In Vivo Imaging in Pharmaceutical Development and Its Impact on the 3Rs

Abstract

It is well understood that the biopharmaceutical industry must improve efficiency along the path from laboratory concept to commercial product. In vivo imaging is recognized as a useful method to provide biomarkers for target engagement, treatment response, safety, and mechanism of action. Imaging biomarkers have the potential to inform the selection of drugs that are more likely to be safe and effective. Most of the imaging modalities for biopharmaceutical research are translatable to the clinic. In vivo imaging does not require removal of tissue to provide biomarkers, thus reducing the number of valuable preclinical subjects required for a study. Longitudinal imaging allows for quantitative intra-subject comparisons, enhancing statistical power, and further reducing the number of subjects needed for the evaluation of treatment effects in animal models. The noninvasive nature of in vivo imaging also provides a valuable approach to alleviate or minimize potential pain, suffering or distress.

Keywords: 3Rs; drug development; drug safety; imaging; mechanism of action; target engagement; treatment response.

Figure 1.

Summed PET images (30–90 min) of [¹¹C] MK-8193 in rhesus monkey brain overlaid on MRI under baseline conditions (A) and after administration of THPP-1 (B). The baseline PET study shows high tracer retention (red color) in the striatum. Tracer binding in the striatum is blocked after administration of THPP-1. Scale is in SUV (standardized uptake value). [Reprinted from Cox CD, Hostetler ED, Flores BA, Evelhoch JL, Fan H, Gantert L, Holahan M, Eng W, Joshi A, McGaughey. 2015. Discovery of [¹¹C]MK-8193 as a PET tracer to measure target engagement of phosphodiesterase 10A (PDE10A) inhibitors, Bioorganic Medical Chemistry Letters, with permission from Elsevier.]

Figure 2.

Plasma concentration vs PDE10A enzyme occupancy relationship in a monkey brain and b rat brain for THPP-1 as determined by PET studies with [¹¹C]MK-8193. [Reprinted from Hostetler ED, Fan H, Joshi AD, Zeng Z, Eng W, Gantert L, Holahan M, Meng X, Miller P, O'Malley S, Purcell M, Riffel K, Salinas C, Williams M, Ma B, Buist N, Smith SM, Coleman PJ, Cox CD, Flores BA, Raheem IT, Cook JJ, Evelhoch JL. 2015. Preclinical characterization of the phosphodiesterase 10A PET tracer [¹¹C]MK-8193, Mol Imaging Biol, with permission of Springer.]

Figure 3.

Visualization of lung tumor development in K-rasLSL-G12D/ p53LSL-R270H (KP) models. Panel 1: Example of CT images of a control KP mouse with no tumor and H&E stain. Panel 2: Example of CT images of a KP mouse infected with a high dose of Adeno-Cre virus with isolated lung tumors and H&E stain. Panel 3: Example of CT images of a KP mouse infected with a high dose of Adeno-Cre virus with small multifocal tumors and H&E stain. [Reprinted from Haines BB, Bettano KA, Chenard M, Sevilla RS, Ware C, Angagaw MH, Winkelmann CT, Tong C, Reilly JF, Sur C, Zhang W. 2009. A quantitative volumetric micro-computed tomography method to analyze lung tumors in genetically engineered mouse models, Neoplasia, with permission from Elsevier.]

Figure 4.

MicroPET images (coronal slice and transverse slice through tumor and kidneys) of 2 different nude mice with single BT-474 tumors. (A) A mouse at 3 hours after injection with ⁶⁸Ga-DCHF and before 17- allylaminogeldanamycin (17-AAG) treatment. (B) The same mouse after it had received 3 × 50 mg/kg of 17-AAG and rescanned 24 hours later. (C,D) Comparable images of a control mouse 3 hours after 1 dose of ⁶⁸Ga-DCHF (C) and after a second dose 24 hours later (D). [Reprinted from Smith-Jones PM, Solit DB, Akhurst T,Afroze F, Rosen N, Larson SM. 2004. Imaging the pharmacodynamics of HER2 degradation in response to Hsp90 inhibitors. Nat Biotechnol, by permission from Macmillan Publishers Ltd: NATURE BIOTECHNOLOGY.]

Figure 5.

Examples of small (A), medium (B), large (C), and very-large (D) lateral brain ventricles in the adult dogs (top) and juvenile dogs (bottom) at baseline MRI images. No very large ventricles were found in the juvenile group based on adult dog experience, so only small (E), medium (F), and large (G) juvenile lateral ventricles are shown along with a small right and a large left lateral ventricle to demonstrate an example of asymmetry seen in this study (H). While G of the juvenile dogs appears similar to D of the adult dogs, baseline assessment was based on 3D visualization, whereas the images in this 2D figure were chosen to show the ventricles at a similar cross section of all animals. Qualitative assessment of the ventricle size and distribution of differently sized ventricles between groups was warranted as not to skew group means for the adult and juvenile dogs’ treatment groups. Arrows point to the left lateral, right lateral, and third ventricle in A, B, and C, respectively. [Reprinted from Hines CDG, Song X, Kuruvilla S, Farris G, Markgraf CG. 2015. Magnetic resonance imaging assessment of the ventricular system in the brains of adult and juvenile beagle dogs treated with posaconazole IV Solution, J Pharmacol Toxicol Methods, with permission from Elsevier.]