The Importance Of Bioequivalence

The Importance Of BioequivalenceBioequivalence is specify as the absence of a significant variation in the swan extent to which the active ingredient or active moiety in pharmaceutical equivalent or pharmaceutical alternative become forthcoming at the site of do drugs action when administered at the same hoagie dose on a lower floor similar conditions in an appropriately designed tuition (Huixiao et al., 2009).The importance of bioequivalence studies is increasing due to the large growth of the production and wasting disease of generic product (Vetch et al., 2007). Bioequivalence also assess the relative bioavailability of twain drug products therefore focuses on comparative drug product performance (Mei-Ling et al., 2001). The principle of bioequivalence study is the monitoring of pharmacokinetic and pharmacodynamic parameters after the administration of tested drugs (Vetch et al., 2007). A timeworn pharmacokinetic study is the conventional method for evaluating the pharmacokinetics of a drug in serviceman subjects.Deferiprone (DFP, Ferriprox, Kelfer, L1, CP20) was synthetic hydroxypyridinone iron chelator isolated from legume Mimosa paduca (Clarke and Martell 1992) to be taken orally, and bind iron in conditions of iron overload (Kontoghiorghes, G.J, 1985). Iron was demand to all species and there was no physiologic excretory pathway for this internal element (Andrews, 1999). In conditions of primary iron overload (eg, hemochromatosis) or second-string iron overload (eg, transfusion-dependant thalassemia), accumulation of this potentially toxic element results in massive iron accumulation and lead to generation of toxic step down radical damage (Rund and Rachmilewitz 2005). DFP was used in the treatment of Thalassemia major(ip) and was also used worldwide to treat cancer, leukemia, hemodialysis and other diseases exchangeable detoxification metals, such as aluminum in hemodialysis patients (Paschalidis et al., 1999 Di-Ji et al., 2004). Deferiprone was the worlds first and altogether orally active iron chelating drug, which was effective and inexpensive to synthesize consequently increasing the prospects of making it available to most thalassemia patients in trey world countries who are not currently receiving any form of chelation therapy (Kontoghiorghes et al., 2004).DFP is a bidentate chelator and has a devil pka of 3.6 and 9.9 (Hider and Liu 2003) with strong iron binding properties of pFe3+ 19.6 and pFe2+ 5.6 thus binding it in 31 complex indicating a senior high degree of relative specificity for trivalent iron (Clarke and Martell 1992 Tam et al 2003). It was a water soluble compound with wearition coefficient of 0.11 and has a molecular encumbrance of 139 Da which made them move freely through cell membranes of the body. DFP jailed quickly and completely after oral administration. . Deferiprone appears in germ plasm inwardly 5 to 10 minutes of ingestion and Peak plasma levels achieved inwardly 1 hour after administration. Food reduces the site of absorption except not the extent of absorption thus reducing the peak concentration with Cmax of about 100mol/L in fasting assert and about 85mol/L (Matsui et al 1991 Al-Refaie et al 1995a). Deferiprone is metabolized to the dormant glucuronide that is the predominant form recovered in the urine (James et al., 2001). The drug was eliminated rapidly with a half-life of about 2 hours due to hepatic biotransformation. It was metabolized by glucuronidation and about 90% of the drug excreted in urine as glucuronide. half-life was shorter in healthy subjects of about 1.3 hours than that of thalassemia subjects having 2.3 hours (Stobie et al 1993).Most much occurring side effects are transient gastrointestinal symptoms (GI) such as nausea, vomiting, and abdominal pain (Cohen et al 2003).OBJECTIVEThe purpose of this study was to gauge bioequivalence of new digs formulation of Deferiprone with Ferriprox (Apotex, Canada).MATERIALS AND METHODSMaterialsTwo drug products of deferiprone 500 mg tablet were used for invivo bioequivalence study. One was the test product (Test) manufactured locally and another was the Reference or innovators products. Deferiprone standard was supplied by Assistant medicine Controller, Ministry of Health, Islamabad. Acetonitrile and methanol HPLC grade were purchased from MERCK.Study productsThe test formulations were Ferrinil 500 mg tablet Batch No. , expiry , and the reference product Ferriprox 500 mg tablet Batch No expiry (Apotex INC., Canada).Human subjectsThe study was authorize by the Ethics Committee of BeSt Center, Faculty of Biosciences, University of Veterinary and animate being Sciences, Lahore. Twelve healthy Pakistani male volunteers aged between 18-55 historic period were included in the study. All volunteers were in good health support by physical and clinical laboratory examination including serology, hematology and biochemical test. All volunteers were abstaine d from other drug brainchild and alcoholic preparations three weeks prior to and throughout the study. Those volunteers who had chronic smoking history, alcoholic intake and caffeine intake were excluded.Study designThe study carried out was randomized, two-treatment, two-period, two-sequence, individual(a) dose interbreeding study with two weeks wash-out period. Each volunteer was in fasted state somewhat 10 hours prior to the study. Each volunteer received a single dose of 1000 mg deferiprone with 240 ml of water. Blood samples were collected without delay before and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8 and 12 hours after drug intake. A regulate lunch is consumed after blood sampling at 4 hours. The plasma were separated by centrifugation and stored at -80C.ANALYTICAL METHODThe analytical method was modified by the method of Goddard et al.1990 utilize validated HPL method entropy ANALYSISThe pharmacokinetic parameters of both test and reference drug were compared an d was determined by taking Cmax and Tmax directly from the individual concentration versus time data. Elimination rate constant was determined from log-linear least squared regression of the terminal part of the plasma concentration versus time curve. Half-life was estimated from equation 0.693/Kel. The area under the concentration versus time curve was calculated by linear trapezoidal rule.The comparison of generic product of deferiprone 500 mg with innovators product was assessed using relevant pharmacokinetic parameters, Cmax, Tmax, AUC (0-t) and AUC (0-) and was transformed to logarithmic scale before statistical analysis. The difference of the mean corresponding log Cmax, log AUC(0-t) and log AUC(0-) between the two products will be determined by 2-way analysis of variance (ANOVA) for a crossover design at the significant level of = 0.05. The 90% effrontery interval (CI) (two-one sided test) for the differences of the mean log Cmax, log AUC(0-t) and log AUC(0-) between the tw o products were calculated.The two products are considered to be bioequivalent when 90% CI of the differences of all parameters were within WHO accepted range of 80%-125%.