Pharmacokinetics of a Single Oral or Rectal Dose of Concurrently Administered Isoniazid, Rifampin, Pyrazinamide, Ethambutol in Asian Elephants (Elephas maximus)
1Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL, USA; 2Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL, USA; 3Elanco Animal Health, Greenfield, IN, USA
Tuberculosis (TB), caused by Mycobacterium tuberculosis, is a concern in captive Asian elephants (Elephas maximus). Treatment of TB in elephants utilizes multidrug protocols including isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and/or ethambutol (EMB). In this study, a single combined dose of INHa 5 mg/kg, RIFb 10 mg/kg, PZAc 30 mg/kg and EMBd 30 mg/kg was administered orally to six Asian elephants, and a single combined dose of INH, RIF, and PZA was administered rectally to five elephants. Blood samples were collected at 14 time points. PZA and EMB concentrations were determined using validated gas chromatography assays. INH and RIF concentrations were determined using validated high performance liquid chromatography assays. Rectal INH produced an early Tmax. Oral INH produced comparatively lower Cmax but higher AUC values. Oral RIF and oral EMB were well-absorbed, with RIF Cmax values approaching the human normal range and EMB Cmax values at the upper end of the range. Rectal RIF was not absorbed. Rectal PZA produced faster but lower median Cmax values, at the low end of the human normal range. Oral PZA produced comparatively higher Cmax and higher AUC values. Results of this study indicate that currently recommended monitoring times for rectal INH and oral RIF do not provide an accurate assessment of PK parameters for these drugs.1 This study demonstrates notable individual variability indicating that dosing of these medications requires individual elephant monitoring and adjustment. This study provides an update to previous pharmacokinetic studies of these medications in Asian elephants.
a. Isonicotinic Acid Hydrazide, Spectrum Chemical Mfg. Corp., 769 Jersey Ave., New Brunswick, NJ 08901-3605 USA.
b. Rifamycin AMP, Spectrum Chemical Mfg. Corp., 769 Jersey Ave., New Brunswick, NJ 08901-3605 USA.
c. Pyraznamide, Grove Pharmacy, 3050 S. National Ave, Ste 109, Springfield, MO 65804 USA.
d. Ethambutol hydrochloride tablets, USP, West-Ward Pharmaceutical Corp., 401 Industrial Way West, Eatontown, NJ 07724 USA.
The authors thank Gary Jacobson and the staff of the Center for Elephant Conservation. We also thank Feld Entertainment, Inc. for financial support of this research.
1. U.S. Department of Agriculture (USDA). 2008. Guidelines for the control of tuberculosis in elephants 2008. United States Department of Agriculture, Animal and Plant Health Inspection Service, Animal Care Policies.