PBPK Assists with DDI Prediction Without a Rifampin Study for Cobimetinib
Cobimetinib (Cotellic®), approved by the US FDA in 2015, is a kinase inhibitor for treating advanced melanoma. As in the best practice case of ibrutinib, we generally perform physiologically-based pharmacokinetic (PBPK) simulations with model verification based on CYP3A4 strong inhibitor and inducer clinical data. However, with cobimetinib, which is a CYP3A4/UGT2B7 drug, the sponsor had only conducted a study with itraconazole, a strong CYP3A4 inhibitor. There was no rifampin data available to verify the effect of CYP3A4 inducers.
To build the model, the one itraconazole study, along with mass balance, human PK, and in vitro data was used to predict the effects of those inducers and inform the final drug label. By leveraging the Simcyp Simulator and its oncology population file, the effects of CYP3A4 modulators on cobimetinib PK in healthy and cancer patients were predicted, with only one clinical study.
The label language clearly indicates that the final label was informed by simulations alone. This is a huge benefit in that the sponsor was able to avoid having to conduct a specific clinical trial to evaluate the effects of rifampin.
Melanoma is a type of skin cancer. In advanced melanoma, the cancer has spread to other parts of the body through the blood or lymphatic system. Advanced melanoma is also known as stage 4 melanoma or metastatic melanoma. Individuals with advanced melanoma generally experience weight loss, loss of appetite, and extreme fatigue, but these symptoms change depending on where the melanoma has spread to in the body.