title: Pharmacokinetic Evaluation of Darunavir Administered Once or Twice Daily in Combination with Ritonavir or the Three-Direct-Acting Antiviral Regimen of Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir in Adults Coinfected with Hepatitis C and Human Immunodeficiency Viruses.
abstract: The three-direct-acting antiviral (3D) regimen containing ombitasvir, paritaprevir, ritonavir, and dasabuvir with or without ribavirin (RBV) is approved for treatment of hepatitis C virus (HCV) genotype 1 (GT1)/human immunodeficiency virus type 1 (HIV-1) coinfection. Results of a pharmacokinetic substudy of 3D and darunavir are presented. HCV/HIV-1-coinfected subjects were randomized to maintain an antiretroviral regimen with darunavir at 800 mg once daily (QD) or switched to a regimen with darunavir at 600 mg twice daily (BID). On study day 1, subjects received 3D and RBV plus darunavir for 12 weeks. Pharmacokinetic parameters were compared for darunavir and ritonavir with and without 3D (week 4 and day -1). Pharmacokinetic parameters of 3D were compared to historical data. Ten subjects received darunavir QD, and 12 subjects received darunavir BID. The central value ratios (90% confidence interval [CI]) for maximum concentrations (Cmax), area under the plasma concentration-time curve between 0 and 24 h postdose (AUC24), and trough plasma concentration at 24 h postdose (C24) of darunavir administered QD with 3D versus administration of darunavir alone were 0.92 (0.72, 1.18), 0.83 (0.71, 0.98), and 0.64 (0.44, 0.93), respectively. The ratios (90% CI) for darunavir Cmax, AUC12, and C12administered BID with 3D were 0.92 (0.76, 1.12), 0.88 (0.73, 1.05), and 0.73 (0.58, 0.92), respectively. Exposures of 3D were similar to or slightly lower than those in historical data. All darunavir trough concentrations (Ctrough) associated with an HIV-1 RNA level of >40 copies/ml were above the darunavir 50% effective concentration (EC50) of 550 ng/ml for resistant virus. In conclusion, the 3D regimen with darunavir QD or BID did not affect darunavir Cmaxand AUC, whereas the darunavir Ctroughdecreased. Changes in pharmacokinetic parameters of 3D were not considered clinically significant. Episodes of intermittent HIV-1 viremia were infrequent and were not associated with darunavir Ctroughvalues below 550 ng/ml. (This study has been registered at ClinicalTrials.gov under identifier NCT01939197.).
authors.affiliation: AbbVie Inc., Clinical Pharmacology and Pharmacometrics, North Chicago, Ilinois, USA.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: King
authors.affiliation: AbbVie Inc., Clinical Pharmacology and Pharmacometrics, North Chicago, Ilinois, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Khatri
authors.affiliation: AbbVie Inc., Infectious Disease Development, North Chicago, Ilinois, USA.
authors.forename: Roger
authors.initials: R
authors.lastname: Trinh
authors.affiliation: AbbVie Inc., Infectious Disease Development, North Chicago, Ilinois, USA.
authors.forename: Rolando M
authors.initials: RM
authors.lastname: Viani
authors.affiliation: AbbVie Inc., Biometrics, North Chicago, Ilinois, USA.
authors.forename: Bifeng
authors.initials: B
authors.lastname: Ding
authors.affiliation: AbbVie Inc., Clinical Pharmacology and Pharmacometrics, North Chicago, Ilinois, USA.
authors.forename: Jiuhong
authors.initials: J
authors.lastname: Zha
authors.affiliation: AbbVie Inc., Clinical Pharmacology and Pharmacometrics, North Chicago, Ilinois, USA Rajeev.menon@abbvie.com.
authors.forename: Rajeev
authors.initials: R
authors.lastname: Menon
mesh_terms: D015081:2-Naphthylamine; D000328:Adult; D000368:Aged; D000813:Anilides / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002219:Carbamates / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D060085:Coinfection / Q000188:drug therapy / Q000378:metabolism; D003521:Cyclopropanes; D000069454:Darunavir / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004334:Drug Administration Schedule; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000378:metabolism; D006526:Hepatitis C / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D011392:Proline / Q000031:analogs & derivatives; D019438:Ritonavir / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013449:Sulfonamides / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014498:Uracil / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D014633:Valine
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; D000069454:Darunavir
keywords: DAA; HCV; HIV; darunavir; dasabuvir; ombitasvir; paritaprevir