Pharmacokinetic mAb–mAb Interaction: Anti-VEGF mAb Decreases the Distribution of Anti-CEA mAb into Colorectal Tumor Xenografts

Abstract

Abstract. To date, there has been little investigation of the risk for drug-drug interactions involving monoclonal antibodies. The present work examined the effects of an anti-vascular endothelial growth factor (anti-VEGF) antibody on the plasma, tissue, and tumor disposition of T84.66, an anticarcinoembryonic antigen (CEA) antibody, in mice. SCID mice bearing CEA-expressing human colorectal cancer (LS174T) xenografts were divided into control and anti-VEGF-treated groups. When tumors reached 200-300 mm 3 in size, 125 I-T84.66 was administered intravenously at 10 mg/kg (400 μCi/kg). Radioactivity in plasma and tissue samples was counted, and T84.66 concentrations were determined. Areas under the concentration vs. time curves (AUC) were calculated. In separate groups of mice, Evans Blue Dye was administered to evaluate the effect of anti-VEGF on tumor vascular permeability. The investigations did not demonstrate significant effects of anti-VEGF therapy on T84.66 pharmacokinetics in plasma or in nontumor tissues. T84.66 plasma AUC (0-10 days) values were 2.37×10 3 ±1.54×10 2 and 2.56×10 3 ±1.01×10 2 nM× day, for the control and treated groups (p=0.148). Conversely, anti-VEGF treatment significantly reduced tumor vascular permeability to Evans Blue Dye by 45.0 % (p=0.0012), and anti-VEGF therapy decreased T84.66 tumor AUC (0-10 days) by more than 60 % (7.27×10 2 ±51.4 vs. 1.98×10 3 ±90.1 nM×day, p<0.0001). Our findings suggest that anti-VEGF therapies may lead to a substantial reduction in the delivery of monoclonal antibodies to tumor tissues. It is interesting and important to note that this pharmacokinetic interaction occurs at the target site, and that no alterations in T84.66 disposition were visible based on assessment of plasma pharmacokinetics alone.

Application of PBPK modeling to predict monoclonal antibody disposition in plasma and tissues in mouse models of human colorectal cancer

“…This assumption was based on our previous observation of ~50 % reduction in tumor permeability to Evans blue dye [28], and the observations of 50 % reduction in blood flow by Pastuskovas and coworkers in anti-VEGF treated ovarian cancer xenografts [43]. Anti-VEGF treated tumor growth rate was expressed as $$V_{italic\text{tumor}}^{italic\text{total}}\left(\text{treated}\mathit{Ls}174T\right)=\begin{array}{c}{V}_{\text{tumor}\left(0\right)}\hfill \\ \times \exp (0.0000555\times {italic\text{time}}_{\mathrm{italicmin}})\hfill \end{array}$$ The plasma flow rate to the lung was calculated as: $$Q_{italic\text{lung}}=\Sigma (Q_i-L_i)$$ where Q i is plasma flow rate and L i is lymph flow rate to organ i .…”

“…For all other PK studies, three mice were sacrificed, from each treatment group, at each time point. Plasma samples were separated and TCA-precipitated as described previously [28]. Radioactivity was counted using a gamma counter (LKB Wallac 1272, Wallac, Turku, Finland).…”

“…The mean parameter estimate and the variance (SD 2 ) were used to simulate mAb concentrations, assuming log-normal distributions for each parameter. Simulations predicted mAb concentration versus time data for the following: (i) T84.66 administered to LS174T xenograft-bearing SCID mice at 1, 10, and 25 mg/kg, (ii) T84.66 mAb administered to HT29 xenograft-bearing SCID mice at 0.025, 0.1, 1, 10, and 25 mg/kg, (iii) 8C2 mAb administered to LS174T-bearing SCID mice at 1 and 10 mg/kg, and (iv) T84.66 mAb administered at 10 mg/kg to LS174T xenograft mice that had been treated with anti-VEGF mAb [28]. For each treatment group, at each dose level, 1,000 virtual animals were simulated up to 10 days post dosing.…”

Antibody biodistribution coefficients

“…Twenty-one different mouse tissue distribution studies from published references other than the ones used to develop the mouse training data set, with various kinds of mAbs and ADC, in various animal models and with diverse radiolabels, were used to build the mouse validation data set. [13][14][15][20][21][22][23][24][25][26][27][28] Details about the individual biodistribution studies are provided in Table S2. Based on Equation 1, using the plasma mAb concentration and ABC values, expected tissue concentrations were calculated for each tissue.…”

Therapeutic Protein Drug–Drug Interactions: Navigating the Knowledge Gaps–Highlights from the 2012 AAPS NBC Roundtable and IQ Consortium/FDA Workshop

“…For example, tumor uptake of trastuzumab decreases with concomitant administration of an anti-VEGF antibody. Mechanistic studies suggested that the observed changes in tumor uptake were attributable to the reduction in both tumor blood flow and vascular permeability to macromolecules (35).…”