gms | German Medical Science

Aim: Individualized therapies have gained growing interest in oncology. Pharmacogenetic and pharmacogenomic approaches are often proposed to select the best individual treatment for the patient. However, appropriate drug dosing is also crucial for an effective and safe therapy. In oncology, the dosage of anticancer drugs is usually adapted to the patient´s body surface area (BSA). Although many studies have shown that PK/PD variability is not sufficiently controlled by BSA-based dosing more individualized dose adaptation strategies are not frequently used in clinical routine so far. Moreover, there is a lack of large, prospective trials investigating their efficacy.

Method: Two recent examples of novel PK/PD model-based individualization strategies are presented.

Results: Neutropenia is a frequent and severe adverse event in patients receiving paclitaxel. In order to evaluate the efficacy of a pharmacokinetic (PK) dosing approach for paclitaxel, a randomized controlled study is currently being performed (CEPAC-TDM study). The time above a paclitaxel threshold concentration of 0.05 µmol/L (T_c>0.05) is used as target PK parameter for dose adaptation to reduce paclitaxel-related severe neutropenia. In the study, individual T_c>0.05 values are estimated based on published PK models of paclitaxel [1] by using the software NONMEM^®. Since many clinicians are not familiar with the use of NONMEM^®, an Excel^®-based dosing tool was developed providing comparable parameter estimates and facilitating dose adjustment of paclitaxel in clinical routine.

Biomarkers as measures for the pharmacodynamic (PD) response to a therapeutic intervention may identify potential responders as well as patients at risk for severe toxicity. Therefore, the integration of biomarkers into PK/PD models offers an interesting future perspective for individualization. This approach has been investigated for sunitinib in healthy volunteers [2] and patients with metastatic colorectal cancer (C-II-005 study). The concentration-time profiles of sVEGFR-2 and sVEGFR-3 as circulating biomarkers could be well described by indirect response models. The extent of biomarker response in patients and healthy volunteers was comparable. Time to progression (TTP) was correlated with pharmacokinetics.

Conclusion: In summary, novel approaches for dose individualization in oncology include the development of easy-to-use dosing tools and the integration of circulating biomarkers and clinical endpoints as PD markers into PK/PD models.