TABLE 3

Pharmacodynamic parameter estimates of PF06463922 and PF06471402 for ALK phosphorylation by the precursor model in athymic mice implanted with H3122 non–small cell lung carcinomas expressing EML4-ALKL1196M

Precision of the estimates is expressed as S.E. in parentheses. Emax was fixed at unity in all studies. PF06463922 and PF06471402 were administered to animals orally twice daily, 7 hours apart (studies 1 and 3) or continuously via subcutaneous infusion with ALZET osmotic pumps (studies 2 and 4).

ALK InhibitorStudyEC50koutkmdγ
ng/mlh−1
PF064639221a581.80.0211.1
(14)(0.4)(0.003)(0.07)
21620.0100.0111.3
(44)(0.0003)(0.003)(0.4)
PF064714023405.00.0120.81
(7)(0.1)(0.001)(0.01)
41400.0400.00621.2
(92)(0.003)(0.0015)(0.3)
  • EC50, drug concentration causing 50% of maximum effect; γ, Hill coefficient; kmd, first-order rate degradation rate constant for a modulator; kout, first-order degradation rate constant.

  • a Values in study 1 are cited from the previous report (Yamazaki et al., 2014).