A PRELIMINARY ANALYSIS OF PROLONGED ABSORPTION RATE OF PONAZURIL IN RED-FOOTED TORTOISES, CHELONOIDIS CARBONARIA.

Coccidial disease is significant in tortoises; Testudines intranuclear coccidiosis (TINC), caused by an unnamed coccidia, causes high mortality in diverse tortoise species. There is a lack of information on anticoccidial drugs in tortoises. The drug ponazuril has demonstrated efficacy in treating mammals infected with similar coccidial disease. Previous empirical use of ponazuril in TINC cases suggests that it may be an effective treatment. In this study, 20 mg/kg of ponazuril was orally administered to tortoises with the goal of achieving blood concentrations known to be effective for anticoccidial therapy in mammals. Ponazuril was measured in tortoise plasma, and noncompartmental analyses of pharmacokinetic parameters were attempted. Ponazuril in these tortoises did not achieve the desired concentrations known to be effective for anticoccidial treatment in mammals. Tortoises showed prolonged oral absorption, and despite sampling for 168 hr (1 wk), a terminal elimination rate constant and half-life were not able to be determined. Additional studies are needed to fully characterize ponazuril pharmacokinetics in red-footed tortoises. The optimal dose for treating TINC remains to be determined.

Factors associated with variability in rifampin plasma pharmacokinetics and the relationship between rifampin concentrations and induction of efavirenz clearance.

STUDY OBJECTIVES: To identify factors associated with variability in rifampin plasma pharmacokinetics and explore the relationship between rifampin pharmacokinetics and change in efavirenz plasma pharmacokinetics with rifampin coadministration. METHODS: In this randomized, cross-over study, 12 healthy volunteers received either efavirenz 600 mg/day or efavirenz 600 mg with rifampin 600 mg/day for 8 days. After a washout period of at least 2 weeks, subjects crossed over to the alternate 8-day regimen. Samples were obtained for pharmacokinetic assessment on day 8 of each study cycle. Drugs concentrations were determined by a validated high-performance liquid chromatography. Pharmacokinetic parameters were calculated using noncompartmental analysis. Multivariate analysis was used to examine factors associated with rifampin pharmacokinetics. Spearman correlation analysis was used to investigate relationship between rifampin pharmacokinetics and change in efavirenz plasma pharmacokinetics with rifampin coadministration. MEASUREMENTS AND MAIN RESULTS: Of 11 evaluable subjects, the median interquartile range, rifampin peak concentration (Cmax) , area under the concentration-time curve (AUC0-24 hour ), and weight-normalized clearance were 8.9 (7.3-13.8) µg/ml, 48.8 (29.6-67.4) µg·h/ml, and 0.19 (0.11-0.29) L/h/kg, respectively. Solute carrier organic anion transporter family member 1B1 (SLCO1B1) c.388A→G and SLCO1B1 c.463C→A polymorphisms jointly had significant effect on rifampin Cmax (R(2)  = 0.75). Male sex and SLCO1B1 c.463C→A polymorphism together influenced rifampin AUC0-24 hour (R(2)  = 0.52) and weight-normalized clearance (R(2)  = 0.65). All four volunteers with rifampin Cmax less than 8 µg/ml (lower end of the normal range) had c.463CA genotype. Rifampin Cmax and AUC0-24 hour had no significant relationship with the efavirenz AUC0-24 hour ratio or weight-normalized clearance ratio in the presence versus absence of rifampin (p>0.05). CONCLUSIONS: Men with the SLCO1B1c.463CA genotype are at increased risk of lower rifampin plasma exposure. However, plasma rifampin concentrations did not correlate with the extent of induction of efavirenz clearance by rifampin during coadministration.