Prediction of human serum concentration-time profiles of therapeutic monoclonal antibodies using common marmosets (Callithrix jacchus): Initial assessment with canakinumab, adalimumab, and bevacizumab.

1. Cynomolgus monkeys and human FcRn transgenic mice are generally used for pharmacokinetic predictions of therapeutic monoclonal antibodies (mAbs). In the present study, the application of the common marmoset, a small nonhuman primate, as a potential animal model for prediction was evaluated for the first time.2. Canakinumab, adalimumab, and bevacizumab, which exhibited linear pharmacokinetics in humans, were selected as the model compounds. Marmoset pharmacokinetic data were reportedly available only for canakinumab, and those for adalimumab and bevacizumab were acquired in-house.3. Four pharmacokinetic parameters for a two-compartment model (i.e., clearance and volume of distribution in the central and peripheral compartments) in marmosets were extrapolated to the values in humans with allometric scaling using the average exponents of the three mAbs. As a result, the observed human serum concentration-time curves of the three mAbs following intravenous administration and those of canakinumab and adalimumab following subcutaneous injections (with an assumed absorption rate constant and bioavailability) were reasonably predicted.4. Although further prediction studies using a sufficient number of other mAbs are necessary to evaluate the versatility of this model, the findings indicate that marmosets can be an alternative to preceding animals for human pharmacokinetic predictions of therapeutic mAbs.

Salivary alpha-amylase stress reactivity in advanced-aged marmosets (Callithrix jacchus): Impacts of cognitive function and oral health status.

Salivary alpha-amylase (sAA) is an enzyme found in saliva and is considered a noninvasive biomarker for sympathetic nervous system activity. While a wide range of sAA activity in response to stress has been reported in nonhuman primates, the effects of stress on sAA activity in common marmosets are still unknown. We tested the hypothesis that advanced age and cognitive function may have an impact on stress-related sAA reactivity in marmosets. Thirteen marmosets (nine males and five females) had saliva samples collected during a stressful condition (manual restraint stress) at two different time points, with a 60-min interval. On the next day, the animals underwent the object recognition test (ORT, a type of cognitive test), and then oral examinations. The animals were categorized into two age groups: old (10-13 years), and very old (15-22 years). Irrespective of age, sAA levels showed a significant difference between T1 (mean 2.07 ± 0.86 U/mL) and T2 samples (mean 1.03 ± 0.67 U/mL), with higher values observed at T1 (p < 0.001). The intra-assay coefficients of variation (CV) for low and high sAA concentrations were 10.79% and 8.17%, respectively, while the interassay CVs for low and high sAA concentrations were 6.39% and 4.38%, respectively. Oral health issues were common but did not significantly impact sAA levels. The ORT indicated that the animals could recognize an object placed in the cage 6 h after familiarization. In conclusion, all marmosets showed a higher sAA concentration in the first saliva sample as compared to the second saliva sample collected 1 h later, indicating adaptation to stress. No significant differences in sAA levels were observed between sexes, ORT performance, or oral health. Our results indicate that autonomic responsivity and cognitive (memory) functions were preserved even in very old marmosets.

Selection of the candidate compound at an early stage of new drug development: retrospective pharmacokinetic and metabolic evaluations of valsartan using common marmosets.

Valsartan is an antihypertensive drug that was developed using common marmosets (Callithrix jacchus) in pivotal toxicity studies as a non-rodent species. The aim of the present study was to investigate the utility of marmosets in the candidate selection of this drug from a pharmacokinetic and metabolic viewpoint.Valsartan, as well as three other angiotensin II type-I receptor blockers, assumed as competitive candidates, were administered to common marmosets. Human pharmacokinetic parameters predicted by single-species allometric scaling and Wajima superposition suggested that valsartan may exhibit promising pharmacokinetic properties in humans.In vitro metabolic studies of valsartan using isolated rat, dog, marmoset, cynomolgus monkey, and human hepatocytes revealed that the marmoset was the most relevant animal species to humans presenting with the most abundant human metabolite, 4-hydroxyvalsartan. Oral administration of an elevated dose of valsartan to a common marmoset demonstrated that the level of 4-hydroxyvalsartan in the plasma was comparable to that in clinical practice and suggested that safety of the human metabolite might have been confirmed in the toxicity studies using common marmosets.These results suggest that common marmosets, the small, non-human primates, had been a suitable species for the development of valsartan.

Anatomical, behavioural and physiological analyses of craniofacial development by cineradiographic imaging in marmosets.

BACKGROUND: Non-human primates are the closest animal models to humans regarding genetics, physiology and behaviour. Marmoset monkeys in particular are one of the most versatile species for biomedical research. OBJECTIVE: To assess the craniofacial growth and development of the masticatory function in the common marmoset (Callithrix jacchus), from birth to the fourth month of life through minimally invasive cineradiographic imaging. METHODS: Ten individuals were followed-up from 0 to 4 months of age regarding craniofacial growth and masticatory function assessed by cineradiography. For the experimental procedure, we used a microfocal X-ray source apparatus and a beryllium fast-response image-intensifier. RESULTS: The duration of the masticatory cycles was stable across age groups. Chewing a very soft Castella cake or the slightly harder Marshmallow did not change the masticatory cycle in the time domain. On the other hand, linear and angular measurements of the jaw-opening movement showed a tendency for bigger movements at the latter stages of craniofacial growth. Qualitative analysis showed that marmosets had a small preference for Castella over Marshmallow, that they most often bit off pieces of food to chew with their posterior teeth, that they manipulated the food with their hands, and that they chewed the food continuously. CONCLUSION: We observed critical developmental events during the first 3 months of life in marmosets. Cineradiographic imaging in marmosets may provide valuable information on craniofacial form and function for basic and preclinical research models.

Characterization of oral microbiota in marmosets: Feasibility of using the marmoset as a human oral disease model.

With rapid aging of the world's population, the demand for research, for a better understanding of aging and aging-related disorders, is increasing. Ideally, such research should be conducted on human subjects. However, due to ethical considerations, animals such as rodents and monkeys are used as alternatives. Among these alternative models, non-human primates are preferred because of their similarities with humans. The small South American common marmoset (Callithrix jacchus) may offer several advantages over other non-human primates in terms of its smaller size, shorter life-span, and dental anatomy identical to humans. The purpose of this study was to determine the viability of using the marmoset as a human oral disease model. We collected saliva samples from eight marmosets and eight human subjects. Prokaryotic DNA was extracted from the saliva samples, and 16S bacterial rRNA gene sequencing was performed on each of the samples. Our results indicated that the types of oral microbiomes detected among human and marmoset samples were nearly indistinguishable. In contrast, the oral microbiomes of our human and marmoset subjects were distinctly different from those reported for rats and dogs, which are currently popular research animals. The oral microbiomes of marmosets showed greater diversity than those of humans. However, the oral microbiota of marmosets exhibited less variation than those of humans, which may be attributed to the fact that the marmoset subjects were kept in a controlled environment with identical lifestyles. The characteristics of its oral microbiota, combined with other technical advantages, suggest that the marmoset may provide the best animal model thus far for the study of oral health. This study characterized the oral microbes of the marmoset, thereby providing information to support future application of the marmoset as a model for age-related oral disease.