Exploration of the African green monkey as a preclinical pharmacokinetic model: oral pharmacokinetic parameters and drug–drug interactions

Abstract

African green monkeys (vervets) have been proposed as an alternate species that might allow improved access and provide high-quality pharmacokinetic results comparable with other primates. However, no oral data are available in vervets to evaluate cross-species predictive performance. Therefore, this study was conducted to evaluate the use of the vervet to predict human oral pharmacokinetics and drug interactions. Oral pharmacokinetic studies were conducted in the vervet for eight compounds: phenytoin, moxifloxacin, erythromycin, lidocaine, propranolol, ciprofloxacin, metroprolol, and prednisolone. To assess drug-drug interactions, co-administration experiments were conducted with ketoconazole and either propranolol or erythromycin. In general, the vervet provided similar predictivity for human oral exposure as cynomolgus or rhesus monkeys. In all non-human primates, human exposure to phenytoin would be over-predicted, and erythromycin, lidocaine, and propranolol under-predicted, with good predictivity for the other compounds studied. Furthermore, in the vervet, ketoconazole co-administration resulted in a six-fold increase in exposure to erythromycin, demonstrating proof of concept for drug-drug interaction screening. These data support further exploration of the vervet as an alternate primate species for use in preclinical pharmacokinetic screening.

Application of an Inter-Species Extrapolation Method for the Prediction of Drug Interactions between Propolis and Duloxetine in Humans

“…Approaches to predict human PK profiles from in vitro and/or PK profiles in preclinical species, utilizing both physiological and empirical approaches, are highly desirable [32][33][34][35][36][37][38][39], because this can drastically reduce the time and expense of drug development and dose regiment. Allometric scaling, an empirical method, has been intensively studied and widely applied to predict many important PK parameters, including CL, Vd, and t 1/2 , due to its simplicity [23][24][25][26].…”

Pharmacokinetics and anti-inflammatory pharmacodynamics of prednisolone in cynomolgus monkey

“…Although, de Kruif et al did not publish any pharmacokinetic data for PRED in their study, the fact that the plasma-free PK of PRED in monkeys is similar to man (this study) means it is reasonable to assume that the sensitivity of the cytokine response is similar between monkey and man. This is not unusual as non-human primate studies (cynomolgus, rhesus, marmoset) are sometimes used to help predict pre-clinical pharmacokinetic (Ward et al 2009) and pharmacodynamic (Meno-Tetang and Lowe 2005) responses to humans. However, the costs of doing such studies may be prohibitive, and a compelling argument would have to be made for its necessity.…”

Ocular examination findings and selected ophthalmic diagnostic tests in African green monkeys (Chlorocebus aethiops sabaeus)

“…11,12 Research has shown that African green monkeys are an appropriate model for estimating human pharmacokinetic predictability and display similar pharmacokinetic properties to cynomolgus and rhesus macaques for intravenous, oral, and ophthalmic topical pharmaceuticals. [13][14][15] Several studies have established standard hematological and biochemical parameters for AGMs, [16][17][18][19] as well as demonstrated the influence of acclimatization to captivity, diet, gender, weight, and age on these parameters. [20][21][22][23][24] However, to the authors' knowledge, no normative ocular data for common ophthalmic diagnostic tests or descriptions of common ocular lesions have been reported in widely available scientific literature for this species.…”

“…Completion of genome sequencing in the African green monkey discovered a high degree of sequence conservation and genome collinearity between vervets, rhesus macaques, and humans, implying that investigations in vervets will have appropriate translatability to human studies 11,12 . Research has shown that African green monkeys are an appropriate model for estimating human pharmacokinetic predictability and display similar pharmacokinetic properties to cynomolgus and rhesus macaques for intravenous, oral, and ophthalmic topical pharmaceuticals 13–15 …”