Early tumor drug pharmacokinetics is influenced by tumor perfusion but not plasma drug exposure

Abstract

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; rho = 0.79; P = 0.002], tumor radiotracer exposure over 10 minutes [area under the time-activity curve (AUC)0-10; predominantly parent drug; rho = 0.86; P < 0.001], and tumor radiotracer exposure over 60 minutes (AUC0-60; predominantly radiolabeled metabolites; rho = 0.80; P = 0.002). Similarly, fractional volume of distribution of radiolabeled water in tumor (Vd) was significantly correlated with SUV4-6 (rho = 0.80; P = 0.002), AUC0-10 (rho = 0.85; P < 0.001), and AUC0-60 (rho = 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 Vd (rho = 0.69; P = 0.014), underlying the interdependence of tumor perfusion and Vd.

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.

Figure 1

Mean plasma time-activity curves after injection of (a) [¹¹C]DACA and (b) 5-[¹⁸F]FU. The total [¹¹C]- or [¹⁸F]- radiolabelled parent and metabolites are shown as broken lines, while [¹¹C]DACA and 5-[¹⁸F]FU are shown as unbroken lines. Individual tumour TACs for all 12 patients (18 tumour TACs) are illustrated in (c) and for comparison in (d) all tumour TACs and hepatic TACs (broken lines) for DACA (patient 5) and 5-FU (patient 7) are illustrated. Both 5-FU and DACA undergo hepatic metabolism.

Figure 2

Scatter plot (a) illustrating the significant relationship between tumour perfusion parameters flow and V_d (ρ= 0.69; p = 0.014). Scatter plots (b) and (c) illustrate the lack of relationship between tumour drug exposure over 60 minutes (AUC_0-60) with plasma exposure to total plasma radiotracer over 60 minutes (ρ= 0.04; p = 0.9) and plasma exposure to parent drug over 60 minutes (ρ= −0.13; p = 0.7 ), respectively. In (d) the lack of relationship between plasma exposure to parent drug over 10 min and tumour exposure over 10 min (AUC_0-60) is illustrated (ρ= 0.24; p = 0.47).

Figure 3

Scatter plots showing statistically significant relationship between (a) tumour blood and SUV_4-6 (ρ= 0.79; p = 0.002), (b) tumour blood and AUC_0-60 (ρ= 0.80; p = 0.002), (c) V_d and SUV_4-6 (ρ= 0.8; p = 0.002) and (d) V_d and AUC_0-60 (ρ= 0.66; p = 0.02).

Figure 4

Schematic diagram illustrating normally (top) and abnormally (bottom) perfused tissue. Radiolabelled water, a freely diffusible and inert radioligand enters tissue via arterioles, diffusing to and back from the tissue (white background) and leaving it via the venous system. With PET, tissue perfusion is quantified as tissue blood flow, which is volume of blood perfused through unit volume of tissue per min (ml blood/ml tissue/min) and V_d, which is the fractional volume of tissue with which radiolabelled water exchanges at equilibrium. In tumours, necrotic tissue (dark blocks) are likely to result in a reduction in V_d. Similarly, an increase in interstitial fluid pressure would result in a decrease in V_d and result in a further compromise of tumour vasculature (arrows), which is inherently unstable and poor, resulting in reduction in tissue flow.