Drug–Drug Interactions of Newly Approved Direct-Acting Antiviral Agents in Patients with Hepatitis C

Figures & data

Figure 1 Mechanism of DAAs. Elbasvir, an inhibitor of NS5A; Grazoprevir, an inhibitor of the NS3/4A protease; Glecaprevir, an inhibitor of NS3/4A protease; Pibrentasvir, an inhibitor of NS5A; Velpatasvir, an inhibitor of the NS5A protein; Voxilaprevir, an inhibitor of the NS3/4A protease. Solid diamonds denote sites of the hepatitis C virus (HCV) polyprotein precursor cleavaged by the endoplasmic reticulum signal peptidase. Amino acid positions are shown above each protein. The open diamond indicates further processing of the core protein by signal peptide peptidase. Arrows indicate sites cleavaged by HCV NS2–3 and NS3 proteases. Asterisks in the E1 and E2 region indicate the glycosylation of the envelope proteins. Reproduced from Moradpour D, Brass V, Gosert R, Wölk B, Blum HE, Hepatitis C: molecular virology and antiviral targets, Trends in Molecular Medicine, 2002;8:476–482. Copyright (2002), with permission from Elsevier.⁸⁸

Abbreviation: NCR, noncoding region.

Table 1 Drug–Drug Interactions Associated with Elbasvir and Grazoprevir^#

Concomitant Drugs	EBR’s Effects on AUC*	GZR’s Effects on AUC*	EBR/GZR’s Effects on AUC*	Subjects	Comments^Citation9
Famotidine^Citation20			GZR 1.10↑, EBR 1.05↑	Healthy	No dose adjustments are needed.
Pantoprazole^Citation20			GZR 1.12↑, EBR 1.05↑	Healthy	No dose adjustments are needed.
Ethinyl estradiol^Citation30	Ethinyl estradiol 1.01↑	Ethinyl estradiol 1.10↑		Healthy	No dose adjustments are needed.
Levonorgestrel^Citation30	Levonorgestrel 1.14↑	Levonorgestrel 1.23↑		Healthy	No dose adjustments are needed.
Buprenorphine/naloxone^Citation25	EBR 1.22↑, buprenorphine 0.98↓, norbuprenorphine 0.97↓, naloxone 0.88↓			Healthy	No dose adjustments are needed.
Atazanavir/ritonavir^Citation19		Atazanavir 1.43↑, GZR 10.58↑		Healthy	Co-use of atazanavir/ritonavir with EBR/GZR is contraindicated.
Darunavir/ritonavir^Citation19		Darunavir 1.11↑, GZR 7.50↑		Healthy	Co-use of darunavir/ritonavir with EBR/GZR is contraindicated.
Lopinavir/ritonavir^Citation19		Lopinavir 1.03↑, GZR 12.86↑		Healthy	Co-use of lopinavir/ritonavir with EBR/GZR is contraindicated.
Efavirenz^Citation18		GZR 0.16↓, efavirenz unaffected		Healthy	Co-use of efavirenz with EBR/GZR is contraindicated.
Atorvastatin^Citation10		Atorvastatin 3.00↑		Healthy	Dose adjustments may be needed.
Pitavastatin^Citation10		Pitavastatin 1.11↑		Healthy	No dose adjustments are needed.
Midazolam^Citation10		Midazolam 1.34↑		Healthy
Rifampin†^Citation11		GZR 12.61↑, 8.35↑, 0.93↓		Healthy	Co-use of rifampin with EBR/GZR is contraindicated.
Tacrolimus^Citation27			Tacrolimus 1.43↑, EBR/GZR almost unaffected	Healthy	Frequent monitoring of tacrolimus is required.
Cyclosporine^Citation27			EBR 1.98↑, GZR 15.21↑, cyclosporine almost unaffected	Healthy	Co-use of cyclosporine with EBR/GZR is contraindicated.
Mycophenolate mofetil^Citation27			Mycophenolic acid 0.95↓, EBR 1.07↑, GZR 0.74↓	Healthy	No dose adjustments are needed.
Prednisone^Citation27			Prednisone 1.08↑, prednisolone 1.08↑, EBR 1.17↑, GZR 1.09↑	Healthy	No dose adjustments are needed.

Notes: ^#This table is not all inclusive; *, ^↑Increase; ^↓Decrease; The value refers to a ratio of AUCs of a tested drug with or without co-administered drugs; AUCs include AUC_0-12, AUC_0-24 (area under the concentration-time curve from time 0 to 12 or 24 hours), and AUC_0-∞ (that from time 0 to infinity); ^†Co-administration with a single intravenous, oral, or multiple oral dose of 600mg rifampin.

Abbreviations: EBR, elbasvir; GZR, grazoprevir; AUC, area under concentration-time curve; ORT, opioid replacement therapy; DDI, drug–drug interaction.

Table 2 Drug–Drug Interactions Associated with Velpatasvir and Voxilaprevir^#

Concomitant Drugs	VEL’s Effects on AUC*	VOX’s Effects on AUC*	SOF/VEL’s Effects on AUC*	SOF/VEL/VOX’s Effects on AUC*	Subjects	Comments^Citation31,Citation32
Pravastatin^Citation34,Citation44	Pravastatin 1.35↑			Pravastatin 2.16↑	Healthy	Pravastatin may be administered with SOF/VEL/VOX at an adequate dose but does not incur clinically relevant DDIs with SOF/VEL.
Rosuvastatin^Citation34,Citation44	Rosuvastatin 2.70↑			Rosuvastatin 7.39↑	Healthy	Rosuvastatin may be administered with SOF/VLE at an adequate dose and is not recommended for co-use with SOF/VEL/VOX.
Digoxin^Citation34	Digoxin 1.34↑				Healthy	Therapeutic concentration monitoring of digoxin is recommended when co-administered with SOF/VEL or SOF/VEL/VOX.
Rifampin†^Citation34,Citation44	VEL 1.47↑, 0.18↓	VOX 7.91↑, 0.27↓			Healthy	Rifampin is not recommended for co-use with SOF/VEL and contraindicated with SOF/VEL/VOX.
Cyclosporine^Citation34,Citation44	VEL 2.03↑	VOX 9.39↑			Healthy	Cyclosporine may be co-administered with SOF/VEL without restriction but is not recommended for co-use with SOF/VEL/VOX.
Ketoconazole^Citation34	VEL 1.70↑				Healthy	No dose adjustments are needed.
Famotidine^Citation39			VEL almost unaffected		Healthy	Dose adjustments of famotidine may be required.
Omeprazole‡^Citation39			VLE 0.44–0.63↓, 0.62–0.74↓, 0.47↓		Healthy	Omeprazole may be co-administered with SOF/VEL or SOF/VEL/VOX at an adequate dose and should be taken 4 hours later.
Atazanavir/ritonavir^Citation40,Citation44			Atazanavir almost unaffected, VEL 2.42↑	VOX 4.31↑	Healthy	Atazanavir can be administered with SOF/VEL but is not recommended for co-use with SOF/VEL/VOX.
Darunavir/ritonavir^Citation40,Citation44			No clinically relevant changes	Darunavir not affected	Healthy	No dose adjustments are needed.
Lopinavir/ritonavir^Citation40			No clinically relevant changes		Healthy	Lopinavir can be administered with SOF/VEL but is not recommended for co-use with SOF/VEL/VOX.
Cobicistat^Citation40,Citation44			No clinically relevant changes	Cobicistat not affected	Healthy	No dose adjustments are needed.
Dolutegravir^Citation40			No clinically relevant changes		Healthy	No dose adjustments are needed.
Efavirenz^Citation40,Citation44			Efavirenz almost unaffected, VEL 0.47↓	VEL 0.47↓	Healthy	Co-administration of efavirenz with SOF/VEL or SOF/VEL/VOX is not recommended.
Elvitegravir^Citation40,Citation44			No clinically relevant changes	Elvitegravir not affected	Healthy	No dose adjustments are needed.
Emtricitabine^Citation40,Citation44			No clinically relevant changes	Emtricitabine not affected	Healthy	No dose adjustments are needed.
Raltegravir^Citation40			No clinically relevant changes		Healthy	No dose adjustments are needed.
Rilpivirine^Citation40,Citation44			No clinically relevant changes	Rilpivirine not affected	Healthy	No dose adjustments are needed.
Tenofovir alafenamide^Citation40,Citation44			No clinically relevant changes	Tenofovir not affected	Healthy	No dose adjustments are needed.
Tenofovir disoproxil fumarate^Citation40,Citation44			Tenofovir 1.40–1.81↑	Tenofovir not affected	Healthy	No dose adjustments are needed.
Bictegravir^Citation44				Bictegravir not affected	Healthy
Dabigatran etexilate^Citation44				Dabigatran 2.61↑	Healthy	Clinical monitoring of dabigatran is needed.
Ethinyl estradiol^Citation41,Citation44	Ethinyl estradiol 1.06↑			No changes	Healthy	No dose adjustments are needed.
Norgestimate^Citation41,Citation44	Norelgestromin 0.89↓, norgestrel 0.91↓			No changes	Healthy	No dose adjustments are needed.
Voriconazole^Citation44				VOX 1.84↑	Healthy	No dose adjustments are needed.

Notes: ^#This table is not all inclusive; *, ^↑Increase; ^↓Decrease; The value refers to a ratio of AUCs of a tested drug with or without co-administered drugs; AUCs include AUC_0-24 (area under the concentration-time curve from time 0 to 24 hours) and AUC_0-∞ (that from time 0 to infinity); ^†Co-administration with a single dose and multiple-dose of rifampin; ^‡Co-administration with 20mg omeprazole under fasted or fed conditions, or with 40mg omeprazole under fed conditions.

Abbreviations: VEL, velpatasvir; AUC, area under the concentration-time curve; VOX, voxilaprevir; SOF, sofosbuvir; DDI, drug–drug interaction.

Table 3 Drug–Drug Interactions Between Glecaprevir/Pibrentasvir and Co-Administered Drugs^#

Concomitant Drugs	GLE/PIB’s Effects on AUC*	Subjects	Comments^Citation45
Ritonavir†^Citation46,Citation47	GLE 2.01↑, PIB 1.89↑	Healthy	Co-use is not recommended.
Methadone^Citation58	Methadone almost unaffected	On ORT	No dose adjustment is required.
Buprenorphine/Naloxone^Citation58	Buprenorphine 1.17↑, norbuprenorphine 1.30↑, Naloxone almost unaffected	On ORT	No dose adjustment is required.
Caffeine^Citation54	Caffeine 1.35↑	Healthy	No dose adjustment is required.
Midazolam^Citation54	Midazolam 1.27↑	Healthy	No dose adjustment is required.
Omeprazole^Citation54	Omeprazole almost unaffected	Healthy	No dose adjustment is required.
Tolbutamide^Citation54	Tolbutamide almost unaffected	Healthy	No dose adjustment is required.
Dextromethorphan^Citation54	Dextromethorphan 0.75↓	Healthy	No dose adjustment is required.
Digoxin^Citation55	Digoxin 1.48↑, GLE/PIB almost unaffected	Healthy	Monitoring and dose adjustments of digoxin are needed.
Losartan^Citation56	Losartan 1.56↑, GLE/PIB almost unaffected	Healthy	No dose adjustment is required
Valsartan^Citation56	Valsartan 1.31↑, GLE/PIB almost unaffected	Healthy	No dose adjustment is required
Felodipine^Citation59	Felodipine 1.31↑, GLE/PIB almost unaffected	Healthy	No dose adjustment is required
Amlodipine^Citation59	Amlodipine 1.21↑, GLE/PIB almost unaffected	Healthy	No dose adjustment is required
Cyclosporine^Citation57	Cyclosporine almost unaffected, GLE 1.37↑, PIB 1.22↑	Healthy	Co-use is not recommended.
Tacrolimus^Citation57	Tacrolimus 1.45↑, GLE/PIB almost unaffected	Healthy	No dose adjustment is required

Notes: ^#This table is not all inclusive; *, ^↑Increase; ^↓Decrease; The value refers to a ratio of AUCs of a tested drug with or without co-administered drugs. AUCs include AUC_0-24 (area under the concentration-time curve from time 0 to 24 hours) and AUC_0-∞ (that from time 0 to infinity); ^†Ritonavir is co-administered with GLE or PIB, respectively in two phase-1 trials.

Abbreviations: VEL, velpatasvir; VOX, voxilaprevir; AUC, area under the curve; ORT, opioid replacement therapy; DDI, drug–drug interaction.

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