title: Antimalarial pharmacodynamics and pharmacokinetics of a third-generation antifolate--JPC2056--in cynomolgus monkeys using an in vivo in vitro model.
abstract: OBJECTIVE
  To assess the antimalarial pharmacodynamics and pharmacokinetics of the novel dihydrofolate reductase (DHFR) inhibitor, JPC2056 and its principal active metabolite JPC2067 in cynomolgus monkeys using an in vivo-in vitro model.
  
  
  METHODS
  In a two-phase crossover design, five cynomolgus monkeys were administered a single dose (20 mg/kg) and multiple doses (20 mg/kg daily for 3 days) of JPC2056. Plasma samples collected from treated monkeys were assessed for in vitro antimalarial activity against Plasmodium falciparum lines having wild-type (D6), double-mutant (K1) and quadruple-mutant (TM90-C2A) DHFR-thymidylate synthase (TS) and a P. falciparum line transformed with a Plasmodium vivax dhfr-ts quadruple-mutant allele (D6-PvDHFR). Plasma JPC2056 and JPC2067 concentrations were measured by LC-mass spectrometry.
  
  
  RESULTS
  The mean inhibitory dilution (ID(90)) of monkey plasma at 3 h after drug administration against D6, K1 and TM90-C2A was, respectively, 1253, 585 and 869 after the single-dose regimen and 1613, 1120 and 1396 following the multiple-dose regimen. Less activity was observed with the same monkey plasma samples against the D6-PvDHFR line, with a mean ID(90) of 53 after multiple dosing. Geometric mean plasma concentrations of JPC2056 and JPC2067 at 3 h after drug administration were, respectively, 113 and 12 ng/mL after the single dose and 150 and 17 ng/mL after multiple dosing. The mean elimination half-life of JPC2056 was shorter than its metabolite after both regimens (single dose, 7.3 versus 11.8 h; multiple doses, 6.6 versus 11.1 h).
  
  
  CONCLUSIONS
  The high potency of JPC2056 against P. falciparum DHFR-TS quadruple-mutant lines provides optimism for the future development of JPC2056 for the treatment of malaria infections.
authors.affiliation: Australian Army Malaria Institute, Gallipoli Barracks, Enoggera, QLD 4051, Australia. mike.edstein@defence.gov.au
authors.forename: Michael D
authors.initials: MD
authors.lastname: Edstein
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Kotecka
authors.forename: Arba L
authors.initials: AL
authors.lastname: Ager
authors.forename: Kirsten S
authors.initials: KS
authors.lastname: Smith
authors.forename: Charles A
authors.initials: CA
authors.lastname: DiTusa
authors.forename: Damaris S
authors.initials: DS
authors.lastname: Diaz
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Kyle
authors.forename: Guy A
authors.initials: GA
authors.lastname: Schiehser
authors.forename: David P
authors.initials: DP
authors.lastname: Jacobus
authors.forename: Karl H
authors.initials: KH
authors.lastname: Rieckmann
authors.forename: Michael T
authors.initials: MT
authors.lastname: O'Neil
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001288:Attention; D002851:Chromatography, High Pressure Liquid; D004352:Drug Resistance, Microbial / Q000235:genetics; D006207:Half-Life; D008252:Macaca fascicularis; D008297:Male; D013058:Mass Spectrometry; D021261:Parasitic Sensitivity Tests; D010949:Plasma / Q000737:chemistry; D010963:Plasmodium falciparum / Q000187:drug effects; D010966:Plasmodium vivax / Q000187:drug effects
chemical_list: D000962:Antimalarials