Summary Background With the global efforts to eradicate hepatitis C virus (HCV), treatment during pregnancy is becoming a priority for research as this, and maternal cure should reduce vertical transmission. However, as information on the efficacy and safety of direct‐acting antivirals (DAAs) in pregnancy is generally lacking, treatment of HCV infection during pregnancy is not currently recommended. Aim To provide an overview of current knowledge regarding maternal exposure, placental handling and safety of DAAs during pregnancy and lactation Methods A literature search was performed focusing on the effect of pregnancy on maternal exposure to DAAs, the placental handling of DAAs, the safety of DAAs for mother and child during pregnancy and the safety of DAAs during lactation. Results Exposure to all DAAs studied is likely to be altered during pregnancy, mostly related to pregnancy‐induced effects on drug absorption and metabolism. Although animal studies show that most DAAs are reported to cross the placenta and transfer into breast milk, most DAA combinations show a favourable safety profile. Because of the rapid viral decline after treatment initiation, and to avoid the critical period of organogenesis, treatment may be started at the end of the second trimester or early third trimester. Conclusions Treatment of HCV infection during pregnancy is realistic, as DAAs are highly effective and treatment duration is relatively short. There is an urgent need to study DAAs during pregnancy and lactation to contribute to the goal of HCV elimination.

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We read with great interest the Snapshot 'Treatment of chronic hepatitis C" recently published by Forns and Sarrazin in the Journal of Hepatology. 1 The authors defined several special populations which require special attention. We believe, that patients on strong inducing anti-epileptic drugs (AEDs) such as carbamazepine, phenytoin and phenobarbital are an additional population that requires special attention as treatment of individual cases remains a major challenge. 2 Co-administration of direct-acting antivirals (DAAs) with these AEDs is contraindicated as plasma concentrations are markedly reduced 2 potentially leading to loss of efficacy and virological failure. A recent study in Sweden showed that carbamazepine was prescribed in 2% of all patients diagnosed with HCV. Carbamazepine was the most commonly used contraindicated drug for the several DAA combinations. 3 The majority of drug-drug interactions (DDIs) with other drugs classes, an interacting drug can temporarily be stopped or substituted. However, it is our experience that in some cases, patients are not able or willing to stop or substitute AEDs, to prevent DDIs. 4,5 Therefore, some patients on enzyme inducing AEDs, based on product labels, cannot be treated for HCV. 6,7

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Background Finding a suitable treatment for HCV patients with swallowing disorders is still a major challenge. In practice, direct-acting antivirals are crushed without knowledge of adequate absorption. Crushing can alter drug exposure, possibly leading to treatment failure, development of resistance or toxicity. Currently, there is no information about crushing of the fixed-dose combination tablet of elbasvir/grazoprevir; therefore, crushing of this tablet is not recommended. Objectives To investigate the influence of crushing on the pharmacokinetics of the elbasvir/grazoprevir fixed-dose combination tablet. Methods We conducted an open-label, two-period, randomized, cross-over, Phase I, single-dose trial in 11 healthy adult volunteers. Subjects randomly received whole-tablet elbasvir/grazoprevir or crushed and suspended elbasvir/grazoprevir in a fasted state. Pharmacokinetic similarity criteria (90% CIs lie within 70%–143% acceptance range) were used for AUC0–∞ and AUC0–72. Results Mean plasma concentration–time curves of elbasvir and grazoprevir showed similar pharmacokinetic profiles. The primary pharmacokinetic parameters AUC0–∞ and AUC0–72 of elbasvir and grazoprevir after intake of a crushed tablet were on average 12%–16% higher compared with the whole tablet, but 90% CIs were all within the predefined boundaries of pharmacokinetic similarity. Crushing leads to a higher Cmax of grazoprevir (42%); no significant difference was found between treatments with regard to the Cmax of elbasvir. No serious adverse events were reported during the trial. Conclusions Pharmacokinetic similarity could be demonstrated for a crushed and suspended tablet compared with a whole tablet, without impacting drug safety or efficacy. Crushed and suspended administration of elbasvir/grazoprevir can be used in patients with swallowing disorders.

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We aimed to evaluate the effect of the acid beverage Coca‐Cola on the pharmacokinetics of velpatasvir (VEL) when given with omeprazole. This was an open‐label, randomized, crossover trial in 11 healthy adults. A single dose of sofosbuvir/velpatasvir (SOF/VEL) 400/100 mg was administered alone (reference) or with omeprazole 40 mg once daily with water (intervention I); in the intervention II arm, omeprazole 40 mg was combined with 250 mL of Coca‐Cola. Geometric mean ratios (GMRs) were calculated for VEL area under the concentration‐time curve from zero to infinity (AUC 0−inf) and maximum plasma concentration (Cmax). VEL exposure was reduced by 26.7% when SOF/VEL was coadministered with omeprazole vs. reference: GMRs (90% confidence interval (CI)) were 73.3% (55.6–96.8) and 69.1% (52.3–91.2) for AUC 0‐inf and Cmax, respectively. Intake of SOF/VEL with Coca‐Cola compensated for the interaction with omeprazole and resulted in a higher VEL exposure. GMRs (90% CI) were 161.6% (122.4–213.3) for AUC 0‐inf and 143.9% (109.0–190.0) for Cmax. Therefore, Coca‐Cola can be used to overcome the drug–drug interaction between VEL and omeprazole.

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