Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 811-818 |
| Number of pages | 8 |
| Journal | Journal of Antimicrobial Chemotherapy |
| Volume | 60 |
| Issue number | 4 |
| DOIs | |
| State | Published - Oct 2007 |
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Keywords
- Antifolates
- DHFR inhibitors
- JPC2056
- Malaria
- WR99210
ASJC Scopus subject areas
- Pharmacology
- Microbiology
Cite this
Antimalarial pharmacodynamics and pharmacokinetics of a third-generation antifolate - JPC2056 - In cynomolgus monkeys using an in vivo - in vitro model. / Edstein, Michael D.; Kotecka, Barbara M.; Ager, Arba L; Smith, Kirsten S.; Ditusa, Charles A.; Diaz, Damaris S.; Kyle, Dennis E.; Schiehser, Guy A.; Jacobus, David P.; Rieckmann, Karl H.; O'Neil, Michael T.
In: Journal of Antimicrobial Chemotherapy, Vol. 60, No. 4, 10.2007, p. 811-818.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Antimalarial pharmacodynamics and pharmacokinetics of a third-generation antifolate - JPC2056 - In cynomolgus monkeys using an in vivo - in vitro model
AU - Edstein, Michael D.
AU - Kotecka, Barbara M.
AU - Ager, Arba L
AU - Smith, Kirsten S.
AU - Ditusa, Charles A.
AU - Diaz, Damaris S.
AU - Kyle, Dennis E.
AU - Schiehser, Guy A.
AU - Jacobus, David P.
AU - Rieckmann, Karl H.
AU - O'Neil, Michael T.
PY - 2007/10
Y1 - 2007/10
N2 - 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.
AB - 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.
KW - Antifolates
KW - DHFR inhibitors
KW - JPC2056
KW - Malaria
KW - WR99210
UR - http://www.scopus.com/inward/record.url?scp=34548731273&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34548731273&partnerID=8YFLogxK
U2 - 10.1093/jac/dkm280
DO - 10.1093/jac/dkm280
M3 - Article
C2 - 17646199
AN - SCOPUS:34548731273
VL - 60
SP - 811
EP - 818
JO - Journal of Antimicrobial Chemotherapy
JF - Journal of Antimicrobial Chemotherapy
SN - 0305-7453
IS - 4
ER -