Research Article POPULATION PHARMACOKINETICS AND CLINICAL RESPONSE OF METOPROLOL IN SOUTH INDIAN HYPERTERNSIVE PATIENTS MAHENDER VATTIPALLY, ARUN KUMAR MAHESH, DEVENDER KODATI, NARSIMHA REDDY YELLU* Department of Pharmacology and Clinical Pharmacy, University College of Pharmaceutical Sciences, Kakatiya University, Warangal – 506 009, Andhra Pradesh, INDIA. Email: ynrkuc@gmail.com Received: 10 January 2014, Revised and Accepted: 2 February 2014 ABSTRACT Population pharmacokinetics (PPK) is the study of the 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 metoprolol, indicated for treating hypertension and to study the effect of covariates like age, body surface area [BSA] and creatinine clearance [CRCL] on the population pharmacokinetics of metoprolol in South Indian hypertensive patients. Methods: A simple, rapid and sensitive isocratic HPLC-UV method for detection and quantification of metoprolol in plasma had been developed. Intra-and inter-assay variations were <1and <2% respectively. Recovery of metoprolol was 98-99%. Total 258 blood samples for metoprolol plasma concentration measurements following a single 100 mg and 300 mg /day dose of metoprolol were obtained from 86 subjects having age in between 18-75 years. The population PK model was built using NONMEM 7.2.0. The FO and FOCE method was used to estimate base and covariate models for metoprolol. Results: One-compartment model with first-order absorption and elimination (ADVAN 2 TRANS 2) was best fit to the plasma concentration-time data of metoprolol. A combined error model was best described the pattern of residual and between subject variability .The final model estimates of CL and V estimated by FOCE method were 93.4 L/h and 83.1 L. Discussion: There were no past reports on PopPK of metoprolol. With covariate models, significant decrease was observed in OFV, between and within subject variability when compared to base model. The model found to best describe the data following the FOCE method was: Clearance (CL) = θ1*(CLCR/0.75) *EXP (1) and Volume (V) = θ2*(AGE/50) *EXP (2). These parameters are utilized for individualizing the loading and maintenance doses in hypertensive patients. CRCL for CL; AGE for V were found as an informative covariates of metoprolol. Conclusion: In order to minimize the variability associated with drug exposure in Indian hypertensive patients, the results of the population PK analysis support AGE and CRCL adjusted dosing of metoprolol. Keywords: NONMEM, Creatinine clearance, Covariate, Residual variability, Metoprolol. INTRODUCTION Metoprolol is the cardio selective (β1) blocker. Metoprolol is well absorbed after oral administration and are widely distributed in body tissues. Peak serum level of the metoprolol is obtained within 1-3 hours of oral administration of the drug [1]. Bioavailability of the metoprolol is between 40 to 50% [2]. The mean terminal plasma elimination half-life of metoprolol ranges from approximately 3 to 4 hours following single or multiple doses of metoprolol given orally or intravenously [3]. Population pharmacokinetics (PPK) is the study of this variability, its source and magnitude in populations [4]. This information is used to design dosage regimens that account for individual patient characteristics [5]. Population pharmacokinetics therefore seeks to identify and measure factors, and define the extent of their influence on the dose concentration interaction. [6] Dosage regimens have traditionally been determined based on detailed pharmacokinetic studies of a few, typically healthy, individuals. This dosage may therefore not be appropriate in the clinical use of a drug. Diseased humans frequently have disturbed metabolic systems, which may alter drug absorption and disposition when compared to healthy individuals [5]. Flexible dosing may prove to be more appropriate [7]. Determining appropriate drug doses requires estimating the pharmacokinetic parameters (such as clearance and volume of distribution) as they relate to covariates or variables, including the precision of these estimates [5,8]. Therapeutic response to antihypertensive drugs can show large intra and inter individual variability therefore it is necessary for serum/plasma concentrations to be monitored during the drug administration, if target serum concentrations are to be achieved. The hypothesis tested in this study was that the population pharmacokinetic modeling approach can be used to evaluate and describe the concentration time data collected in the metoprolol clinical trials. Using this approach, precise estimates of the pharmacokinetic parameters and their variability has to be quantifiable and significant covariates would be identified. Population PK analysis is helpful to identify factors that affect PK of drug or to explain variability in target population. To date, however there is no report on POP PK of metoprolol although this drug is widely used as anti hypertensive drug in India. In present study we developed a PPK model for metoprolol by analyzing the pooled data obtained from Indian hypertensive patients. Since metoprolol shows large individual variability in pharmacokinetics, it is useful to develop a PPK model by integrating the currently available information for this drug. The obtained PPK model explains several factors that can cause inter individual variability in pharmacokinetics, and the model is capable to describe and predict the plasma concentration-time profile for the patients with various backgrounds. Vol 7, Issue2, 2014 ISSN - 0974-2441