Journal of Veterinary Pharmacology and TherapeuticsVolume 29, Issue 6 p. 581-585 Dose selection and pharmacokinetics of rifampin in elephants for the treatment of tuberculosis C. A. PELOQUIN, C. A. PELOQUIN National Jewish Medical and Research Center, Denver, CO, USA University of Colorado Schools of Pharmacy and Medicine, Denver, CO, USASearch for more papers by this authorJ. N. MASLOW, J. N. MASLOW Section of Infectious Diseases, VA Medical Center and the Division of Infectious Diseases, University of Pennsylvania, Philadelphia, PA, USASearch for more papers by this authorS. K. MIKOTA, S. K. MIKOTA Elephant Care International, Waveland, MS, USASearch for more papers by this authorA. FORREST, A. FORREST Department of Pharmacy Practice, Pharmaceutics & Biostatistics, SUNY-Buffalo Schools of Pharmacy & of Medicine Buffalo, NY, USASearch for more papers by this authorF. DUNKER, F. DUNKER San Francisco Zoological Gardens, San Francisco, CA, USASearch for more papers by this authorR. ISAZA, R. ISAZA Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL, USASearch for more papers by this authorL. R. PEDDIE, L. R. PEDDIE Faria Road, Ventura, CA, USASearch for more papers by this authorJ. PEDDIE, J. PEDDIE Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL, USASearch for more papers by this authorM. ZHU, M. ZHU National Jewish Medical and Research Center, Denver, CO, USASearch for more papers by this author C. A. PELOQUIN, C. A. PELOQUIN National Jewish Medical and Research Center, Denver, CO, USA University of Colorado Schools of Pharmacy and Medicine, Denver, CO, USASearch for more papers by this authorJ. N. MASLOW, J. N. MASLOW Section of Infectious Diseases, VA Medical Center and the Division of Infectious Diseases, University of Pennsylvania, Philadelphia, PA, USASearch for more papers by this authorS. K. MIKOTA, S. K. MIKOTA Elephant Care International, Waveland, MS, USASearch for more papers by this authorA. FORREST, A. FORREST Department of Pharmacy Practice, Pharmaceutics & Biostatistics, SUNY-Buffalo Schools of Pharmacy & of Medicine Buffalo, NY, USASearch for more papers by this authorF. DUNKER, F. DUNKER San Francisco Zoological Gardens, San Francisco, CA, USASearch for more papers by this authorR. ISAZA, R. ISAZA Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL, USASearch for more papers by this authorL. R. PEDDIE, L. R. PEDDIE Faria Road, Ventura, CA, USASearch for more papers by this authorJ. PEDDIE, J. PEDDIE Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL, USASearch for more papers by this authorM. ZHU, M. ZHU National Jewish Medical and Research Center, Denver, CO, USASearch for more papers by this author First published: 02 November 2006 https://doi.org/10.1111/j.1365-2885.2006.00789.xCitations: 10 Joel Maslow, ACOS for Research, VA Medical Center (151), University and Woodland Aves., Philadelphia PA, 19104. Email: [email protected] Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat References Burman, W.J., Gallicano, K. & Peloquin, C.A. (2001) Comparative pharmacokinetics and pharmacodynamics of the rifamycin antibaterials. Clinical Pharmacokinetics, 40, 327–341. Griffith, M.E. & Bodily, H.L. (1992) Stability of antimycobacterial drugs in susceptibility testing. Antimicrobial Agents and Chemotherapy, 36, 2398–2402. Isaza, R. & Ketz, C. (1999) A trunk wash technique for the diagnosis of tuberculosis in elephants. Proceedings of 39th International Symposium of European Zoo and Wildlife Medicine Association, Vienna, Austria, May 12-16. pp. 121–124. Lewerin, S.S., Olsson, S.-L., Eld, K., Roken, B., Ghebremichael, S., Koivula, T., Kallenius, G. & Bolske, G. (2005) Outbreak of Mycobacterium tuberculosis infection among captive Asian elephants in a Swedish zoo. Veterinary Record, 156, 171–175. Maslow, J.N., Mikota, S.K., Zhu, M., Isaza, R., Peddie, L.R., Dunker, F., Peddie, J., Riddle, H. & Peloquin, C.A. (2005a) Pharmacokinetics of isoniazid (INH) in the treatment of Mycobacterium tuberculosis among Asian and African elephants (Elephas maximus and Loxodonta africana). Journal of Veterinary Pharmacology and Therapeutics, 28, 21–28. Maslow, J.N., Mikota, S.K., Zhu, M., Riddle, H. & Peloquin, C.A. (2005b) Pharmacokinetics of ethambutol (EMB) in the treatment of Mycobacterium tuberculosis in Elephants. Journal of Veterinary Pharmacology and Therapeutics, 28, 321–323. Michalak, K., Austin, C., Diesel, S., Bacon, J.M., Zimmerman, P. & Maslow, J.N. (1998) Mycobacterium tuberculosis infection as a zoonotic disease: transmission between humans and elephants. Emerging Infectious Diseases, 4, 283–287. Mikota, S.K., Larsen, R.S. & Montali, R.J. (2000) Tuberculosis in elephants in North America. Zoo Biology, 19, 393–403. Mikota, S.K., Peddie, L., Peddie, J., Isaza, R., Dunker, F., West, G., Lindsay, W.,Larsen, S., Salman, M., Chatterjee, D., Payeur, J.,Whipple, D.,Thoen, C.,Davis, D.S.,Sedgwick, C.,Montali, R.J.,Zicacardi, M. & Maslow, J.N. (2001) Epidemiology and diagnosis of Mycobacterium tuberculosis in captive Asian elephants (Elephas maximus). Journal of Zoo and Wildlife Medicine, 32, 1–16. Nahata, M.C., Morosco, R.S. & Hipple, T.F. (1994a) Effect of preparation method and storage on rifampin concentration in suspensions. Annals of Pharmacotherapy, 28, 182–185. Nahata, M.C., Morosco, R.S. & Hipple, T.F. (1994b) Stability of rifampin in two suspensions at room temperature. Journal of Clinical Pharmacy and Therapeutics, 19, 263–265. Peloquin, C.A. (2002) Therapeutic drug monitoring in the treatment of tuberculosis. Drugs, 62, 2169–2183. Peloquin, C.A., Jaresko, G.S., Yong, C.L., Keung, A.C.F., Bulpitt, A.E. & Jellife, R.W. (1997) Population pharmacokinetic modeling of isoniazid, rifampin, and pyrazinamide. Antimicrobial Agents and Chemotherapy, 41, 2670–2679. Peloquin, C.A., Namdar, R., Singleton, M.D. & Nix, D.E. (1999) Pharmacokinetics of rifampin under fasting conditions, with food, and with antacids. Chest, 115, 12–18. USDA. (2003) Guidelines for the control of tuberculosis in elephants: Policy #21. United States Department of Agriculture, Animal and Plant Health Inspection Service, Animal Care Policies. From the National Tuberculosis Working Group for Zoo and Wildlife Species. Whipple, D.L., Meyer, R.M., Berry, D.F., Jarnagin, J.L. & Payeur, J.B. (1997) Molecular epidemiology of tuberculosis in wild white-tailed deer in Michigan and elephants. Proceedings of the One Hundred First Annual Meeting of the United States Animal Health Association. pp. 543–546, Louisville, KY. Zhu, M., Starke, J.R., Burman, W.J., Steiner, P., Stambaugh, J.J., Ashkin, D., Bulpitt, A.E., Berning, S.E. & Peloquin, C.A. (2002) Population pharmacokinetic modeling of pyrazinamide in children and adults with tuberculosis. Pharmacotherapy, 22, 686–695. Zhu, M., Maslow, J.N., Mikota, S.K., Isaza, R., Dunker, F., Riddle, H. & Peloquin, C.A. (2005) Population pharmacokinetis of pyrazinamide in elephants. Journal of Veterinary Pharmacology and Therapeutics, 28, 403–409. Citing Literature Volume29, Issue6December 2006Pages 581-585 ReferencesRelatedInformation

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 microg/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 microg/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 microg/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 microg/mL range.

We recently described the clinical presentation and treatment of 18 elephants from six herds infected with TB. Treatment protocols and methods varied between herds to include both oral and rectal dosing using multiple drug doses and formulations. In this paper we present information regarding the pharmacokinetics (PK) of isoniazid (INH) in elephants and provide suggestions regarding initial treatment regimens. Forty-one elephants received INH daily by either oral or rectal administration with different formulations. Population PK analysis was performed using Non-linear Mixed Effect Modeling (NONMEM). Results of oral administration indicated that compared with premixed INH solution, the drug exposure was highest with a suspension prepared freshly with INH powder. When INH was concomitantly given as an admixture over food, Tmax was delayed and variability in drug absorption was significantly increased. Compared with oral administration, similar drug exposures were found when INH was dosed rectally. The data generated suggest that a starting dose of 7.5 mg/kg of INH is appropriate for initial TB treatment in elephants when premixed solution is administered directly into the oropharynx or rectal vault and 4 mg/kg are when INH is administered following immediate suspension from powdered form.

The deaths of two Asian elephants (Elephas maximus) in August 1996 led the United States Department of Agriculture to require the testing and treatment of elephants for tuberculosis. From August 1996 to September 1999. Mycobacterium tuberculosis infection was confirmed by culture in 12 of 118 elephants in six herds. Eight diagnoses were made antemortem on the basis of isolation of M. tuberculosis by culture of trunk wash samples; the remainder (including the initial two) were diagnosed postmortem. We present the case histories, epidemiologic characteristics, diagnostic test results, and therapeutic plans from these six herds. The intradermal tuberculin test, enzyme-linked immunosorbent assay serology, the blood tuberculosis test, and nucleic acid amplification and culture are compared as methods to diagnose M. tuberculosis infection in elephants.

Inflammatory bowel disease was diagnosed in a 3-year-old, captive-born, hand-raised, female spider monkey (Ateles geoffroyi). The diagnosis was based on clinical signs, positive-contrast radiographic series, endoscopy, histologic appearance of intestinal biopsy specimens, and the monkey's response to treatment. Treatment consisted of oral administration of prednisone, sulfasalazine, and trimethoprim-sulfamethoxazole. Supportive care included a bland diet and an electrolyte solution given free choice. Although several infective agents were considered, this case illustrates that recurrent enteritis in primates may be noninfectious and may respond to anti-inflammatory agents.