Semi-mechanistic population pharmacokinetic/pharmacodynamic model for neutropenia following therapy with the Plk-1 inhibitor BI 2536 and its application in clinical development

Abstract

Purpose (1) To describe the neutropenic response of BI 2536 a polo-like kinase 1 inhibitor in patients with cancer using a semi-mechanistic model. (2) To explore by simulations (a) the neutropenic effects for the maximum tolerated dose (MTD) and the dose at which dose-limiting toxicity occurred, (b) the possibility to reduce the cycle duration without increasing neutropenia substantially, and (c) the impact of the initial absolute neutrophil count (ANC) on the degree of neutropenia for different doses. Experimental design BI 2536 was administered as intravenous infusion over 60 min in the dose range from 25 to 250 mg. Three different administration schedules were explored: (a) day 1, (b) days 1, 2, and 3 or (c) days 1 and 8 within a 3 week treatment cycle. BI 2536 plasma concentrations and ANC obtained during the first treatment cycle from 104 patients were analysed using the population approach with NONMEM VI. Results Neutropenia was described by a semi-mechanistic model resembling proliferation at the stem cell compartment, maturation, degradation, and homeostatic regulation. BI 2536 acts decreasing proliferation rate.Simulations showed that (1) all MTD doses showed an acceptable risk of neutropenia, (2) when BI 2536 is given as 200 mg single administration, cycle duration can be reduced from 3 to 2 weeks, and (3) baseline ANC might be considered to individualise the dose of BI 2536. Conclusions A semi-mechanistic population model was applied to describe the neutropenic effects of BI 2536. The model was used for simulations to support further clinical development.

An Open-Label, Phase I Study of the Polo-like Kinase-1 Inhibitor, BI 2536, in Patients with Advanced Solid Tumors

“…Because BI 2536 induces cell-cycle arrest and apoptosis, systemic effects, such as hematotoxicity, cellular depletion of the bone marrow, and gastrointestinal effects, may be explained by the pharmacologic activity of the drug. Although no pharmacodynamic endpoints were analyzed as part of this study, neutropenia is a characteristic side effect observed with mitotic inhibitors and may be seen as a surrogate for target inhibition by BI 2536 (12).…”

A simultaneous analysis of the time-course of leukocytes and neutrophils following docetaxel administration using a semi-mechanistic myelosuppression model

“…This model has since the original publication been successfully applied to both leukocyte and neutrophil measurements following several additional anti-cancer drugs and regimens [6][7][8][9][10][11][12][13][14][15][16]. It has also been shown to satisfactorily describe thrombocyte and lymphocyte measurements following chemotherapy [17][18][19].…”

Small Molecule Kinase Inhibitor Screen Identifies Polo-Like Kinase 1 as a Target for Neuroblastoma Tumor-Initiating Cells

“…Toxicity in these animals was limited to a significant reduction in the numbers of neutrophils in the bone marrow ( Supplementary Fig. 1), which is the most common side effect described in humans following treatment with BI 2536 (18,19).…”