Population pharmacokinetics of pyrazinamide in elephants M. ZHU* J. N. MASLOW   S. K. MIKOTA à R. ISAZA § F. DUNKER – H. RIDDLE** & C. A. PELOQUIN* ,    *The National Jewish Medical and Research Center, Denver, CO, USA;   Section of Infectious Diseases, VA Medical Center and the Division of Infectious Diseases, University of Pennsylvania, Philadelphia, PA, USA; à Elephant Care International, Waveland, MS, USA; § The Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL, USA; – The San Francisco Zoological Gardens, One Zoo Road, San Francisco, CA, USA; **Riddle Elephant and Wildlife Sanctuary, Greenbriar, AR, USA;    University of Colorado Schools of Pharmacy and Medicine, Denver, CO, USA Zhu, M., Maslow, J. N., Mikota, S. K., Isaza, R., Dunker, F., Riddle, H., Peloquin, C. A. Population pharmacokinetics of pyrazinamide in elephants. J. vet. Phar- macol. Therap. 28, 403–409. This study was undertaken to characterize the population pharmacokinetics (PK), therapeutic dose, and preferred route of administration for pyrazinamide (PZA) in elephants. Twenty-three African (Loxodonta africana) and Asian (Elephas maximus) elephants infected with or in contact with others culture positive for Mycobacterium tuberculosis were dosed under treatment conditions. PZA was dosed daily at 20–30 mg/kg via oral (fasting or nonfasting state) or rectal (enema or suppository) administration. Blood samples were collected 0–24 h postdose. Population PK was estimated using nonlinear mixed effect modeling. Drug absorption was rapid with T max at or before 2 h regardless of the method of drug administration. C max at a mean dose of 25.6 (±4.6) mg/kg was 19.6 (±9.5 lg/mL) for PZA given orally under fasting conditions. Under nonfasting conditions at a mean dose of 26.1 ± 4.2 mg/kg, C max was 25% (4.87 ± 4.89 lg/mL) and area under concentration curve (AUC) was 30% of the values observed under fasting conditions. Mean rectal dose of 32.6 ± 15.2 mg/kg yielded C max of 12.3 ± 6.3 lg/mL, but comparable AUC to PZA administered orally while fasting. Both oral and rectal administration of PZA appeared to be acceptable and oral dosing is preferred because of the higher C max and lower inter-subject variability. A starting dose of 30 mg/kg is recommended with drug monitoring between 1 and 2 h postdose. Higher doses may be required if the achieved C max values are below the recommended 20– 50 lg/mL range. (Paper received 14 February 2005; accepted for publication 28 April 2005) Joel Maslow, ACOS for Research, VA Medical Center (151), University and Woodland Aves., Philadelphia, PA 19104, USA. E-mail: joel.maslow@med.va.gov INTRODUCTION In contrast to other domesticated large mammals for which Mycobacterium bovis is the most common infecting species of the Mycobacterium tuberculosis complex, elephants appear to be at increased risk for infection with M. tuberculosis (TB) a species typically associated with infection in humans (Mikota et al., 2000; Montali et al., 2001). Prior to 1996, only sporadic reports of TB in elephants had appeared in the literature (Mikota et al., 1994, 2000; Montali et al., 2001). However, the identification of M. tuberculosis among elephants of a single herd that resulted in two deaths (Binkley, 1997; Frankel, 1997; Furley, 1997) led to increased interest in this disease. Through a comprehensive program of testing initiated in 1997, a total of 18 of 539 registered US elephants were identified as culture positive for M. tuberculosis as of 2000 (Mikota et al., 2000). Based on the experience gained treating the initial cases of active TB and treating those animals exposed to culture positive animals, the Elephant TB Advisory Panel together with the National Tuberculosis Working Group for Zoo and Wildlife Species (formed in 1997 to address bovine tuberculosis in nondomestic hoofstock) formulated treatment and testing recommendations for elephants. These guidelines, initially pub- lished in 1998 (USDA, 1998) have been updated twice, most recently in 2003 (USDA, 2000, 2003). Using the treatment of TB in humans as a model, multi-drug regimens were established for the treatment in elephants using first-line anti-tuberculous antimicrobials. We have previously reported on the pharmaco- kinetics (PK) of two first-line drugs: isoniazid (INH) and ethambutol (EMB) (Maslow et al., 2005a,b). Pyrazinamide (PZA) is a third antimicrobial considered as a first-line agent in the treatment of TB. While active against M. tuberculosis, M. bovis is inherently resistant to PZA with the exception of M. bovis subsp. caprae that has caused infections in large mammals, including red deer, cattle, and tigers (Prodinger et al., 2002; Lantos et al., 2003). In this report, PK parameters of PZA in elephants were estimated via population modeling under actual treatment conditions. As the optimal route of administration of PZA for elephants is unknown and because some elephants may not J. vet. Pharmacol. Therap. 28, 403–409, 2005. ANTIINFECTANTS Ó 2005 Blackwell Publishing Ltd 403