In vitro models to predict the in vivo mechanism, rate, and extent of placental transfer of dideoxynucleoside drugs against human immunodeficiency virus,☆☆,

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Abstract

Objective: We tested the hypothesis that the mechanism, rate, and extent of in vivo placental transfer of dideoxynucleoside drugs against human immunodeficiency virus can be predicted by the in vitro perfused human placenta and the drug octanol-water partition coefficient. Study Design: Near-term pregnant macaques (Macaca nemestrina) underwent long-term catheterization for the administration of 4 dideoxynucleosides against human immunodeficiency virus: zidovudine, didanosine, zalcitabine, and stavudine. Maternal plasma, fetal plasma, and amniotic fluid concentrations were determined frequently after intravenous bolus and/or infusion of the drugs administered into the maternal or fetal circulation on separate occasions. Antipyrine was included in all experiments as a marker of placental blood flow. The mechanism, rate, and extent of placental transfer of the 4 dideoxynucleosides in perfused human placenta were determined and compared with the findings obtained by others. Results: The mechanism and rate of the antipyrine-normalized placental transfer of the 4 dideoxynucleosides in perfused human placenta were highly correlated with those observed in vivo. The extent of placental transfer (fetal/maternal steady-state plasma concentration ratio) was also highly correlated with both the antipyrine-normalized placental transfer clearance (clearance index) determined in the in vitro perfused human placenta model (r 2 = 0.95, in vitro clearance-index model) and the drug octanol-water partition coefficient (r 2 = 0.99, in vitro partition-coefficient model). To determine the predictive capacity of these correlative models, we predicted the fetal/maternal steady-state plasma concentration ratio of each drug after excluding the data on that drug from the model fit. Both in vitro models to predict in vivo placental transfer of drug models resulted in good predictions of the observed fetal/maternal steady-state plasma concentration ratio (mean error: in vitro clearance-index model = −1.2%; in vitro partition-coefficient model = 3.9%). Conclusions: We propose that our models will accurately predict the extent of placental transfer of dideoxynucleoside drugs against human immunodeficiency virus. The models may also be applicable to other classes of drugs, regardless of therapeutic category, provided that these drugs passively diffuse across the placenta. Such a result will expedite phase 1 clinical trials of drugs in pregnant women. (Am J Obstet Gynecol 1999;180:198−206.)

Section snippets

In vivo catheterized pregnant macaque model

Each of the 4 drugs was tested in 3 or 4 near-term pregnant pigtailed macaques. The protocol for the care and use of the animals was approved by the University of Washington Institutional Animal Care and Use Committee. The experimental design and data analyses of dideoxynucleoside studies in our laboratory are described elsewhere.1, 2, 3, 4, 5, 6, 7, 8, 9 Briefly, the macaques underwent long-term catheterization at 125 to 130 days of gestation. With the animals under general anesthesia,

Results

The mechanism of placental transfer of zidovudine, stavudine, zalcitabine, and didanosine was found to be passive in both the in vivo pregnant macaque model and the in vitro perfused human placenta model. The rates of placental transfer (clearance indexes) determined in vivo and in vitro were significantly correlated with each other (r 2 = 0.93, P < .05; Fig 1).

. In vitro and in vivo placental transfer clearance indexes are highly (r 2 = 0.93) and significantly (P < .05) correlated. CLmf (

Comment

We chose the pigtailed macaque as a representative animal model primarily because it has a discoid placenta with multivillous fetal-maternal interdigitation and a hemo-monochorionic barrier similar to that found in humans. In addition, the disposition of dideoxynucleosides in the macaque is comparable to that in humans,1, 2, 3, 4, 5, 6, 7, 8, 9 and both HIV-2 and the simian immunodeficiency virus can be transmitted from the mother to the fetus in this animal species. Therefore the macaque may

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    Supported by grants HD27438, HD02274, and RR00166 from the National Institutes of Health.

    ☆☆

    Reprint requests: Jashvant D. Unadkat, PhD, Professor, Department of Pharmaceutics, Box 357610, School of Pharmacy, University of Washington, Seattle, WA 98195-7610.

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