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


METHODS
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.
Soto
Elena
E
Department of Pharmacy and Pharmaceutical Technology; School of Pharmacy, University of Navarra, Pamplona, Spain.
Staab
Alexander
A
Tillmann
Christiane
C
Trommeshauser
Dirk
D
Fritsch
Holger
H
Munzert
Gerd
G
Trocóniz
Iñaki F
IF
D000465:Algorithms; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D002851:Chromatography, High Pressure Liquid; D003627:Data Interpretation, Statistical; D006207:Half-Life; D006801:Humans; D007958:Leukocyte Count; D013058:Mass Spectrometry; D020714:Maximum Tolerated Dose; D015233:Models, Statistical; D009503:Neutropenia / Q000139:chemically induced* / Q000453:epidemiology; D009504:Neutrophils; D047428:Protein Kinase Inhibitors / Q000009:adverse effects* / Q000493:pharmacokinetics*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D011621:Pteridines / Q000009:adverse effects* / Q000493:pharmacokinetics*; D000097869:Polo-Like Kinase 1
D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011621:Pteridines; D000097869:Polo-Like Kinase 1; C518477:BI 2536