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Interindividual variability in plasma concentrations after systemic exposure of swine to dietary doxycycline supplied with and without paracetamol: A population pharmacokinetic approach¹

J. R. E. del Castillo^*,2, V. Laroute^*, P. Pommier, C. Zémirline, A. Keïta, D. Concordet^* and P.-L. Toutain^*,3

^* UMR 181 de physiopathologie et toxicologie expérimentales INRA/ENVT, 23 Chemin des Capelles, F-31076, Toulouse cedex 3, France; and Centre Technique des Productions Animales et agro-alimentaires, Rond point du Zoopole, BP 7, F-22440 Ploufragan, France; and and Laboratoires Sogéval. 200, avenue de Mayenne, BP 2227, F-53022 Laval cedex 9, France

³ Corresponding author: pl.toutain{at}envt.fr

Anorexigenic substances released during infection may hinder the therapeutic efficacy of in-feed antibiotics. Paracetamol (acetaminophen; PARA) inhibits the anorexia of infection and seems to improve the clinical efficacy of doxycycline (DOX) against bacterial respiratory disease in swine herds. In order to verify whether PARA selectively stimulates intake of DOX-medicated feed in diseased pigs, we documented the pharmacokinetics (PK) of DOX when coadministered with PARA and examined the effect of in-feed PARA on the interindividual variability in plasma concentrations after systemic exposure to in-feed DOX in swine herds with respiratory disease. Systemic exposure to DOX was measured with the area under the curve (AUC) of its plasma concentrations over time. First, a rich-sampling PK study of in-feed and i.v. DOX (10 mg/kg of BW) and PARA (30 and 10 mg/kg of BW, respectively) was performed on 5 pigs. The PK profiles of in-feed DOX were used in mathematical simulations to determine 5 optimal sampling times for the farm-based population PK study. A randomized, blind, parallel PK study was performed in 2 herds with bacterial respiratory disease, where liquid feed was fortified with DOX alone (5 mg·kg of BW^–1·meal^–1) or combined with PARA (15 mg·kg of BW^–1·meal^–1). Medicated meals were given twice, 12 h apart, to group-housed growing pigs (n > 50 pigs·treatment^–1·herd^–1, totaling 215 pigs). Plasma concentrations of DOX and PARA were measured with HPLC. At variance with our expectations, PARA decreased (P = 0.069) mean AUC of in-feed DOX and did not decrease its variability (P > 0.34). Mean AUC of DOX increased with feed intake and with initial exposure to DOX, and was greater in sick animals. Therefore, symptomatic PARA-induced improvement in bacterial respiratory disease control with DOX is more likely caused by its analgesic/antipyretic effects than by its orexigenic effect. Interindividual variation in the AUC of DOX was large in pigs given group medication, even when sufficient feeding space was allowed and the amount of feed offered was greater than their requirements. Therefore, future studies to improve the efficacy of group antibiotic therapy should focus on feeding behavior characteristics as well as biopharmaceutical properties of medicated feeds.

Key Words: acetaminophen • doxycycline • feed supplement • pharmacokinetics • pig • respiratory disease