Relationship between in vivo drug exposure of the tumor interstitium and inhibition of tumor cell growth in vitro: a study in breast cancer patients

A novel approach is described to simulate effect site pharmacodynamics of a nticancer drugs. This approach is based on (i) the in vivo measurement of u nbound, interstitial drug pharmacokinetics (PK) in solid tumor lesions in p atients and (ii) a subsequent pharmacodynamic (PD) simulation of the time v ersus drug concentration profile in an in vitro setting. For this purpose, breast cancer cells (MCF-7) were exposed in vitro to the time versus inters titial tumor concentration profiles of 5-fluorouracil (5-FU) and methotrexa te (MTX) from primary breast cancer lesions in patients. This led to a maxi mal reduction in the viable cell count of 69% on day 4, and of 71% on day 7 for 5-FU and MTX, respectively. This effect was dependent on the initial c ell count and was characterized by a high interindividual variability. For 5-FU there was a significant correlation between the maximum antitumor effe ct and the intratumoral AUC (r = 0.82, p = 0.0005), whereas no correlation could be shown for MTX (r = 0.05, p = 0.88). We conclude, that the in-vivo- PK / in-vitro-PD model presented in this study may provide a rational appro ach for describing and predicting pharmacodynamics of cytotoxic drugs at th e target site. Data derived from this approach support the concept that tum or penetration of 5-FU may be a response-limiting event, while the response to MTX may be determined by events beyond interstitial fluid kinetics.