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PHARMACOKINETICS |
From Takeda Global Research & Development Center, Inc, Lincolnshire, Illinois (Dr Karim, Ms Slater, Ms Bradford, Ms Schwartz, Ms Zhao, Dr Cao) and PPD Development, LP, Austin, Texas (Dr Laurent).
Address for reprints: Aziz Karim, PhD, ABCP, FCP, Takeda Global Research & Development Center, Inc, 475 Half Day Road, Lincolnshire, IL 60069; e-mail: akarim{at}tgrd.com.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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) were 0.95 (0.86-1.05) and 1.02 (0.98-1.08), respectively, for pioglitazone and 0.99 (0.95-1.03) and 1.03 (0.98-1.08), respectively, for metformin. Bioequivalency for pioglitazone and metformin between fixed-dose combination tablets and coad treatments was met for both strengths of fixed-dose combination tablets. In a post hoc metaanalysis of combined data from the 2 studies (n = 124), there was considerable overlapping in AUC values between gender and race (Caucasians, Blacks, and Hispanics), making neither gender-nor racial-based dosing of pioglitazone or metformin necessary.
Key Words: oral antidiabetic drugs • pioglitazone • metformin • fixed-dose combination tablets • effect of body weight, gender, and race on systemic exposures
and altering expression of components that influence insulin signaling and the glucose transport system. Another widely used oral antidiabetic agent, metformin (MET), acts primarily by reducing hepatic glucose production through an unknown mode of action and has been shown to have lesser effects on peripheral insulin sensitivity.5,6 Patients with inadequately controlled type 2 diabetes are frequently required to take multiple medications, and there is a widespread perception that an increasing "pill burden" is associated with reduced convenience and compliance.7,8 Given their complementary mechanisms of action,9,10 combining PIO and MET as a single tablet would allow for convenient administration of the dual therapy. Safety and efficacy issues also justify a fixed-dose combination (FDC) product of PIO with MET because the FDC product may allow patients to achieve equal or greater glycemic control with lesser doses of each agent, thus minimizing undesirable side effects associated with higher doses of each drug.8 In addition to its glycemic effects, PIO alone and together with MET favorably affects lipid profiles in patients with type 2 diabetes,9,11 thus making it a good drug candidate for an FDC product. Pioglitazone is almost completely metabolized by the liver, whereas MET is predominantly excreted in the urine as unchanged drug. These different disposition characteristics suggest an unlikely pharmacokinetic (PK) interaction between these 2 antidiabetic agents. Multiple oral doses of PIO (45 mg once a day given for 7 days) have been shown4,12 to have no effect on the single-dose PK of MET (1000 mg).
A new FDC tablet containing PIO and MET has been developed to provide more treatment options for patients with type 2 diabetes. This article describes the bioavailability characteristics of PIO and MET from 2 strengths of FDC tablets—namely, 15 mg PIO/500 mg MET (15/500) and 15 mg PIO/850 mg MET (15/850)—relative to equivalent oral doses of commercial tablets given concomitantly. In a post hoc meta-analysis, we also examined the effects of body weight, gender, and race on the systemic exposures to PIO and MET after combining exposure parameters in studies I and II following coadministration treatments.
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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, were postmenopausal or surgically sterile, or agreed to practice acceptable methods of nonhormonal contraception. Subjects could not have clinically significant 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 was not allowed within 1 week prior to first dose. Other exclusion criteria included a positive result on the urine drug and alcohol screen and use of alcohol, caffeine, grapefruit, Seville oranges, or vitamin supplements within 48 hours prior to dose. Studies were 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, Tex), approved the study protocol prior to the enrollment of study subjects. All volunteers gave written informed consent prior to their participation in the study.
Study Design
A randomized, open-label, 6-sequence, 3-period crossover design was used for each of the 2 separate bioequivalency studies. Subjects in each study received single oral doses of 3 treatments consisting of (1) 1 FDC bilayer tablet, (2) 1 FDC micronized PIO tablet, and (3) coadministration of commercial tablets of PIO and MET (coad). A washout period of 7 days was maintained between each treatment.
A pretreatment screening visit was conducted between 2 and 28 days prior to the first dose of study drug. After obtaining a potential participant's 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 subjects returned to the clinic for baseline evaluations on day -1. Subjects were housed in the clinical research facility for 3 consecutive nights during each period, from the day prior to dosing through 48 hours postdose. While confined to the clinic, subjects were provided with a standard low-fat diet, and no additional food or drink (except water) was allowed.
Subjects fasted for 10 hours overnight and then received each treatment with 240 mL of water. Treatment compliance was monitored by checking the oral cavity (mouth) to ensure that the dose was swallowed. During each period, serial blood samples (10 mL each) were collected at time periods listed below for the measurement of PIO and MET concentrations in serum. Subjects were discharged from the clinical site after collection of the 48-hour postdose blood sample: subjects then returned for a follow-up visit to collect the PK blood sample at 72 hours after each treatment. 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. Blood samples for PK analysis were collected according to the following schedule: within 0.5 hours prior to each dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose. Each blood sample was 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, Ind) for measurement of PIO and MET concentrations.
Determination of Pioglitazone and Metformin in Serum
Serum concentrations of PIO were measured by the use of liquid chromatography/tandem mass spectrometry (LC/MS/MS). The mass spectrometer, a QuattroLC tandem quadrupole (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 2.0 mm) with a Thermo Hypersil Betasil C-18 (20 x 2.0 mm) precolumn at a temperature of 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 134 for PIO and m/z 343 to 120 for the internal standard. The standard curve range for PIO was 25.0 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 MET were measured by the use of LC/MS/MS. The mass spectrometer, a Sciex 4000, was operated with positive Turbo Ionspray ionization. The internal standard used for the determination of MET was deuterated MET. Chromatography was performed on a Restek Allure PFP Propyl column (150 x 3.2 mm) 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 metformin and internal standard. The ion transitions monitored were m/z 130 to 71 for MET and m/z 136 to 77 for the deuterated MET internal standard. The standard curve range for MET was 10.0 ng/mL (LLOQ) to 3500 ng/mL. The interassay coefficient of variation during validation ranged from 2.7% to 7.6%, and the analytical recovery ranged from 91.5% to 100%.
Analysis of Data
Pharmacokinetics
For each subject, the following PK parameters were calculated from serum concentrations of unchanged MET and PIO, as base, according to the modelindependent approach: maximum observed serum concentration (Cmax), the time at which Cmax occurred (tmax), terminal-phase elimination rate constant (
z), area under the serum concentration-time curve from time 0 to time of the last quantifiable concentration (AUClqc), area under the serum concentration-time curve from time 0 to infinity (AUC), and terminal elimination half-life (t
). These PK parameters were obtained using WinNonlin® Professional version 3.1 (Pharsight Corp, Mountain View, Calif). AUC was calculated as AUClqc + Clast/z, where Clast is the last quantifiable serum concentration in the log-linear phase of the concentration-time curve. Criteria for accepting AUC values in PK and statistical analysis included the following: (1) the correlation coefficient (r2) in the slope of the log-linear regression for z had to be equal to or higher than 0.80, and (2) the extrapolated AUC had to be equal to or less than 20% of the AUClqc.
Statistical Analysis for Bioequivalency
The sample size for the bioequivalency studies was based on the probability of meeting the bioequivalence criterion using the test/reference ratio limits between 0.80 and 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 are between 0.93 and 1.07, then the data from at least 60 subjects, 10 subjects for each sequence, would provide a 90% probability of claiming bioequivalence. Assuming that the error term variances for the natural logarithms of Cmax and AUC of MET were less than those of PIO, the probability of meeting the criterion for MET was greater. A sample size of 66 was chosen to allow for dropouts during the course of each of the studies.
Inferential statistics were performed using SAS® release 8.2 (SAS Institute, Cary, NC). An ANOVA with fixed effects for sequence, period, and treatment and random effect for subject nested within sequence was the primary analysis performed on tmax, z, and the natural logarithms of AUClqc, AUC, and Cmax of PIO and MET. The possibility of unequal carryover effect was also examined by including the carryover effect in the ANOVA model. The 90% confidence intervals (CIs) for the ratio of the least squares (LS) mean of the FDC tablets (test treatment) relative to the LS mean of coadministered commercial tablets (reference treatment) were calculated. If the 90% CIs for AUClqc, AUC, and Cmax of PIO and MET were within the (0.80, 1.25) interval, bioequivalence between test and reference treatments was concluded.
Effect of Body Weight, Gender, and Race on Drug Exposure
The post hoc meta-analysis was performed using SAS® software version 8.2. In the meta-analysis, PK data from studies I and II were combined to assess the effect of body weight, gender, and race on the systemic exposures of PIO and MET following the coadministration of the 2 commercial tablets. In total, 123 subjects from 3 different races—Caucasian, Black, and Hispanic—were included in the analysis. Because MET doses were different in the 2 studies, the PK parameters for MET were normalized for the 500-mg dose, and both PIO and MET PK parameters were also normalized for a 70-kg body weight as follows:
PIO: [PK parameter x (70/weight)],
MET: [((PK parameter/dose) x 500) x (70/weight)].
The ANOVA with race and gender effects and weight as a covariate was performed on the natural logarithms of weight-normalized AUClqc, AUC, and Cmax of PIO and the dose- and weight-normalized AUClqc, AUC, and Cmax of MET. Within the framework of the ANOVA for natural logarithms of AUClqc, AUC, and Cmax, the 90% CIs for the ratio of the test race LS mean (Black or Hispanic) relative to the reference race LS mean (Caucasian) were provided, as well as the 90% CIs for the ratio of the LS mean of females relative to the LS mean of males. The 90% CIs were obtained by taking the antilog of the 90% CI for the difference between the LS means on the natural logarithmic scale. Screening body weights for 124 subjects were used to evaluate the effect of body weight on the PK of PIO and dose-normalized MET.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Twenty-two (33%) of 66 subjects in the 15/500 study I and 25 (39%) of 64 subjects in the 15/850 study II experienced at least 1 adverse event. All adverse events were mild or moderate in intensity. The most commonly reported adverse events were gastrointestinal system disorders, primarily abdominal pain, diarrhea, loose stools, or nausea. Eight subjects (12%) in study I and 15 subjects (23%) in study II reported gastrointestinal-related adverse events. One subject withdrew prior to study completion because of adverse events, mild allergic reaction and pruritis considered probably related to study drug and mild facial edema considered most likely related to study drug. No serious adverse events were reported, and no deaths occurred during the studies. No clinically significant abnormal laboratory values or changes in vital signs, ECGs, or physical examination findings were reported. Four subjects in each of the 2 studies discontinued early. In the 15/500 study I, 1 subject withdrew voluntarily, 1 subject had an adverse event (mild allergic reaction), 1 subject became pregnant, and 1 subject had a protocol violation. In the 15/850 study II, 2 subjects withdrew voluntarily, 1 subject became pregnant, and 1 subject was lost to follow-up.
Based on the results of the present studies, clinical development of the FDC bilayer tablets was discontinued. The present work describes results of bioequivalency of the 15/500 and 15/850 FDC micronized PIO tablets that were developed for regulatory approval and marketing.
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of both PIO and MET and with respect to the Cmax of MET. In addition, the 90% confidence intervals of the LS mean ratios for these parameters were within the 0.80 to 1.25 bioequivalence range. For the 15/500 FDC tablet, a statistically significant carryover effect on the Cmax of PIO was noted across treatments; however, the 90% confidence interval of the LS mean ratio of Cmax for the FDC tablet was within 0.80 to 1.25, satisfying the bioequivalency criteria.
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Effect of Body Weight, Gender, and Race on Systemic Exposures
The relationship between individual body weight and AUC of PIO or MET is illustrated in Figure 2. Considerable variability in the AUC values was found, and there was no meaningful correlation between body weight and systemic exposure for either PIO or MET in the body weight range between 50 and 123 kg. Results of the effect of gender and race on the systemic exposures to PIO and MET are summarized in Table III. The relationships between individual AUC values in males and females and in different racial groups are illustrated in Figures 3 and 4, respectively. For either PIO or MET, exposure differences in AUC between males and females or in 3 racial groups did not exceed 20%, and there was considerable overlap in AUC values.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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We determined the bioequivalence of 2 strengths of FDC tablets compared with corresponding doses of commercial PIO and MET tablets. Peak and total exposures (Cmax and AUCs) to PIO and MET after single-dose administration of each strength showed that the FDC tablets were bioequivalent to equivalent doses of the commercial tablets. 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.
In our studies, average Cmax and AUC values of MET after administration of 15/850 FDC tablets were about 1.5-fold higher, instead of the expected 1.7-fold higher, compared to 15/500 dosing. This lack of precise dose proportionality has also been reported by others.13 However, in our studies, the ratio (850/500) of average Cmax or AUC values among the various subgroups studied remained approximately the same, ranging between 1.42 and 1.74, making it valid to normalize MET dose to 500 mg when studying the effects of gender and race on the systemic exposure to MET.
Pioglitazone has 2 active metabolites, as evaluated in animal studies.4 In humans, the elimination t of these active metabolites is longer14 than the t of PIO. Some investigators have used "total" PIO (sum of unchanged drug and active metabolites) concentrations in bioavailability studies.14 We used only the parent drug serum concentrations in assessing bioequivalency of the FDC tablets because the time course of the metabolite serum concentration is confounded by the formation rate of the metabolite from PIO, as well as the elimination rate of metabolite from the systemic circulation. For this reason, determination of the time course of the unchanged drug in the serum represents the most accurate method for assessing bioequivalency of various dosage forms. Metabolite determination is useful in a detailed PK evaluation of a drug or in bioequivalency determinations, where the parent drug is inactive or is rapidly converted to active metabolites and cannot be measured in blood.
The immediate-release formulation of MET is labeled to be taken twice a day,13 whereas that of PIO is labeled to be taken once a day.4 For FDC tablets containing these 2 antidiabetic agents, it is recommended that the dosing frequency be twice a day (bid)12 based on the rationale that for thiazolidinediones (TZDs), the total daily systemic exposure (AUC
) is clinically more relevant than peak exposure (Cmax). This conclusion is supported by the fact that with another TZD, rosiglitazone, which has a similar range of elimination t (3-4 hours) to unchanged PIO (3-7 hours), safety and efficacy of rosiglitazone was similar when it was given once daily (qd) or bid.15 An unpublished study from our institute has shown an approximately linear relationship between single or multiple doses of PIO and AUC (single dose) or AUC (multiple dose) in the 15- to 60-mg dose range. Total daily exposure to pioglitazone was also found to be similar when 60 mg of PIO was given once a day (60 mg qd) or twice a day (30 mg bid). As expected, lower Cmax and higher Cmin values of PIO were obtained with bid dosing (resulting in less fluctuation in the serum concentration-time curve during 1 dose interval) compared to qd dosing. These findings indicate that, like rosiglitazone, qd or bid dosing of pioglitazone should result in similar safety and efficacy response, indicating that bid dosing of the FDC tablets of PIO and MET is therefore appropriate.
There is limited information published on the effects of age, gender, body weight, and race on the disposition kinetics of PIO or MET. By combining the systemic exposure data obtained in the 2 bioequivalency studies, enough subject exposure values were available to assess these covariate effects. Figure 2 illustrates extensive variability in the body weight versus AUC relationship with both compounds. As expected, female body weights were generally lower than those in males. In view of the extreme variability in body weight versus systemic exposure relationship, it is neither practical nor necessary to adjust doses of PIO or MET based on body weight. However, it is important to note that in our studies, body weights ranged between 50 and 123 kg, and no subject had a BMI >35 kg/m2. Therefore, our recommendation for no dose adjustment on the basis of body weight applies only to subjects within this body weight range.
The effect of age on the systemic exposures could not be ascertained because the entry criteria in our 2 studies restricted the age range between 18 and 55 years. Because the doses of MET in the 2 studies were different, we normalized the dose of metformin to 500 mg in assessing the effect of gender or race on MET exposure. Also, to eliminate any influence of body weight differences in the exposure parameters, we also normalized the body weight to 70 kg. The commercial PIO label states that mean Cmax and AUC values were increased 20% to 60% in women compared to men. In our studies, we found an approximate 20% difference in body weights between men and women. When exposure parameters were not normalized for a 70-kg body weight, arithmetic mean AUC values in our studies were 18% higher in females. However, when AUC was normalized for 70-kg body weight, gender or racial (Caucasians, Hispanics, and Blacks) differences in LS mean AUC values were less than 10%. There was also considerable overlapping in AUC between males and females or between various races, indicating that neither gender-nor race-dependent dosing of either PIO or MET is necessary.
In conclusion, our studies have demonstrated bioequivalency of 15/500-mg and 15/850-mg fixed-dose combination tablets of PIO and MET relative to corresponding strengths of each drug coadministered as commercial tablets. Availability of these FDC tablets would enhance convenience and thereby increase compliance in those patients with diabetes whose therapy requires administration of these widely used oral antidiabetic agents. No differences of any clinical relevance in systemic exposures to either PIO or MET were found that could be attributed to race, gender, or body weight.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Financial disclosure: This study was supported by Takeda Global Research & Development Center, Inc.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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1. Yki-Jarvinen H. Thiazolidinediones. N Engl J Med. 2004; 351: 1106-1118.
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8. Mooradian AD. Towards single-tablet therapy for type 2 diabetes mellitus: rationale and recent developments. Treat Endocrinol. 2004;3: 279-287.[CrossRef][Medline] [Order article via Infotrieve]
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10. Matthews DR, Charbonnel BH, Hanefeld M, Brunetti P, Schernthaner G. Long-term therapy with addition of pioglitazone to metformin compared with the addition of gliclazide to metformin in patients with type 2 diabetes: a randomized, comparative study. Diabetes Metab Res Rev. 2005;21: 167-174.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
11. Khan M, Xu Y, Edwards G, Urquhart R, Mariz S. Effects of pioglitazone on the components of diabetic dyslipidaemia: results of double-blind, multicentre, randomised studies. Int J Clin Pract. 2004;58: 907-912.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
12. ACTOplus met prescribing information, www.actos.com/sub_sec8_about_plus.asp.
13. Glucophage/Glucophage XR prescribing information, www.glucophagexr.com/index.html.
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