Population Pharmacokinetics of Paritaprevir, Ombitasvir, and Ritonavir in Japanese Patients with Hepatitis C Virus Genotype 1b Infection.
Hepatitis C virus (HCV) infection is of considerable clinical concern in Japan. We modeled the population pharmacokinetics of an oral interferon-free, direct-acting antiviral agent (DAA) regimen (i.e., the 2D regimen) recently approved for the treatment of chronic HCV genotype 1 infection as a new option for affected Japanese patients.



Using data from a phase III clinical trial (GIFT-I) that enrolled Japanese patients with HCV genotype 1b infection, population pharmacokinetic models were developed for the drugs that comprise the 2D regimen: paritaprevir, ombitasvir, and ritonavir. Demographic and clinical covariates with potential to influence 2D pharmacokinetics were evaluated for their effects on drug exposures. Proposed models were assessed using goodness-of-fit plots, visual predictive checks, and bootstrap evaluations.



One-compartment models with first-order absorption and elimination adequately described the population pharmacokinetics of paritaprevir, ombitasvir, and ritonavir. On average, patients with cirrhosis had approximately 95-145 % higher, 19-24 % lower, and 58-68 % higher exposures of paritaprevir, ombitasvir, and ritonavir, respectively. Female patients had 58-81 % higher ombitasvir exposures, whereas patients with mild renal impairment (creatinine clearance 75 mL/min) had 9-14 % higher ombitasvir exposures than did patients with normal renal function (creatinine clearance 105 mL/min). The DAA exposure values were comparable between responders and non-responders.



Population pharmacokinetic modeling did not reveal any patient-related or clinical parameters that would require dose adjustment of the 2D regimen when used for the treatment of HCV genotype 1b infection in Japanese patients.
Clinical Pharmacology and Pharmacometrics, AbbVie Deutschland GmbH & Co. KG, Knollstrasse, 67061, Ludwigshafen am Rhein, Germany. Sathej.gopalakrishnan@abbvie.com.
Sathej M
SM
Gopalakrishnan
Clinical Pharmacology and Pharmacometrics, AbbVie Inc., North Chicago, IL, USA.
Akshanth R
0000-0002-5938-6062
AR
Polepally
Clinical Pharmacology and Pharmacometrics, AbbVie Deutschland GmbH & Co. KG, Knollstrasse, 67061, Ludwigshafen am Rhein, Germany.
Sven
S
Mensing
Clinical Pharmacology and Pharmacometrics, AbbVie Inc., North Chicago, IL, USA.
Amit
A
Khatri
Clinical Pharmacology and Pharmacometrics, AbbVie Inc., North Chicago, IL, USA.
Rajeev M
RM
Menon
D000293:Adolescent; D000328:Adult; D000368:Aged; D000813:Anilides / Q000493:pharmacokinetics / Q000627:therapeutic use; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D002219:Carbamates / Q000493:pharmacokinetics / Q000627:therapeutic use; D003521:Cyclopropanes; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D005355:Fibrosis / Q000453:epidemiology; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000453:epidemiology; D006801:Humans; D007564:Japan; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D011392:Proline / Q000031:analogs & derivatives; D051437:Renal Insufficiency / Q000453:epidemiology; D019438:Ritonavir / Q000493:pharmacokinetics / Q000627:therapeutic use; D012737:Sex Factors; D013449:Sulfonamides; D014633:Valine; D055815:Young Adult
D000813:Anilides; D000998:Antiviral Agents; D002219:Carbamates; D003521:Cyclopropanes; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds; D013449:Sulfonamides; C586094:ombitasvir; D011392:Proline; D014633:Valine; D019438:Ritonavir; C585405:paritaprevir