Exploration of the African green monkey as a preclinical pharmacokinetic model: oral pharmacokinetic parameters and drug-drug interactions.
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.
Ward
K W
KW
RxGen, Hamden, CT, USA. Keith.W.Ward@bausch.com
Coon
D J
DJ
Magiera
D
D
Bhadresa
S
S
Struharik
M
M
Lawrence
M S
MS
D000818:Animals; D001372:Aza Compounds / Q000493:pharmacokinetics; D002522:Chlorocebus aethiops; D002851:Chromatography, High Pressure Liquid; D002939:Ciprofloxacin / Q000493:pharmacokinetics; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004917:Erythromycin / Q000493:pharmacokinetics; D024841:Fluoroquinolones; D008012:Lidocaine / Q000493:pharmacokinetics; D013058:Mass Spectrometry; D023421:Models, Animal; D000077266:Moxifloxacin; D010599:Pharmacokinetics; D010672:Phenytoin / Q000493:pharmacokinetics; D011239:Prednisolone / Q000493:pharmacokinetics; D011433:Propranolol / Q000493:pharmacokinetics; D011804:Quinolines / Q000493:pharmacokinetics; D013045:Species Specificity
D001372:Aza Compounds; D024841:Fluoroquinolones; D011804:Quinolines; D002939:Ciprofloxacin; D010672:Phenytoin; D004917:Erythromycin; D008012:Lidocaine; D011239:Prednisolone; D011433:Propranolol; D000077266:Moxifloxacin