title: Pharmacokinetics and dose-range finding toxicity of a novel anti-HIV active integrase inhibitor.
abstract: Integration of viral DNA into human chromosomal DNA catalyzed by HIV integrase represents the "point of no return" in HIV infection. For this reason, HIV integrase is considered a crucial target in the development of new anti-HIV therapeutic agents. We have discovered a novel HIV integrase inhibitor 1, that exhibits potent antiviral activity and a favorable metabolism profile. This paper reports on the pharmacokinetics and toxicokinetics of compound 1 and the relevance of these findings with respect to further development of this integrase-targeted antiviral agent. Oral administration of compound 1 in Sprague Dawley rats revealed rapid absorption. Drug exposure increased with increasing drug concentration, indicative of appropriate dose-dependence correlation. Compound 1 exhibited suitable plasma half-life, extensive extravascular distribution and acceptable bioavailability. Toxicity studies revealed no compound-related clinical pathology findings. There were no changes in erythropoietic, white blood cell or platelet parameters in male and female rats. There was no test-article related change in other clinical chemistry parameters. In addition, there were no detectable levels of bilirubin in the urine and there were no treatment-related effects on urobilinogen or other urinalysis parameters. The preclinical studies also revealed that the no observed adverse effect level and the maximum tolerated dose were both high (>500mg/kg/day). The broad and significant antiviral activity and favorable metabolism profile of this integrase inhibitor, when combined with the in vivo pharmacokinetic and toxicokinetic data and their pharmacological relevance, provide compelling and critical support for its further development as an anti-HIV therapeutic agent.
authors.affiliation: Center for Drug Discovery and the College of Pharmacy University of Georgia, Athens, GA 30602, USA. Electronic address: vnair@uga.edu.
authors.forename: Vasu
authors.initials: V
authors.lastname: Nair
authors.affiliation: Center for Drug Discovery and the College of Pharmacy University of Georgia, Athens, GA 30602, USA.
authors.forename: Maurice
authors.initials: M
authors.lastname: Okello
authors.affiliation: Center for Drug Discovery and the College of Pharmacy University of Georgia, Athens, GA 30602, USA.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Mishra
authors.affiliation: Biosciences Division, SRI International, Menlo Park, CA 94025, USA.
authors.forename: Jon
authors.initials: J
authors.lastname: Mirsalis
authors.affiliation: Biosciences Division, SRI International, Menlo Park, CA 94025, USA.
authors.forename: Kathleen
authors.initials: K
authors.lastname: O'Loughlin
authors.affiliation: Biosciences Division, SRI International, Menlo Park, CA 94025, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhong
mesh_terms: D000284:Administration, Oral; D000818:Animals; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D019428:HIV Integrase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D008297:Male; D010949:Plasma / Q000737:chemistry; D017207:Rats, Sprague-Dawley
chemical_list: D019428:HIV Integrase Inhibitors
keywords: Antiviral drug development; Integrase; Pharmacokinetics; Toxicokinetics