett Healthcare, One Atwell Road, Cooperstown, NY 13326-1394.


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
S-warfarin area under the concentration-time curve (AUC0-{infty}) and clearance are used as measures of cytochrome P450 (CYP) 2C9 activity. In addition, warfarin S/R ratios are used to assess CYP2C9 activity. The determination of S-warfarin AUC0-{infty} requires multiple blood samples. Limited sampling strategy (LSS) is a validated technique that estimates AUC0-{infty} using limited blood samples. The objective of this study was to evaluate LSS of S-warfarin concentrations and warfarin S/R ratios to predict S-warfarin AUC0-{infty} during CYP2C9 baseline activity and inhibition with fluvastatin. Fifty-one healthy subjects, genotyped as CYP2C9 extensive metabolizers, were administered oral warfarin 10 mg. Blood samples were collected over 96 hours. S-warfarin AUC0-{infty} equations were derived from a training set of 20 subjects using multiple linear regression. Validation of the equations used data from the remaining 31 subjects. All derived equations were within acceptable limits for measures of bias and precision. Single-point and two-point S-warfarin concentrations, but not warfarin S/R ratios, were predictive of S-warfarin AUC0-{infty} during CYP2C9 baseline activity and inhibition. No correlation was observed between CYP2C9*1/*1 and *1/*2 genotypes and either S-warfarin concentrations or warfarin S/R ratios. The equation using two-point S-warfarin concentrations at 24 and 48 hours was the most accurate predictor of S-warfarin AUC0-{infty}. LSS using S-warfarin concentrations is an efficient and accurate technique to evaluate S-warfarin AUC0-{infty} when using warfarin as a CYP2C9 probe drug.

Key Words: CYP2C9 • S-warfarin • warfarin S/R ratios • limited sampling strategy • drug metabolism

The cytochrome P450 (CYP) enzymes are drug-metabolizing enzymes that metabolize > 50% of all drugs.1 The CYP2C9 isoenzyme accounts for approximately 18% of all CYP-mediated reactions and is responsible for the metabolism of several drugs with a narrow therapeutic index.2,3 CYP2C9 also exhibits genetic polymorphism, with the allelic variants CYP2C9*2 and *3 coding for decreased enzyme activity in comparison to the CYP2C9*1 wild-type allele.4 The CYP2C9*4-*12 variant alleles have also been recently identified.4

In vivo CYP enzyme activity can be assessed from phenotyping studies involving the use of a specific probe drug. Numerous probe drugs to assess phenotypic CYP2C9 activity exist, with S-warfarin as the currently preferred in vivo CYP2C9 probe drug.5 Warfarin is an oral anticoagulant formulated as a racemic mixture that undergoes regio- and stereoselective metabolism by several CYP enzymes.6 The major metabolic pathways of S-warfarin are CYP2C9 mediated, resulting in the formation of S-6- and S-7-hydroxy-warfarin.6 Several warfarin parameters have been used to evaluate CYP2C9 activity. These include S-warfarin area under the concentration-time curve (AUC0-{infty}), S-warfarin clearance, and warfarin S/R ratios.7,8

Limited sampling strategy (LSS) is a validated technique that can provide accurate estimations of pharmacokinetic parameters, including AUC0-{infty}, from a reduced number of blood samples. LSS has been used to estimate pharmacokinetic parameters for immunosuppressant agents,9,10 antineoplastic agents,11 acetaminophen,12 amlodipine,13 and midazolam.14 The use of S-warfarin as a CYP2C9 probe drug can be inconvenient and expensive as up to nine blood samples collected over 96 hours are needed to determine S-warfarin AUC0-{infty} and subsequently clearance. If LSS can be used to estimate S-warfarin AUC0-{infty}, the number of blood samples obtained, the time commitment by subjects and staff, and the assay costs associated with current sampling methods could be decreased.

The purpose of this study was to evaluate whether LSS of S-warfarin concentrations and warfarin S/R ratios can predict S-warfarin AUC0-{infty} in CYP2C9 extensive metabolizers. The predictive ability of the LSS equations was also evaluated during CYP2C9 inhibition with fluvastatin. In addition, we examined the correlation between CYP2C9 extensive metabolizer genotype and S-warfarin concentrations and warfarin S/R ratios.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects and Study Procedure
Data from 51 healthy subjects from four previously published or presented studies15-18 were used for these analyses. In each study, approval was obtained from the institutional review board of Bassett Healthcare (Cooperstown, NY), and written informed consent was obtained from each subject prior to study procedures. Screening procedures included a medical history, physical exam, and blood and urine laboratory tests. Subjects genotyped as CYP2C9 extensive metabolizers were at least 18 years of age, limited alcohol intake to <= 1 beer (12 ounces) or equivalent per day, and were not on medications known to affect CYP2C9 activity. All subjects refrained from consuming cruciferous vegetables (broccoli, cabbage, kale, brussels sprouts) 48 hours before the study and 24 hours after study completion. Subjects genotyped as CYP2C9 poor metabolizers and individuals with clinically significant findings by history or physical exam, a history of gastrointestinal bleeding, clinically significant abnormalities on laboratory testing, or hypersensitivity to warfarin or heparin were excluded.

CYP2C9 baseline activity consisted of subjects receiving a single oral dose of 10 mg warfarin (Coumadin®, Bristol-Myers Squibb) after a minimum 8-hour fast. Of the subjects, 40 out of 51 simultaneously received a single oral dose of 10 mg vitamin K (Mephyton®, Merck & Co.). The administration of oral vitamin K attenuates warfarin pharmacodynamics without affecting warfarin pharmacokinetics.15 Following a minimum 3-week washout period, 13 of 51 subjects received oral fluvastatin 40 mg twice daily for 18 days (CYP2C9 inhibition). Fluvastatin is a selective CYP2C9 inhibitor19-21 shown to inhibit S-warfarin metabolism.17 Single oral doses of 10 mg warfarin and 10 mg vitamin K were repeated on day 14 of fluvastatin administration.

Blood samples were collected into EDTA-containing tubes at predose and at 3, 6, 12, 24, 36, 48, 72, and 96 hours after warfarin administration. Blood samples were collected via an intravenous catheter kept patent with 2.5 mL of 10 U/mL heparin in 0.9% sodium chloride or by venipuncture. Blood samples were centrifuged at 2800 rpm at 4°C for 15 minutes, with the isolated plasma stored at -80°C until analysis.

Analytical Procedure
Plasma S- and R-warfarin concentrations were analyzed using high-performance liquid chromatography/ultraviolet spectrometry (HPLC/UV). Details of this procedure have been previously described.22 Intra- and interday coefficients of variation were < 7% for S- and R-warfarin concentrations. The range of linearity was 0.25 to 1.5 µg/mL for each enantiomer, with an accuracy of > 93%.

CYP2C9 Genotyping
Genotyping for CYP2C9*2, *3, and *4 variant alleles was carried out as described with slight modifications.23,24 In brief, genomic DNA was isolated from whole blood using a QIAamp blood kit (Qiagen, Inc., Valencia, CA). The CYP2C9*2 allele was identified by AvaII restriction digestion of a 190-bp PCR product. Wild-type-derived fragments were cut into 115 + 75 bp, while CYP2C9*2 fragments remained uncut. For CYP2C9*3, the forward PCR primers contained either a partial NsiI or a KpnI restriction recognition site. After amplification with the NsiI primer and NsiI digestion, wild-type-derived fragments were cut into 140 + 30-bp fragments, while CYP2C9*3 or *4 fragments remained uncut at 190 bp. In reverse, wild-type and CYP2C9*4-derived products generated with the KpnI primer remained uncut after KpnI digestion, and CYP2C9*3 fragments were restricted. PCR digestion products were separated on 3% agarose gels complemented with Synergel gel additive (Diversified Biosystems, Boston, MA) and documented on a Kodak 440CF Image Station.

Pharmacokinetic Analysis
S-warfarin AUC0-{infty} was determined using the linear trapezoidal rule with noncompartmental analysis of S-warfarin concentration versus time data using WinNonlin, version 3.1 (Pharsight Corporation, Cary, NC).

Data Analysis
All analyses were done using SAS, version 8 (SAS Institute, Cary, NC). Using a random-number list generated by SAS, 20 subjects were randomly selected to comprise the training set. The remaining 31 subjects comprised the validation set. S- and R-warfarin concentrations were log-transformed to obtain a normal distribution prior to analyses. In addition, warfarin S/R ratios were calculated at each time point.

Using multiple linear regression, equations to predict S-warfarin AUC0-{infty} were derived from the training set during CYP2C9 baseline activity. Coefficients of determination (r2) were determined and examined the proportion of variance of S-warfarin AUC0-{infty} that is explained by either S-warfarin concentrations or warfarin S/R ratios at specific time points. The derived S-warfarin AUC0-{infty} equations were then validated using data from the validation set. S-warfarin-predicted AUC0-{infty} values were calculated from the equations. Correlations of S-warfarin-predicted AUC0-{infty} versus observed AUC0-{infty} were evaluated by Pearson correlation coefficient (r).

Bias and precision of the derived equations were calculated by mean prediction error (MPE), mean absolute error (MAE), and root mean square error (RMSE), with acceptable percentage limits <= 5%, <= 10%, and <= 15%, respectively.25 The following equations were used:

Logistic regression analyses were done to evaluate the correlation between CYP2C9 extensive metabolizer genotype and either S-warfarin concentrations or warfarin S/R ratios. A p-value less than or equal to 0.05 was considered statistically significant. Data are expressed as mean ± standard deviation (SD) unless otherwise noted.


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Demographic information and CYP2C9 genotype of the subject cohort are shown in Table I. Most subjects were genotyped CYP2C9*1/*1. There were no subjects who possessed the CYP2C9*4 variant allele.


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  		Table I Demographic Information and Genotype Data for 51 Healthy Subjects

 

Three S-warfarin AUC0-{infty} equations using S-warfarin concentrations were derived from the training set (Table II). Single-point equations using S-warfarin concentrations at 24 hours and at 48 hours had corresponding r2 of 0.86 and 0.80 (p <= 0.05). A two-point equation using S-warfarin concentrations at 24 and 48 hours had an r2 of 0.92 (p <= 0.05). S-warfarin concentrations at 3, 6, 12, 36, 72, and 96 hours and warfarin S/R ratios at all the evaluated time points did not meet criteria for entry into the regression equations (p <= 0.15) and therefore were not predictive of S-warfarin AUC0-{infty}.


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  		Table II Derived S-Warfarin AUC0-{infty} Equations from the Training Set with 20 Subjects

 

Mean ± SD S-warfarin-observed AUC0-{infty} was 1.206 ± 0.092 µg•h/mL. During CYP2C9 baseline activity, mean ± SD S-warfarin-predicted AUC0-{infty} with single-point S-warfarin concentrations at 24 hours and at 48 hours was 1.202 ± 0.096 and 1.224 ± 0.105 µg•h/mL. S-warfarin-predicted AUC0-{infty} using two-point S-warfarin concentrations at 24 and 48 hours was 1.211 ± 0.101 µg•h/mL (Table III). Figure 1 illustrates the correlation between S-warfarin-predicted AUC0-{infty} and S-warfarin-observed AUC0-{infty} for the three equations (r = 0.80-0.91, p <= 0.05). All three equations demonstrated acceptable predictive performance by MPE, MAE, and RMSE (Table III).


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  		Table III Validation of S-Warfarin-Predicted AUC0-{infty} with 31 Subjects and Percentage Errors for Bias and Precision

 




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  		Figure 1. (A) S-warfarin-predicted versus S-warfarin-observed AUC0-{infty} using S-warfarin concentrations during CYP2C9 baseline activity at (A) 24 hours, (B) 48 hours, and (C) 24 and 48 hours, with corresponding Pearson correlation coefficients (r). AUC0-{infty},areaunder the concentration-time curve from 0 to infinity.

 

Using S-warfarin concentrations during CYP2C9 inhibition, S-warfarin-predicted AUC0-{infty} values were determined from the previously derived S-warfarin AUC0-{infty} equations. Mean ± SD S-warfarin-observed AUC0-{infty} was 1.335 ± 0.112 µg•h/mL. Mean ± SD S-warfarin-predicted AUC0-{infty} was 1.418 ± 0.124, 1.421 ± 0.122, and 1.441 ± 0.112 µg•h/mL at 24, 48, and 24 and 48 hours, respectively. Pearson correlation coefficients were statistically significant between S-warfarin-predicted and S-warfarin-observed AUC0-{infty} (r = 0.61-0.79, p <= 0.05), as illustrated in Figure 2.





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  		Figure 2. (A) S-warfarin-predicted versus S-warfarin-observed AUC0-{infty} using S-warfarin concentrations during CYP2C9 inhibition at (A) 24 hours, (B) 48 hours, and (C) 24 and 48 hours, with corresponding Pearson correlation coefficients (r). AUC0-{infty},areaunder the concentration-time curve from 0 to infinity.

 

No correlation was observed between CYP2C9*1/*1 and *1/*2 genotypes and either S-warfarin concentrations (p = 0.79) or warfarin S/R ratios (p = 0.60). As only 1 subject was CYP2C9*1/*3, analyses with this CYP2C9 genotype were not done.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The ability to accurately predict CYP2C9 activity using S-warfarin currently requires multiple blood sampling. LSS using single-point S-warfarin concentrations at 24 and 48 hours, as well as two-point concentrations at 24 and 48 hours, accurately predicted S-warfarin AUC0-{infty} during CYP2C9 baseline activity. Although a single-point equation was derived, the two-point equation was a more accurate predictor of S-warfarin AUC0-{infty}. The two-point equation had the highest r2 value (r2 = 0.92), the strongest correlation coefficient (r = 0.91), and the lowest percentages of MPE, MAE, and RMSE (Table III).

LSS of S-warfarin concentrations also accurately predicted S-warfarin AUC0-{infty} during CYP2C9 inhibition with fluvastatin. Although correlation coefficients between S-warfarin-predicted and S-warfarin-observed AUC0-{infty} were lower in comparison to CYP2C9 baseline activity, statistical significance was still maintained. During CYP2C9 inhibition, as with CYP2C9 baseline activity, the strongest relationship between S-warfarin-predicted and S-warfarin-observed AUC0-{infty} was with the two-point equation (r = 0.79). These results carry implications for future studies since characterization of CYP2C9 inhibition may be accurately measured with S-warfarin using fewer blood samples. This may be of a cost- and time-savings benefit.

Warfarin S/R ratios have been used as a phenotypic marker for the evaluation of CYP2C9 activity.8,26 Our results found that warfarin S/R ratios were not predictive of S-warfarin AUC0-{infty}, a surrogate for CYP2C9 activity. In vitro studies have reported that CYP1A1, CYP1A2, CYP2C9, CYP2C19, and CYP3A4 are involved in R-warfarin metabolism.6 R-warfarin metabolism by other CYP isoenzymes may influence the predictive ability of warfarin S/R ratios. However, a recent study found no difference in R-warfarin clearance based on CYP2C9 and CYP2C19 genotypes.8 This suggests that these CYP isoenzymes play a minimal role in R-warfarin metabolism in vivo.

The CYP2C9 isoenzyme displays genetic polymorphism resulting in reduced metabolic activity based on CYP2C9 genotype.4,27,28 Our results found no correlation between CYP2C9*1/*1 and *1/*2 genotypes and S-warfarin concentrations or warfarin S/R ratios. This may be because of the small sample size (n = 51) and small number of subjects genotyped as CYP2C9*1/*2. In addition, other CYP2C9 genotypes (e.g., CYP2C9*2/*2, *2/*3, *3/*3) known to significantly influence warfarin pharmacokinetics29 and warfarin S/R ratios26 were not included in this study.

The derived LSS equations involved data exclusively from healthy subjects who were CYP2C9 extensive metabolizers. Reproducibility of these results in other populations is needed. These results may not be extrapolated to individuals on chronic warfarin dosing and to patients with acute or chronic diseases since such individuals were excluded from the study population. Studies are also needed to evaluate the predictability of these equations in CYP2C9 poor metabolizers. Differences in the metabolic activity of CYP2C9 poor metabolizers compared to CYP2C9 extensive metabolizers may influence the LSS of S-warfarin concentrations in accurately predicting S-warfarin AUC0-{infty}. In addition, although ethnicity was not an exclusionary criterion for study participation, all subjects were of Caucasian ethnicity. Interpopulation differences of S-warfarin metabolism have been reported.29

The predictability of the derived S-warfarin AUC0-{infty} equations during CYP2C9 induction and for the evaluation of drug-drug interactions remains to be established. Studies with other CYP enzymes have reported that a single-point plasma concentration readily predicts CYP activity during induction.30 However, additional or different plasma concentration-time points may be needed to predict the magnitude of change of S-warfarin AUC0-{infty}. Preliminary pharmacokinetic studies that use multiple sampling will be needed first to obtain knowledge of specified pharmacokinetic parameters. The information can then be evaluated in the context of LSS to determine if the derived equations remain an accurate and predictive measure of S-warfarin AUC0-{infty}.

In summary, in healthy subjects who are CYP2C9 extensive metabolizers, LSS using S-warfarin concentrations is a validated, convenient, and cost-effective technique that accurately estimates S-warfarin AUC0-{infty} during CYP2C9 baseline and inhibition with fluvastatin. Furthermore, the derived two-point equation of S-warfarin concentrations at 24 and 48 hours is the most accurate predictor of S-warfarin AUC0-{infty}.


   FOOTNOTES
 
Presented in part at the 2003 annual meeting of the American Society for Clinical Pharmacology and Therapeutics, Washington, DC, April 2003. No official support or endorsement of this article by the FDA is intended or should be inferred.

DOI: 10.1177/0091270004265366

Submitted for publication December 3, 2003; Revised version accepted March 14, 2004.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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