Using deconvolution to understand the mechanism for variable plasma concentration-time profiles after intramuscular injection

To introduce better antibiotics for the treatment of some infectious diseases in sheep and to expand the range of antibiotics available for veterinary medicine, pharmacokinetics of two antibiotics marbofloxacin (MBX) and trovafloxacin (TVX) were investigated in sheep after intramuscular injection. Variable and irregular plasma concentration-time profiles were observed for TVX but not for MBX. To understand the mechanism of this phenomenon, intravenous studies were performed for both drugs and data were analyzed using a population approach. Deconvolution was then performed using various approaches to obtain absorption profiles of both drugs in sheep after intramuscular injection. The Loo-Riegelman and staircase deconvolution function methods were found to provide more reliable estimates of absorption rate than the Spath-spline and B-spline constraining break points deconvolution methods. The absorption profiles resulting from deconvolution indicated a zero-order absorption process for TVX and a first-order process for MBX. Precipitation of TVX at the injection site was suspected to cause the pseudo zero-order absorption. This hypothesis was supported by the observation of crystalline deposits of TVX in sheep meat after direct injection, using reflectance confocal microscopy. Refereed/Peer-reviewed