Direct-acting Antiviral Interactions With Opioids, Alcohol or Illicit Drugs of Abuse in HCV-infected Patients

Kuntheavy Ing Lorenzini; François Girardin

Disclosures

Liver International. 2020;40(1):32-44. 

In This Article

Clinical Pharmacology of DAA

The currently available drugs in Europe are presented in Table 1, and their main PK and PD characteristics in Table 2, and in Figures 1 and 2.

Figure 1.

Transmembrane transport of direct-acting antiviral (substrates are underlined) and inhibition effect (╧) (alphabetic order). BCRP, breast cancer resistance protein; DCV, daclatasvir; EBR, elbasvir; GLE, glecaprevir; GRZ, grazoprevir; LED, ledipasvir; OATP, organic-anion-transporting polypeptide; P-gp, P-glycoprotein; PIB, pibrentasvir; SOF, sofosbuvir; VEL, velpatasvir; VOX, voxilaprevir

Figure 2.

Metabolism of direct-acting antiviral and inhibitor (╧) (alphabetic order). DCV, daclatasvir; EBR, elbasvir; GLE, glecaprevir; GRZ, grazoprevir; PIB, pibrentasvir; VEL, velpatasvir; VOX, voxilaprevir

Daclatasvir

Daclatasvir (DCV) is an inhibitor of the HCV non-structural 5A (NS5A) protein approved for HCV genotypes 1, 3 and 4 in association with sofosbuvir, with or without ribavirin.[13] It is readily absorbed after oral administration, with maximal concentrations (Cmax) achieved after 1–2 hours, and an absolute bioavailability of 67%, and is highly bound to plasma proteins (99%). DCV is a substrate of the P-glycoprotein (P-gp) efflux transporter, and is metabolized by cytochrome P450 (CYP) 3A isoenzymes, predominantly CYP3A4. A majority of the dose (88%) is excreted in the faeces and 7% in urine. The mean terminal half-life after multiple dosing is 12–15 hours. DCV is an inhibitor of P-gp, organic-anion-transporting polypeptide (OATP) 1B1 and breast cancer resistance protein (BCRP) transporters.[14] Interactions may occur when DCV is used concomitantly with CYP3A and P-gp inhibitor or inducers, and with P-gp, OATP and BCRP substrates.

From a safety point of view, the most common adverse events (AEs) in studies combining DCV and sofosbuvir were headache, nausea, diarrhoea, arthralgia and cough.[14] Regarding cardiac safety, a thorough QT study with therapeutic (60 mg) and supratherapeutic doses (180 mg) showed the absence of QTc variations or related repolarization abnormalities.[15]

Elbasvir/Grazoprevir

Elbasvir (EBR) and grazoprevir (GZR) are available as a 50/100 mg fixed-dose combination, approved for HCV genotypes 1a, 1b and 4.[16] EBR is an inhibitor of the HCV NS5A while GZR inhibits NS3/4A protease. EBR and GZR's bioavailability is 20% to 40%, and Cmax is achieved after 2–4 hours.[17,18] Both compounds display extensive protein binding (free fraction: 1%).[18] Excretion into faeces as parent drugs accounts for 75% to 80% of elimination of both EBR and GZR, the remaining 20% being excreted as oxidative metabolites formed via CYP3A.[17] Both compounds are P-gp substrates. In addition, GZR (but not EBR) is a substrate of OATP1B1 and OATP1B3.[17,18] Their steady-state elimination half-lives in HCV-infected subjects were 24 and 31 hours for EBR and GZR respectively.[18] Neither EBR nor GZR are potent inhibitors or inducers of CYP or uridine glucuronosyltransferase (UGT) enzymes in vitro,[18] but GZR is a weak inhibitor of CYP3A. EBR is a mild inhibitor of intestinal P-gp and BCRP, and GZR is an intestinal BCRP inhibitor.[17] Clinically relevant DDI are likely to occur with moderate and strong CYP3A and P-gp inducers (but not with CYP3A inhibitors), and when GZR is combined with OATP1B inhibitors.[17] CYP3A and P-gp/BCRP substrates with a narrow therapeutic range may be subject to DDI with EBR/GZR (increases in plasma concentrations).

The most frequently reported AEs were fatigue (17.0%), headache (16.4%), nausea and dose-dependent increases in liver function markers.[18,19]

Glecaprevir/Pibrentasvir

Glecaprevir and pibrentasvir are available as a 100/40 mg fixed-dose combination, approved for all HCV genotypes.[19] The recommended dose is 300/120 mg once daily (three tablets) to be taken with a meal. Glecaprevir is HCV NS3/4A protease inhibitor while pibrentasvir inhibits HCV NS5A.[20] Their Cmax is attained after 5 hours. Both drugs are extensively bound to plasma proteins (>95%). Glecaprevir undergoes limited CYP3A-mediated metabolism,[20] with 26% of the dose excreted as oxidative metabolites,[19] whereas pibrentasvir is not metabolized.[20] Both drugs are excreted in the faeces. Their elimination half-lives are 6–9 and 23–29 hours respectively.[20] Glecaprevir is a substrate and inhibitor of P-gp, BCRP and OATP1B1/B3. Pibrentasvir is a substrate of P-gp and of BCRP,[21] and inhibits P-gp, BCRP and OATP1B1/B3.[19] Clinical DDI studies have confirmed clinically relevant inhibition of P-gp, BCRP and OATP1B1/B3.[22] Finally, glecaprevir and pibrentasvir are weak inhibitors of CYP3A and UGT 1A1 in vitro and in vivo.[19,21] Therefore, CYP3A, UGT1A1, P-gp/BCRP and OATP1B substrates with a narrow therapeutic range are subject to DDI with glecaprevir and pibrentasvir.

The most frequently reported AEs were headache (13%), fatigue (11%) and nausea (8%).[20]

Sofosbuvir/Ledipasvir

The fixed-dose combination of sofosbuvir and ledipasvir contains 400 and 90 mg of each active substance respectively. It is approved for the treatment of HCV genotypes 1, 4, 5 and 6.[23] Sofosbuvir is a prodrug that requires several steps bioactivation to GS-461203, the pharmacologically active nucleoside analog triphosphate metabolite, which inhibits NS5B,[24,25] and is ultimately dephosphorylated to an inactive metabolite, GS-331007.[24,25] Ledipasvir inhibits NS5A. Sofosbuvir and ledipasvir Cmax are reached after 1 and 4 hours respectively. Their protein bound fractions are, respectively, 65% and 99%.[24] Sofosbuvir and its metabolites are not substrates of CYP or UGT enzymes. Ledipasvir and sofosbuvir itself are substrates for P-gp and BCRP, but not GS-331007.[24,26] Sofosbuvir elimination is essentially non-renal, whereas renal clearance is the major elimination pathway for GS-331007.[25] The latter has a half-life of 27 hours.[24] Ledipasvir half-life is 50 hours and it is mainly excreted in faeces (>70%).[27] Sofosbuvir and GS-331007 do not display significant inhibition or induction of CYP, UGT1A1 and main drug transporters.[25] Ledipasvir does not inhibit major human CYP,[27] but has shown to inhibit the transporters P-gp and BCRP in vitro.[23,26] The concomitant use of P-gp and/or BCRP inducers may result in virologic failure. P-gp and/or BCRP substrates with a narrow therapeutic range may see their exposure increase in the presence of sofosbuvir/ledipasvir.

Patients treated with the association may experience headaches, fatigue, insomnia, nausea and diarrhoea.[24] In healthy volunteers, the corrected QT interval was not prolonged after single therapeutic (400 mg) and after supratherapeutic doses of sofosbuvir (1200 mg) and ledipasvir 120 mg (twice daily) in thorough QT studies.[25,28]

Sofosbuvir/Velpatasvir

The pangenotypic combination of sofosbuvir and velpatasvir contains 400 and 100 mg of each active substance respectively.[29] Velpatasvir is an HCV NS5A protein inhibitor. Its Cmax is reached 3 hours after oral administration. Velpatasvir is extensively bound to plasma proteins (>99%), and undergoes minor metabolism by CYP2B6, CYP2C8 and CYP3A4, and is excreted (77% as parent drug) in the faeces with a median terminal plasma half-life of 15 hours. Velpatasvir is transported by P-gp and BCRP, and is also an inhibitor of P-gp, BCRP, OATP1B1/B3 and OATP2B1.[30,31] There is a risk of therapeutic failure when the association is administered with P-gp and/or BCRP inducers. Substrates of P-gp, BCRP and OATP can be subject to an increase in their exposure when administered with sofosbuvir/velpatasvir.[30]

The most common AEs when sofosbuvir/velpatasvir is used without ribavirin are headache and fatigue.[30,31] In healthy volunteers, the corrected QT interval was not significantly prolonged by therapeutic sofosbuvir (400 mg) or supratherapeutic doses of velpatasvir (500 mg) or sofosbuvir (1200 mg).[30]

Sofosbuvir/Velpatasvir/Voxilaprevir

The pangenotypic combination of sofosbuvir, velpatasvir and voxilaprevir contains 400, 100 and 100 mg of each active substance.[32] Voxilaprevir is a reversible NS3/4A protease inhibitor. It reaches Cmax 4 hours after administration. Food substantially increases the systemic exposure. It is extensively bound to plasma proteins (>99%) and undergoes metabolism by CYP3A4. Voxilaprevir is eliminated through biliary excretion, 40% as the parent drug, with a half-life of 33 hours.[11,33] Voxilaprevir is a substrate of P-gp, BCRP and OATP1B1/B3.[34] Inhibition of OATP1B1/B3 at clinically achieved concentrations is reported.[34] There is a risk of therapeutic failure when inducers of CYP3A, P-gp and/or BCRP are co-administered. Concentrations of OATP1B1/B3 substrates can increase when administered with sofosbuvir/velpatasvir/voxilaprevir.[33]

The most frequently reported AEs with this association are headache, fatigue, diarrhoea and nausea. Voxilaprevir was not shown to significantly prolong the QTc interval when given at nine times the recommended dose.[33]

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