In vivo maternal-fetal pharmacokinetics of stavudine (2',3'-didehydro-3'-deoxythymidine) in pigtailed macaques (Macaca nemestrina)

Abstract

To determine whether stavudine (2',3'-didehydro-3'-deoxythymidine) is actively transported in vivo across the placenta and to determine the extent of its transfer, stavudine was administered as an intravenous bolus to four near-term macaques (Macaca nemestrina) (5 mg/kg of body weight via the femoral vein) or to their fetuses (10 mg/kg via the carorid artery) at gestational age 134 +/- 5 days, with the administrations about 1 week apart. Antipyrine (a passive diffusion marker) was always coadministered (20 mg/kg) with stavudine. Samples of maternal and fetal plasma and amniotic fluid were collected at frequent intervals up to 240 min after the dose. In a separate experiment, three animals received stavudine for 30 h at a low rate of infusion (22 micrograms/min/kg via the femoral vein) to the dam or at a 10-fold-higher rate of infusion (220 micrograms/min/kg), separated by at least one week, in order to determine if the transplacental transfer of stavudine is saturable. Antipyrine (41.7 micrograms/min/kg) was coinfused with stavudine. Samples of maternal and fetal plasma and amniotic fluid were collected at regular intervals for up to 30 h. The concentrations of stavudine and antipyrine were determined by high-performance liquid chromatography. The transplacental maternal-fetal drug clearances were compared by the paired Student t test. The clearance associated with maternal-fetal transfer of the drug (CLdf) (0.54 +/- 0.08 ml/min/kg) was not significantly different (P > 0.05) from the clearance associated with fetal-maternal transfer of the drug, CLfd (0.66 +/- 0.11 ml/min/kg). Also, CLdf was not significantly different (P > 0.05) from CLfd when normalized with respect to the corresponding transplacental clearance of antipyrine (0.23 +/- 0.04 versus 0.36 +/- 0.25). The ratios of the steady-state plasma stavudine concentration in the fetus to that in the dam were 0.77 +/- 0.06 at the low stavudine infusion rate and 0.81 +/- 0.09 at the high stavudine infusion rate. The obtained data indicate that transfer of stavudine across the placenta is passive and constant over the dose range studied.

Antiviral and antiretroviral use in pregnancy

“…Exposure of early embryos to stavudine inhibited progression to the blastocyst stage. Studies in pregnant rats and rabbits that were administered 183 to 400 times the human serum concentrations did not show an increase in birth defects [92,93].…”

British HIV Association guidelines for the management ofHIVinfection in pregnant women 2012

“…The pharmacokinetics of most NRTIs (zidovudine [104], stavudine [105], lamivudine [106], abacavir [107]) are not significantly affected by pregnancy and dose adjustment is not required. Renal excretion of didanosine is increased in pregnancy, but dose alteration is probably not required [108].…”

Prenatal and postpartum pharmacokinetics of stavudine (2',3'-didehydro-3'-deoxythymidine) and didanosine (dideoxyinosine) in pigtailed macaques (Macaca nemestrina)

“…Before such clinical studies can be conducted in pregnant women, the toxicity (including fetal toxicity) and pharmacokinetics of these drugs must be determined in a representative animal model. In previous communications we have reported data from our study on the in vivo placental transfer of stavudine and didanosine in pigtailed macaques (Macaca nemestrina) (17,18). Since the pharmacokinetics of a drug may be affected significantly by pregnancy (9,15), in this study we have investigated the effect of pregnancy on the pharmacokinetics of these two drugs in M. nemestrina.…”

“…All other chemicals used were of reagent grade. Pregnant near-term macaques were chronically catheterized, as described before, at least 2 weeks before the studies (14,17). Stavudine (5 mg/kg of body weight; n ϭ 7) was administered (via the femoral vein) as a bolus dose at gestation age 139 Ϯ 8 days (weight, 7.92 Ϯ 0.52 kg; term is ϳ170 days) and repeated at 36 Ϯ 2 days (7.62 Ϯ 0.92 kg) after parturition.…”

“…Urine was collected for 24 h on dry ice after drug administration. Some of the animals reported here also participated in the study of transplacental transfer of stavudine and didanosine (17,18).…”