Mechanistic understanding of translational pharmacokinetic-pharmacodynamic relationships in nonclinical tumor models: a case study of orally available novel inhibitors of anaplastic lymphoma kinase.
The orally available novel small molecules PF06463922 [(10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbonitrile] and PF06471402 [(10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(azeno)pyrazolo[4,3-h][2,5,11]benzoxadiazacyclo-tetradecine-3-carbonitrile] are second-generation anaplastic lymphoma kinase (ALK) inhibitors targeted to both naïve and resistant patients with non-small cell lung cancer (NSCLC) to the first-generation ALK inhibitor crizotinib. The objectives of the present study were to characterize and compare the pharmacokinetic-pharmacodynamic (PKPD) relationships of PF06463922 and PF06471402 for target modulation in tumor and antitumor efficacy in athymic mice implanted with H3122 NSCLC cells expressing a crizotinib-resistant echinoderm microtubule-associated protein-like 4 (EML4)-ALK mutation, EML4-ALK(L1196M). Furthermore, the PKPD relationships for these ALK inhibitors were evaluated and compared between oral administration and subcutaneous constant infusion (i.e., between different pharmacokinetic [PK] profiles). Oral and subcutaneous PK profiles of these ALK inhibitors were adequately described by a one-compartment PK model. An indirect response model extended with a modulator fit the time courses of PF06463922- and PF06471402-mediated target modulation (i.e., ALK phosphorylation) with an estimated unbound EC50,in vivo of 36 and 20 nM, respectively, for oral administration, and 100 and 69 nM, respectively, for subcutaneous infusion. A drug-disease model based on the turnover concept fit tumor growth curves inhibited by PF06463922 and PF06471402 with estimated unbound tumor stasis concentrations of 51 and 27 nM, respectively, for oral administration, and 116 and 70 nM, respectively, for subcutaneous infusion. Thus, the EC50,in vivo to EC60,in vivo estimates for ALK inhibition corresponded to the concentrations required tumor stasis in all cases, suggesting that the pharmacodynamic relationships of target modulation to antitumor efficacy were consistent among the ALK inhibitors, even when the PK profiles with different administration routes were considerably different.
Yamazaki S
，Lam JL
，Zou HY
，Wang H
，Smeal T
，Vicini P
... -
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Translational pharmacokinetic-pharmacodynamic modeling for an orally available novel inhibitor of anaplastic lymphoma kinase and c-Ros oncogene 1.
An orally available macrocyclic small molecule, PF06463922 [(10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbonitrile], is a selective inhibitor of anaplastic lymphoma kinase (ALK) and c-Ros oncogene 1 (ROS1). The objectives of the present study were to characterize the pharmacokinetic-pharmacodynamic relationships of PF06463922 between its systemic exposures, pharmacodynamic biomarker (target modulation), and pharmacologic response (antitumor efficacy) in athymic mice implanted with H3122 non-small cell lung carcinomas expressing echinoderm microtubule-associated protein-like 4 (EML4)-ALK mutation (EML4-ALK(L1196M)) and with NIH3T3 cells expressing CD74-ROS1. In these nonclinical tumor models, PF06463922 was orally administered to animals with EML4-ALK(L1196M) and CD74-ROS1 at twice daily doses of 0.3-20 and 0.01-3 mg/kg per dose, respectively. Plasma concentration-time profiles of PF06463922 were adequately described by a one-compartment pharmacokinetic model. Using the model-simulated plasma concentrations, a pharmacodynamic indirect response model with a modulator sufficiently fit the time courses of target modulation (i.e., ALK phosphorylation) in tumors of EML4-ALK(L1196M)-driven models with EC50,in vivo of 36 nM free. A drug-disease model based on an indirect response model reasonably fit individual tumor growth curves in both EML4-ALK(L1196M)- and CD74-ROS1-driven models with the estimated tumor stasis concentrations of 51 and 6.2 nM free, respectively. Thus, the EC60,in vivo (52 nM free) for ALK inhibition roughly corresponded to the tumor stasis concentration in an EML4-ALK(L1196M)-driven model, suggesting that 60% ALK inhibition would be required for tumor stasis. Accordingly, we proposed that the EC60,in vivo for ALK inhibition corresponding to the tumor stasis could be considered a minimum target efficacious concentration of PF06463922 for cancer patients in a phase I trial.
Yamazaki S
，Lam JL
，Zou HY
，Wang H
，Smeal T
，Vicini P
... -
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