Population pharmacokinetics of paritaprevir, ombitasvir, dasabuvir, ritonavir and ribavirin in hepatitis C virus genotype 1 infection: analysis of six phase III trials.
The aim of the current study was to characterize the population pharmacokinetics of a triple direct-acting antiviral (DAA) regimen (3D) (ombitasvir, paritaprevir-ritonavir and dasabuvir) and adjunctive ribavirin, and estimate covariate effects in a broad spectrum of subjects with hepatitis C virus (HCV) genotype 1 infection.



Pharmacokinetic data from six phase III studies and one phase II study in subjects receiving the currently approved doses of the 3D ± ribavirin regimen for treating HCV genotype 1 infection for 12 weeks or 24 weeks were characterized using separate population pharmacokinetic models, built using each component of the regimen from nonlinear mixed-effects methodology in NONMEM 7.3. In the models, demographic and clinical covariates were tested. Models were assessed via goodness-of-fit plots, visual predictive checks and bootstrap evaluations.



The population pharmacokinetic models for each component of the 3D ± ribavirin regimen (DAAs and ritonavir, n = 2348) and ribavirin (n = 1841) adequately described their respective plasma concentration-time data. Model parameter estimates were precise and robust, and all models showed good predictive ability. Significant covariate effects associated with apparent clearance and volume of distribution included age, body weight, gender, cirrhosis, HCV subtype, opioid or antidiabetic agent use, and creatinine clearance.



The population pharmacokinetics of the 3D ± ribavirin regimen components in HCV-infected patients were characterized using phase II and III HCV clinical trial data. Although several statistically significant covariates were identified, their effects were modest and not clinically meaningful to necessitate dose adjustments for any component of the 3D regimen.
Clinical Pharmacology and Pharmacometrics, AbbVie Deutschland GmbH & Co., KG, Knollstrasse 50, 67061, Ludwigshafen am Rhein, Germany.
Sven
S
Mensing
Clinical Pharmacology and Pharmacometrics, AbbVie Deutschland GmbH & Co., KG, Knollstrasse 50, 67061, Ludwigshafen am Rhein, Germany.
Doerthe
D
Eckert
Clinical Pharmacology and Pharmacometrics, Dept. R4PK, Bldg. AP31-3, AbbVie, Inc., 1 North Waukegan Road, North Chicago, IL, 60064, USA.|Department of Clinical Pharmacology, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA, 94404, USA.
Shringi
S
Sharma
Clinical Pharmacology and Pharmacometrics, Dept. R4PK, Bldg. AP31-3, AbbVie, Inc., 1 North Waukegan Road, North Chicago, IL, 60064, USA.
Akshanth R
AR
Polepally
Clinical Pharmacology and Pharmacometrics, Dept. R4PK, Bldg. AP31-3, AbbVie, Inc., 1 North Waukegan Road, North Chicago, IL, 60064, USA.
Amit
A
Khatri
Virology, R48U, AP-30, AbbVie, Inc., 1 North Waukegan Road, North Chicago, IL, 60064, USA.
Thomas J
TJ
Podsadecki
Clinical Pharmacology and Pharmacometrics, Dept. R4PK, Bldg. AP31-3, AbbVie, Inc., 1 North Waukegan Road, North Chicago, IL, 60064, USA.
Walid M
WM
Awni
Clinical Pharmacology and Pharmacometrics, Dept. R4PK, Bldg. AP31-3, AbbVie, Inc., 1 North Waukegan Road, North Chicago, IL, 60064, USA.
Rajeev M
RM
Menon
Clinical Pharmacology and Pharmacometrics, Dept. R4PK, Bldg. AP31-3, AbbVie, Inc., 1 North Waukegan Road, North Chicago, IL, 60064, USA.
Sandeep
S
Dutta
D015081:2-Naphthylamine; D000293:Adolescent; D000328:Adult; D000368:Aged; D000813:Anilides / Q000097:blood / Q000493:pharmacokinetics*; D000998:Antiviral Agents / Q000097:blood / Q000493:pharmacokinetics; D002219:Carbamates / Q000097:blood / Q000493:pharmacokinetics*; D017322:Clinical Trials, Phase II as Topic / Q000706:statistics & numerical data; D017326:Clinical Trials, Phase III as Topic / Q000706:statistics & numerical data; D003521:Cyclopropanes; D004338:Drug Combinations; D005260:Female; D006526:Hepatitis C / Q000097:blood*; D006801:Humans; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011392:Proline / Q000031:analogs & derivatives; D012254:Ribavirin / Q000097:blood / Q000493:pharmacokinetics*; D019438:Ritonavir / Q000097:blood / Q000493:pharmacokinetics*; D013449:Sulfonamides / Q000097:blood / Q000493:pharmacokinetics*; D014498:Uracil / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D014633:Valine; D055815:Young Adult
D000813:Anilides; D000998:Antiviral Agents; D002219:Carbamates; D003521:Cyclopropanes; D004338:Drug Combinations; 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
3D regimen; HCV genotype 1; direct-acting antivirals; dosing recommendations; population pharmacokinetics
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