Suitability of the Cynomolgus Monkey as an Animal Model for Drug Absorption Studies of Oral Dosage Forms from the Viewpoint of Gastrointestinal Physiology

Ikegami, Kengo; Tagawa, Kozo; Narisawa, Shinji; Ôsawa, Takashi

doi:10.1248/bpb.26.1442

Cited by 45 publications

(33 citation statements)

References 27 publications

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“…The primate cynomolgus monkey is close to mankind in anatomic structures, physiological functions, and biochemical characteristics. Experimental results obtained from the use of cynomolgus monkeys could be reliably extended to human use [21,22] . Therefore, in the present study we chose cynomolgus monkeys as experimental animals to investigate the pharmacokinetics and pharmacodynamics of rhIL-12.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and Pharmacodynamics of Subcutaneous Injection and Intravenous Infusion of Recombinant Human Interleukin-12 and Recombinant Human Interleukin-12 Combined with Hepatitis B Surface Antigen in Cynomolgus Monkeys

Deng²,

Yong-hang³

et al. 2010

Pharmacology

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Background/Aims: Interleukin-12 (IL-12) is a cytokine that plays an important role in cell-mediated immunity and shows great potential as a therapeutic agent for the treatment of tumors and infectious diseases. Methods: We investigated the pharmacokinetics (PK) and pharmacodynamics of recombinant human IL-12 (rhIL-12) and rhIL-12 combined with hepatitis B surface antigen (HB_sAg) after administration by subcutaneous (s.c.) injection or intravenous infusion in cynomolgus monkeys. Results: After s.c. injection of rhIL-12 at doses of 0.15–1.5 µg/kg, the monkey’s metabolism showed linear kinetic characteristics. The intramuscular injection of HB_sAg vaccine did not affect the pharmacokinetic profile of rhIL-12. In monkeys administered rhIL-12 in a continuous dosing fashion, serum rhIL-12 was undetectable, probably due to the neutralizing effect of anti-rhIL-12 antibodies. In monkeys receiving high-dose s.c. injection of rhIL-12, the T_max for serum rhIL-12 concentration was 4–8 h, and the T_max for serum interferon-γ (IFN-γ) concentration was 24–72 h. However, in monkeys receiving continuous dosing of rhIL-12, serum IFN-γ concentration was very low or even undetectable. Conclusion: We found that the PK of rhIL-12 was dose-dependent and its pharmacological effects appeared after T_max and lasted much longer than mean retention time.

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and Pharmacodynamics of Subcutaneous Injection and Intravenous Infusion of Recombinant Human Interleukin-12 and Recombinant Human Interleukin-12 Combined with Hepatitis B Surface Antigen in Cynomolgus Monkeys

Deng²,

Yong-hang³

et al. 2010

Pharmacology

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“…The gastrointestinal physiology in cynomolgus monkeys (Macaca fascicularis), i.e., gastric pH, gastric emptying time, gastrointestinal agitation intensity and small intestine transit time, is in general similar to that in humans (19). Thus, in spite of some obstacles in animal supply and experimental handling/study cost, monkeys are viewed to be useful as an animal model to predict the bioavailability of oral dosage forms.…”

Section: Non-human Primatesmentioning

confidence: 99%

Use of In Vivo Animal Models to Assess Pharmacokinetic Drug-Drug Interactions

Tang

Prueksaritanont

2010

Pharm Res

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Animal models are used commonly in various stages of drug discovery and development to aid in the prospective assessment of drug-drug interaction (DDI) potential and the understanding of the underlying mechanism for DDI of a drug candidate. In vivo assessments in an appropriate animal model can be very valuable, when used in combination with in vitro systems, to help verify in vivo relevance of the in vitro animal-based results, and thus substantiate the extrapolation of in vitro human data to clinical outcomes. From a pharmacokinetic standpoint, a key consideration for rational selection of an animal model is based on broad similarities to humans in important physiological and biochemical parameters governing drug absorption, distribution, metabolism or excretion (ADME) processes in question for both the perpetrator and victim drugs. Equally critical are specific in vitro and/or in vivo experiments to demonstrate those similarities, usually both qualitative and quantitative, in the ADME properties/processes under investigation. In this review, theoretical basis and specific examples are presented to illustrate the utility of the animal models in assessing the potential and understanding the mechanisms of DDIs.

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“…Although there have been numerous studies to determine the gastrointestinal pH and transit time in human and other laboratory animals (21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36), limited information exists in Cynomolgus monkeys, a frequently used non-rodent species in the evaluation of clinical formulation prototypes and prediction of human oral bioavailability (37,38). Methods commonly used to monitor gastrointestinal function involve intubation and aspiration of gastrointestinal contents or employment of a trans-nasally delivered pH electrode.…”

Section: Introductionmentioning

confidence: 99%

“…Methods commonly used to monitor gastrointestinal function involve intubation and aspiration of gastrointestinal contents or employment of a trans-nasally delivered pH electrode. These methods [which were used to obtain the only reported Cynomolgus monkey gastric pH values (37,38)] may cause substantial discomfort and stress for the subjects (39). These methods may perturb gastrointestinal homeostasis, and therefore may affect the reliability of pH measurements.…”

Section: Introductionmentioning

confidence: 99%

Gastric pH and Gastric Residence Time in Fasted and Fed Conscious Cynomolgus Monkeys Using the Bravo® pH System

et al. 2007

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Suitability of the Cynomolgus Monkey as an Animal Model for Drug Absorption Studies of Oral Dosage Forms from the Viewpoint of Gastrointestinal Physiology

Cited by 45 publications

References 27 publications

Pharmacokinetics and Pharmacodynamics of Subcutaneous Injection and Intravenous Infusion of Recombinant Human Interleukin-12 and Recombinant Human Interleukin-12 Combined with Hepatitis B Surface Antigen in Cynomolgus Monkeys

Pharmacokinetics and Pharmacodynamics of Subcutaneous Injection and Intravenous Infusion of Recombinant Human Interleukin-12 and Recombinant Human Interleukin-12 Combined with Hepatitis B Surface Antigen in Cynomolgus Monkeys

Use of In Vivo Animal Models to Assess Pharmacokinetic Drug-Drug Interactions

Gastric pH and Gastric Residence Time in Fasted and Fed Conscious Cynomolgus Monkeys Using the Bravo® pH System

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