Prediction of Neutropenia-Related Effects of a New Combination Therapy With the Anticancer Drugs BI 2536 (a Plk1 Inhibitor) and Pemetrexed

• Published in: Clinical pharmacology and therapeutics 2010-11, Vol.88 (5), p.660-667
• Main Authors: Soto, E, Staab, A, Freiwald, M, Munzert, G, Fritsch, H, Döge, C, Trocóniz, I F
• Format: Article
• Language: English
• Subjects: Antimetabolites, Antineoplastic - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics; Biological and medical sciences; Carcinoma, Non-Small-Cell Lung - drug therapy; Cell Cycle Proteins - antagonists & inhibitors; Cell Cycle Proteins - metabolism; Clinical Trials, Phase I as Topic; Computer Simulation; Feasibility Studies; Glutamates - administration & dosage; Guanine - administration & dosage; Guanine - analogs & derivatives; Hematologic and hematopoietic diseases; Humans; Lung Neoplasms - drug therapy; Medical sciences; Models, Biological; Neutropenia - chemically induced; Other diseases. Hematologic involvement in other diseases; Pemetrexed; Pharmacology. Drug treatments; Polo-Like Kinase 1; Protein Kinase Inhibitors - administration & dosage; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - metabolism; Pteridines - administration & dosage; Treatment Outcome
• ISSN: 0009-9236; 1532-6535
• DOI: 10.1038/clpt.2010.148

This study investigated the feasibility of predicting the neutropenia‐related effects of a therapy that combines the investigational drug BI 2536 (inhibitor of Polo‐like kinase 1) and pemetrexed, an approved anticancer drug. Predictions were arrived at using the pharmacokinetic/pharmacodynamic (PK/PD) parameters of each of the drugs obtained from monotherapy studies and assuming that the neutropenic effect is additive when the drugs are administered as a combination therapy. Subsequently, a PK/PD model was developed to determine whether this assumption of additive effect was reasonable in relation to these two drugs. All analyses and simulations were performed using the population approach in NONMEM, version VI. Clinical Pharmacology & Therapeutics (2010) 88 5, 660–667. doi: 10.1038/clpt.2010.148