Human Clinical Relevance of the Porcine Model of Pseudoallergic Infusion Reactions

Abstract

Pigs provide a highly sensitive animal model for pseudoallergic infusion reactions, which are mild-to-severe hypersensitivity reactions (HSRs) that arise following intravenous administration of certain nanoparticulate drugs (nanomedicines) and other macromolecular structures. This model has been used in research for three decades and was also proposed by regulatory bodies for preclinical assessment of the risk of HSRs in the clinical stages of nano-drug development. However, there are views challenging the human relevance of the model and its utility in preclinical safety evaluation of nanomedicines. The argument challenging the model refers to the "global response" of pulmonary intravascular macrophages (PIM cells) in the lung of pigs, preventing the distinction of reactogenic from non-reactogenic particles, therefore overestimating the risk of HSRs relative to its occurrence in the normal human population. The goal of this review is to present the large body of experimental and clinical evidence negating the "global response" claim, while also showing the concordance of symptoms caused by different reactogenic nanoparticles in pigs and hypersensitive man. Contrary to the model's demotion, we propose that the above features, together with the high reproducibility of quantifiable physiological endpoints, validate the porcine "complement activation-related pseudoallergy" (CARPA) model for safety evaluations. However, it needs to be kept in mind that the model is a disease model in the context of hypersensitivity to certain nanomedicines. Rather than toxicity screening, its main purpose is specific identification of HSR hazard, also enabling studies on the mechanism and mitigation of potentially serious HSRs.

Keywords: adverse drug reactions; anaphylactoid reactions; anaphylaxis; complement; nanomedicine; nanoparticle; pigs; pulmonary intravascular macrophages; shock.

Figure 1

Time course of liposome-induced changes in plasma TXB2 and PAP in pigs. Two animals were repetitively injected with liposome boluses, and changes in PAP (circles) and plasma TXB2 (bars) were plotted as a function of time for the first two injections in one pig (A) or over 7 h in another pig (B). Other details are in Ref. [15], from where this figure was reproduced with permission. Arrows here indicate the timing of liposome injection.

Figure 2

Complex mechanism of liposome-induced CARPA in pigs; schematic (A) and visual (B) illustration of causally related events, reproduced from Refs. [15] and [66], respectively. (A) The arrows indicate causal relationships among the physiological changes; solid and dashed lines indicate experimentally established and hypothetical changes. (B) Imaginary snapshot of a pulmonary capillary during CARPA in pigs; the PIM’s TXA2 response to C5a and liposome binding is combined with microthrombus formation on the capillary wall, amplifying the vasoconstrictive effect of TXA2. Abbreviations: (A) C, complement; HR, heart rate; Mf, macrophage; Indo, indomethacin; CVR, coronary vascular resistance; ST-depr, ST-segment depression on the ECG; sCR1, soluble C receptor type 1, a C inhibitor; GS1, anti-porcine C5a antibody, PVR, pulmonary vascular resistance, CVR, central vascular resistance, CO, cardiac output, SVR, systemic vascular resistance, HR, heart rate, SAP, systemic arterial pressure, PAP, pulmonary arterial pressure; (B) Lip, liposome, aPL, activated platelet; Mo, monocyte; L-P aggr, leukocyte-platelet aggregate; PRR, pattern recognition receptors; En, endothelial cells; SMC, smooth muscle cells.

Figure 3

Variation of PAP and SAP waveforms. Panels (A–J) represent reactions to identical or different NPs, selected from different experiments, wherein the CARPAgenic potential of nanoparticulate drugs or drug carriers were tested in pigs. Minutes indicate the timespan of reactions. Blue, red, and green are PAP, SAP, and heart rate curves, respectively. Changes are shown in percent of baseline. Abbreviations (only here): com, commercial; prep, self-prepared; lpd, lipophilic prodrug-containing liposomes; PEI25, 25 kD pegylated poly(ethylene imine); G4 dendrimer, 4th generation dendrimer; MW-CNT, multiwall carbon nanotube. Reproduced from Ref. [17].

Figure 4

Changes of hemodynamic parameters in pigs after i.v. injection of polystyrene nanoparticles of different shape: spheres (circles), rods (triangles), and disks (squares). Time-dependent changes in pulmonary arterial pressure (PAP) (A), systemic arterial pressure (SAP) (B), and thromboxane B2 (TxB2) (C) following particle injection compared with background (resting phase, before 0 min). injection compared with background (resting phase, before 0 min). Particles (on an equivalent surface area of ~114,300 mm² per 20 kg body weight) were injected at 0 min. Inset: integrated area under the curve (AUC) of the changes in PAP during the first 10 min of injection. d, the results from pig experiments are expressed as mean ± SEM (n = 3). Reproduced from Ref. [44] with permission.

Figure 5

Hemodynamic effects of oversulfated chondroitin sulfate (OSCS) in pigs. Anesthetized Yorkshire crossbred pigs (3–6 pigs per group) were treated with a single intravenous bolus (5 mg per kilogram) of synthetic OSCS. Representative data for the heart rate (red), the mean arterial pressure (gray), the systolic blood pressure (blue), and the diastolic blood pressure (yellow) are shown. Figure reproduced from Ref. [29], with permission.