JAC Advance Access originally published online on July 23, 2007
Journal of Antimicrobial Chemotherapy 2007 60(4):811-818; doi:10.1093/jac/dkm280
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Antimalarial pharmacodynamics and pharmacokinetics of a third-generation antifolate—JPC2056—in cynomolgus monkeys using an in vivo–in vitro model
1 Australian Army Malaria Institute, Gallipoli Barracks, Enoggera, QLD 4051, Australia 2 University of Miami School of Medicine, Miami, Florida, USA 3 Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA 4 Jacobus Pharmaceutical Company, Princeton, New Jersey, USA
Received 28 February 2007; returned 23 April 2007; revised 23 May 2007; accepted 2 July 2007
* Corresponding author. Tel: +61-7-33324930; Fax: +61-7-33324800; E-mail: mike.edstein{at}defence.gov.au
Objectives: 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 (ID90) 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 ID90 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.
Keywords: malaria , antifolates , WR99210 , JPC2056 , DHFR inhibitors