Pharmacokinetics of Intravenous Acyclovir, Zidovudine, and Acyclovir-Zidovudine in Pregnant Rats

Abstract

The pharmacokinetics and placental transfer of acyclovir and zidovudine monotherapies and acyclovirzidovudine combination therapy were compared in the pregnant rat. Timed-pregnancy Sprague-Dawley rats were used for the study. Doses of 60 mg of each drug/kg of body weight in monotherapy and in combination therapy were given by intravenous bolus, and samples of maternal plasma, amniotic fluid, fetal tissue, and placental tissue were collected over a period of 8 h postdose. Concentrations of each drug in the various matrices were measured by high-performance liquid chromatography. All data were analyzed by using WinNonlin. A one-compartment model with first-order elimination was used to fit the AZT plasma data from the combination therapy rats, but the plasma data from the other groups were fit to a two-compartment model. Tissue data were analyzed by noncompartmental analysis to generate area-under-the-concentration-time-curve values. Implementation of the combination therapy altered the pharmacokinetics of each drug compared to its monotherapy pharmacokinetics. The combination of these two drugs may potentiate fetal and amniotic fluid exposures to each drug., an acyclic analog of the natural nucleoside 2Ј-deoxyguanosine ( Fig. 1), is active against the members of the herpes group of DNA viruses (14, 42). For over 2 decades, ACV has been considered the first choice of treatment for herpes simplex virus types 1 and 2 (HSV-1 and -2), but it has also been shown to effectively treat varicella-zoster virus and provide protection from cytomegalovirus in immunosuppressed patients receiving transplants (12, 32). The success of ACV in treating HSV has prompted the synthesis of several structural analogs, but none has shown to be as tolerable as and have shown to have such a high therapeutic index as ACV (13,35,40). Zidovudine (3Ј-azido-3Ј-deoxythymidine [AZT]) (Fig. 1) is the premier reverse transcriptase inhibitor released for the treatment of human immunodeficiency virus (HIV). A therapy involving the combination of ACV and AZT is not uncommon to help suppress symptoms in patients who are both HIV positive and HSV-2 positive. These drugs, both in monotherapy and in combination, have been used to prevent vertical (mother-to-child) transmission of HSV-2 and HIV.The Acyclovir in Pregnancy Registry has compiled a large amount of case study information regarding the relative safety and efficacy of ACV use in HSV-2-positive pregnant women (1). Although a great deal is known about the pharmacokinetic properties of ACV, little work has been done to characterize the placental transfer of ACV in vivo, because pregnant women are routinely excluded from clinical trials. Pharmacokinetic parameters may be altered during pregnancy due to the increase in body fat content, cardiac output, and total body water seen in pregnant women (15,41,48). There may also be changes in plasma albumin concentration and protein binding affinities (25,39). The perfused human placenta model has been used on occasion in attempts to characterize the placenta...

Valacyclovir Suppressive Therapy Reduces Plasma and Breast Milk HIV-1 RNA Levels During Pregnancy and Postpartum: A Randomized Trial

“…It is possible that the additional viral suppression during pregnancy was due to synergy between ZDV and valacyclovir. However, although in vitro studies suggest that acyclovir may potentiate the action of ZDV [38,39], an in vivo study did not support these findings [40]. During the postpartum period the effect of suppressive therapy on HIV-1 RNA continued and was sustained for 12 months after the effect of sdNVP on plasma and breast milk HIV-1 RNA waned.…”

Determination of lamivudine in plasma, amniotic fluid, and rat tissues by liquid chromatography

“…This dose was chosen because of its comparability to human dosing and to allow comparison to previous animal studies involving antiviral agents in the pregnant rat [15][16][17][18][19][20][21]. Plasma, amniotic fluid, placental and fetal tissues were processed and analyzed as mentioned.…”

Determination of didanosine in maternal plasma, amniotic fluid, fetal and placental tissues by high‐performance liquid chromatography–tandem mass spectrometry

“…Therefore, an animal model must be utilized that will provide clinically useful mechanistic information. A pregnant rat model has been developed and used for the investigation of the basic mechanisms involved in the placental transfer of nucleoside analogs (Huang et al, 1996;Brown et al, 2003). The rat model has proved to be useful due to the similarities of the hemochorial placenta and hemodynamic pregnancy changes experienced in both rats and humans (Faber et al, 1983;Boike et al, 1989a).…”

“…The large litter size and individual fetal sacs allow for serial maternal blood, placental, fetal and amniotic fluid sampling, making it even more useful for pharmacokinetic studies. The pregnant rat model has been utilized in maternal-fetal drug transfer studies of a variety of compounds, including AZT (Boike et al, 1989a,b;Heffez et al, 1990;Dawson et al, 1990;Fujinaga et al, 1991;Beachy et al, 1993;Ostrea et al, 1994;Huang et al, 1996;Brown et al, 2003).…”