No abstract

Generic drugs are cost effective alternatives for the brand name drugs and the savings are estimated in the average $8 to $10 billion a year. Over the years the prescription of generic drugs has increased from 19% to 60-70% (1984: 19% & 2009-60-70%). Bioequivalence testing is playing a vital role in generic drug development. But to make a generic drug enter in to a regulated market a company has to meet the stringent criteria in the same way as innovative drugs. But the criterion's set forth by the regulatories are not always very descriptive and entrepreneur friendly. The prevailing fi erce competition also makes the manufacturers to keep low prices. In order to keep the tight price schedule for generic drugs one must have a clear picture on bioequivalence studies from industry perspective. There are some issues constantly faced by the industry for proper conduct of the BA/BE studies.

& A highly sensitive liquid chromatography-tandem mass spectrometry (LC-MS=MS) method was developed and validated for the quantification of venlafaxine (VEN) and its active metabolite O-desmethyl venlafaxine (ODV) in human plasma using fluoxetine as an internal standard. The VEN and ODV were extracted by liquid-liquid extraction using MTBE-n Hexane (60:40), and chromatographed on X-terra RP8 (50 mm  4.6 mm, 5-lm particle size) column eluted with a isocratic mobile phase of 10 mM Ammonium acetate (pH 4.50 AE 0.05) and acetonitrile in 10:90 (v=v). The detection was performed by positive ion electrospray ionization in multiple reactions monitoring mode, monitoring the transitions m=z 278.27! 121.08 and 264.33 ! 57.72 for venlafaxine and O-desmethyl venlafaxine, respectively. The assay was linear over the concentration ranges of 0.100-300.010 ng=mL for VEN and 0.200-600.050 ng=mL for ODV with limits of detection and quantification of 0.050 ng=mL for VEN and 0.100 ng=mL for ODV, respectively. This LC-MS=MS method was validated with Intra-batch and Inter-batch precision 1.65-10.80 for VEN and 1.27-7.08 for ODV, respectively. The Intra-batch and Inter-batch %accuracy was 91.77%-104.39 % for VEN and 95.87%-106.28% for ODV, respectively. This method was successfully applied to a pharmacokinetic study of venlafaxine hydrochloride extended release capsules 150 mg steady-state bioequivalence study.

Circadian variation in the disease activity of rheumatoid arthritis has been established. Several nonsteroidal anti-inflammatory drugs have been studied for their chronokinetic behaviour. Time dependent influence of diazepam on the pharmacokinetics of diclofenac and naproxen has been reported. We report the time dependent influence of diazepam on the pharmacokinetics of ibuprofen in healthy subjects. Either ibuprofen or ibuprofen with diazepam was administered at 10.00 or 22.00 hours to eight healthy volunteers in a randomized crossover study. Serum ibuprofen levels were estimated by high performance liquid chromatography. There was a significant (p < 0.05) increase in mean elimination half life (2.39 +/- 0.42 to 3.59 +/- 0.35 h) following ibuprofen and diazepam administration compared to ibuprofen alone administered at 22.00 hours. The mean clearance of ibuprofen was therefore lowered from 62.7 +/- 8.9 to 41.7 +/- 2.6 ml/h/kg under the influence of diazepam during the night. Such a time dependent influence of diazepam on the pharmacokinetics of ibuprofen may be due to circadian variation in the pattern of protein production in the liver and/or competitive protein binding of the two drugs during the dark period.

A rapid, robust and selective high pressure liquid chromatography–positive electrospray ionization tandem mass spectrometry method has been developed and validated for the quantification of quetiapine (QUE) in human plasma with K2EDTA using oxcarbazepine (IS) as an internal standard. Analyte and internal standard were extracted from human plasma by solid-phase extraction using acetonitrile. The eluted samples were chromatographed on a C18 column by using a 10:75:15v/v mixture of ammonium formate buffer (5 mM, pH 4.50) and acetonitrile and methanol as an isocratic mobile phase at a flow rate of 0.4 mL/min and analyzed by mass spectrometry in the multiple reaction monitoring mode using the respective [M+H]+ions,m/z384.3/253.2 for Quetiapine andm/z253.1/208.1 for the internal standard. The assay exhibited a linear dynamic range of 5.01 - 2501.04 ng/mL for quetiapine in human plasma. Acceptable precision and accuracy were obtained for concentrations over the standard curve range. A run time of 2.5 min for each sample made it possible to analyze 300 patient plasma samples per day. The validated method has been successfully used for the estimation of quetiapine in real time schizophrenia patient’s plasma samples for pharmacokinetic study.