Intestinal and hepatic contributions to the pharmacokinetic interaction between gamithromycin and rifampicin after single-dose and multiple-dose administration in healthy foals

Abstract

Background: Standard treatment of foals with severe abscessing lung infection caused by Rhodococcus equi using rifampicin and a macrolide antibiotic can be compromised by extensive inhibition and/or induction of drug metabolising enzymes (e.g. CYP3A4) and transport proteins (e.g. P-glycoprotein), as has been shown for rifampicin and clarithromycin. The combination of rifampicin with the new, poorly metabolised gamithromycin, a long-acting analogue of azithromycin and tulathromycin with lower pharmacokinetic interaction potential, might be a suitable alternative.

Objectives: To evaluate the pharmacokinetic interactions and pulmonary distribution of rifampicin and gamithromycin in healthy foals, and to investigate the cellular uptake of gamithromycin in vitro.

Study design: Controlled, four-period, consecutive, single-dose and multiple-dose study.

Methods: Pharmacokinetics and lung distribution of rifampicin (10 mg/kg) and gamithromycin (6 mg/kg) were measured in nine healthy foals using LC-MS/MS. Enzyme induction was confirmed using the 4β-OH-cholesterol/cholesterol ratio. Affinity of gamithromycin to drug transport proteins was evaluated in vitro using equine hepatocytes and MDCKII-cells stably transfected with human OATP1B1, OATP1B3 and OATP2B1.

Results: Rifampicin significantly (P<0.05) increased the plasma exposure of gamithromycin (16.2 ± 4.77 vs. 8.57 ± 3.10 μg × h/mL) by decreasing the total body clearance. Otherwise, gamithromycin significantly lowered plasma exposure of single- and multiple-dose rifampicin (83.8 ± 35.3 and 112 ± 43.1 vs. 164 ± 96.7 μg × h/mL) without a change in metabolic ratio and half-life. Gamithromycin was identified as an inhibitor of human OATP1B1, OATP1B3 and OATP2B1 and as a substrate of OATP2B1. In addition, it was extracted by equine hepatocytes via a mechanism which could be inhibited by rifampicin.

Main limitations: Influence of gamithromycin on pulmonary distribution of rifampicin was not evaluated.

Conclusion: The plasma exposure of gamithromycin is significantly increased by co-administration of rifampicin which is most likely caused by inhibition of hepatic elimination.

Keywords: Rhodococcus equi; drug-drug interaction; gamithromycin; healthy foals; horse; lung distribution; rifampicin.