title: Drug-Drug Interactions Between the Anti-Hepatitis C Virus 3D Regimen of Ombitasvir, Paritaprevir/Ritonavir, and Dasabuvir and Eight Commonly Used Medications in Healthy Volunteers.
abstract: The three direct-acting antiviral regimen of ombitasvir/paritaprevir/ritonavir and dasabuvir (3D regimen) is approved for treatment of hepatitis C virus (HCV) genotype 1 infection. Drug-drug interaction (DDI) studies of the 3D regimen and commonly used medications were conducted in healthy volunteers to provide information on coadministering these medications with or without dose adjustments.
  
  
  
  Three phase I studies evaluated DDIs between the 3D regimen (ombitasvir/paritaprevir/ritonavir 25/150/100 mg once daily + dasabuvir 250 mg twice daily) and hydrocodone bitartrate/acetaminophen (5/300 mg), metformin hydrochloride (500 mg), diazepam (2 mg), cyclobenzaprine hydrochloride (5 mg), carisoprodol (250 mg), or sulfamethoxazole/trimethoprim (SMZ/TMP) (800/160 mg twice daily), all administered orally. DDI magnitude was determined using geometric mean ratios and 90 % confidence intervals for the maximum plasma concentration (C max) and area under the plasma concentration-time curve (AUC).
  
  
  
  Changes in exposures (C max and AUC geometric mean ratios) of acetaminophen, metformin, sulfamethoxazole, trimethoprim, and diazepam were ≤25 % upon coadministration with the 3D regimen. The C max and AUC of nordiazepam, an active metabolite of diazepam, increased by 10 % and decreased by 44 %, respectively. Exposures of cyclobenzaprine and carisoprodol decreased by ≤40 and ≤46 %, respectively, whereas exposures of hydrocodone increased up to 90 %. Ombitasvir, paritaprevir, ritonavir, and dasabuvir exposures changed by ≤25 %, except for a 37 % decrease in paritaprevir C max with metformin and a 33 % increase in dasabuvir AUC with SMZ/TMP.
  
  
  
  Acetaminophen, metformin, sulfamethoxazole, and trimethoprim can be coadministered with the 3D regimen without dose adjustment. Higher doses may be needed for diazepam, cyclobenzaprine, and carisoprodol based on clinical monitoring. A 50 % lower dose and/or clinical monitoring should be considered for hydrocodone. No dose adjustment is necessary for the 3D regimen.
authors.affiliation: Clinical Pharmacokinetics and Pharmacodynamics, AbbVie Inc., Dept. R4PK, Bldg. AP31-3, 1 North Waukegan Road, North Chicago, IL, 60064, USA. akshanth.r.polepally@abbvie.com.
authors.forename: Akshanth R
authors.initials: AR
authors.lastname: Polepally
authors.affiliation: Clinical Pharmacokinetics and Pharmacodynamics, AbbVie Inc., Dept. R4PK, Bldg. AP31-3, 1 North Waukegan Road, North Chicago, IL, 60064, USA.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: King
authors.affiliation: Biometrics, AbbVie Inc., Dept. R43V, Bldg. AP31-2, 1 North Waukegan Road, North Chicago, IL, 60064, USA.
authors.forename: Bifeng
authors.initials: B
authors.lastname: Ding
authors.affiliation: Clinical Pharmacokinetics and Pharmacodynamics, AbbVie Inc., Dept. R4PK, Bldg. AP31-3, 1 North Waukegan Road, North Chicago, IL, 60064, USA.
authors.forename: Diana L
authors.initials: DL
authors.lastname: Shuster
authors.affiliation: Infectious Disease Development, AbbVie Inc., Dept. R48U, Bldg. AP30-3, 1 North Waukegan Road, North Chicago, IL, 60064, USA.
authors.forename: Emily O
authors.initials: EO
authors.lastname: Dumas
authors.affiliation: Clinical Pharmacokinetics and Pharmacodynamics, AbbVie Inc., Dept. R4PK, Bldg. AP31-3, 1 North Waukegan Road, North Chicago, IL, 60064, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Khatri
authors.affiliation: Biometrics, AbbVie Inc., Dept. R43V, Bldg. AP31-2, 1 North Waukegan Road, North Chicago, IL, 60064, USA.
authors.forename: Yi-Lin
authors.initials: YL
authors.lastname: Chiu
authors.affiliation: Infectious Disease Development, AbbVie Inc., Dept. R48U, Bldg. AP30-3, 1 North Waukegan Road, North Chicago, IL, 60064, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Podsadecki
authors.affiliation: Clinical Pharmacokinetics and Pharmacodynamics, AbbVie Inc., Dept. R4PK, Bldg. AP31-3, 1 North Waukegan Road, North Chicago, IL, 60064, USA.
authors.forename: Rajeev M
authors.initials: RM
authors.lastname: Menon
mesh_terms: D015081:2-Naphthylamine; D000293:Adolescent; D000328:Adult; D000813:Anilides / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D002219:Carbamates / Q000008:administration & dosage* / Q000493:pharmacokinetics; D003521:Cyclopropanes; D004347:Drug Interactions; D004359:Drug Therapy, Combination / Q000379:methods*; D005260:Female; D064368:Healthy Volunteers; D016174:Hepacivirus / Q000187:drug effects; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D010599:Pharmacokinetics; D011392:Proline / Q000031:analogs & derivatives; D019438:Ritonavir / Q000008:administration & dosage* / Q000493:pharmacokinetics; D013449:Sulfonamides / Q000008:administration & dosage* / Q000493:pharmacokinetics; D014498:Uracil / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D014633:Valine; D055815:Young Adult
chemical_list: D000813:Anilides; D000998:Antiviral Agents; D002219:Carbamates; D003521:Cyclopropanes; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds; D013449:Sulfonamides; C586094:ombitasvir; D014498:Uracil; D011392:Proline; D015081:2-Naphthylamine; C588260:dasabuvir; D014633:Valine; D019438:Ritonavir; C585405:paritaprevir