title: Effect of co-medications on paritaprevir, ritonavir, ombitasvir, dasabuvir and ribavirin pharmacokinetics: analysis of data from seven Phase II/III trials.
abstract: The three drug direct-acting antiviral regimen (3D regimen) of ombitasvir, paritaprevir/ritonavir and dasabuvir, with and without ribavirin, was evaluated in one Phase II trial and six Phase III trials in over 2,300 HCV genotype-1-infected patients. Patients continued taking their protocol-permitted co-medications while receiving the 3D ± ribavirin regimen. The effects of the co-medications on exposures of the 3D regimen and ribavirin were examined.
  
  
  
  Population pharmacokinetic model-predicted steady-state area under the curve (AUC24,ss) values were evaluated in the presence/absence of the co-medications. Interactions resulting in a greater than 50% reduction or 100% increase in an AUC24,ssvalue were examined as covariates for an effect on apparent clearance (CL/F).
  
  
  
  More than 1,200 co-medications belonging to 15 drug classes and/or 19 enzyme and transporter inhibitor and/or inducer categories were used concomitantly with the 3D regimen in the trials. Approximately 1,500 patients (65%) in Phase III trials received two or more co-medications from multiple drug classes or categories. No co-medication class/category decreased or increased ombitasvir, dasabuvir, ritonavir or ribavirin AUC24,ssby more than half or twofold, respectively. Opioids, antipsychotics, anti-epileptics, antidiabetics and non-ethinyl estradiol-containing hormone replacement therapies appeared to have an effect (AUC24,ssratio ≤0.5 or ≥2.0) on paritaprevir exposures. However, when these classes were included in the paritaprevir population pharmacokinetic model, only opioids and antidiabetics had a statistically significant effect on CL/F, but with no clinically meaningful increase in exposures (≤55%).
  
  
  
  No dose adjustment is necessary for the 3D ± ribavirin regimen when used with the co-medications included in this analysis as there were no clinically meaningful effects on exposures of the DAAs.
authors: Clinical Pharmacology and Pharmacometrics, AbbVie Inc., North Chicago, IL, USA.
authors: Akshanth R
authors: AR
authors: Polepally
authors: Clinical Pharmacology and Pharmacometrics, AbbVie Inc., North Chicago, IL, USA.
authors: Prajakta S
authors: PS
authors: Badri
authors: Clinical Pharmacology and Pharmacometrics, AbbVie Inc., North Chicago, IL, USA.
authors: Apurvasena
authors: A
authors: Parikh
authors: Infectious Disease Development, AbbVie Inc., North Chicago, IL, USA.
authors: Lino
authors: L
authors: Rodrigues
authors: Global Pharmacovigilance, AbbVie Inc., North Chicago, IL, USA.
authors: Barbara A
authors: BA
authors: Da Silva-Tillmann
authors: Clinical Pharmacology and Pharmacometrics, AbbVie Inc., North Chicago, IL, USA.
authors: Sven
authors: S
authors: Mensing
authors: Infectious Disease Development, AbbVie Inc., North Chicago, IL, USA.
authors: Thomas J
authors: TJ
authors: Podsadecki
authors: Clinical Pharmacology and Pharmacometrics, AbbVie Inc., North Chicago, IL, USA.
authors: Walid M
authors: WM
authors: Awni
authors: Clinical Pharmacology and Pharmacometrics, AbbVie Inc., North Chicago, IL, USA.
authors: Sandeep
authors: S
authors: Dutta
authors: Clinical Pharmacology and Pharmacometrics, AbbVie Inc., North Chicago, IL, USA.
authors: Rajeev M
authors: RM
authors: Menon
mesh_terms: D015081:2-Naphthylamine; D000813:Anilides / Q000008:administration & dosage / Q000493:pharmacokinetics; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002219:Carbamates / Q000008:administration & dosage / Q000493:pharmacokinetics; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D003521:Cyclopropanes; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics; D011392:Proline / Q000031:analogs & derivatives; D012254:Ribavirin / Q000008:administration & dosage / Q000493:pharmacokinetics; 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
chemical_list: D000813:Anilides; D000998:Antiviral Agents; D002219:Carbamates; D003521:Cyclopropanes; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds; D013449:Sulfonamides; C586094:ombitasvir; D012254:Ribavirin; D014498:Uracil; D011392:Proline; D015081:2-Naphthylamine; C588260:dasabuvir; D014633:Valine; D019438:Ritonavir; C585405:paritaprevir