A physiology-based model predicts pharmacokinetics, target occupancy in the tumour, and HSP70 biomarker response in serum for the HSP90 inhibitor, 17-AAG
R. Austin, J. Grevel
BAST Inc Ltd. Nottingham, United Kingdom
Objectives: HSP90 inhibitors of various structures (geldamycin analogs, ATP analogs) are currently in clinical evaluation [1]. The front-runner, 17-allylamino-17-demethoxygeldamycin, 17-AAG, was in phase 2 [2] but its development has been stopped. All HSP90 inhibitors lack a reliable biomarker to guide dose selection in the absence of typical cytotoxic effects. This simulation study predicts an increase in HSP70 serum levels in cancer patients.
Methods: A LC-MS/MS method determined conc. of both 17-AAG and 17-AAGH2. A two-comp. model [3] was used to simulate plasma 17-AAG level in patients of 80 kg body weight (BSA=1.96m2, HCT=0.4) bearing a 500g solid tumour and being treated with six weekly i.v. infusions of 450 mg/m2. The uptake of 17-AAG into tumour cells was predicted from the scaled permeability surface-area product (0.26 L/h)[4], from the ratio of tumour plasma (0.02 L) versus peripheral volume (90 L), and from the rate constants between interstitial and cellular space [4]. Tumour tissue conc. of 17-AAG, CT, were calculated. The relationship between CT and % occupancy of HSP90, OCC, was obtained by fitting (LL.3 in R) published data [5]. The relationship between intracellular 17-AAG and levels of HSP70 was obtained by fitting published data [6]. Secreted HSP70 was predicted from intracellular HSP70 [6] and the latter was diluted to arrive at the HSP70 serum level.
Results: Plasma conc. of 17-AAG reached 15000 nM at the end of the infusion and were BLQ at 48 h. Interstitial and cellular 17-AAG reached 1800 nM and 4800 nM at 6 h and 24 h after the end of the infusion, respectively. CT reached 2700 nM. There was little accumulation of 17-AAG tumour conc. between the 1st and 6th week. OCC varied between 35% and 10%. High intracellular levels of HSP70 (2500 ng/mL) contrasted with 100 ng/mL in the tumour interstitial space and with only a 6 ng/mL increase from baseline serum HSP70.
Conclusions: This simulation shows the possibility to monitor HSP90 inhibitors with increases in serum HSP70 and to simulate OCC from plasma PK. The simulations show that the clinical development of 17-AAG was stopped when the highest doses resulted in only 35% OCC while xenografts (NSCLC) in mice were maximally inhibited at 70% [5].
References:
[1] Trepel J et al. Nature Rev Cancer 2010;10:537-549.
[2] Solit DB et al. Clin Cancer Res 2008;14:8302-7.
[3] Chen X et al. Cancer Chemother Pharmacol 2005;55:237-243.
[4] Xu L et al. J Pharmacokin Pharmacodyn 2003;30:185-219.
[5] Tillotson B et al. J Biol Chem 2010;285:39835-43.
[6] Dakappagari N et al. Biomarkers 2010;15:31-38.
