PAGE. Abstracts of the Annual Meeting of the Population Approach Group in Europe.
PAGE 18 (2009) Abstr 1462 [www.page-meeting.org/?abstract=1462]
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Oral Presentation : Lewis Sheiner Student Session
Elena Soto(1), Alexander Staab(2), Gerd Munzert(2), Holger Fritsch(2), and Iñaki F. Trocóniz(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
BI 2536 is a inhibitor of Polo-like kinase 1 (Plk1) currently in clinical development. Plk1 plays an essential role in the regulation of mitotic progression, (Nigg 1998). Pemetrexed is a cytotoxic anticancer drug approved for the treatment of several cancers.
The haematological effects of BI 2536 have previously been described using Phase I study data (Soto et al; 2008), and the same semi-mechanistic model (Friberg et al; 2002) has been used to describe neutropenia caused by pemetrexed without vitamin supplementation (Latz et al; 2005a, Latz et al; 2005b).
To predict the neutropenic effects for the novel combination of BI 2536 and pemetrexed including supplementary administration of folic acid, vitamin B12 and dexamethasone in non-small-cell lung cancer (NSCLC) patients, using a semi-mechanistic modeling approach.
To achieve this goal, first a semi-mechanistic model for pemetrexed related neutropenia in presence of vitamin supplementation and dexamethasone was developed. Then, under the assumption of an additive interaction [as described previously for other chemotherapy combination treatments (Sandstrom et al; 2005, Sandstrom et al; 2006)], the models for neutropenia developed for pemetrexed and BI 2536 when given as single cytotoxic anticancer drugs were combined to predict the outcome of a combination study of these two drugs in NSCLC patients.
Patients and Methods:
Data from 66 NSCLC patients receiving either: (i) Pemetrexed, vitamin supplementation therapy (folic acid and vitamin B12) and dexamethasone, together with BIBF 1120, a novel potent triple angiokinase inhibitor (without neutropenic effects on its own) (Study A, n=26) or (ii) BI 2536, pemetrexed, vitamin supplementation therapy and dexamethasone (Study B, n=40) were included in the analysis.
In both studies patients received a 10 minutes infusion of pemetrexed every 21 days at doses of 500 mg/m2 or 375 mg/m2 and a concomitant therapy of twice daily dexamethasone (4 mg the day before, the day of and the day after pemetrexed administration), daily folic acid (350-1000 mg) and vitamin B12 (1000 mg every 9 weeks). In Study B BI 2536 was given as an one hour infusion starting 30 minutes after the pemetrexed infusion. The BI 2536 doses ranged from 100 mg to 325 mg.
The analysis of the time course of the absolute neutrophil count (ANC) following the combination therapy was done sequentially using the population modelling approach in NONMEM VI.
The analyses were performed as follows:
(i) Development of the neutropenia model for pemetrexed with vitamin and dexamethasone treatment. Given the lack of model information regarding the neutropenic effects of pemetrexed in presence of vitamin supplementation and dexamethasone, the model was evaluated in detail by reproducing clinical haematological results from literature using simulations.
(ii) Simulations based on the developed model for BI 2536 and pemetrexed under the assumption of an additive neutropenic effect of the two compounds were conducted and the model based results were compared with raw data obtained from a recent clinical trial in which BI 2536 and pemetrexed were given in combination (Study B).
(iii) Finally a model building process was performed with the data from Study B to refine model parameters and to explore the significance of other types of interaction (antagonism/synergism) using the response surface analysis (Minto et al; 2002). During this modelling exercise the PRIOR subroutine in NONMEM was used allowing the estimation of the drug dependent parameters based on the estimates from the previous studies.
(i) The neutropenic effects of pemetrexed given together with vitamin supplementation and dexamethasone therapy were adequately described by an extension of Friberg's model in which the initial increase in ANC due to dexamethasone administration is considered (Ozawa et al; 2007). The slope parameter was estimated in 0.000121 mL/ng which represents a 50% reduction of the estimate reported for pemetrexed when no vitamin supplementation was given, and very similar to the one just recently reported for white population receiving vitamin supplementation (Latz et al; 2009)
The external validation using literature data showed that the percentages of patients showing neutropenia grade III or IV predicted from this model (30% and 15%) was similar to the ones reported by Takimoto et al, 2007 (32% and 18%, respectively).
(ii) Results showed a very good agreement between simulated and observed data from study B. For example for the first treatment cycle the model predicted 38% of patients experiencing grade IV neutropenia and an average nadir of 1.2. These values very close to the ones obtained from the clinical trial; 43% and 1.3 respectively.
(iii) The additive neutropenic effect of BI 2536 and pemetrexed was further supported by the analysis of the Study B data, in which a synergistic or antagonistic interaction was not supported by the observations. The estimates of the slope (mL/ng) parameters for both BI 2535 and pemetrexed using prior knowledge (0.0158, 0.000121) were similar to those obtained from the analysis from the single drug trials (0.0147, 0.000190).
The neutropenic effects of the combination of BI 2536 and pemetrexed were adequately predicted assuming an additive interaction between the drugs, and based on information from previous single drug studies. The drug related parameters in this model are consistent between studies and independent of study type (single drug or combination therapy) suggesting a promising opportunity for predicting future trial outcomes.