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PHARMACOKINETICS |
From Takeda Global Research & Development Center, Inc, Deerfield, Illinois (Dr Karim, Ms Zhao, Ms Slater, Ms Bradford, Ms Schuster), and PPD Development, LP, Austin, Texas (Dr Laurent).
Address for correspondence: Aziz Karim, PhD, ABCP, FCP, Takeda Global Research & Development Center, Inc, One Takeda Parkway, Deerfield, IL 60015; e-mail: akarim{at}tgrd.com.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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for coadministered and fixed-dose combination treatments were similar: 16% to 19% (intra) and 23% to 25% (inter) for pioglitazone and 18% to 19% (intra) and 29% to 30% for glimepiride (inter, excluding 1 poor metabolizer). Fixed-dose combination/coadministered least squares mean ratios of 
0.86 and the 90% confidence intervals of these ratios for pioglitazone and glimepiride of between 0.80 and 1.25 for Cmax, AUClqc, and AUC met the bioequivalency standards. Gender analysis showed that women showed mean of 16% and 30% higher exposure than men for glimepiride (excluding 1 poor metabolizer) and pioglitazone, respectively. There was considerable overlapping in the AUC values, making gender-dependent dosing unnecessary. Patients taking pioglitazone and glimepiride as cotherapy may replace their medication with a single fixed-dose combination tablet containing these 2 oral antidiabetic drugs.
Key Words: Fixed-dose combination • oral antidiabetics • pioglitazone • glimepiride • intersubject and intrasubject systemic exposure variability • bioequivalency • replicate study design
For patients with poorly controlled type 2 diabetes mellitus, multiple drugs may be necessary to achieve target glycemic goals. Secondary failure of sulfonylurea monotherapy and the need for combination therapy occur in most patients with type 2 diabetes because of a progressive decrease in beta-cell function.3 Combination therapy of antidiabetic agents with different mechanisms of action maintains greater glycemic control at lower doses than a high dose of 1 agent while causing fewer side effects.4,5 A randomized, controlled clinical study demonstrated that combination therapy with PIO and a sulfonylurea produced significantly greater improvements in glycosylated hemoglobin A1C and fasting plasma glucose than those observed for sulfonylurea monotherapy.6 Other clinical trials have shown similar or superior glycemic control with PIO in combination with a sulfonylurea compared to other antidiabetic drug combinations.7-9
Both PIO and GLIM are almost completely metabolized by the liver via cytochrome P450 (CYP) isozymes; PIO metabolism10,11 is mediated via CYP 2C8 (major) and 3A4 (minor) isozymes, whereas GLIM metabolism is mediated by CYP 2C9.12,13 Hydroxylated metabolites of PIO10 and GLIM13 have shown weak pharmacologic activities of the parent molecule. When another second-generation sulfonylurea was administered after multiple oral doses of PIO (45 mg once a day given for 7 days), no pharmacokinetic (PK) interaction between PIO and glipizide was noted.14 Given that glipizide, like GLIM, is a substrate of the CYP 2C9 isozyme, these findings suggest that no significant PK interaction between PIO and GLIM should be anticipated.
Two dosage strengths of a fixed-dose combination (FDC) tablet containing 30 mg of PIO and either 2 or 4 mg of GLIM have been developed15 as a once-daily treatment for type 2 diabetes in patients who require combination oral therapy. The PIO plus GLIM FDC product offers the convenience of a single-tablet product when multiple oral therapies are needed to achieve and maintain glycemic control.16 Here we describe the bioavailability of 1 dose strength (30/4 mg) of FDC tablets containing 30 mg of PIO and 4 mg of GLIM relative to concomitant administration of equivalent doses of the individual component commercial tablets, as well as the gender effect on the systemic exposures (AUC) of PIO and GLIM. Last, we discuss the advantages and limitations of the replicate study design17 used in the present investigation in evaluating bioavailability of drugs/dosage forms.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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30 kg/m2. Female participants could not be pregnant (as confirmed by laboratory testing) or lactating and were postmenopausal, were surgically sterile, or agreed to practice acceptable methods of nonhormonal contraception. Participants could not have clinically abnormal findings on the medical history, physical examination, 12-lead electrocardiogram (ECG), or clinical laboratory tests. Receipt of any investigational drug within 30 days or use of prescription and nonprescription drugs or herbal supplements was not allowed within 1 week prior to first dose. Other exclusion criteria included a known hypersensitivity to the study drugs or related compounds, any positive result on the urine drug and alcohol screens, and use of alcohol, caffeine, grapefruit, Seville oranges, or vitamin supplements within 2 days prior to dose. The study was conducted in accordance with the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice guidelines and the ethical principles of the Declaration of Helsinki. The institutional review board (IRB), Research Consultants' Review Committee (Austin, Texas), approved the study protocol prior to the enrollment of study participants. All volunteers gave written informed consent prior to their participation in the study.
Study Design
The study was conducted at a single site, PPD Development, LLC, Clinics (Austin, Texas). A randomized, open-label, 4-period crossover, 2-sequence replicate design18 was used to assess the bioequivalence of single oral doses of the FDC tablet (test treatment) relative to concomitant administration of the commercial tablets (reference treatment). Participants received both treatments (test [T] and reference [R]) on 2 different occasions in 1 of the following 2 sequences as specified by the randomization schedule: TRTR and RTRT. A 7-day washout period separated consecutive treatments.
A pretreatment screening visit was conducted between 2 and 28 days prior to the first dose of study drug. After obtaining written consent, the following procedures were performed: medical history, 12-lead ECG, vital signs, physical examination, and clinical laboratory tests, including urine drug and alcohol screens, hepatitis panel, and serum human chorionic gonadotropin pregnancy test (women only). Eligible participants returned to the clinic for baseline evaluations on day -1. Participants were housed in the clinical research facility for 3 consecutive nights during each period, from the day prior to dosing through 48 hours postdose, and returned for a follow-up visit at 72 hours after dosing. While confined to the clinic, participants were provided a standard, low-fat diet, and no additional food or drink (except water) was allowed.
Participants fasted for 10 hours overnight and then received each treatment with 240 mL of water, followed by a 4-hour postdose fast. During each period, serial blood samples (10 mL each) were collected at predetermined time points, according to the following schedule: within 0.5 hours prior to dose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 48, and 72 hours postdose for measurement of PIO and GLIM serum concentrations. Blood samples were collected in a Vacutainer tube and allowed to clot at room temperature for 30 to 60 minutes. The Vacutainer was then centrifuged at 1100 to 1300 RCF for 10 minutes at 4°C. The serum fraction was separated, frozen at -20°C, and shipped on dry ice to BASi, Inc (West Lafayette, Indiana) for measurement of PIO and GLIM concentrations.
Adverse events and concomitant medications were monitored and recorded throughout the study. Other safety evaluations included clinical laboratory tests, vital signs, ECGs, and physical examinations.
Determination of Pioglitazone and Glimepiride in Serum
Serum concentrations of PIO, as base, were measured using liquid chromatography/tandem mass spectrometry (LC/MS/MS). The mass spectrometer, a QuattroLC tandem quadrapole (Micromass, Manchester, UK), was operated with positive ionization electrospray. The internal standard used for the determination of PIO was an analog, AD-4875. Chromatography was performed on a Shiseido Fine Chemicals Capcell Pak C-18 column (150 x 2 mm) with a Thermo Hypersil Betasil C-18 (20 x 2 mm) precolumn at 40°C using a mobile phase of 1 mM ammonium acetate/acetonitrile/glacial acetic acid (50:50:1) at 0.2 mL/min. The samples were analyzed via selected reaction monitoring by using the transition of the precursor ion to a product ion for PIO and internal standard. The ion transitions monitored were mass-to-charge ratio (m/z) 357 to m/z 134 for PIO and m/z 343 to m/z 120 for the internal standard. The standard curve range for PIO was 25 ng/mL (lower limit of quantitation [LLOQ]) to 2500 ng/mL. The interassay coefficient of variation during validation ranged from 2.2% to 5.2%, and the analytical recovery ranged from 91.2% to 102%.
Serum concentrations of GLIM were measured using LC/MS/MS. The mass spectrometer, a Sciex 4000 or 3000, was operated with positive turbo ionspray ionization. The internal standard used for the determination of GLIM was glibenclamide. Chromatography was performed on a Zorbax SB-18 column (2.1 x 50 mm, 5 µ) at 30°C using a mobile phase of water/methanol/250 mM formate buffer (32:64:4) at 0.5 mL/min. The samples were analyzed via selected reaction monitoring by using the transition of the precursor ion to a product ion for GLIM and internal standard. The ion transitions monitored were m/z 491 to m/z 352 for GLIM and m/z 494 to m/z 369 for the glibenclamide internal standard. The standard curve range for GLIM was 1 ng/mL (LLOQ) to 500 ng/mL. The interassay coefficient of variation during validation ranged from 3.8% to 9.1%, and the analytical recovery ranged from 95.5% to 101%.
Analysis of Data
Pharmacokinetic Parameters
Prior to the estimation of the pharmacokinetic parameters, PIO or GLIM concentrations below LLOQ were assigned a value of 0. For each subject, the following pharmacokinetic parameters were calculated from serum concentrations of PIO and GLIM, with WinNonlin Professional Version 4.01 (Pharsight Corp, Mountain View, Calif), using noncompartmental methods: maximum observed concentration (Cmax), time to reach Cmax (tmax), area under the concentration-time curve from time 0 to time of last quantifiable concentration (AUClqc), AUC from time 0 to infinity (AUC), terminal phase elimination rate constant (
z), terminal elimination half-life (t
), and apparent oral clearance (CL/F = Dose/AUC). AUC was calculated as AUClqc + Clast/z, where Clast is the last quantifiable concentration. Criteria used for inclusion of AUC values in the statistical analysis included the following: (1) the correlation coefficient (r2) in the regression analysis for z had to be equal to or greater than 0.80, and (2) the extrapolated AUC had to be equal to or less than 20% of the AUClqc.
Statistical Analysis of Bioequivalency
The sample size for this replicate, crossover study was based on the probability of meeting the bioequivalence criterion using the limits (0.80, 1.25) and assuming an analysis of variance (ANOVA) error term variance equal to 0.08 for the natural logarithms of Cmax and AUC of PIO. Under these assumptions, if the ratio of the central values for Cmax and AUC is between 0.93 and 1.07, then the data from at least 30 subjects, 15 subjects for each sequence, provide a 90% probability of determining bioequivalence. Assuming that the error term variance for the natural logarithms of Cmax and AUC of GLIM is similar to PIO, the probability of meeting the bioequivalence criterion for GLIM is the same. A sample size of 38 subjects was chosen to allow for dropouts during the course of study.
Inferential statistics were performed using SAS Version 8.2 (SAS Institute, Cary, NC). An ANOVA with fixed effects for sequence, period, treatment with different intrasubject variability for each formulation, and random effect for subject was performed on tmax, z, and the natural logarithms of AUClqc, AUC, and Cmax. Carryover effect was also explored by adding it to the model.
Within the framework of the ANOVA, the 90% confidence interval (CI) for the ratio of the least squares (LS) mean of the FDC tablet (test treatment) relative to the LS mean of commercial tablets (reference treatment) was provided. The 90% CI on the original scale was obtained by taking the antilog of the 90% CI for the difference between the LS means on the natural logarithmic scale. If the 90% CIs of the LS mean ratios for AUClqc, AUC, and Cmax of PIO and GLIM were within the (0.80, 1.25) interval, bioequivalence of test and reference treatments was concluded.
Analysis of Variability for Pioglitazone and Glimepiride
The intrasubject and intersubject variances of PIO and GLIM were determined using the linear mixed-effect model recommended for average bioequivalence analysis of replicate crossover studies.18 The linear mixed-effect model with fixed effects for sequence, period, treatment with different intrasubject variability for each formulation, and random effect for subject was performed on the natural logarithms of AUClqc, AUC, and Cmax of PIO and GLIM. The intrasubject and intersubject variabilities (% coefficient of variation [CV]) were estimated as follows:
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Effect of Gender on Drug Exposure
Because approximately equal numbers of male and female subjects were enrolled in the study, a post hoc analysis was performed using SAS Version 8.2 to assess the effect of gender on systemic exposures to PIO and GLIM following the initial coadministration treatment. A total of 18 men and 19 women were included in the analysis for PIO; for GLIM, 17 men and 18 women were included (1 woman's GLIM concentration values were all below LLOQ; therefore, no PK parameters were derived). Both PIO and GLIM pharmacokinetic parameters were normalized for a 70-kg weight before performing the statistical analysis to adjust for potential weight differences between men and women. An ANOVA with gender effect was performed on the natural logarithms of weight-normalized AUClqc, AUC, and Cmax of PIO and GLIM. Within the framework of the ANOVA, the 90% CIs for the ratios of the LS mean of women relative to the LS mean of men were determined. The 90% CIs on the original scale were obtained by taking the antilog of the 90% CI for the difference between LS means on the natural logarithmic scale.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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The most commonly reported adverse events were mild nervous system disorders (8 of 37 subjects [22%]), such as dizziness, headache, or tremor, and mild gastrointestinal disorders, such as nausea (3 of 37 subjects [8%]). No serious adverse events were reported, and no deaths occurred during the study. No laboratory values or changes in vital signs, ECGs, or physical examination findings were considered clinically important.
Bioequivalence of Fixed-Dose Combination Tablet Relative to Concomitant Administration of Commercial Tablets
Figure 1 shows mean serum concentration-time curves of PIO and GLIM following administration of the FDC and coadministered treatments. The ANOVA for assessing bioequivalence for Cmax and AUC showed that 90% CIs for the test/reference ratios of both PIO and GLIM were within the accepted (0.80, 1.25) range (Table I). Median values for tmax of GLIM (about 2.5 hours) were similar following FDC or coadministered treatments. For PIO, tmax values were slightly shorter (about 1.5 hours) with FDC compared to coadministered (about 2 hours) treatments. These differences, however, were not considered clinically relevant for drugs intended for chronic administration. Results from the additional analysis that included carryover effect in the ANOVA model revealed no statistically significant carryover effect with respect to AUC and Cmax of PIO or GLIM.
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One subject (#67) was determined to be a phenotypic poor metabolizer of CYP2C9 based on his markedly higher GLIM concentration values with both treatments. This subject's GLIM AUC values were 19 281 and 19 874 ng·h/mL after initial and repeat FDC treatments, respectively, and 21 006 and 19 855 ng·h/mL after initial and repeat coadministration treatments, respectively. These values are approximately 11-fold higher than the mean values for each treatment in the remaining subjects. Table I shows PK parameters of GLIM and results of the analysis of average bioequivalence with and without this subject.
Table II shows the results of the analysis of intra-subject and intersubject variability of PIO and GLIM AUClqc, AUC, and Cmax after FDC and coadministration treatments. No significant treatment differences were found for intrasubject and intersubject variabilities for either PIO or GLIM. For PIO AUC, intersubject variability was slightly higher (CV = 23.5% and 24.9% for FDC and coadministered treatments, respectively) than intrasubject variability (CV = 19.3% and 16.5% for FDC and coadministered treatments, respectively). For GLIM AUC, intersubject variability also was higher (CV = 29.4% and 29.9% for FDC and coadministered treatments, respectively) than intrasubject variability (CV = 19.1% and 17.7% for FDC and coadministered treatments, respectively).
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No statistically significant gender differences were found in PIO or GLIM AUC, AUClqc, and Cmax values (Table III). Weight-normalized Cmax and AUC of PIO were between 27% and 30% higher in women compared to men, whereas for GLIM, they were between 16% and 34% higher in women than in men. These values did not include PK parameters for GLIM poor-metabolizer male subject #67.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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We determined the bioequivalence of 2 strengths of FDC tablets containing PIO and GLIM compared with corresponding doses of commercial PIO and GLIM tablets. Peak and total exposures (Cmax and AUC) to PIO and GLIM after single-dose administration of each strength showed that the FDC tablets were bioequivalent to equivalent doses of the commercial tablets. Data for 1 strength (30 mg PIO/4 mg GLIM) are described in detail in this article. Single doses of FDC tablets in the present study were well tolerated. No clinically significant changes in clinical laboratory results, vital signs, or physical examination results were noted during the studies.
There has been a debate on the merits of average versus individual bioequivalency19,20 determinations of dosage forms intended for therapeutic substitution. Replicate design study is essential in determining individual bioequivalency, but after a great deal of scientific discussion, the US Food and Drug Administration (FDA) no longer requires assessment of individual bioequivalency as a requirement for proof of bioequivalency. Nevertheless, a replicate design study offers a great deal of useful information even if one uses average18 bioequivalency as proof of similarities in the systemic availabilities of the dosage forms. For example, an FDA guidance makes a note that replicate design studies are useful for assessing bioequivalency of highly variable drugs/dosage forms and allow precise assessment of the intrasubject variability of the drug and/or the dosage form. Intrasubject and intersubject variabilities of PIO and GLIM in our studies were similar after coadministered and FDC treatments. For PIO AUC, intrasubject variabilities ranged from 16% to 19%, whereas the intersubject variability ranged from 23% to 25%. For GLIM AUC, these variabilities were 18% to 19% and 29% to 30% (poor metabolizer subject #67 excluded). The intersubject and intrasubject variabilities for GLIM AUC in our study are similar to those previously reported (17% and 29%, respectively).2 Neither PIO nor GLIM can be classified as a highly variable drug20 that has intrasubject variability greater than 30%. Both PIO and GLIM had apparent clearance values of about 2.5 L/h following coadministered or FDC treatments, indicating that these oral antidiabetics cannot be considered high-extraction, high-clearance drugs.21
A replicate design study also allows identification of a true outlier subject. In our study, a male subject (#67) showed almost 11-fold higher exposure (21 006 ng·h/mL) of GLIM relative to the mean (%CV) exposure of 1963 (41%) ng·h/mL in the remaining 34 subjects (Table I) following initial coadministered treatment; high AUC values for GLIM were also observed for FDC treatments during both the initial and repeat treatments. These findings strongly indicate that the high exposure to GLIM in this subject was not a random event or an analytical artifact. A most likely explanation for this observation is that subject #67 was a poor metabolizer of GLIM. We did not do any genotyping studies to confirm that subject #67 was a heterozygous carrier of CYP 2C9*3. Niemi et al22 found similarities in the metabolism of glyburide and GLIM, both sulfonylureas. These sulfonylurea-antidiabetics are substrates for CYP 2C9, and their metabolism was greatly influenced by the CYP 2C9*3 variant allele. With GLIM, systemic exposure (AUC) in patients who were heterozygous carriers of the CYP2C9*3 allele was more than 100% higher than in those homozygous for the wild-type allele, and there were no differences in AUC between heterozygous carriers of the CYP 2C9*2 allele and homozygous carriers of wild-type alleles. It is noteworthy that subject #67 had only 8% lower exposure to PIO (AUC = 11 106 ng·h/mL in subject #67 vs 12 012 [33%] ng·h/mL {arithmetic mean (%CV)} in the remainder), indicating that CYP 2C9 is not an important isozyme involved in the metabolic clearance of PIO. Jaakkola et al11 found that CYP 2C8 and CYP 3A4 are the major and minor, respectively, isozymes involved in the metabolic clearance of PIO.
Some of the issues related to replicate design studies involve a larger volume of blood taken from each subject and a longer duration of study period because one has to use a 2-treatment, 4-period crossover design instead of a 2-treatment, 2-period crossover study. Chances of subjects dropping out of the study are also increased, and it is impractical to assess bioequivalency of more than 2 formulations by replicate design study. Even with 2 formulations, it is important to use only 2 sequences; otherwise, statistical evaluation of bioequivalency becomes too complex. Another possible issue related to replicate design study is how to handle a situation where only the initial or repeat administration phases show bioequivalency, but the overall study does not. It is not appropriate to do separate bioequivalency evaluations of the initial or repeat treatment phases in a replicate design study. Overall, the replicated crossover design is recommended for increasing the power of the study when the variability in the systemic exposure of the test drug/formulation is high. However, once the design is selected, the statistical analysis has to be based on the selected study design.
Yamazaki and Tabata23 found a marked (1.70-fold) increase in the exposure to GLIM in female compared to male rats, indicating the potential for gender differences in the metabolism of GLIM. To evaluate such a potential, we conducted a post hoc analysis based on gender (men, n = 18; women, n = 19) on the systemic availability of PIO and GLIM using Cmax, AUClqc, and AUC obtained following the initial coadministration treatment (excluding data from subject #67). To eliminate any influence of body weight differences between genders in the exposure parameters, body weight was normalized to 70 kg for this analysis. No statistically significant gender differences in the systemic exposure to either PIO or GLIM were found when these 2 drugs were coadministered. Comparing our results to those of Yamazaki and Tabata,23 species differences are indicated in the gender exposure response to GLIM.
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of both PIO and GLIM are similar and less than 20% when commercial PIO and GLIM tablets were coadministered or given as single FDC tablets. Based on these intrasubject variability values, neither PIO nor GLIM can be classified as a highly variable drug. However, we did find 1 subject out of 37 in whom the AUC of GLIM was almost 11-fold greater than the mean of the remaining subjects. We attributed this high exposure to genetic polymorphism in the metabolism of GLIM. No statistically significant differences in the exposures (AUC) of either PIO or GLIM between men and women were found, and there was considerable overlapping in the AUC values, making gender-dependent dosing unnecessary. The bioequivalency of 30/2-mg FDC tablets, not described in the present study, was also evaluated and gave similar results to 30/4-mg FDC tablets. Availability of these FDC tablets would enhance convenience, with the resultant potential to increase compliance in those diabetic patients whose therapy requires administration of these widely used oral antidiabetic agents.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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1. ACTOS [prescribing information]. Available at: www.actos.com/pi.pdf.
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7. Hanefeld M, Brunetti P, Schernthaner GH, Matthews DR, Charbonnel BH. One-year glycemic control with a sulfonylurea plus pioglitazone versus a sulfonylurea plus metformin in patients with type 2 diabetes. Diabetes Care. 2004;27: 141-147.
8. Derosa G, Cicero AFG, Gaddi A, et al. Metabolic effects of pioglitazone and rosiglitazone in patients with diabetes and metabolic syndrome treated with glimepiride: a twelve-month, multicenter, double-blind, randomized, controlled, parallel-group trial. Clin Ther. 2004;26: 744-754.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
9. Moules I, Edwards G, Mariz S, Urquhart R, Tan MH. Two-year efficacy of the addition of pioglitazone to sulfonylurea therapy in patients with T2DM [abstract 584-P]. Diabetes. 2004;53(suppl 2): A139.
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13. Badian MKA, Lehr KH, Malrcyk V, et al. Pharmakokinetik und pharmakodynamik nach intravenoser verabreichung des hydroxymetaboliten (M1) von glimpirid (HQE 490). Naunyn Schmiedebergs Arch Pharmacol. 1993;347(suppl): R27.
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15. DUETACT [prescribing information]. Available at: www.FDA.Gov/CDER/FOI/Label/2006/021925lbl.pdf.
16. Melikian C, White TJ, Vanderplas A, Dezii CM, Chang E. Adherence to oral antidiabetic therapy in a managed care organization: a comparison of monotherapy, combination therapy, and fixed-dose combination therapy. Clin Ther. 2002;24: 460-467.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
17. Food and Drug Administration. Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug Products—General Considerations. Rockville, Md: US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research; March 2003.
18. Food and Drug Administration. Guidance for Industry: Statistical Approaches to Establishing Bioequivalence. Rockville, Md: US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research; January 2001.
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22. Niemi M, Cascorbi I, Timm R, et al. Glyburide and glimepiride pharmacokinetics in subjects with different CYP2C9 genotypes. Clin Pharmacol Ther. 2002;72: 326-332.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
23. Yamazaki H, Tabata S. Sex differences in pharmacokinetics of novel sulfonylurea antidiabetic glimepiride in rats. Arzneium-Forsch/Drug Res. 1993;43: 1317-1321.
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