Pharmacodynamics provide critical insight in drug development

CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS

The rational design of novel therapeutic molecules that interact with a well-defined molecular target relies on both specificity and selectivity to achieve a positive therapeutic advantage. Validation of the kinetics of this interaction in the malignant cell following drug administration constitutes the major emphasis of studies in pharmacodynamics. Careful investigation of pharmacokinetics is supplemented by studies in both pharmacodynamics and pharmacogenomics to better understand the success or failure of new therapies. Repetitive sampling of malignant cells in patients with a solid tumor is extremely difficult. An enormous opportunity exists to carefully evaluate these critical molecular events in acute leukemia. Smith and colleagues (page 3669) make a valiant effort to investigate the biologic impact of a new therapeutic agent, CEP-701, in patients with high-risk acute myeloid leukemia (AML).

Activating mutations of the Fms-like tyrosine kinase-3 (FLT-3) in leukemic cells enhance the cell's survival, decrease its ability for differentiation, and promote its proliferation.¹  The mutations found in approximately 20% to 30% of patients with AML are associated with a lower cure rate. Preclinical studies suggest that inhibitors of FLT-3 have the potential for inducing cytotoxicity in leukemic cells harboring these mutations. Furthermore, successful inhibition of FLT-3 kinase improves survival in murine models of leukemia. CEP-701, a chemically synthesized derivative of a fermentation product of Nonomurea longicatena, displays low nanomolar inhibition of specific receptor tyrosine kinases. Thus, this orally bio-available agent might prove to be useful in the treatment of poor-risk AML.

CEP-701 was well tolerated in this phase 1 clinical trial. Despite the limited number of patients, it appears that in vitro resistance of leukemic cells predicts lack of clinical benefit. There is an intriguing observation that serial plasma samples following onset of treatment are capable of decreasing autophosphorylation of FLT-3 exposed ex vivo to leukemic cell lines harboring the mutations. While the authors believe that this ex vivo bioassay represents a surrogate for measuring the persistence of FLT-3 inhibition in the patient, it is equivalent to a bioassay for quantifying the plasma concentration of the actual drug. Expanded clinical trials will enable the authors to determine if this bioassay is a simple surrogate marker for the drug concentration in the plasma or if it actually reflects ongoing FLT-3 inhibition in vivo. An important assessment that must be made using actual leukemic cells from patients will be whether the FLT-3 kinase activity is persistently inhibited within the malignant cells following failure of treatment.

While this phase 1 trial makes a valiant effort to evaluate the pharmacodynamic effects of CEP-701 administration in AML, the objective clinical responses are limited. Specific inhibitors of FLT-3 may potentiate the in vitro effects of other antileukemic agents against malignant cells harboring these mutations.²  New trials will ultimately be necessary to see if CEP-701 (or other similar potent FLT-3 inhibitors) can induce meaningful clinical responses in enhancing the effects of known cytotoxic agents. The importance of pharmacodynamic studies to investigate the FLT-3 kinase activity in the leukemic cells following exposure to CEP-701 cannot be underestimated. Smith et al have shown that effective inhibition of the target enzyme is initially achieved, but we need to know more about the kinetics of inhibition within the malignant cell. Understanding the molecular events associated with clinical failure is key to circumventing this undesirable outcome. Clarification of these issues will enable strategic addition of other specific enzyme inhibitors to enhance molecular synergy in curing more patients with this fatal disease.