Abstract
The effect of age dependent pharmacokinetics (PK) on the clinical efficacy of oxytetracycline (OTC) against Bovine Respiratory Disease (BRD) in beef cattle was studied, using a Physiologically Based Pharmacokinetic (PBPK) model. The model includes a bodyweight dependent renal clearance. To mimic/reproduce the long terminal half-live a bone forming tissue compartment was considered. Data for the development, calibration and validation of the model were obtained from public literature. To integrate the PK with the pharmacodynamics (PD) of OTC, Monte Carlo simulations were performed using this PBPK model to predict time-concentration curves for two commonly used dosing regimens of short-acting and long-acting injectable OTC formulations in virtual populations of 5,000 steer calves of 100 kg and 400 kg. These curves were then used to calculate the value of the PKPD index for OTC, which is the ratio of the area under the concentration-time curve for 24 h (AUC24h) over the minimum inhibitory concentration (MIC) of the target pathogen (AUC24h/MIC). The MIC values were for Mannheimia haemolytica, the dose-limiting pathogen for BRD. This integration of PBPK and PD for OTC used for the treatment of BRD in calves indicated that the Probability of Target Attainment (PTA) was sufficient for efficacy in calves of 400 kg, but insufficient for calves of 100 kg, when using a long acting dosing regimen of 20 mg/kg BW, twice, with a 48-h interval. The use of a dosing regimen of 10 mg/kg BW/day for 4 days predicted sufficient PTAs in both age groups.
Highlights
Dose determination for veterinary medicinal products (VMPs) is commonly performed under controlled experimental conditions in an often homogeneous subset of the target population
Clinical field studies are performed that presumably cover a representation of the total target population, and the clinical benefit for the total study population is statistically evaluated against negative and/or positive controls. This approach could still neglect the PK of Physiologically Based Pharmacokinetic (PBPK)/PD of OTC in Cattle specific subpopulations, and does not determine whether or not adjustments to the dosage regimen is required for subpopulations to achieve concentrations that maximise the probability of a positive clinical outcome
Since the renal clearance of OTC is mainly related to the glomerular filtration rate (GFR) and other processes may play a role, we introduced a factor A in order to be able to fit the data on renal clearance found in literature according to Equation 12
Summary
Dose determination for veterinary medicinal products (VMPs) is commonly performed under controlled experimental conditions in an often homogeneous subset of the target population. Such studies do not normally address the effects of important factors that can influence the pharmacokinetics (PK), such as age, production stage, health status, or breed. Gorden et al [3] showed that meloxicam persisted at higher concentrations in the plasma for longer in post-partum vs mid-lactation dairy cows This difference was shown to be caused by a 2-fold lower hepatic clearance in post-partum cows [4] and may, according to the authors, necessitate the adjustment of dose and/or withdrawal period (WP). Howard et al [6] studied different pig breeds and found significant differences in clearance and volume of distribution for i.v. administered flunixin meglumine, and in AUC for i.v. administered oxfendazole, indicating differences in hepatic drug clearance
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