Camila de Almeida (1), Frank Gibbons (2) and James Yates (1)
(1) Oncology iMed DMPK, AstraZeneca, Alderley Park, UK; (2) Oncology iMed DMPK, AstraZeneca, Boston, USA
Objectives: Irinotecan (CPT-11, Camptosar) is a topoisomerase I inhibitor, approved for use in colorectal cancer. Although CPT-11 shows anti-tumor activity alone, its active metabolite SN-38 is up to 100-fold more potent. The conversion from parent to active metabolite by carboxylesterases in preclinical species and humans is different in that different ratios of parent/metabolite are observed. The major toxicities in patients treated with this drug are gastrointestinal and myelosuppresion. It is important to account for both parent and metabolite when considering the overall anti-tumour activity, toxicity and to understand the additive/synergistic effects of combinations with novel anti-cancer agents. Literature and internal evidence shows profound species differences in pharmacokinetics (PK) [1], SN-38 levels and half-life [2], as well as bone marrow sensitivities to the active metabolite [3]. This highlights the need for mathematical models to describe the preclinical results and allow a more robust translation to the observed clinical results.
Methods: Efficacy studies were conducted in a xenograft mouse model at 50 mg/kg of CPT-11 given once weekly. PK studies to support efficacy modelling were carried out at two dose levels (30 and 50 mg/kg) in mice bearing patient-derived xenograft (PDX) tumours.
To assess toxicity, a time course study on neutrophil count was carried out, following a single dose of 100 mg/kg CPT-11 in non-tumour bearing rats. PK studies supported the neutrophil modelling by measuring CPT-11 and SN-38 levels at a range of different doses (from 50 to 150 mg/kg).
Results: A PK model for CPT-11 and SN-38 was developed to describe the PK in tumour bearing mice and non-tumour bearing rats across a dose range.
A tumour growth inhibition model [4], driven by SN-38 PK was developed to describe the efficacy of CPT-11 in mouse xenografts.
To model CPT-11 toxicity, the Friberg model [5] was fit to time course data on neutrophils after a single dose of 100 mg/kg CPT-11 in non-tumour bearing rats.
Conclusions: Modelling and simulation provide a useful tool to quantify the levels of CPT-11’s active metabolite in different species and assess its pre-clinical efficacy and toxicity. It offers a robust method to translate pre-clinical results to the clinic and provides a useful starting point to better understand enhanced/synergistic effects of combination approaches using this cytotoxic agent with novel anti-cancer agents.
References:
[1] Clin Cancer Res. 1998 Feb;4(2):455-62.
[2] British Journal of Cancer (2002) 87, 144-150.
[3] Mol Cancer Ther. 2008 Oct;7(10):3212-22.
[4] Cancer Res. 2004 Feb 1;64(3):1094-101.
[5] Invest New Drugs. 2010 Dec;28(6):744-53.
Reference: PAGE 22 (2013) Abstr 2962 [www.page-meeting.org/?abstract=2962]
Poster: Oncology