Antimalarial pharmacodynamics and pharmacokinetics of a third-generation antifolate--JPC2056--in cynomolgus monkeys using an in vivo in vitro model.
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.
Edstein
Michael D
MD
Australian Army Malaria Institute, Gallipoli Barracks, Enoggera, QLD 4051, Australia. mike.edstein@defence.gov.au
Kotecka
Barbara M
BM
Ager
Arba L
AL
Smith
Kirsten S
KS
DiTusa
Charles A
CA
Diaz
Damaris S
DS
Kyle
Dennis E
DE
Schiehser
Guy A
GA
Jacobus
David P
DP
Rieckmann
Karl H
KH
O'Neil
Michael T
MT
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
D000962:Antimalarials