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

Safety of Direct-acting Antivirals During the Lactation

As studies have shown that avoidance of breastfeeding does not seem to reduce the chance of vertical HCV transmission, breastfeeding is considered safe among women with chronic HCV, except for women with cracked nipples.[110] Since breastfeeding is currently not contra-indicated in these patients living with HCV, it is important to gather information of the potential use and safety of DAAs during the lactation period.

To evaluate safety of drug use during the lactation period the following aspects should be considered: the effect of drugs on milk production; drug concentrations in milk; and the effects of exposure on the breastfed child. In the absence of human data, data on DAA exposure in milk are limited to rat studies. They should be interpreted with caution due to species-specific differences in lactation physiology such as mammary gland anatomy, storage and release of milk into ducts, protein and fat composition of milk and the expression of drug transporters in mammary tissue, as these factors play a major role in the extent passage of drugs into milk.[111] Data obtained from rat studies showed that DAAs are transferred into milk, but no effects on growth and development were observed in nursing pups exposed to DAAs via milk.[97,99,104,107] Maternal plasma-to-milk ratios have been reported to differ considerably between DAAs in rat studies. Whereas glecaprevir concentrations in milk are <8% of maternal plasma levels, grazoprevir milk concentrations exceed maternal plasma concentrations (400%). This disparity in extent of milk transfer is, however, difficult to explain based on the physicochemical differences and transporter profiles of the two compounds.[112] Grazoprevir and glecaprevir have a comparable molecular weight with a similar degree of plasma protein binding. Moreover, glecaprevir is known to be a BCRP substrate, whereas grazoprevir is not. As this transporter is considered to contribute to excretion of drugs into milk,[113] the proportion of glecaprevir transferred to milk is expected to be high, but extensive plasma protein binding impedes its transfer into breastmilk.

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