Oral Antidiabetic Drugs: Bioavailability Assessment of Fixed‐Dose Combination Tablets of Pioglitazone and Metformin. Effect of Body Weight, Gender, and Race on Systemic Exposures of Each Drug

Karim, Aziz; Slater, Margaret; Bradford, Dawn; Schwartz, Lisa; Zhao, Zhen; Cao, Charles; Laurent, Angélique

doi:10.1177/0091270006293755

Cited by 18 publications

(21 citation statements)

References 13 publications

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“…7) Although the findings in our study differ from what is reported in prescribing information, they are consistent with a report by Karim and colleagues, which showed no effect of sex or body weight on the pharmacokinetics of pioglitazone after oral administration in healthy volunteers. 20) These investigators also reported no differences in pioglitazone plasma exposure between Caucasians, Blacks, and hispanics. 20) Unfortunately, we could not assess the effects of race or ethnicity on pioglitazone disposition in the population given that all of the subjects were Caucasian.…”

Section: Discussionmentioning

confidence: 94%

Effect of Cytochrome P450 2C8*3 on the Population Pharmacokinetics of Pioglitazone in Healthy Caucasian Volunteers

Kadam

Bourne

Kompella

et al. 2013

Biological & Pharmaceutical Bulletin

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Pioglitazone, a peroxisome proliferator-activated receptor-γ agonist, is indicated for the treatment of type 2 diabetes. Pioglitazone undergoes hepatic metabolism by cytochrome P450 2C8 (CYP2C8) and interindividual variability exists in pioglitazone disposition and response. In previous analyses, it has been shown that the CYP2C8*3 polymorphism significantly impacts pioglitazone pharmacokinetics in humans. The purpose of this investigation was to develop a population pharmacokinetic model using nonlinear mixed effects analysis to evaluate and quantify the effect of CYP2C8*3, demographic, and clinical variables on interindividual variability in pioglitazone pharmacokinetics in nondiabetic adults. Data were obtained from 31 healthy volunteers (n=16 CYP2C8*1/*1, n=15 CYP2C8*3 carriers) who had previously participated in the monotherapy phase of a pioglitazone drug-drug interaction study. Participants received a single 15 mg dose of pioglitazone followed by a 48-h sampling period. A two-compartment model with first order absorption and elimination (Akaike Information Criteria (AIC)=2889) showed a better fit for pioglitazone than a one-compartment model (AIC=3008). Covariate analysis revealed that CYP2C8*3 had a significant effect on pioglitazone central compartment clearance (CL/F; p=0.0005) and intercompartmental clearance (Q/F; p=0.004). Pioglitazone CL/F and Q/F were 52% and 286% higher, respectively, in carriers of the CYP2C8*3 allele than in CYP2C8*1 homozygotes. Furthermore, inclusion of CYP2C8*3 as a covariate on CL/F and Q/F decreased interindividual variability in these parameters by 5.2% and 14%, respectively. Other variables (e.g., sex, body weight) were not significant covariates on pioglitazone pharmacokinetics in the model. In summary, CYP2C8*3 significantly affected pioglitazone CL/F, Q/F, and interindividual variability in these parameters in this healthy volunteer cohort.Key words pioglitazone; cytochrome P450 2C8; population pharmacokinetic; pharmacogenetic; NONMEM; modeling Pioglitazone, a thiazolidinedione peroxisome proliferatoractivated receptor-γ agonist, improves insulin sensitivity and is used for the treatment of type 2 diabetes.1) Pioglitazone has also been shown to substantially reduce the risk of developing type 2 diabetes in patients with impaired glucose tolerance (i.e., prediabetes).2) In terms of clinical pharmacology, pioglitazone is administered in doses of 15 to 45 mg once daily. The drug is hepatically metabolized by cytochrome P450 2C8 (CYP2C8), and to a lesser extent by CYP3A4, CYP1A2, CYP2C9 and CYP2D6.3-7) M-III (keto-derivative) and M-IV (hydroxyl/derivative) are the main circulating active metabolites of pioglitazone in humans.3) Pioglitazone is well-absorbed after oral administration with a mean absolute bioavailability of 83% and a T max of 0.5 to 3 h. The drug is highly protein bound (>99%) and the volume of distribution ranges from 0.2 to 0.3 L/kg. The mean apparent oral clearance is 2.4 L/h and the terminal elimination half-life is about 9 h. 3)Interindividual variabil...

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Section: Discussionmentioning

confidence: 94%

Effect of Cytochrome P450 2C8*3 on the Population Pharmacokinetics of Pioglitazone in Healthy Caucasian Volunteers

Kadam

Bourne

Kompella

et al. 2013

Biological & Pharmaceutical Bulletin

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“…Using an intrasubject coefficient of variation of 22% for C max and 19% for AUC based on published data on pioglitazone (Karim et al, 2007), a sample size of 12 subjects was considered sufficient for point estimates of the geometric mean ratios (GMRs) of C max and AUC, with and without coadministration of abiraterone acetate, to fall within 85% and 117% and within 87% and 115% of their true values, respectively, with 90% confidence. A sample size of 16 subjects was planned, assuming a dropout rate of 25%.…”

Section: Downloaded Frommentioning

confidence: 99%

In Vitro and In Vivo Drug-Drug Interaction Studies to Assess the Effect of Abiraterone Acetate, Abiraterone, and Metabolites of Abiraterone on CYP2C8 Activity

Monbaliu

Gonzalez

Bernard

et al. 2016

Drug Metabolism and Disposition

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Abiraterone acetate, the prodrug of the cytochrome P450 C17 inhibitor abiraterone, plus prednisone is approved for treatment of metastatic castration-resistant prostate cancer. We explored whether abiraterone interacts with drugs metabolized by CYP2C8, an enzyme responsible for the metabolism of many drugs. Abiraterone acetate and abiraterone and its major metabolites, abiraterone sulfate and abiraterone sulfate N-oxide, inhibited CYP2C8 in human liver microsomes, with IC 50 values near or below the peak total concentrations observed in patients with metastatic castration-resistant prostate cancer (IC 50 values: 1.3-3.0 mM, 1.6-2.9 mM, 0.044-0.15 mM, and 5.4-5.9 mM, respectively). CYP2C8 inhibition was reversible and time-independent. To explore the clinical relevance of the in vitro data, an open-label, single-center study was conducted comprising 16 healthy male subjects who received a single 15-mg dose of the CYP2C8 substrate pioglitazone on day 1 and again 1 hour after the administration of abiraterone acetate 1000 mg on day 8. Plasma concentrations of pioglitazone, its active M-III (keto derivative) and M-IV (hydroxyl derivative) metabolites, and abiraterone were determined for up to 72 hours after each dose. Abiraterone acetate increased exposure to pioglitazone; the geometric mean ratio (day 8/day 1) was 125 [90% confidence interval (CI), 99.9-156] for C max and 146 (90% CI, 126-171) for AUC last . Exposure to M-III and M-IV was reduced by 10% to 13%. Plasma abiraterone concentrations were consistent with previous studies. These results show that abiraterone only weakly inhibits CYP2C8 in vivo.

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“…In the clinical trial mentioned above, pioglitazone in combination with metformin was shown to have similar pharmacokinetic properties in healthy non-Hispanic white, African American, and Hispanic populations 28 . In a non-randomized study consisting of African Americans with IGT and T2DM, rosiglitazone increased post-glucose challenge hepatic insulin extraction, and glycemic control was improved, but not normalized 34 .…”

Section: Thiazolidinedionesmentioning

confidence: 99%

“…Antihyperglycemic therapy typically begins with metformin. The drug has been relatively well studied among racial and ethnic minorities, and clinical findings have demonstrated similar pharmacokinetic properties in healthy non-Hispanic white, African American, and Hispanic populations when metformin is given with pioglitazone 28 . Recent observational data for 19,672 patients suggest that African Americans may respond to metformin treatment better than non-Hispanic white Americans 29 .…”

Section: Biguanides: Metforminmentioning

confidence: 99%

Racial/ethnic disparities in prevalence and care of patients with type 2 diabetes mellitus

Ferdinand

Nasser

2015

Current Medical Research and Opinion

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Background: As of 2012, nearly 10% of Americans had diabetes mellitus. People with diabetes are at approximately double the risk of premature death compared with those in the same age groups without the condition. While the prevalence of diabetes has risen across all racial/ethnic groups over the past 30 years, rates are higher in minority populations. The objective of this review article is to evaluate the prevalence of diabetes and disease-related comorbidities as well as the primary endpoints of clinical studies assessing glucoselowering treatments in African Americans, Hispanics, and Asians.

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Oral Antidiabetic Drugs: Bioavailability Assessment of Fixed‐Dose Combination Tablets of Pioglitazone and Metformin. Effect of Body Weight, Gender, and Race on Systemic Exposures of Each Drug

Cited by 18 publications

References 13 publications

Effect of Cytochrome P450 2C8*3 on the Population Pharmacokinetics of Pioglitazone in Healthy Caucasian Volunteers

Effect of Cytochrome P450 2C8*3 on the Population Pharmacokinetics of Pioglitazone in Healthy Caucasian Volunteers

In Vitro and In Vivo Drug-Drug Interaction Studies to Assess the Effect of Abiraterone Acetate, Abiraterone, and Metabolites of Abiraterone on CYP2C8 Activity

Racial/ethnic disparities in prevalence and care of patients with type 2 diabetes mellitus

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