Population Pharmacokinetics of Pioglitazone in South Indian Type-II Diabetic Patients
Abstract
Introduction: Population pharmacokinetics (PPK) is the study of this variability, its source and magnitude in populations. This information is used
to design dosage regimens that account for individual patient characteristics.
Objective: The objective of this study was to perform a non-linear mixed-effects analysis of the pharmacokinetics of pioglitazone, indicated for
treating diabetes and to study the effect of covariates such as age, body surface area and creatinine clearance on the PPK of pioglitazone in South
Indian diabetic patients.
Materials and Methods: A simple, rapid, and sensitive isocratic high-performance liquid chromatography-ultra violet method for detection and
quantification of pioglitazone in plasma had been developed. Intra- and inter-assay variations were <1 and <2% respectively. Recovery of pioglitazone
was 98-99%. A total of 137 blood samples for pioglitazone plasma concentration measurements following a single 15 mg dose of pioglitazone were
obtained from 43 subjects having age in between 18 and 75 years. The PPK model was built using NONMEM 7.2.0. The first-order (FO) and first-order
conditional estimation (FOCE) method was used to estimate base and covariate models for pioglitazone.
Results: One-compartment model with FO absorption and elimination (ADVAN 2 TRANS 2) was best-fit to the plasma concentration-time data
of pioglitazone. A combined error model was best-described the pattern of residual and between subject variability. The final model estimates of
clearance (CL) and volume (V) estimated by FOCE method were 3.4 lt/hr and 43 L.
Discussion: There were no past reports on PPK of pioglitazone. With covariate models, a significant decrease was observed in object function value,
between and within subject variability when compared with base model. The model found to best describe the data following the FOCE method was:
CL=CL=θ1*EXP ([η1] and V=θ2*EXP [η2]). These parameters are utilized for individualizing the loading and maintenance doses in diabetic patients.
No factor was found as informative covariate of pioglitazone.
Conclusion: In order to minimize the variability associated with drug exposure in Indian diabetic patients, the population parameter estimates were
given without influence of covariates.
Keywords: Covariate, Creatinine clearance, NONMEM, Pioglitazone, Residual variability.
Downloads
References
Hanefeld M. Pharmacokinetics and clinical efficacy of pioglitazone. Int
J Clin Pract Suppl 2001;121:19-25.
Eckland DA, Danho M. Clinical Pharmacokinetics of pioglitazone. Exp
Clin Endocrinol Diabetes 2000;108:234-42.
Collste P, Haglund K, Von Bahr C. Plasma levels and effects of pioglitazone
after single and multiple oral doses. Clin Pharmacol Ther 1980;27:441-9.
Borg KO, Carlsson E, Hoffmann KJ, Jönsson TE, Thorin H, Wallin B.
Metabolism of pioglitazone in man. Acta Pharmacol Toxicol 1975;36
(Suppl V):125-35.
Sheiner LB, Ludden TM. Population pharmacokinetics/dynamics.
Annu Rev Pharmacol Toxicol 1992;32:185-209.
MartÃn-Jiménez T, Riviere JE. Population pharmacokinetics in
veterinary medicine: Potential use for therapeutic drug monitoring and
prediction of tissue residues. J Vet Pharmacol Ther 1998;21(3):167-89.
Sun H, Fadiran EO, Jones CD, Lesko L, Huang SM, Higgins K,
et al. Population pharmacokinetics. A regulatory perspective. Clin
Pharmacokinet 1999;37(1):41-58.
Whiting B, Kelman AW, Grevel J. Population pharmacokinetics. Theory
and clinical application. Clin Pharmacokinet 1986;11(5):387-401.
Sheiner LB, Rosenberg B, Marathe VV. Estimation of population
characteristics of pharmacokinetic parameters from routine clinical
data. J Pharmacokinet Biopharm 1977;5(5):445-79.
Mamidi RN, Chaluvadi MR, Benjamin B, Ramesh M, Katneni K, Babu
AP, et al. HPLC method for the determination of rosiglitazone in human
plasma and its application in a clinical pharmacokinetic study. USA:
John Wiley & Sons; 2003. p. 65-8.
Brahmaiah B, Sujana K, Prameela Rani A. Development and validation
of RP-HPLC method for simultaneous determination of ramipril and
valsartan in bulk and pharmaceutical dosage forms. Asian J Pharm Clin
Res 2013;6(1):23-5.
Harish KK, Vijay SK, Satish BK, Reddy NY, Raghavaiah VK,
Devarakonda KR. Population pharmacokinetics of cisplatin in Asian
Indian cancer patients. Clin Res Regul Aff 2009;26(4):84-92.
Mahender V, Arun Kumar M, Devender K, Narsimha Reddy Y.
Population pharmacokinetics and clinical response of metoprolol
in South Indian hyperternsive patients. Asian J Pharm Clin Res
;7(2):140-3.
Aarons L, Balant LP, Mentre F, Morselli PL, Rowland M, Steimer JL,
et al. Practical experience and issues in designing and performing
population pharmacokinetic/pharmacodynamic studies. Eur J Clin
Pharmacol 1996;49(4):251-4.
Adler AI, Stratton IM, Neil HA, Yudkin JS, Matthews DR, Cull CA,
et al. Association of systolic blood pressure with macrovascular
and microvascular complications of type 2 diabetes (UKPDS 36):
Prospective observational study. BMJ 2000;321(7258):412-9.
Budde K, Neumayer HH, Fritsche L, Sulowicz W, Stompôr T,
Eckland D. The pharmacokinetics of pioglitazone in patients with
impaired renal function. Br J Clin Pharmacol 2003;55(4):368-74.
Published
How to Cite
Issue
Section
The publication is licensed under CC By and is open access. Copyright is with author and allowed to retain publishing rights without restrictions.