title: 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.
authors.affiliation: Department of Pharmacology, PGIMER, Chandigarh, India.
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authors.lastname: Shafiq
authors.affiliation: Department of Pharmacology, PGIMER, Chandigarh, India.
authors.forename: S
authors.initials: S
authors.lastname: Rajagopalan
authors.affiliation: Pharmacokinetics and Metabolism Division, Central Drug Research Institute, Lucknow, India.
authors.forename: H N
authors.initials: HN
authors.lastname: Kushwaha
authors.affiliation: Department of Pharmacology, PGIMER, Chandigarh, India.
authors.forename: N
authors.initials: N
authors.lastname: Mittal
authors.affiliation: IPCA Laboratories Ltd., Mumbai, Maharashtra, India.
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authors.lastname: Chandurkar
authors.affiliation: Department of Internal Medicine, PGIMER, Chandigarh, India.
authors.forename: A
authors.initials: A
authors.lastname: Bhalla
authors.affiliation: Department of Pharmacology, PGIMER, Chandigarh, India.
authors.forename: S
authors.initials: S
authors.lastname: Kaur
authors.affiliation: Department of Pharmacology, PGIMER, Chandigarh, India.
authors.forename: P
authors.initials: P
authors.lastname: Pandhi
authors.affiliation: Department of Anaesthesia Incharge, Critical Care, PGIMER, Chandigarh, India.
authors.forename: G D
authors.initials: GD
authors.lastname: Puri
authors.affiliation: Department of Pharmacology, PGIMER, Chandigarh, India.
authors.forename: S
authors.initials: S
authors.lastname: Achuthan
authors.affiliation: IPCA Laboratories Ltd., Mumbai, Maharashtra, India.
authors.forename: A
authors.initials: A
authors.lastname: Pareek
authors.affiliation: Pharmacokinetics and Metabolism Division, Central Drug Research Institute, Lucknow, India.
authors.forename: S K
authors.initials: SK
authors.lastname: Singh
authors.affiliation: Clinical and Experimental Medicine, Central Drug research Institute, Lucknow, India.
authors.forename: J S
authors.initials: JS
authors.lastname: Srivastava
authors.affiliation: Clinical and Experimental Medicine, Central Drug research Institute, Lucknow, India.
authors.forename: S P S
authors.initials: SP
authors.lastname: Gaur
authors.affiliation: Department of Pharmacology, PGIMER, Chandigarh, India.
authors.forename: S
authors.initials: S
authors.lastname: Malhotra