Role of Pharmacokinetic/Pharmacodynamic Biomarkers in Drug Development

Appropriate pharmacokinetic (PK)/pharmacodynamic (PD) biomarkers facilitate proof-of-concept demonstrations for target modulation; enhance the rational selection of an optimal drug dose and schedule; and decision making such as whether to continue or discontinue a drug development project. In addition measurement of PK/PD biomarkers can minimize the uncertainty associated with prediction of drug safety and efficacy as well as reduce the high rate of drug attrition during development.

Pharmacodynamic (mechanism of action) biomarkers can be used to measure acute target inhibition in vivo and potentially for interpreting dose response relationships. Some examples are as follows:

• 1. Candidate RNA transcripts, identified and qualified by using quantitative PCR, can be used as potential pharmacodynamic markers for a selective inhibitor of T cell receptor signaling.
• 2. A computational approach is used at Merrimack Pharmaceuticals to rationally identify pharmacodynamic biomarkers that are the most sensitive indicators of insulin-like growth factor-1 receptor (IGF1-R) antagonism at the molecular level. A detailed mathematical model of the IGF signaling pathway is trained with experimental data, and validated by comparing the predicted activity of a novel IGF1-R antagonist on downstream ERK and AKT phosphorylation to in vitro experimental results. Using the validated model, a portfolio of sensitivity analyses and simulations is generated that highlights the key proteins regulating the IGF pathway and identifies the biomarkers that characterize the efficacy of the antagonist.
• 3. Scientists at Bristol-Myers Squibb have predicted active drug plasma concentrations achieved in cancer patients by pharmacodynamic biomarkers. Using human tumor xenografts grown in nude mice, they have determined the in vivo pharmacodynamic response at efficacious doses of cetuximab - an anti-EGFR chimeric mouse/human MAb that has been approved for the treatment of advanced colon cancer (Luo et al. 2005). Three pharmacodynamic end points were evaluated: tumoral phospho-EGFR, tumoral mitogen-activated protein kinase (MAPK) phosphorylation, and Ki67 expression. A pharmacokinetic/pharmacodynamic model was established and predicted that the plasma concentration of cetuximab required to inhibit 90% of phospho-EGFR was 67.5 mug/mL. CONCLUSIONS: Phospho-EGFR/phospho-MAPK could be useful clinical biomarkers to assess EGFR inhibition by cetuximab.
• 4. Pharmacokinetic-pharmacodynamic correlations and biomarkers have been used for the development of COX-2 inhibitors. This solves a major problem in the development of COX inhibitors, where it is difficult to predict the appropriate dosing regimen for the treatment of chronic inflammatory pain, based upon information from preclinical studies and early clinical trials. Endogenous mediators of inflammation might be used as biomarkers for the analgesic effect and safety assessment. Such a biomarker can be an intermediate step between drug exposure and response. COX-2 inhibition, as determined by modelling of prostaglandin E2 (PGE2) levels in the whole blood assay in vitro can be used as a biomarker to predict drug effects (analgesia) in humans.
• 5. Pharmacodynamic biomarkers are used to measure receptor occupancy as a guide to the determination of optimal dose. Most direct estimate, however, is provided by ligand-displacement imaging using PET.