Publication related to RSI or an RSI staff member
Pharmacokinetics of oseltamivir phosphate and oseltamivir carboxylate in non-pregnant and pregnant rhesus monkeys.
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(0-infinity) 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.
Authors
- Loukotkova, Lucie, Loukotkova L, FDA National Center for Toxicological Research, Jefferson, AR, USA.
- Basavarajappa, Mallikarjuna, Basavarajappa M, FDA National Center for Toxicological Research, Jefferson, AR, USA.
- Lumen, Annie, Lumen A, FDA National Center for Toxicological Research, Jefferson, AR, USA.
- Roberts, Rosemary, Roberts R, FDA Center for Drug Evaluation and Research, Silver Spring, MD, USA.
- Mattison, Donald, Mattison D, Risk Sciences International, Ottawa, Ontario, Canada and Hilton Head Island, SC USA and University of Ottawa, Ontario, Canada.
- Morris, Suzanne M, Morris SM, FDA National Center for Toxicological Research, Jefferson, AR, USA.
- Fisher, Jeffrey, Fisher J, FDA National Center for Toxicological Research, Jefferson, AR, USA.
- Beland, Frederick A, Beland FA, FDA National Center for Toxicological Research, Jefferson, AR, USA.
- Gamboa da Costa, Goncalo, Gamboa da Costa G, FDA National Center for Toxicological Research, Jefferson, AR, USA. Electronic address: goncalo.gamboa@fda.hhs.gov.
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(0-infinity) 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.
