Reference values of clinical pathology parameters in cynomolgus monkeys (<i>Macaca fascicularis</i>) used in preclinical studies

Park, Hyun Kyu; Cho, Jae-Woo; Lee, Byoung‐Seok; Park, Heejin; Han, Ji Seok; Yang, Mi-Jin; Im, Wan Jung; Park, Do Yong; Kim, Woo Jin; Han, Sang-Seop; Kim, Yong Bum

doi:10.5625/lar.2016.32.2.79

Cited by 42 publications

(81 citation statements)

References 15 publications

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“…Treatment with an SD was also associated with significant monocytosis (>1 Â 10 3 cells/mL; ref. 30), likely secondary to kidney injury, on day 15 that persisted until day 64 (Fig. 3D).…”

Section: Fractionated Dosing Improved the Tolerability Of 1c1-sg3249 mentioning

confidence: 97%

Fractionated Dosing Improves Preclinical Therapeutic Index of Pyrrolobenzodiazepine-Containing Antibody Drug Conjugates

Hinrichs¹,

Ryan²,

Zheng³

et al. 2017

Clinical Cancer Research

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To use preclinical models to identify a dosing schedule that improves tolerability of highly potent pyrrolobenzodiazepine dimers (PBDs) antibody drug conjugates (ADCs) without compromising antitumor activity. A series of dose-fractionation studies were conducted to investigate the pharmacokinetic drivers of safety and efficacy of PBD ADCs in animal models. The exposure-activity relationship was investigated in mouse xenograft models of human prostate cancer, breast cancer, and gastric cancer by comparing antitumor activity after single and fractionated dosing with tumor-targeting ADCs conjugated to SG3249, a potent PBD dimer. The exposure-tolerability relationship was similarly investigated in rat and monkey toxicology studies by comparing tolerability, as assessed by survival, body weight, and organ-specific toxicities, after single and fractionated dosing with ADCs conjugated to SG3249 (rats) or SG3400, a structurally related PBD (monkeys). Observations of similar antitumor activity in mice treated with single or fractionated dosing suggests that antitumor activity of PBD ADCs is more closely related to total exposure (AUC) than peak drug concentrations (). In contrast, improved survival and reduced toxicity in rats and monkeys treated with a fractionated dosing schedule suggests that tolerability of PBD ADCs is more closely associated with than AUC. We provide the first evidence that fractionated dosing can improve preclinical tolerability of at least some PBD ADCs without compromising efficacy. These findings suggest that preclinical exploration of dosing schedule could be an important clinical strategy to improve the therapeutic window of highly potent ADCs and should be investigated further. .

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“…Treatment with an SD was also associated with significant monocytosis (>1 Â 10 3 cells/mL; ref. 30), likely secondary to kidney injury, on day 15 that persisted until day 64 (Fig. 3D).…”

Section: Fractionated Dosing Improved the Tolerability Of 1c1-sg3249 mentioning

confidence: 97%

Fractionated Dosing Improves Preclinical Therapeutic Index of Pyrrolobenzodiazepine-Containing Antibody Drug Conjugates

Hinrichs¹,

Ryan²,

Zheng³

et al. 2017

Clinical Cancer Research

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“…In CBC differential results, increases in MCHC were observed with UV‐C, which may indicate slight hemolysis. However, the changes were less than that observed with PDT, and they were within the normal reference range . The total UV‐C exposure dose was calculated to ~ 0.028 J cm −2 (accounting for the reduced transmittance of UV‐C light through PDMS tube ~ 70%, refer to Section 2.4 for transmittance measurement), but distributed partially across the blood sample due to recirculation.…”

Section: Discussionmentioning

confidence: 99%

Light‐based methods for whole blood bacterial inactivation enabled by a recirculating flow system

Kim

Karbaschi

Cooke

et al. 2018

Photochem & Photobiology

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Light of certain wavelengths can be used to inactivate pathogens. Whole blood is opaque; thus, the penetration of light is reduced. Here, we overcame this limitation using a thin transparent tube that is illuminated from all angles. Three light-based techniques were evaluated: photodynamic therapy (PDT) using a 660-nm light and antibody-photosensitizer conjugates, ultraviolet, and violet light. We observed a reduction of 55-71% of Staphylococcus aureus after 5 h of exposure (starting concentration 10 CFU mL ) and an 88-97% reduction in methicillin-resistant Staphylococcus aureus (MRSA) (starting 10 CFU mL ). An 83-92% decrease for S. aureus and 98-99.9% decrease for MRSA were observed when combined with an immunocapture approach. Complete blood count with differential analysis did not reveal any significant changes in the blood cell numbers. Genotoxicity studies showed that violet and ultraviolet did not induce any significant level of single strand breaks and alkali labile sites in the peripheral blood mononuclear cells (PBMC). In contrast, ultraviolet did induce a very low level of cyclobutane pyrimidine dimers, a UV damage indicator. PDT generated a significant level of single strand breaks and 8-oxoGua in these cells. The approaches showed promise for whole blood pathogen inactivation with minimal collateral damage to PBMC.

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“…In the case of the analyses that compared the age groups, the enzymes LDH, GGT, and CK, which exist in greater concentrations in skeletal muscle tissue, showed statistical differences in Groups B (KX) and C (TZ), principally between Groups 1 and 2, which manifested higher concentrations of these enzymes compared to the older age groups (Tables ). There are reports that both enzymes tend to increase due to muscular lesions caused by intramuscular administration of drugs and the toxicity of these substances for muscles . Increases in CK have also been associated with a decrease in body temperature .…”

Section: Discussionmentioning

confidence: 99%

Effect of different anesthetic mixtures—ketamine‐xylazine, ketamine‐acepromazine and tiletamine‐zolazepam—on the physiological and blood biochemistry parameters of male rhesus monkeys (Macaca mulatta) at different ages

Hernández-Godínez

Jaime²,

Poblano

et al. 2019

Anim Models and Exp Med

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Background Anesthetic agents are commonly utilized in the handling of non‐human primates for prevent the stress caused in physical exploration or physical restrain. For this reason, the objective of this work was to describe the effect of age and dissociative anesthetics (ketamine and tiletamine), and their combinations with acepromazine, xylazine and zolazepam, on the physiological and blood biochemical parameters in Macaca mulatta . Methods Eighty male Macaca mulatta were divided into four experimental groups depending on the anesthetic mixture applied. Each group of 20 males was divided into five sub‐groups according to age. Physiological parameters were recorded every 5 minutes during a 30‐minute period. A blood sample was drawn to analyze blood biochemistry. Results Statistical analyses revealed significant differences in the physiological parameters between the ketamine‐acepromazine and ketamine‐xylazine groups compared to the control group. The analysis of blood biochemistry found significant differences by age and by anesthetic mixture among all groups. Conclusion These findings contribute to standardizing this animal model in biological research.

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Reference values of clinical pathology parameters in cynomolgus monkeys (Macaca fascicularis) used in preclinical studies

Cited by 42 publications

References 15 publications

Fractionated Dosing Improves Preclinical Therapeutic Index of Pyrrolobenzodiazepine-Containing Antibody Drug Conjugates

Fractionated Dosing Improves Preclinical Therapeutic Index of Pyrrolobenzodiazepine-Containing Antibody Drug Conjugates

Light‐based methods for whole blood bacterial inactivation enabled by a recirculating flow system

Effect of different anesthetic mixtures—ketamine‐xylazine, ketamine‐acepromazine and tiletamine‐zolazepam—on the physiological and blood biochemistry parameters of male rhesus monkeys (Macaca mulatta) at different ages

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