Antimalarial pharmacodynamics and pharmacokinetics of a third-generation antifolate - JPC2056 - In cynomolgus monkeys using an in vivo - in vitro model

Michael D. Edstein, Barbara M. Kotecka, Arba L Ager, Kirsten S. Smith, Charles A. Ditusa, Damaris S. Diaz, Dennis E. Kyle, Guy A. Schiehser, David P. Jacobus, Karl H. Rieckmann, Michael T. O'Neil

Research output: Contribution to journalArticle

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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 languageEnglish (US)
Pages (from-to)811-818
Number of pages8
JournalJournal of Antimicrobial Chemotherapy
Volume60
Issue number4
DOIs
StatePublished - Oct 2007

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Folic Acid Antagonists
Macaca fascicularis
Antimalarials
Pharmacokinetics
Plasmodium falciparum
Haplorhini
Plasmodium vivax
Pharmaceutical Preparations
Cross-Over Studies
Malaria
Half-Life
Mass Spectrometry
Alleles
In Vitro Techniques
Infection

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 journalArticle

Edstein, MD, Kotecka, BM, Ager, AL, Smith, KS, Ditusa, CA, Diaz, DS, Kyle, DE, Schiehser, GA, Jacobus, DP, Rieckmann, KH & O'Neil, MT 2007, 'Antimalarial pharmacodynamics and pharmacokinetics of a third-generation antifolate - JPC2056 - In cynomolgus monkeys using an in vivo - in vitro model', Journal of Antimicrobial Chemotherapy, vol. 60, no. 4, pp. 811-818. https://doi.org/10.1093/jac/dkm280
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. / Antimalarial pharmacodynamics and pharmacokinetics of a third-generation antifolate - JPC2056 - In cynomolgus monkeys using an in vivo - in vitro model. In: Journal of Antimicrobial Chemotherapy. 2007 ; Vol. 60, No. 4. pp. 811-818.
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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.",
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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

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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

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