title: Pharmacokinetics of the antimalarial drug, AQ-13, in rats and cynomolgus macaques.
abstract: The purpose of this study was to evaluate the bioavailability and pharmacokinetics of a new antimalarial drug, AQ-13, a structural analog of chloroquine (CQ) that is active against CQ-resistant Plasmodium species, in rats and cynomolgus macaques. Sprague-Dawley rats (n = 4/sex) were administered a single dose of AQ-13 intravenously (i.v.) (10 mg/kg) or orally (20 or 102 mg/kg). Blood and plasma samples were collected at several timepoints. AQ-13 achieved C(max) after oral administration at approximately 3 to 4 h and could be detected in blood for 2 to 5 days after oral administration. The ratio of area under the curve (AUC) values at the high and low dose for AQ-13 deviated from an expected ratio of 5.0, indicating nonlinear kinetics. A metabolite peak was noted in the chromatograms that was identified as monodesethyl AQ-13. Oral bioavailability of AQ-13 was good, approximately 70%. The pharmacokinetics of AQ-13 was also determined in cynomolgus macaques after single (i.v., 10 mg/kg; oral, 20 or 100 mg/kg) and multiple doses (oral loading dose of 50, 100, or 200 mg/kg on first day followed by oral maintenance dose of 25, 50, or 100 mg/kg, respectively, for 6 days). The AUC and C(max) values following single oral dose administration were not dose proportional; the C(max) value for AQ-13 was 15-fold higher following an oral dose of 100 mg/kg compared to 20 mg/kg. Monodesethyl AQ-13 was a significant metabolite formed by cynomolgus macaques and the corresponding C(max) values for this metabolite increased only 3.8-fold over the dose range, suggesting that the formation of monodesethyl AQ-13 is saturable in this species. The bioavailability of AQ-13 in cynomolgus macaques following oral administration was 23.8% for the 20-mg/kg group and 47.6% for the 100-mg/kg group. Following repeat dose administration, high concentrations of monodesethyl AQ-13 were observed in the blood by day 4, exceeding the AQ-13 blood concentrations through day 22. Saturation of metabolic pathways and reduced metabolite elimination after higher doses are suggested to play a key role in AQ-13 pharmacokinetics in macaques. In summary, the pharmacokinetic profile and metabolism of AQ-13 are very similar to that reported in the literature for chloroquine, suggesting that this new agent is a promising candidate for further development for the treatment of chloroquine-resistant malaria.
authors.affiliation: SRI International, Menlo Park, California 94025, USA.
authors.forename: Sandhya
authors.initials: S
authors.lastname: Ramanathan-Girish
authors.forename: Paul
authors.initials: P
authors.lastname: Catz
authors.forename: Moire R
authors.initials: MR
authors.lastname: Creek
authors.forename: Benjamin
authors.initials: B
authors.lastname: Wu
authors.forename: David
authors.initials: D
authors.lastname: Thomas
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Krogstad
authors.forename: Dibyendu
authors.initials: D
authors.lastname: De
authors.forename: Jon C
authors.initials: JC
authors.lastname: Mirsalis
authors.forename: Carol E
authors.initials: CE
authors.lastname: Green
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000097:blood* / Q000378:metabolism; D019540:Area Under Curve; D001682:Biological Availability; D001798:Blood Proteins / Q000378:metabolism; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008252:Macaca fascicularis; D008297:Male; D008657:Metabolic Clearance Rate; D011485:Protein Binding; D011804:Quinolines / Q000008:administration & dosage / Q000097:blood* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C434089:(N1-(7-chloro-quinolin-4yl)-3-(N3,N3-diethylamino)propylamine) dihydrochloride trihydrate; D000962:Antimalarials; D001798:Blood Proteins; D011804:Quinolines