. 2018 Oct 6;106(1):148–163. doi: 10.1002/cpt.1211

Table 1.

State‐of‐the‐art technologies that can be applied to assess specific aspects of drug penetration related to the systemic level, the tumor tissue level, and the cellular or molecular level

Levels	Aim	Tools		Potential clinical relevance	Examples
Levels	Aim	Macroscopic level	Microscopic level	Potential clinical relevance	Examples
1. Systemic exposure	Ensure optimal bioavailability in blood to reach the maximal binding capacity in tumor tissues	* PK measurements in blood: ✓ Immunoassays for large molecules ✓ LC‐MS(MS)/HP‐LC for small molecules ✓ (radio)‐labeled drugs * Molecular imaging: ✓ PET/SPECT (noninvasive)		Optimize dose (to overcome the tissue sink)	* ⁸⁹Zr‐Trastuzumab PET imaging and plasma PK to understand the tissue sink effect18 * Plasma PK of RG7356, an anti‐CD44 humanized antibody to define optimal dose for phase II study instead of MTD19 * Linear plasma PK of nivolumab and durvalumab may reflect severity of the disease, and may not be useful to guide dose adjustments21, 22
2. Tissue penetration	Assess tumor vascularization, immune infiltration and other factors in the tumor microenvironment	* (Labeled drug)‐ molecular imaging: ✓ PET/SPECT ✓ DCE‐MRI ✓ Angio‐CT/SPECT * Microdialysis * Optical imaging	✓ IHC/immunofluorescence ✓ MALDI‐MSI ✓ Multiplexed ion beam imaging	Optimize treatment selection and understand mechanism of action	* Microdialysis of methotrexate40 * Immunofluorescence imaging T‐DM141 * Fluorescent labeled bevacizumab/cetuximab‐guided surgery44, 45 * Immunotherapies: radiolabeled PD‐L146 or granzyme B PET imaging48
3. Cellular/molecular concentrations	Ensure the presence/accessibility of the target	* Labeled drug‐molecular imaging: ✓ PET/SPECT Imaging barriers of target engagement ✓ Genomics	Biopsy‐based assay to detect the presence of the target and the presence of factors that limit target: ✓ IHC/immunofluorescence	Optimize treatment selection	Macroscopic imaging: * ⁸⁹Zr trastuzumab and T‐DM149 * Dose escalation guided by89Zr cetuximab50 * Somatostatin receptor imaging (e.g., 68Ga for imaging and ¹⁷⁷Lu‐Dotatate treatment)54 Interference factors: * ICD/ECD HER2 expression58 MUC4 and trastuzumab60 * TAM uptake of lipidic nanoparticles63 * ABCB1 polymorphism anthracycline and cytarabine67
4. Expression of pharmacology	Ensure that sufficient target modulation has been achieved, assess drug efficacy and predict drug resistance	Molecular imaging: * PET/SPECT	* Imaging of PD markers ✓ For example, platinum adduct by immunofluorescence	Change treatments, and optimize dosing	* ¹⁸F‐fluorodihydrotestosterone androgen receptor imaging post apalutamide70 and enzalutamide69 * ¹⁸FES imaging post‐RAD1901/fulvestrant/Z‐endoxifen73, 74, 75, 76 * ⁸⁹Zr trastuzumab HER2 response imaging post‐HSP90 inhibitor78 * Platinum adducts after carboplatin administration79, 81, 82

¹⁸FES, FES16α‐[18F]‐fluoro‐17β‐estradiol; CT, computed tomography; DCE‐MRI, dynamic contrast‐enhanced magnetic resonance imaging; HP‐LC, high‐performance liquid chromatography; HSP90, heat shock protein 90; ICD/ECD HER2, intracellular or extracellular domains of the human epidermal growth factor receptor; IHC, immunohistochemistry; LC‐MS, liquid chromatography‐mass spectrometry; MALDI‐MSI, matrix‐assisted laser desorption ionization mass spectrometry imaging; MTD, maximum tolerated dose; PD, pharmacodynamic; PD‐L1, programmed cell death‐ligand 1; PET, positron emission tomography; PK, pharmacokinetics; SPECT, single photon emission computed tomography; TAM, tumor‐associated macrophage; T‐DM1, ado‐trastuzumab emtansine.