PK/PD OF MOLECULAR-TARGETING DRUGS

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Abstract

Pharmacokinetics (PK) and pharmacodynamics (PD) are frameworks to quantitatively describe the dose exposure–response (efficacy and safety) relationships. PK/PD provides an important rationale for dose setting of molecular targeting drugs to which the empiric MTD paradigm is not applicable.

The dosage regimen of trastuzumab was designed to achieve and maintain serum trough concentrations >20 µg/ml. This target concentration was decided based on growth inhibition of human breast cancer cell line in vitro and nude mice xenograft model in vivo. Therefore, neither MTD determination nor dose–response analysis in clinical studies was conducted. A more sophisticated strategy was applied for development of trastuzumab-DM1 (T-DM1), using animal experimental data, population PK/PD modeling and tumor response model. Based on this modeling, early clinical trials of T-DM1 were designed to target the translational pharmacology parameter which is a drug concentration with no tumor growth. PK/PD modeling and simulation together with tumor progression model are expected to be an alternative or complement to the empiric MTD paradigm in early phase, particularly first in human studies for molecular targeting drugs.

The PK/PD concept is also applied to tyrosine kinase inhibitors. In the development of sunitinib, pharmacologically effective concentration was determined by preclinical mice in vivo study which measured time and dose dependency of target receptor phosphorylation and VEGF-induced vascular permeability. The phase 1 clinical trial was designed to find a recommended dose by achievement of the target concentration in plasma (50–100 ng/ml) and relationships with tumor shrinkage response and toxicity. They also measured serum VEGF and sVEGFR2 concentrations as potential biomarkers of drug response. A number of useful evidences on PK/PD (exposure–response) relationships were published for other tyrosine kinase inhibitors; e.g. efficacy of imatinib depended on plasma concentration of imatinib, and toxicity risk of erlotinib rose with increasing erlotinib AUC.

The oncology community needs to pay more attention to PK/PD and clinical pharmacology for development and optimal use of molecular targeting drugs.

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