A semi-mechanistic population pharmacokinetic/pharmacodynamic model for neutropenia following therapy with the new PLK-1 inhibitor BI 2536 and its application in clinical development
Elena Soto(1), Alexander Staab(2), Christiane Tillmann(2), Dirk Trommeshauser(2), Holger Fritsch(2), Gerd Munzert(2) and I˝aki F. Trocˇniz(1)
(1)Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona 31080, Spain; (2)Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
Background & Objectives: BI 2536 represents the first in a class of small molecules targeting and blocking activation of Polo-like kinase 1 currently under early clinical development in oncology. The first objective of this analysis was to describe the pharmacokinetic (PK) properties of BI 2536 in humans and to correlate the PK with the neutropenic effects of BI 2536 observed in cancer patients using a semi-mechanistic modeling approach. The second objective was to use the model for simulations to support clinical development of BI 2536.
Methods: BI 2536 was administered as intravenous infusion over 60 minutes in the dose range from 25 to 250 mg. Three different administration schedules were explored: (i) day 1, (ii) days 1, 2 and 3 or (iii) days 1 and 8 within a three week treatment cycle. Plasma concentrations of BI 2536 in plasma and absolute neutrophil cell counts obtained during the first treatment cycle from 104 patients with advanced solid tumours were analyzed using the population approach with NONMEM VI. Simulations were performed to address among other aspects the impact of the tested administration schedules on the neutropenic effects of BI 2536 assuming a large patient population and the possibility to reduce the cycle duration from three to two weeks with administration at day 1.
Results: A three compartment model described the disposition of BI 2536 in plasma. BI 2536 showed a linear PK behaviour over the dose range studied. The neutropenic effects were described by a semi-mechanistic model resembling proliferation, maturation, degradation, homeostatic, and drug action processes. The administration schedules of a single 60 minutes infusion of 200 mg at day 1, or 100 mg at days 1 and 8 as well as 60 mg at days 1, 2 & 3 elicit an acceptable risk of neutropenia, with percentage of patients showing neutropenia grade 4 at all or for more than 7 consecutive days of less than 22 and 7%, respectively. In addition it could be shown that for the day 1 administration scheme the cycle duration could be reduced to 14 days without a relevant increase in the percentage of patients developing a grade 4 neutropenia.
Conclusions: A semi-mechanistic population PK-neutropenic response model for BI 2536 was successfully developed. The model was used for various simulations and was a very helpful tool to support further clinical development.