The pharmacokinetics of a single oral or rectal dose of concurrently administered isoniazid, rifampin, pyrazinamide, and ethambutol in Asian elephants (Elephas maximus)

Abstract

Tuberculosis, caused by Mycobacterium tuberculosis, is a disease of concern in captive Asian elephants (Elephas maximus). Treatment for tuberculosis in elephants utilizes multidrug protocols combining isoniazid, rifampin, pyrazinamide, and/or ethambutol. In this study, a single, coformulated dose of isoniazid 5 mg/kg, rifampin 10 mg/kg, pyrazinamide 30 mg/kg, and ethambutol 30 mg/kg was administered orally to six Asian elephants, and rectally to five elephants using a cross-over design. Blood samples were collected serially over 24 h. Pyrazinamide and ethambutol concentrations were determined using validated gas chromatography assays. Isoniazid and rifampin concentrations were determined using validated high-performance liquid chromatography assays. Rectal isoniazid produced an earlier Tmax compared with oral administration. Oral isoniazid resulted in a comparatively lower Cmax , but higher AUC values compared with rectal isoniazid. Oral rifampin and oral ethambutol were well absorbed while rectal rifampin was not. Oral pyrazinamide produced comparatively higher Cmax and AUC values compared with rectal pyrazinamide. Results of this study indicate that currently recommended therapeutic monitoring sample collection times for rectal isoniazid and oral rifampin do not provide an accurate assessment of exposure for these drugs. This study demonstrates notable individual variability, indicating that dosing of these medications requires individual monitoring and provides additional information to guide the clinician when treating elephants.

Pharmacokinetic Evidence from the HIRIF Trial To Support Increased Doses of Rifampin for Tuberculosis

“…The standard range was 0.05 to 50 g/ml, the overall precision was 1.12 to 10.29% (coefficient of variation), and the quality control sample precision was 6.33 to 7.57%. Isoniazid (HPLC UV, 0.4 to 20 g/ml), pyrazinamide (gas chromatography [GC]/MS, 5 to 100 g/ml), and ethambutol (GC/MS, 0.2 to 10 g/ml) concentrations were determined with validated assays (11). Phoenix v6.2 (Certara LP, Princeton, NJ) was used for noncompartmental analysis, and JMP 10 (SAS Institute, Cary, NC) and Stata/SE 14.2 (StataCorp LP, College Station, TX) were used for statistical analysis.…”

Population pharmacokinetics of rifampin in the treatment of Mycobacterium tuberculosis in Asian elephants

“…The median C max for the combined subsets was 6.07 lg/mL, which is below the targeted 8-24 lg/mL range. Subsets 2 and 3 consisted of TDM data which may not have captured the C max for multiple reasons: (i) a limited sampling strategy, (ii) data from the intensive data set (Subset 1) indicate C max is best captured between 6 and 8 h rather than 2 to 3 h, and (iii) multiple oral formulations were used which affects bioavailability (Brock et al, 2014). The median C max of 7.07 from Subset 1 more accurately reflects the C max experienced with current dosing but also is below the targeted range.…”

“…Rifampin was administered orally at 10 mg/kg to six elephants and rectally at 10 mg/kg to five of these elephants both as a single dose. Elephants were allowed food and water ad libitum (Brock et al, 2014).…”

“…Currently, elephants are treated with the same drug regimen used in humans, with doses based on linear scaling of weight (USDA, 2008). Only recently have pharmacokinetic studies been conducted to determine the concentration-time profiles and pharmacokinetic parameters associated with the doses used in the treatment of TB in elephants (Maslow et al, 2005a,b;Zhu et al, 2005;Peloquin et al, 2006;Brock et al, 2014). At the time of this writing, only one previous paper exists which examines the population pharmacokinetics of rifampin in elephants (Peloquin et al, 2006).…”

Treatment for active tuberculosis in giraffe (Giraffa camelopardalis) in a Zoo and potential consequences for public health – Case report

“…In the absence of relevant information, the treatment schedule designed for elephants was applied [12,13,14]. The cost of the planned treatment was about 1,750 EUR.…”