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Many drugs of same generic are marketed by more than one pharmaceutical manufacturer in market. Many studies have shown that method of manufacturing and composition of active and inactive material in the formulation can influence the pharmacokinetics of drug. In last decade, the number of pharmaceutical industries has increased and these are also manufacturing the same drugs which are research product of a multinational company. For example, montelukast's more than 25 brands are available in Pakistan but it is hard to say that every brand present in market have the same efficacy. So, the bioequivalence study is of much important to ensure that this drug can produce desired effects.
Bioequivalence can be defined as, "two pharmaceutical products are bioequivalent if they are pharmaceutically equivalent and their bioavailabilities (rate and extent of availability) after administration in the same molar dose are similar to such a degree that their effects, with respect to both efficacy and safety, can be expected to be essentially the same. Pharmaceutical equivalence implies the same amount of the same active substance(s), in the same dosage form, for the same route of administration and meeting the same or comparable standards." (Birkett, 2003)
It can also be defined as, "the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study." (United states Food and Drug Administration, 2003.; www.fda.gov).
The purpose of bioequivalence studies is to express the bioequivalence between two generic drug products and the corresponding reference drug. Pharmaceutical equivalence is determined and this bioequivalence allows a regulatory conclusion that these drugs are also therapeutic equivalent. Bioequivalence studies also evaluate the systemic exposure profile of a test drug product in comparison to a reference drug product (Huixiao et al.2009). Bioequivalence also plays a very important role in the period of drug development. It is not only for the study of a new drug but also for their generic equivalents. These studies have also importance in the postapproval period as certain manufacturing changes can affect the bioequivalence of drug. Also the safety and effcicay of drug on the basis of systemic exposure is measured (Mei-Ling et al., 2001).
Bioequivalence study also help to adjust the doses in a fixed dose combination (FDC) as recommended by WHO to increase patient compliance. Drugs in fixed dose combination can be compared to their separate dosage form and also drug interactions can be studied. (Agrawal et al. 2001). Bioequivalence studies also help to evaluate the therapeutic comparison of tested drugs (pharmaceutical equivalents or pharmaceutical alternatives). The importance of bioequivalence studies is increasing day by day due to the large availability generic brands in market and their consumptions. (Vetchý et al., 2007). Metabolic profiles can changes the pharmacokinetics of the drugs, so bioequivalence studies also help in study and comparison of metabolism of drug in different population. (Srinivas, N.R. 2009).
In bioequivalence study based on pharmacokinetic parameters and pharmacodynamics parameters.Pharmacokinetic is "the study of the action of drugs within the body, which can, in many respects, be envisioned more accurately as the actions of the body on an administered drug. It includes studies of the mechanisms of drug absorption, distribution, metabolism, and excretion; onset of action; duration of effect; biotransformation; and effects and routes of excretion of the metabolites of the drug." (Mosby's medical dictionary, 2009). So clinical pharmacokinetics studies are very important
In pharmacokinetic/pharmacodynamic study, drug concentration & metabolic profiles are measured in volunteers for the evaluation of efficacy and safety. These pharmacokinetic studies are performed to examine absorption, distribution, metabolism and excretion of drugs in healthy volunteers and/or patients. It helps in the adjustment of dosage according to disease and genotype of drug metabolizing enzyme & on basis of pharmacokinetic drug interactions. Therefore, it is also important to evaluate individual (healthy/patients) pharmacokinetic parameters to minimize adverse drug effects and increase efficacy of the drug (Clinical pharmacokinetics studies; www.nihs.go.jp).
Montelukast sodium is oral leukotriene receptor antagonist (LTRA). It blocks part of the inflammatory process associated with an asthma attack and thus helps to reduce swelling or constriction of airways. It is also used for the treatment of seasonal allergies. (Lipkovitz et al 2001). It is used as an add-on therapy in the long term management of asthma when treatment with inhaled beta-adrenoceptor stimulants and corticosteroids.
Peak plasma concentrations of montelukast are achieved in 3 to 4 hours after oral doses. The mean oral bioavailability is 64%. Montelukast is more than 99% bound to plasma proteins. It is extensively metabolized in the liver by cytochrome P450 isoenzymes CYP3A4, CYP2A6, and CYP2C9, and is excreted principally inthe faeces via the bile (Martindale, the complete drug refrence).
Different gender difference studies were done but it was concluded that it did not affect the pharmacokinetics of montelukast. (Haiyng et al. 1996). It is category B drug and is safe to give pregnant woman. If montelukast is given with Phenobarbital, serum concentration of montelukast will decrease, so dose adjustment is necessary if administered with Phenobarbital (Holland et al.1998).
OBJECTIVE OF THE STUDY:
The main objective of the study is to:-
The purpose of this study is evaluate the bioequivalence of single dose of 10mg montelukast tablet of a locally manufactured locally as test formulation ( T 10 mg) with a reference formulation R (SingularÂ® 10 mg, MERCK SHARP & DHOME).
Compare the pharmacokinetic parameters of both test and reference formulation.
Although several pharmacokinetic studies of montelukast have been published, only few studies are done on bioequivalence (Sripalakit., 2010, Knorr et al.,2010). The present study will be done to determine the pharmacokinetic parameters of two brands of montelukast tablets in fasting, healthy human volunteers belonging to Pakistan for the first time. In this way we will be able to determine concentration of montelukast and check effects of geonetic factors on the pharmacokinetics.These parameters will be statistically compared to assess the bioequivalence between the two brands.
Another the concern of this study is cost-effectiveness. As Singulair, is selling at high price in Pakistan, so by this bioequivalence study it can be ensured that locally manufactured drugs produce the same effects at low price rate as Singuilar do.