Pharmacokinetic–pharmacodynamic integration and modelling of oxytetracycline administered alone and in combination with carprofen in calves

Abstract

The pharmacokinetic (PK) and pharmacodynamic (PD) profiles of oxytetracycline were investigated, when administered both alone and in the presence of carprofen, in healthy calves. The study comprised a four treatment, four sequences, and four period cross-over design and used a tissue cage model, which permitted the collection of serum, inflamed tissue cage fluid (exudate) and non-inflamed tissue cage fluid (transudate). There were no clinically relevant differences in the PK profile of oxytetracycline when administered alone and when administered with carprofen. PK–PD integration was undertaken for a pathogenic strain of Mannheimia haemolytic (A1 76/1), by correlating in vitro minimum inhibitory concentration (MIC) and time-kill data with in vivo PK data obtained in the cross-over study. Based on in vitro susceptibility in cation adjusted Mueller Hinton Broth (CAMHB) and in vivo determined PK variables, ratios of maximum concentration (Cmax) and area under curve (AUC) to MIC and time for which concentration exceeded MIC (T>MIC) were determined. The CAMHB MIC data satisfied integrated PK/PD relationships predicted to achieve efficacy for approximately 48h after dosing; mean values for serum were 5.13 (Cmax/MIC), 49.3h (T>MIC) and 126.6h (AUC96h/MIC). Similar findings were obtained when oxytetracycline was administered in the presence of carprofen, with PK–PD indices based on MIC determined in CAMHB. However, PK–PD integration of data, based on oxytetracycline MICs determined in the biological fluids, serum, exudate and transudate, suggest that it possesses, at most, limited direct killing activity against the M. haemolytica strain A1 76/1; mean values for serum were 0.277 (Cmax/MIC), 0h (T>MIC) and 6.84h (AUC96h/MIC). The data suggest that the beneficial therapeutic effects of oxytetracycline may depend, at least in part, on actions other than direct inhibition of bacterial growth.