Pharmacokinetic study of the novel, synthetic trioxane antimalarial compound 97-78 in rats using an LC-MS/MS method for quantification

Abstract

The present study has been designed to investigate the pharmacokinetic parameters of the novel trioxane antimalarial 97-78 (US Patent 6316493 B1, 2001) in male and female rats after single oral and intravenous administration. The pharmacokinetic profile of 97-78 was investigated in the form of its completely converted metabolite 97-63 after dose administration. Quantification of metabolite 97-63 in rat plasma was achieved using a simple and rapid LC-MS/MS method. The LC-MS/MS method has been validated in terms of accuracy, precision, sensitivity and recovery for metabolite 97-63 in rat plasma. The intra- and interday accuracy (% bias) and precision (% RSD) values of the assay were less than 10% for metabolite 97-63. The chromatographic run time was 4.0 min and the weighted (1/x2) calibration curves were linear over the range 1.56-200 ng/ml. This method was successfully applied for analysis of pharmacokinetic study samples. Maximum plasma concentrations of 97-63 at 47 mg/kg oral administration in male and female rats were 1986.6 ng/ml and 4086.7 ng/ml at time (Tmax) 0.92 h and 0.58 h, respectively. The area under the curve (AUC(0-infinity)), elimination half-life (t(1/2) beta) and mean residence time (MRT) were 4669.98 ng x h/ml, 2.8 h and 4.2 h in male and 11786.0 ng x h/ml, 4.52 h and 4.32 h in female rats respectively. After single oral and intravenous administration of 97-78 to male and female rats significant differences were observed in pharmacokinetic parameters (AUC and t (1/2) beta) for metabolite 97-63.

Rifabutin reduces systemic exposure of an antimalarial drug 97/78 upon co-administration in rats: An in-vivo & in-vitro analysis

“…HPLC elution was carried out in isocratic mode with mobile phase comprising of 80:20 (v/v) ACN (0.1% formic acid) and ammonium acetate buffer (10 mM, pH 4.0) using a Phenomenex C 18 Columbus (50 mm × 2 mm, 5 m particle size) equipped with a security guard cartridge. Separation was achieved at 450 mL/min flow rate with injection volume of 10 mL [13,14]. Processed sample were maintained in auto sampler at 4 C.…”

Development and validation of an LC‐MS/MS method for simultaneous determination of piperaquine and 97‐63, the active metabolite of CDRI 97‐78, in rat plasma and its application in interaction study

“…It has around 50% absolute oral bioavailability. [9] CDRI 97-78 has been found to be safe in healthy human volunteers during single ascending dose safety and pharmacokinetic studies. They also observed that body weight is a significant covariate affecting the clearance of PPQ.…”

“…[3] In a study conducted in Cambodian patients by Hung et al, children were found to have a two-fold higher oral clearance (1.85 L/h/kg) and a shorter terminal half-life (13.5 days) than adults. [9,12] Thus, in the present study, we have developed and validated a simple, sensitive and specific LC-ESI-MS/MS method for the simultaneous quantification of PPQ and 97-63 in 100 μL rat plasma using halofantrine as an internal standard (IS). Viewing the emerging resistance to artemisinin derivatives along the Thailand-Cambodia border, there is a need to develop better alternatives.…”

“…Hence, the pharmacokinetic profile of CDRI 97-78 is described in the form of 97-63. [9] CDRI 97-78 has been found to be safe in healthy human volunteers during single ascending dose safety and pharmacokinetic studies. [10] CDRI 97-78 is predominantly metabolized by rat CYP isoform 3A2 to form 97-63.…”

Single Ascending Dose Safety and Pharmacokinetics of CDRI-97/78: First-in-Human Study of a Novel Antimalarial Drug

“…But 97/78 emerged as lead compound for excellent pharmacological activity in both in vitro and in vivo malarial models. After successful completion of regulatory preclinical studies compound is currently in phase I clinical trials [18, 19]. …”