Review Article

Direct-acting Antivirals for the Treatment of HCV During Pregnancy and Lactation

Implications for Maternal Dosing, Foetal Exposure, and Safety for Mother and Child

Jolien J. M. Freriksen; Minou van Seyen; Ali Judd; Diana M. Gibb; Intira J. Collins; Rick Greupink; Frans G. M. Russel; Joost P. H. Drenth; Angela Colbers; David M. Burger

Disclosures

Aliment Pharmacol Ther. 2019;50(7):738-750. 

In This Article

Placental Handling of Direct-acting Antivirals

Drug transport across the placental barrier is a major determinant of foetal exposure and toxicity. However, for some conditions foetal exposure to maternally administered drugs could potentially provide pre-exposure prophylaxis and thereby reduce the chance of vertical transmission, as has been hypothesised for HIV.[77]

Placental Handling in Human Pregnancy

For ethical reasons, pregnant women have historically often been excluded from clinical trials in the drug development process, resulting in a gap of knowledge regarding both maternal and foetal drug exposure throughout gestation. However, recent reports on the importance of conducting pharmacological research in pregnancy and possible research strategies highlight that times are changing.[78,79] To our knowledge, information on DAA exposure during pregnancy is currently limited to three conference abstracts. However, none of these studies collected data on foetal exposure (eg as umbilical cord blood concentrations) as treatment was either discontinued or completed during pregnancy and it is therefore not known whether or how well these DAAs cross the human placental barrier in vivo.

Placental Handling in Pre-clinical Research

Studies on placental handling of DAAs are solely based on developmental toxicology studies in animal models. As shown in Table 2, placental transfer of sofosbuvir, daclatasvir, glecaprevir, pibrentasvir, grazoprevir and elbasvir has been observed in rats. Placental transfer of grazoprevir and elbasvir has, in addition to rats, also been observed in rabbits, but to a minimal extent. However, because of interspecies differences in placental anatomy, placental transfer data from animal studies is of poor translational value. Compared to the placenta of rabbit, rat and mouse, the structure of the human placenta differs in gross shape, histology of the maternofoetal interface and type of maternofoetal interdigitation, which may all affect placental drug transfer.[80]

Prediction of Placental Drug Handling ex Vivo

To predict transfer of drugs across the human placenta in vivo, data from animal studies may be combined with information on drug-specific physicochemical characteristics. Comparing DAAs based on their specific physicochemical properties provides information on potential changes in their pharmacokinetics during pregnancy (Chapter 2) and a similar approach can yield estimates of placental transfer, and hence provides a rough estimate of foetal exposure. A review by Giaginis et al summarised the factors affecting transport of drugs across the placental barrier.[81] In general, maternofoetal exchange increases with gestational age because of physiological changes, eg reduced membrane thickness and increased uterine blood flow, inherent to the increased foetal demand of oxygen and nutrients.[80] Passive diffusion is the major route of placental transport and is responsible for rapid transfer of lipophilic drugs with a molecular weight of <500 Da. Larger molecules may also be subjected to passive diffusion, which is a relatively slow process;[81] all DAAs are highly lipophilic, indicated by a log P >2.5 (except for sofosbuvir, log P = 1.62), favouring effective passive diffusion. On the other hand, their high molecular weight (all >500 Da) may hamper or at least slow the process. In addition, the degree of ionisation and protein binding also influence the rate and extent of placental transfer. Protein binding will contribute to trapping of drug in the foetal or maternal circulation, and as maternal and foetal plasma protein concentrations differ and change with advancing gestational age, the maternal-to-foetal ratio of total drug plasma concentration may vary accordingly.[82] Next to passive diffusion, drug transport across the placental barrier may also be carrier-mediated, either as facilitated diffusion or via active transporters. All DAAs included in this review are ATP-binding cassette (ABC) transporter substrates of P-gp (ABCB1) and/or Breast Cancer Resistance Protein (BCRP/ABCG2). As these efflux transporters are expressed at the apical side of the syncytiotrophoblast layer, they possibly play a role in reducing foetal exposure. Xenobiotics interacting with these transporters may also influence placental transfer of DAAs.[83] Since placental transporter expression changes during pregnancy, placental transfer may be also dependent on timing of treatment during pregnancy. A reduction in P-gp mRNA and protein levels from first trimester towards term has been reported, likely related to the general decrease in foetal protection after the critical period of organogenesis. Therefore, there is a greater potential of P-gp substrates (eg most DAAs), to reach the unborn child with advancing gestational age. Literature on BCRP expression throughout gestation is inconsistent.[84]

As outlined above, different factors either facilitate or impede drug transport across the placental barrier. Hence, it is difficult to estimate the extent of placental transport of a specific drug at a specific time point during pregnancy. In addition to in vitro techniques using immortalised cell lines or tissue explants, computer-assisted modelling attempts are useful to explore the contribution of the physicochemical properties to placental transport.[85,86] The dual side placental perfusion model has proven to be a valid experimental method to study the transport of xenobiotics ex vivo and is currently used extensively to investigate placental passage.[87] As stated before, it is hypothesised that the extent of placental drug transfer increases towards term.[80] Therefore, data from ex vivo placental perfusion experiments using term placentas potentially overestimate foetal exposure during earlier phases of pregnancy.[87] For a variety of drugs studied, transfer across term placentas ex vivo shows good correlations with in vivo maternal and cord blood concentration. Hence, data from ex vivo placental perfusion experiments may also be used to rank the various DAAs with regard to their potential to cross the placenta.[88]

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