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Early Tumor Drug Pharmacokinetics Is Influenced by Tumor Perfusion but not Plasma Drug Exposure

Authors' Affiliation: Academic Department of Radiation Oncology, The Christie Hospital NHS Foundation Trust, Manchester

Requests for reprints: Azeem Saleem, Academic Department of Radiation Oncology, The Christie Hospital NHS Foundation Trust, Wilmslow Road, Manchester M20 4BX. Phone: 44-161-4468095; Fax: 44-161-4468111; E-mail: azeem.saleem{at}manchester.ac.uk.

Purpose: Pharmacokinetic parameters derived from plasma sampling are used as a surrogate of tumor pharmacokinetics. However, pharmacokinetics-modulating strategies do not always result in increased therapeutic efficacy. Nonsurrogacy of plasma kinetics may be due to tissue-specific factors such as tumor perfusion.

Experimental Design: To assess the impact of tumor perfusion and plasma drug exposure on tumor pharmacokinetics, positron emission tomography studies were done with oxygen-15 radiolabeled water in 12 patients, with 6 patients undergoing positron emission tomography studies with carbon-11 radiolabeled N-[2-(dimethylamino)ethyl]acridine-4-carboxamide and the other 6 with fluorine-18 radiolabeled 5-fluorouracil.

Results: We found that tumor blood flow (mL blood/mL tissue/minute) was significantly correlated to early tumor radiotracer uptake between 4 and 6 minutes [standard uptake value (SUV)_4-6; = 0.79; P = 0.002], tumor radiotracer exposure over 10 minutes [area under the time-activity curve (AUC)_0-10; predominantly parent drug; = 0.86; P < 0.001], and tumor radiotracer exposure over 60 minutes (AUC_0-60; predominantly radiolabeled metabolites; = 0.80; P = 0.002). Similarly, fractional volume of distribution of radiolabeled water in tumor (V_d) was significantly correlated with SUV_4-6 ( = 0.80; P = 0.002), AUC_0-10 ( = 0.85; P < 0.001), and AUC_0-60 ( = 0.66; P = 0.02). In contrast, no correlation was observed between plasma drug or total radiotracer exposure over 60 minutes and tumor drug uptake or exposure. Tumor blood flow was significantly correlated to V_d ( = 0.69; P = 0.014), underlying the interdependence of tumor perfusion and V_d.

Conclusions: Tumor perfusion is a key factor that influences tumor drug uptake/exposure. Tumor vasculature-targeting strategies may thus result in improved tumor drug exposure and therefore drug efficacy.