Liquid chromatographic tandem mass spectrometric validated method for pharmacokinetic estimation of flecainide in human plasma

Abstract

A sensitive high throughput LC/MS/MS method fully validated as per USFDA guidelines is described for pharmacokinetic estimation of flecainide in human plasma using loperamide as the internal standard. Plasma samples were monitored by cation exchange solid phase extraction achieving 78.6% extraction efficiency (mean recovery) followed by chromatographic separation on a PurospherStar RP-18e column. Detection was carried out on an API positive ESI by MRM transitions m/z 415.2/301.1 and 477.3/266.3 for flecainide and loperamide respectively. High sensitivity of 1.17ng/ml, dynamic linearity of 1.17–396.75  ng/ml and short run time within 3 minutes are other interesting aspects of this new bioanalytical method. This method was successfully applied to a pharmacokinetic study with 100mg tablet flecainide administered in Indian population for the first time. A randomized, single dose, two sequence, cross over study design was used to evaluate bioequivalence on 40 healthy male fasted volunteers and blood samples were collected up to 96 hours post dose. Noncompartmental pharmacokinetic analysis was used to evaluate AUC_0-t, AUC_0-inf, C_max, T_max, T_1/2 and λz scaled on a 90% confidence interval approach. Average bioequivalence results showed ratios of least square means and its 90% CIs for ln-transformed C_max, AUC_0-t and AUC_0-inf for flecainide were 99.99 (95.21–104.99) %, 98.27(93.89–102.86)% and 98.08(93.68–102.68)% respectively. Both the test and reference products were closely comparable in terms of rate and extent to which the drugs access the systemic circulation.

Keywords::

• Bioanalytical
• LC-MS/MS method validation
• flecainide tablet
• pharmacokinetics
• bioequivalence

Acknowledgement

The authors would like to thank Ranbaxy Laboratories Ltd. for giving permission to write this paper and to use in-house data. A special thanks to our in-house formulation department for providing the formulation and Clinical Pharmacology Unit, Ranbaxy Research Laboratories, Majeedia Hospital, Delhi for conducting the clinic.

Declaration of interest: The authors report no conflicts of interest.