FDA National Center for Toxicological Research, Jefferson, AR, USA.
FDA Center for Drug Evaluation and Research, Silver Spring, MD, USA.
Regul Toxicol Pharmacol. 2020 Apr;112:104569. doi: 10.1016/j.yrtph.2019.104569. Epub 2020 Jan 9.
Oseltamivir is an antiviral drug approved to treat influenza in humans. Although the dosing regimen of this drug is well established for non-pregnant patients, it is not clear if the significant physiological alterations associated with pregnancy affect the pharmacokinetics of oseltamivir and, thus, warrant different dosing regimens to assure efficacy. In this study, we investigated the suitability of rhesus macaques as an animal model for studying oseltamivir pharmacokinetics during all trimesters of pregnancy in comparison to pre-pregnant conditions. Specifically, we compared the pharmacokinetics of oseltamivir and its pharmacologically active metabolite oseltamivir carboxylate in rhesus monkeys after intravenous and nasogastric administration of 2.5 mg oseltamivir phosphate/kg body weight given prior to and during the first, second, and third trimesters of pregnancy. Pregnancy had only a modest effect upon the pharmacokinetic parameters of oseltamivir and oseltamivir carboxylate. Monkeys treated intravenously in the third trimester had a reduction in Vd and CL, compared to non-pregnant monkeys. These changes did not occur in the other two trimesters. Pregnant monkeys treated intravenously had 20-25% decrease in AUC of oseltamivir carboxylate and a corresponding increase in Vd and CL. Pregnant monkeys treated nasogastrically with oseltamivir phosphate demonstrated a pattern that recapitulated intravenous dosing. Taken together these data indicate that rhesus monkeys are an acceptable model for studying drug-pregnancy interactions.
奥司他韦是一种抗病毒药物，已被批准用于治疗人类流感。尽管该药物的剂量方案已在非孕妇患者中得到很好的确立，但尚不清楚与怀孕相关的重大生理变化是否会影响奥司他韦的药代动力学，从而需要不同的剂量方案以确保疗效。在这项研究中，我们研究了恒河猴是否适合作为研究整个孕期奥司他韦药代动力学的动物模型，并与怀孕前的情况进行比较。具体而言，我们比较了恒河猴在怀孕前和怀孕第一、二、三期间，经静脉和鼻胃管给予 2.5mg 磷酸奥司他韦/公斤体重后，奥司他韦和其具有药理活性的代谢物奥司他韦羧酸的药代动力学。怀孕对奥司他韦和奥司他韦羧酸的药代动力学参数仅有适度影响。与非孕妇猴子相比，在怀孕第三期间接受静脉治疗的猴子的 Vd 和 CL 降低。在其他两个孕期中没有发生这些变化。静脉给予怀孕猴子奥司他韦羧酸的 AUC 降低了 20-25%，Vd 和 CL 相应增加。经鼻胃管给予奥司他韦磷酸盐的怀孕猴子表现出与静脉给药相似的模式。这些数据表明，恒河猴是研究药物与妊娠相互作用的可接受模型。
