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

Abstract

Background. CDRI 97/78 has shown efficacy in animal models of falciparum malaria. The present study is the first in-human phase I trial in healthy volunteers. Methods. The study was conducted in 50 healthy volunteers in a single, ascending dose, randomized, placebo-controlled, double blind design. The dose ranges evaluated were from 80 mg to 700 mg. Volunteers were assessed for clinical, biochemical, haematological, radiographic, and electrocardiographic parameters for any adverse events in an in-house facility. After evaluation of safety study results, another cohort of 16 participants were administered a single oral dose of 200 mg of the drug and a detailed pharmacokinetic analysis was undertaken. Results. The compound was found to be well tolerated. MTD was not reached. The few adverse events noted were of grade 2 severity, not requiring intervention and not showing any dose response relationship. The laboratory and electrocardiographic parameters showed statistically significant differences, but all were within the predefined normal range. These parameters were not associated with symptoms/signs and hence regarded as clinically irrelevant. Mean values of T 1/2, MRT, and AUC0−∞ of the active metabolite 97/63 were 11.85 ± 1.94 h, 13.77 ± 2.05 h, and 878.74 ± 133.15 ng·h/mL, respectively Conclusion. The novel 1,2,4 trioxane CDRI 97/78 is safe and will be an asset in malarial therapy if results are replicated in multiple dose studies and benefit is shown in confirmatory trials.

Antimalaria Drug Development & Pipeline

“…The Central Drug Research Institute, Lucknow, India, is investigating a new chemical enitity (NCE) trioxane CDRI-97/78, currently in Phase I studies. It has 'triaxone core 'and singlet oxygen to yield a peroxide compound [5].…”

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

“…The results of the in-vitro metabolic study were expressed as the % drug remaining, which was calculated as: % Drug remaining = drug conc: after incubation drug conc: at t = 0 × 100 (2) The % plasma protein binding was calculated as, % Plasma protein binding = Drug conc: analyzed at t = 0 Spiked plasma conc: × 100 (3) It has been reported that 97/78 (prodrug) converts into 97/63 (active metabolite) within a few minutes in biological matrices like plasma [15], thus samples were analyzed for the determination of 97/63, post 97/78 oral dose administration alone and with rifabutin in male and female rats. All the results are expressed as mean values ± SEM, n = 4.…”

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

“…[2] Clinically, Tarning et al described the population pharmacokinetics of PPQ in children affected with uncomplicated falciparum malaria by a two-transit compartment absorption model and a three-compartment distribution model. [10] CDRI 97-78 is predominantly metabolized by rat CYP isoform 3A2 to form 97-63. [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] 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. [11] Although, a few methods have been reported for quantification of 97-63, no method is presently available to simultaneously quantify PPQ and 97-63.…”