The AAPS Journal, Vol. 18, No.

1, January 2016 ( # 2015)

DOI: 10.1208/s12248-015-9846-1

Research Article

Population Pharmacokinetics of Paritaprevir, Ombitasvir, Dasabuvir, Ritonavir,

and Ribavirin in Patients with Hepatitis C Virus Genotype 1 Infection: Combined
Analysis from 9 Phase 1b/2 Studies

Sven Mensing,1,3 Akshanth R. Polepally,2 Denise König,1 Amit Khatri,2 Wei Liu,2 Thomas J. Podsadecki,2
Walid M. Awni,2 Rajeev M. Menon,2 and Sandeep Dutta2

Received 25 August 2015; accepted 10 November 2015; published online 23 November 2015

Abstract. Direct-acting antiviral agents (DAAs) are established as the standard of care for chronic
hepatitis C virus (HCV) infection. One of the newest additions to the HCV arsenal is an oral three-DAA
combination therapy (i.e., the 3D regimen) that does not require concomitant use of pegylated
interferon. The clinical development program for the 3D regimen has yielded a robust dataset that is
inclusive of various dosing schemes and a diverse patient population. Using data from nine phase 1b/2a/
2b studies that enrolled patients with HCV genotype 1 infection, population pharmacokinetic models
were developed for each component of the 3D regimen (ombitasvir, paritaprevir, ritonavir, and
dasabuvir) and for ribavirin, an adjunctive therapy used to enhance therapeutic efficacy in some
populations. Formulation effects, accumulation, relative bioavailability, and interactions between DAAs
were assessed during model development, and demographic and clinical covariates were identified and
evaluated for their effects on drug exposures. Proposed models were assessed via goodness-of-fit plots,
visual predictive checks, and bootstrap evaluations. Population pharmacokinetic models adequately
described their respective plasma concentration-time data with precise and reliable model parameter
estimates and with good predictive performance. Covariates, including age, sex, body weight, cytochrome
P450 2C8 inhibitor use, non-Hispanic ethnicity, and creatinine clearance, were associated with apparent
clearance and/or apparent volume parameters; however, the magnitude of effect on drug exposure was
modest and not considered to be clinically significant. No patient-related or clinical parameters were
identified that would necessitate dose adjustment of the 3D regimen in patients with HCV genotype 1
infection.
KEY WORDS: 2D regimen; 3D regimen; direct-acting antiviral; dosing recommendations; population
pharmacokinetics.

INTRODUCTION combination therapy (i.e., the 3D regimen), has proven to be

effective and well tolerated for the treatment of HCV
Direct-acting antiviral agents (DAAs) have become a genotype 1 infection in clinical trials that enrolled diverse
mainstay of hepatitis C virus (HCV) infection treatment. patient groups, including difficult-to-treat populations, such as
They mark an improvement over the previous standard of non-responders to previous treatment with peginterferon and
care, pegylated interferon (peginterferon) and ribavirin, ribavirin, patients with cirrhosis, and liver transplant recipi-
which was burdened by a poor sustained virologic response ents (2–8).
rate, lengthy duration of treatment, and treatment-limiting The 3D regimen consists of ombitasvir (formerly called
toxicities for many patients (1). Newer additions to the DAA ABT-267), a novel non-structural protein 5A inhibitor;
treatment armamentarium are moving toward interferon-free paritaprevir (formerly called ABT-450), a potent non-
therapy that is suitable for a broad range of patient types. structural protein 3/4A protease inhibitor; and dasabuvir
One such combination, a recently approved, oral three-DAA (formerly called ABT-333), a non-nucleoside, non-structural
protein 5B polymerase inhibitor. To enhance the exposure of
Sven Mensing and Akshanth R. Polepally contributed equally to this paritaprevir, a cytochrome P450 (CYP) 3A4 substrate, it is
work. administered with ritonavir (the combination denoted as
1 paritaprevir/r), a potent CYP3A4 inhibitor. A two-DAA
Clinical Pharmacology and Pharmacometrics, AbbVie Deutschland
GmbH & Co. KG, Knollstrasse, 67065, Ludwigshafen am Rhein, combination of ombitasvir, paritaprevir, and ritonavir (i.e.,
Germany. the 2D regimen) has also been evaluated for patients with
2
AbbVie Inc., North Chicago, Illinois, USA. HCV genotype 4 infection (9).
3
To whom correspondence should be addressed. (e-mail: Phase 1b and 2a/b studies of 3D regimen components
[email protected]) have included a variety of dosing regimens and combinations,

1550-7416/16/0100-0270/0 # 2015 American Association of Pharmaceutical Scientists 270

Population PK of a Novel Anti-Hepatitis-C Regimen 271

a large number of both treatment-naive and treatment- formulation effect was fixed to the phase 1 population
experienced patients and patients representing a range of pharmacokinetic model (see Eq. 3) (14). Two different
demographic and clinically important subgroups (10–13). This formulations for ombitasvir, SDD and hot-melt extrusion
varied cross section allows for the assessment of parameters (HME) tablets, were used in study 1 (Table I). All other
that influence drug exposures, which could ultimately affect included studies used the HME tablet of ombitasvir. The
the efficacy and safety profile of the regimen. In this analysis, relative bioavailability of ombitasvir from SDD tablets
pharmacokinetic models were developed for paritaprevir, compared with HME tablets was estimated in the ombitasvir
ombitasvir, dasabuvir, ritonavir, and ribavirin using data from population pharmacokinetic model. Capsule and tablet for-
nine phase 1b and 2a/b studies. As part of the model-building mulations of dasabuvir used in phase 2 clinical trials have
process, formulation effects, accumulation, relative bioavail- equivalent bioavailability, and thus, an effect was not
ability, and interactions between DAAs were characterized. estimated in the dasabuvir population pharmacokinetic
In addition, demographic, clinical covariates, and concomi- model.
tant medication classes or enzyme/transporter inhibitor or Study protocols were institutional review board ap-
inducer categories that influenced apparent clearance (CL/F) proved, and study procedures were conducted in accordance
and/or apparent volume parameters were identified and with the ethical principles set forth in the Declaration of
evaluated for their effects on drug exposures. These data Helsinki, the International Conference on Harmonisation
were used to inform drug dosage recommendations for phase Good Clinical Practice guidelines, and local regulations.
3 studies and to provide safety and efficacy margins that can
be applied to clinical practice.
Assessments
MATERIALS AND METHODS
In the phase 1b/2a studies (Table I), dosing times for the
intensive sampling period (i.e., study days 1–3) were based on
Study Population observed study drug administration. For all other pharmaco-
kinetic samples, drug dosing times were collected for the last
Adult men and women with chronic HCV genotype 1 dose and second-to-last dose, and pharmacokinetic times
infection who were enrolled in a phase 1b, 2a, or 2b study of were calculated based on these dosing times. For the phase 2b
paritaprevir/r, ombitasvir, and/or dasabuvir with or without study, which represents the majority of subjects (571/828;
ribavirin were included in this analysis. Patients were 18 to 69%) in the datasets, study drug doses on day 1 were
70 years of age with a body mass index (BMI) in the range of administered on-site; therefore, exact dosing times were
18 to 38 kg/m2 and were required to be in generally good recorded. Thereafter, the medication event monitoring sys-
health without evidence of cirrhosis and to have negative test tem (MEMS) was utilized. This method provides a detailed
results for HIV and hepatitis B infection. Seven of the studies profile of patient’s adherence behavior and exact dosing times
excluded patients who had previously been treated with an and is a well-accepted measure for adherence (15). The actual
investigational or commercially available anti-HCV drug. The blood sample collection times were used for population
remaining two studies included both treatment-naive patients pharmacokinetics analyses.
and non-responders to previous treatment with peginterferon Blood samples for the assessment of paritaprevir,
and ribavirin. Non-response was defined as treatment for ombitasvir, dasabuvir, ritonavir, and ribavirin were processed
≥12 weeks that did not result in a decrease of ≥2 log10 IU/mL and assayed using validated liquid chromatography methods
in HCV RNA load. All study participants provided written with tandem mass spectrometric detection. Sample collection
informed consent. times varied according to the protocol specifications for each
study; the duration of sampling is summarized in Table I.
Study Design Lower limits of quantification ranges for each analyte were
0.500 to 0.644 ng/mL (paritaprevir), 0.139 to 0.993 ng/mL
Data were extracted from two phase 1b, six phase 2a, (ombitasvir), 0.100 to 4.58 ng/mL (dasabuvir), 4.74 to 5.00 ng/
and one phase 2b studies. Study design features and mL (ritonavir), and 91 to 100 ng/mL (ribavirin).
treatment regimens for these studies are described in
Table I. Study treatments included combinations of DAAs
(paritaprevir/r, ombitasvir, and dasabuvir) or DAA mono- Pharmacokinetic Model Development and Statistical
therapy given with or without peginterferon and ribavirin or Analyses
ribavirin alone. Drug dosing regimens ranged from 50/100 to
250/100 mg once daily for paritaprevir/r, 5 to 200 mg once Population pharmacokinetic models were built using
daily for ombitasvir, and 100 mg once daily to 800 mg twice non-linear mixed-effects models in NONMEM 7.3 (ICON
daily for dasabuvir. Ribavirin dose was determined by body Development Solutions, Hanover, MD). A first-order condi-
weight: patients weighing <75 kg received 1000 mg daily and tional estimation method with η-ε interaction (FOCE-INT)
patients weighing ≥75 kg received 1200 mg daily per ribavirin was used for model building. A base model, including the
prescribing information; both regimens were given in divided models for the inter-individual and residual variabilities, was
doses. developed first that defined the structural model, followed by
Two different formulations of paritaprevir were used in investigation of relevant covariate-parameter relationships.
the studies: a spray-dried dispersion (SDD) tablet and a hard Model development was guided by goodness-of-fit plots,
gelatin capsule. Data from phase 1 studies indicate differ- likelihood ratio tests (significance level of p<0.01 for base
ences in bioavailability between the two formulations; the model development), physiologic reasonability, precise
272 Mensing et al.

Table I. Summary of Clinical Trials

Study (ref no.) Drug dose (mg) and administration Number

[ClinicalTrials.gov of
identifier] Paritaprevir/r Ombitasvir Dasabuvir Ribavirina subjects Study description

1 (13) 5, 25, 50, 18 Phase 1b, randomized, double-blind, placebo-controlled

[NCT01181427] or 200 study in HCV GT1-infected, treatment-naive adults;
OD blood sampling up to 72 h post-dose on days 1–3 (25
samples per patient)
2 [NCT00696904] 100 OD 18 Phase 1b, randomized, double-blind, placebo-controlled
100 BID study in HCV GT1-infected, treatment-naive adults;
600 OD blood sampling up to 72 h post-dose on days 1 and 2
600 BID (up to 19 samples per patient)
3 [NCT00851890] 300 BID 1000 to 30 Phase 2a, 4-week, randomized, double-blind, placebo-
600 BID 1200 controlled study of dasabuvir or placebo for the first
1200 OD 2 days in treatment-naive HCV-infected adults follow-
ed by dasabuvir with pegIFN/RBV for 26 days; blood
sampling up to 16 h post-dose on day 1 and prior to the
morning dose on day 2 (7 samples per patient)
4 [NCT01074008] 50/100 OD 400 BID 1000 or 75 Phase 2a, 12-week, randomized, blinded, placebo-controlled
100/100 OD 800 BID 1200 study of paritaprevir/r, dasabuvir, or ABT-072 monother-
200/100 OD apy for 3 days in HCV GT1–infected, treatment-naive
adults followed by 81 days of pegIFN/RBV added to
paritaprevir/r, dasabuvir, or ABT-072; blood sampling up
to 16 h post-dose on days 1–3, pre-dose on days 4 and 5,
and at each visit thereafter, regardless of study drug
dosing time (23 samples per patient)
5 (10) 5, 50, or 1000 or 37 Phase 2a, 12-week, randomized, blinded, placebo-
[NC- 200 OD 1200 controlled study of ombitasvir or placebo combined
T01314261] with pegIFN/RBV in HCV GT1-infected, treatment-
naive adults; blood sampling up to 8 h post-dose on day
1 and at each visit, regardless of study drug dosing time
(up to 13 samples per patient)
6 [NCT01458535] 150/100 OD 25 OD 1000 or 20 Phase 2a, 12-week, multicenter, open-label study of
1200 ombitasvir and paritaprevir/r±ribavirin in HCV GT1-
infected, treatment-naive adults; blood samples were
collected at each visit, regardless of study drug dosing
time (14 samples per patient)
7 (11) 250/100 OD 400 BID 1000 or 47 Phase 2a, 12-week, multicenter, open-label study of
[NC- 150/100 OD 1200 paritaprevir/r, dasabuvir, and ribavirin in HCV GT1-
T01306617] infected, treatment-naive and treatment-experienced
adults; blood sampling up to 8 h post-dose on study day
1 and at each visit thereafter, regardless of study drug
dosing time (14 samples per patient)
8 [NCT01563536] 150/100 OD 1.5 OD 400 BID 1000 or 12 Phase 2a, 12-week, multicenter, open-label study of
25 OD 1200 ombitasvir as 2-day monotherapy followed by ombitasvir
co-administered with paritaprevir/r, dasabuvir, and riba-
virin in treatment-naive, HCV GT1-infected adults; blood
samples were collected at each visit, regardless of study
drug dosing time (14 samples per patient)
9 (12) 100/100 OD 25 mg OD 400 BID 1000 or 571 Phase 2b, 24-week, multicenter, open-label, randomized
[NC- 150/100 OD 1200 study of paritaprevir/r, ombitasvir, and/or dasabuvir±
T01464827] 200/100 OD ribavirin in HCV GT1-infected, treatment-naive and
treatment-experienced adults; blood sampling up to 4 h
post-dose on study day 1 and at each visit thereafter,
regardless of study drug dosing time (up to 15 samples
per patient)

BID twice daily, GT1 genotype 1, HCV hepatitis C virus, OD once daily, pegIFN/RBV pegylated interferon alpha/ribavirin
a
Ribavirin was dosed at 1000 mg if body weight was <75 kg or 1200 mg if body weight was ≥75 kg, orally daily divided BID

parameter estimates, and previous knowledge of drug covariates included age, sex, race (black versus non-black),
pharmacokinetics. ethnicity (Hispanic/Latino versus non-Hispanic/Latino), body
Covariates were tested using the forward inclusion and weight (BWT), body surface area, BMI, HCV subtype 1a or
backward elimination procedure. For CL/F, the tested 1b, baseline creatinine clearance (CrCL), fibrosis (no/
Population PK of a Novel Anti-Hepatitis-C Regimen 273

minimal, moderate, or severe), treatment experience (naive (BCRP), organic anion transporting polypeptides 1B1 and
or peginterferon/ribavirin experienced), use of ribavirin, and 1B3 (OATP1B1/B3), and uridine diphosphate glucuronosyl-
co-medications. For apparent volume parameters, the tested transferase (UGT) 1A1 (19). Co-medication use was defined
covariates included age, sex, race, ethnicity, BWT, body as receipt for ≥6 weeks (approximately half the treatment
surface area, and BMI. Covariate effects were added in the duration [12 weeks] of a typical HCV DAA regimen) during
model in a multiplicative manner. Continuous covariates were the treatment period. The potential for a drug class or
normalized to a reference value (median value of the category to influence the pharmacokinetics of DAAs, ritona-
covariate) and were included in the model with a power vir, or ribavirin was determined by calculating dose-
function: normalized steady-state exposures (AUC during a 24-hour
dosing interval at steady state [AUC24,ss]) from the base
 θcov models for patients receiving each drug class or inhibitor/
covi
TVP ¼ θ⋅ ð1Þ inducer category and comparing these values with control
covmedian
groups (i.e., patients receiving no co-medications or co-
medications that do not represent the tested drug inhibitor/
where θ is the population estimate of the pharmacokinetic inducer category). For paritaprevir, only the post hoc
model parameter (TVP). COVi refers to the ith individual AUC24,ss values (from the base model) representing the
continuous covariate value (e.g., BMI), COVmedian is the approved 150-mg dose and SDD tablets were considered
median value for the study population, and θCOV refers to the based on the drug’s known dose- and formulation-dependent
estimated covariate effect. non-linear bioavailability (14). Co-medication drug classes/
Categorical covariates were tested with a multiplicative categories that included ≥15 patients and met the base model
model to obtain the fractional difference in the pharmacoki- AUC24,ss ratio criteria (≤0.5 or ≥2.0 for drug classes, ≤0.5 for
netic parameters between the tested categorical groups: inducer categories, or ≥2.0 for inhibitor categories) were
included in covariate model building.
The population pharmacokinetic model for paritaprevir
TVP ¼ θ⋅θlevel
cat ð2Þ
was developed in two steps. In step 1, non-linearity in
bioavailability (dose- and formulation- dependent) and accu-
mulation after multiple doses were characterized by using
where θ is the population estimate of the pharmacokinetic intensive pharmacokinetic data from phase 1 studies in
model parameter (TVP) and θcatlevel was set to 1 for the healthy volunteers (14). In step 2, only the phase 2
reference population and to an estimated parameter for other pharmacokinetic data from patients were characterized by
levels of the categorical covariate. fixing formulation effect and accumulation factor to the
Inferences about the clinical importance of covariate estimates from the model fit of the phase 1 data. The dose-
effects were made based on the magnitude and precision of and formulation-dependent non-linear paritaprevir relative
covariate parameter estimates. The magnitude of covariate bioavailability (FREL) was described by
effect was assessed by estimating steady-state maximum
plasma concentration (Cmax) and area under the plasma ðθcapsule  Dose
50 −1Þ
concentration-time curve (AUC) values for each significant F REL ¼ θbio ð3Þ
covariate. Exposure data were calculated for the approved
doses of paritaprevir (150 mg once daily), ombitasvir (25 mg
once daily), dasabuvir (400 mg twice daily formulation used Formulation effect (θcapsule) was fixed to the phase 1
in the phase 2 studies; it is equivalent to 250 mg twice daily population pharmacokinetic model estimate of 1.27 during
approved formulation), ritonavir (100 mg once daily) (16), phase 2 model development (14). The parameter θbio that
and ribavirin (1000 or 1200 mg/day based on weight) (17,18) represents the fold increase in paritaprevir bioavailability of
in patients with HCV genotype 1 infection. For the stepwise the SDD tablet for each 50-mg increment in dose relative to
covariate selection, significance levels of α=0.01 and α=0.001 bioavailability of the 50-mg paritaprevir SDD tablet was
(approximate χ2 distribution) were implemented in forward estimated. In addition, the effect of dasabuvir on paritaprevir
inclusion and backward elimination procedures, respectively. bioavailability was implemented in a categorical manner to
Several criteria were used to evaluate improvement in model obtain the fractional difference in paritaprevir bioavailability
performance and to select the final model. The likelihood with or without dasabuvir. The effect of ombitasvir on
ratio test was used to discriminate among alternative nested paritaprevir bioavailability was tested in a phase 1 pharma-
models. One additional model parameter, corresponding to 1 cokinetic model and was found to be not significant (14).
degree of freedom in the higher-order model, was considered Therefore, testing the effect of ombitasvir was not pursued in
significant when it lowered the objective function value by this analysis.
more than 6.63, corresponding to p<0.01. For 2 degrees of
freedom, the required reduction in objective function value Model Evaluation
was 9.21.
An extensive list of drug classes and enzyme/transporter Methods used in model evaluation included goodness-of-
inhibitor or inducer categories of co-medications was evalu- fit plots (data not shown), visual predictive checks, and
ated for effects on CL/F. Components of the 3D regimen are bootstrap evaluations. For visual predictive checks, 1000
substrates or inhibitors for a number of metabolic enzymes simulated replicates of the model predictions were generated
and transport proteins, including various CYP family mem- using NONMEM. Relevant visual predictive checks included
bers, P-glycoprotein (P-gp), breast cancer resistance protein plots of observed and predicted concentrations versus time.
274 Mensing et al.

Observed medians and 5th and 95th percentiles were plotted category of CYP2C8 inhibitors (n=16; AUC24,ss ratio, 2.17)
against the 90% prediction interval obtained from these were included in stepwise covariate model building for
simulations for every unique observation time point. In paritaprevir. None of the other drug classes or categories
addition to visual predictive checks, 1000 bootstrap replicates met the selection criteria for ombitasvir, dasabuvir, ritona-
were constructed by randomly sampling (with replacement) N vir, or ribavirin.
patients from the original dataset, where N is the number of
patients in the original dataset. The final model was used to Paritaprevir Population Pharmacokinetics
estimate population parameters for each bootstrap replicate,
and the resulting values were used to estimate medians and A one-compartment model with first-order absorption
2.5th and 97.5th percentiles. Final model parameter estimates and elimination adequately described paritaprevir
based on the original dataset were compared against the concentration-time data. The non-linearity in bioavailability,
bootstrap results. the accumulation compared with the first dose, and the effect
of dasabuvir on paritaprevir bioavailability that was identified
RESULTS in a previous analysis of phase 1 data (14) were implemented
as part of the phase 2 pharmacokinetic model.
Data Sources The bioavailability of paritaprevir increased
supraproportionally and was formulation dependent (Fig. 1).
Paritaprevir and ritonavir assessments were based on Exposures from SDD tablets for the 150-mg dose (approved
7698 and 7655 concentration observations, respectively, that dose) of paritaprevir would be approximately 6.3-fold of
were derived from 676 patients enrolled in five phase 1b/2a/ exposures from the 50-mg dose and approximately 71% lower
2b studies. Five phase 1b/2a/2b studies contributed to the than exposures from the 250-mg dose. On average, co-
6813 concentration observations from 601 patients available administration of dasabuvir with paritaprevir increased
for ombitasvir. Data for dasabuvir were obtained from six paritaprevir bioavailability by 21% in HCV genotype 1-
phase 1b/2a/2b studies that yielded 6479 concentration infected patients. Although this effect was not significant, it
observations from 560 patients. Ribavirin pharmacokinetic was retained in the model based on results of phase 1
information was extracted from six phase 1b/2a/2b studies pharmacokinetic modeling (14).
that included 6977 concentration observations from 670 Model-derived population pharmacokinetic parameter
patients. estimates and significant covariates are presented in
Table III. Sex and CYP2C8 inhibitor use were found to be
Patient Demographic Characteristics covariates significantly associated with CL/F, and ethnicity
was a significant covariate for apparent volume of the central
Demographic characteristics were generally consistent compartment (Vc/F). Because of the known influence of
among populations used to evaluate the various study drugs dasabuvir on paritaprevir bioavailability, co-administration of
(Table II). The majority of patients were male (55–58%) and dasabuvir was included in the assessment of predicted
non-black (86–88%). Hispanic/Latino ethnicity was self- paritaprevir exposures in covariate subgroups. Among pa-
described by 10 to 13% of patients. Moderate or severe liver tients receiving CYP2C8 inhibitors (n=39), CL/F was 32%
fibrosis was present in fewer than half of the patients. lower than patients not on any inhibitor or inducer of
Approximately one fifth of the patients were treatment metabolic enzyme(s) or transporter(s). Females had 19%
experienced, having demonstrated a poor response to previ- lower CL/F than males, and patients representing non-
ous treatment with peginterferon and ribavirin. The dominant Hispanic/Latino ethnicity had 35% higher Vc/F than patients
HCV genotype was 1a, representing 67 to 70% of the of Hispanic/Latino ethnicity. Changes in predicted
evaluated study population. paritaprevir steady-state Cmax and AUC24 based on sex,
ethnicity, use of CYP2C8 inhibitors, or co-administration of
Co-medication Analyses dasabuvir were generally modest (≤50%) (Fig. 2). The
greatest putative AUC elevation (50%) was estimated for
More than 750 co-medications belonging to 15 drug use of a concomitant CYP2C8 inhibitor.
classes (non-opioid analgesics, antihypertensives, antide-
pressants, proton pump inhibitors, antihistamines, opioids, Ombitasvir Population Pharmacokinetics
hormone replacement therapies, steroids, anti-infectives,
antidiabetics, antiepileptics, statins and lipid-lowering A two-compartment model with first-order absorption
agents, antipsychotics, hormonal contraceptives, and phos- and elimination adequately described ombitasvir plasma
phodiesterase type 5 inhibitors) and 20 enzyme (CYP concentration-time data. The bioavailability of ombitasvir
isoenzymes 3A4/5/7, 2C8, 2D6, 1A2, 2C9, 2C19, 2B6, and from an SDD tablet relative to a HME tablet in patients with
UGT) or transporter (P-gp, multidrug resistance-associated HCV genotype 1 infection was 41%. Age, sex, and BWT
protein 2, BCRP, OATP1B1/B3) inhibitor/inducer catego- were found to be significant covariates for CL/F, and sex was
ries were used concomitantly in phase 1b/2a/2b trials. After found to be the sole significant covariate for volume
applying informed selection criteria (n≥15 and AUC24,ss parameters (Vc/F and apparent volume of the peripheral
ratio of ≤0.5 or ≥2.0 for drug classes, ≤0.5 for inducer compartment [Vp/F]; Table III). On average, females had
categories, or ≥2.0 for inhibitor categories), only co- 30% lower CL/F and 17% lower apparent steady state
medications representing the drug class of hormone volume of distribution (Vss/F) than males. Changes in
replacement therapy (n=18; AUC24,ss ratio, 2.10) and the ombitasvir steady-state Cmax and AUC24 values based on
Population PK of a Novel Anti-Hepatitis-C Regimen 275

Table II. Patient Demographic and Disease Characteristics. Data are Presented as Median (Range) Unless Otherwise Indicated

Characteristic Paritaprevir (n=676) Ombitasvir (n=601) Dasabuvir (n=560) Ritonavir (n=676) Ribavirin (n=670)

Male sex, n (%) 374 (55) 332 (55) 323 (58) 374 (57) 383 (57)
Race, n (%)
Black 91 (13) 82 (14) 68 (12) 91 (13) 89 (13)
Other 585 (87) 519 (86) 492 (88) 585 (87) 581 (87)
Ethnicity, n (%)
Hispanic/Latino 67 (10) 59 (10) 66 (12) 67 (10) 86 (13)
Other 609 (90) 542 (90) 494 (88) 609 (90) 584 (87)
Age, years 52.0 (19.0, 70.0) 52.0 (19.0, 70.0) 52.0 (18.0, 70.0) 52.0 (19.0, 70.0) 52.0 (19.0, 70.0)
Weight, kg 78.0 (41.0, 138) 79.0 (41.0, 138) 79.0 (41.0, 138) 78.0 (41.0, 138) 79.0 (44.0, 138)
BSA, kg/m2 1.9 (1.3, 2.7) 1.9 (1.3, 2.7) 1.9 (1.3, 2.7) 1.9 (1.3, 2.7) 1.9 (1.3, 2.7)
BMI, kg/m2 26.6 (18.1, 38.2) 26.7 (17.9, 38.2) 26.8 (18.1, 38.2) 26.6 (18.1, 38.2) 26.6 (17.9, 38.2)
Baseline CrCL, mg/dL 105 (44.0, 214) 106 (44.0, 214) 106 (53.0, 214) 105 (44.0, 214) 107 (44.0, 214)
Fibrosis stage, n (%)
No/minimal 381 (56) 351 (58) 290 (52) 381 (56) 317 (47)
Moderate 118 (18) 112 (19) 86 (15) 118 (18) 108 (16)
Severe 81 (12) 76 (13) 66 (12) 81 (12) 69 (10)
HCV treatment experience, n (%)
Naive 526 (78) 468 (78) 455 (81) 526 (78) 520 (78)
Experienced 150 (22) 133 (22) 105 (19) 150 (22) 150 (22)
HCV genotype, n (%)
1a 465 (69) 404 (67) 393 (70) 465 (69) 468 (70)
1b 204 (30) 190 (32) 160 (29) 204 (30) 198 (30)
Unknown 7 (1.0) 7 (1.2) 7 (1.3) 7 (1.0) 4 (0.6)

BMI body mass index, BSA body surface area, CrCL creatinine clearance, HCV hepatitis C virus

age (±10 years change from reference age [48 years] in the the tested covariates (Table III). Females had 15% lower CL/
model), sex, and BWT (±10 kg change from reference BWT F than males. Predicted changes in dasabuvir steady-state
[79 kg] in the model) were modest (<50%) (Fig. 2). The most Cmax and AUC24 values based on sex were minimal (<20%)
notable difference was between males and females, with 34% (Fig. 2).
higher Cmax and 42% higher AUC24 values estimated for
females compared with males. Ritonavir Population Pharmacokinetics

A one-compartment model with first-order absorption

Dasabuvir Population Pharmacokinetics
and elimination adequately described ritonavir plasma
concentration-time data. Ethnicity was the only covariate
A one-compartment model with first-order absorption
tested that demonstrated a significant effect on Vc/F (p<0.01;
and elimination adequately described dasabuvir plasma
Table III). Vc/F was 79% higher in non-Hispanic/Latino
concentration-time data. Sex was the only covariate that had
patients compared with Hispanic/Latino patients. However,
a significant effect on CL/F; Vc/F was not influenced by any of
Hispanic versus non-Hispanic ethnicity only minimally affect-
ed (≤10% change) ritonavir steady-state Cmax and AUC24
values (Fig. 2).

Ribavirin Population Pharmacokinetics

A three-compartment model with first-order absorption

and elimination adequately described ribavirin plasma
concentration-time data. Sex and baseline CrCL were found
to be significant covariates for CL/F, and sex and BWT for
the volume parameters (Table III). On average, females had
11% lower CL/F and 22% lower Vss/F than males. The
covariates of baseline CrCL, sex, and BWT altered ribavirin
steady-state Cmax and AUC24 values by less than 20%
(Fig. 2).
The low computed η-shrinkage values (≤10%) for CL/F
and volume parameters in the final models for paritaprevir,
ombitasvir, dasabuvir, ritonavir, and ribavirin indicate that
Fig. 1. Dose-related changes in relative bioavailability of paritaprevir sufficient information about the parameter estimates was
for the spray-dried dispersion (SDD) tablet and hard gelatin capsule available from the drug concentration-time data. No substan-
(HGC) formulations tial ε-shrinkage (≤5%) was computed, indicating the
276 Mensing et al.

Table III. Population Pharmacokinetic Parameter Estimates and Significant Covariates. Data are Presented as Population Estimate [Bootstrap
Evaluation 95% Confidence Interval]

Model characteristic Paritaprevira,b,c,d Ombitasvire Dasabuvir Ritonavir Ribavirin

PK model One compartment Two compartment One compartment One compartment Three compartment
ka, day−1 5.97 [5.47, 6.88] 4.97 [4.57, 5.36] 14.0 [12.7, 15.1] 4.08 [3.93, 4.19] 20.64f
CL/F, L/day 3770 [2700, 5070] 579 [556, 603] 1690 [1590, 1790] 378 [354, 402] 492 [470, 512]
Vc/F, L 638 [454, 880] 164 [149, 178] 417 [385, 452] 46.1 [39.8, 52.3] 999 [921, 1080]
Q/F, L/day – 224 [186, 260] – – 254 [192, 365]
Vp/F, L – 345 [304, 392] – – 5110 [4280, 6450]
Q2/F, L/day – – – – 2100 [1840, 2410]
V4/F, L – – – – 3090 [2540, 3620]
IIV on CL/Fg 1.32 [1.17, 1.46] 0.0860 [0.072, 0.328 [0.277, 0.542 [0.456, 0.635] 0.0745 [0.063, 0.086]
CV=166% 0.098] 0.384] CV=85% CV=28%
CV=30% CV=62%
IIV on Vc/F and Vp/Fg 2.08 [1.79, 2.38] 0.296 [0.237, 0.369] 0.431 [0.326, 1.69 [1.33, 2.00] 0.341 [0.281, 0.403]
CV=265% CV=59% 0.556] CV=210% CV=64%
CV=73%
Covariance of IIV 1.49 [1.30, 1.68] 0.0927 [0.073, 0.276 [0.216, 0.702 [0.522, 0.826] 0.055 [0.039, 0.071]
parameters r=0.899h 0.114] 0.346] r=0.733h r=0.345h
r=0.581h r=0.734h
Covariates on CL/F Sex, CYP2C8 Age, sex, BWT Sex – Sex, creatinine
inhibitors clearance
Covariates on volumes Non-Hispanic/Latino Sex – Non-Hispanic/ Sex, BWT
Latino

BWT body weight, CL/F apparent clearance, CV coefficient of variation, CYP2C8 cytochrome P450 2C8, IIV inter-individual variability, ka
first-order absorption rate constant, PK pharmacokinetics, Q/F apparent inter-compartmental clearance from the second compartment, Q2/F
apparent inter-compartmental clearance from the third compartment, Vc/F apparent volume of central compartment, Vp/F apparent volume of
peripheral compartment, V4/F apparent volume of distribution of the third compartment Dose
a
Dose- and formulation-dependent non-linear paritaprevir/r bioavailability: F ¼ 1:45 ð1:27 50 −1Þ
b
Accumulation of paritaprevir/r (multiplicative model) is fixed to 1.57 from the phase 1 population pharmacokinetic model (14)
c
Formulation effect (θcapsule) was fixed to 1.27 from the phase 1 population pharmacokinetic model (14); θbio represents the fold increase in
paritaprevir bioavailability of the SDD tablet for each 50-mg increment in dose relative to bioavailability of the 50-mg paritaprevir SDD tablet,
and was estimated to be 1.45 with bootstrap 95% confidence interval of [1.27, 1.65] in the current population pharmacokinetic model
d
Effect of dasabuvir on paritaprevir bioavailability was estimated to be 1.21 with bootstrap 95% confidence interval of [0.99, 1.48]
e
Formulation effect (SDD vs. HME tablets) was estimated to be 0.41 with bootstrap 95% confidence interval of [0.33, 0.53]
f
ka was based on a previous estimate for ribavirin (28)
g
IIV was modeled with a log normal distribution. Vc/F and Vp/F share the same IIV
h
r (correlation of IIV parameters) was calculated from block OMEGA matrix as OMEGA[1,2]/(sqrt(OMEGA[1,1]) Χ sqrt(OMEGA[2,2]))

adequacy of the models. Goodness-of-fit plots (not shown), paritaprevir, dasabuvir, and ritonavir, as well as the adjunc-
visual predictive checks (Fig. 3), and bootstrap analyses tive medication ribavirin. Data from our assessment show
(Table III) indicate that the data have been well described that population pharmacokinetic models adequately describe
by the pharmacokinetic models for paritaprevir, ombitasvir, their respective plasma concentration-time data with precise
dasabuvir, ritonavir, and ribavirin, with good predictive and reliable model parameter estimates and with good
performance for each. predictive performance.
One of the observations that arose from the popu-
DISCUSSION lation modeling was the comparable pharmacokinetics of
paritaprevir, ombitasvir, dasabuvir, ritonavir, and ribavi-
Direct-acting antiviral combinations of ombitasvir and rin in HCV treatment-naive and treatment-experienced
paritaprevir/r with or without dasabuvir are established patients. Treatment history was included as a potential
treatment options in the HCV armamentarium. Clinical trial covariate but was not identified in either the univariate
data demonstrate high sustained virologic response rates analysis or the subsequent refinement process as signif-
across a variety of patient populations, including those who icantly associated with CL/F for any component of the
are treatment naive, treatment experienced, cirrhotic, non- 3D regimen or ribavirin. These findings are robust as the
cirrhotic, and/or liver transplant recipients (2–7,9). With the study population included substantial representation of
potential for broad use of the 3D and 2D regimens, it is treatment-naive and treatment-experienced patients.
important to establish that the therapy would be comparably Analogous pharmacokinetics are consistent with the
effective and well tolerated regardless of patient-related comparable efficacy between treatment-naive and
variables, such as the use of concomitant medications and treatment-experienced patient populations that have been
demographic characteristics. Given the large dataset and rich reported for both the 3D and 2D regimens (4,9,12). In
pharmacokinetic sampling of the 3D development program, clinical trials, the drug dosage regimen and treatment
these insights could be generated through the development of duration were the same, regardless of patient treatment
population pharmacokinetic models for ombitasvir, history.
Population PK of a Novel Anti-Hepatitis-C Regimen 277

Fig. 2. Population pharmacokinetic evaluations. Model-derived estimates of steady-state maximum

plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) for
covariates identified as significantly associated with apparent clearance or apparent volume
parameters for paritaprevir (150 mg once daily), ombitasvir (25 mg once daily), dasabuvir (400 mg
twice daily), ritonavir (100 mg once daily), and ribavirin (600 mg twice daily). A ratio of 1.0
indicates similar values between the subgroup analyzed and the rest of the patient population.
Error bars represent the 95% confidence intervals. Weight groups for ombitasvir analyses were
stratified as 89 and 69 kg, and age was plotted for 58 and 38 years. Weight groups for ribavirin
analyses were stratified as 89 and 69 kg, and creatinine clearance (CrCL) was plotted for 65 and
120 mL/min. BWT body weight, CYP2C8 cytochrome P450 2C8

The modeling analyses also revealed no difference in the Patients with cirrhosis were excluded from the trials that
pharmacokinetics of paritaprevir, ombitasvir, dasabuvir, rito- comprised our population pharmacokinetic analysis. Howev-
navir, or ribavirin between patients with HCV genotype 1a or er, fibrosis score was collected and included as a covariate.
1b infection. HCV subtype was not identified as a significant Fibrosis did not show any significant association with
covariate in any of the models. Clinical trials of the 3D clearance or volume parameters. Notably, the degree of
regimen have shown high rates of sustained virologic fibrosis among these patients was generally classified as mild
response in patients with either HCV genotype 1a or 1b or moderate in severity. A recent pharmacokinetic study
infection (3–7), and 3D treatment is indicated for both HCV specifically evaluating the 3D regimen in patients with hepatic
subtypes (16). impairment found that exposure changes for paritaprevir,
278 Mensing et al.

Fig. 3. Visual predictive checks for population pharmacokinetic models. Filled circles represent
observed median values (5th and 95th percentile error bars). The simulated median is represented
by a solid line and the associated 90% interval of the simulated median by grey shading. The
simulated 5th and 95th percentiles are represented by dashed lines and the associated 90% interval
of the simulated 5th and 95th percentile by grey shading. The profile for ribavirin starts 2 weeks
into the treatment period, thus illustrating steady-state

ombitasvir, dasabuvir, and ritonavir were minimal and did not inducer of metabolic enzymes or transporters. The co-
necessitate dose adjustment for patients with mild or moder- medication analysis is subject to several limitations based on
ate hepatic impairment (20). The 3D regimen is currently not the design of the studies and the need to best utilize the
recommended for patients with moderate hepatic impairment available data. Perhaps, the most salient of these relates to
(16). Patients with severe hepatic impairment, however, did the timing and duration of concomitant medication use. A 6-
experience higher paritaprevir and dasabuvir exposures, week treatment criterion was utilized as it represents half of
which would preclude use of the 3D regimen in this the treatment period for 3D regimen therapy. It is possible
population. that concomitant medications used over a shorter duration
The only drug or inhibitor/inducer class with a significant could have influenced pharmacokinetic findings. It is also
influence on clearance was CYP2C8 inhibitors, which reduced likely that patients who did not continue a concomitant
CL/F relative to patients who did not receive any inhibitor or medication regimen throughout the study would have had
Population PK of a Novel Anti-Hepatitis-C Regimen 279

some pharmacokinetic samples taken during co-medication associated with substantially higher exposures than doses
use and one or more without. However, we believe that the used for HCV treatment, produce comparable efficacy and
analysis as performed is a valid approach to a large and safety profiles to that of the studied regimen (ombitasvir/
complex dataset. More specific information on the influence paritaprevir/r, 25/150/100 once daily, and dasabuvir,
of concomitant medications can be gained from formal drug- 400 mg twice daily) (10–12). Moreover, no differences in
drug interaction studies, a number of which have been virologic response rates for the 3D regimen have been
conducted with agents representing different enzyme or observed based on age, sex, race, ethnic group, fibrosis
transporter substrates and inhibitor/inducer classes. Descrip- score, or baseline viral load in phase 3 clinical trials (2–6).
tions of these study results have recently been published Interleukin 28B genotype, which is known to influence
(19,21–23) and can be used as a guide for dosing of antiviral efficacy in patients with HCV (31), was associat-
concomitant medications with the 3D regimen. ed with response rate in one phase 3 study (3), but was
Ribavirin may be added to 3D or 2D therapy to not significant in the other phase 3 studies (2,4–6). A
augment therapeutic efficacy. It is needed for patients with pharmacokinetic study of ombitasvir and paritaprevir/r
genotype 1a HCV and patients with genotype 4 HCV (16, with or without dasabuvir in patients with mild, moderate,
24, 25). The population pharmacokinetic modeling indi- or severe renal impairment detected no clinically signifi-
cates that ribavirin co-administration does not affect the cant influence of decreased CrCL on DAA exposures
pharmacokinetics of paritaprevir, ombitasvir, dasabuvir, or (32). Together, these data support standard dosing of the
ritonavir; use of ribavirin was not identified as a covariate 3D regimen across patient groups. Dosing of ribavirin,
in any of the analyses. This is consistent with the fact that however, may require adjustment (17,18). Ribavirin dose
ribavirin is primarily eliminated via renal pathway and modification is recommended for patients who experience
does not share common disposition pathways with adverse reactions or laboratory abnormalities during
paritaprevir, ombitasvir, dasabuvir, or ritonavir and is, treatment with ribavirin. A priori ribavirin dose reduction
therefore, not expected to contribute to drug interactions. is also advised for patients with renal impairment.
Hence, no dose adjustment is necessary when ribavirin is The strength of these analyses lies in the breadth of
given with the 3D regimen. The estimated CL/F and pharmacokinetic data available for assessment. However,
calculated apparent steady-state volume of distribution although the dataset represents a wide range of dose
and t1/2,z are in close agreement with the values reported combinations, not every possible permutation of the five
in the literature (26,27). Other estimated population drugs involved could be tested clinically. Also, the 2D
parameters for ribavirin from our assessment were also regimen is used in the treatment of HCV genotype 4
in good agreement with published results in patients with infection, but this population pharmacokinetic model was
chronic HCV genotype 1 infection (27). A notable developed based on observations in patients with HCV
difference between the previous population pharmacoki- genotype 1 infection.
netic model and our findings was a 50% greater Vp/F for
black versus white patients in the previous study (27). No CONCLUSION
such relationship was observed in our dataset. In our
evaluation, sex and BWT were covariates for volume Using data from the robust clinical development pro-
parameters, and sex and baseline CrCL for CL/F. Demo- gram for the 3D regimen, population pharmacokinetic models
graphic distribution may account for some of the differ- were developed for paritaprevir, ombitasvir, dasabuvir, rito-
ences between studies; for example, the analyses by Jin navir, and ribavirin. The models for each drug adequately
and colleagues (27) included only 39 females (27% of described the respective plasma concentration-time data with
their study population), whereas the present evaluation precise and reliable model parameter estimates and with
good predictive performance. Based on the model-predicted,
included 287 female patients. Jin and colleagues (27) did
steady-state drug exposures at doses used in the treatment of
not assess CrCL because 85% of the participants had
HCV genotype 1 infection, no patient-related or clinical
normal renal function, and decrements were generally
parameters were identified that would necessitate dose
mild in those outside the reference range. Our finding of
adjustment for the 3D regimen.
an influence of CrCL is not unexpected, given the known
effect of renal impairment on the pharmacokinetics of
ribavirin, a renally cleared compound (28–30). ACKNOWLEDGMENTS
Calculation of steady-state exposure (Cmax and AUC)
values for patient groups identified as significant covari- This work was supported by AbbVie Inc. AbbVie
ates for CL/F or apparent volume parameters demonstrat- contributed to the study design, research, and interpretation
ed generally modest variance from the overall population of data and the writing, reviewing, and approving of the
estimates. The resulting changes in exposure were within publication. The authors thank Crystal Murcia, PhD, of The
0.5- to 2.0-fold of exposures from approved doses. A JB Ashtin Group, Inc., for the assistance in preparing this
change in the exposures within a window of 0.5- to 2.0- manuscript for publication.
fold from the population mean exposures for all three
DAAs (paritaprevir, ombitasvir, dasabuvir) are not antic- Author Contributions SM and ARP equally contributed to
ipated to alter the efficacy or safety profile to an extent this work. SM, ARP, DK, AK, WL, RMM, and SD
that requires dose adjustments. Doses of ombitasvir up to contributed to the data analyses. All authors contributed to
200 mg once daily, paritaprevir/r up to 250/100 mg once the study designs, interpretation of results, and writing and
daily, and dasabuvir up to 800 mg twice daily, which are reviewing of the manuscript.
280 Mensing et al.

COMPLIANCE WITH ETHICAL STANDARDS 15. Farmer KC. Methods for measuring and monitoring medication
regimen adherence in clinical trials and clinical practice. Clin
Ther. 1999;21(6):1074–90.
Conflicts of Interest All authors are AbbVie employees 16. Viekira Pak (ombitasvir, paritaprevir, and ritonavir tablets;
and may hold AbbVie stocks or options. dasabuvir tablets) [prescribing information]. North Chicago, IL:
AbbVie Inc.; 2015.
17. Copegus (ribavirin) tablets [prescribing information]. South San
Francisco, CA: Genentech USA, Inc.; 2013.
18. Rebetol (ribavirin USP) capsules [prescribing information].
Whitehouse Station, NJ: Merck Sharp & Dohme Corp; 2013.
REFERENCES 19. Menon RM, Badri PS, Wang T, Polepally AR, Zha J, Khatri A,
et al. Drug-drug interaction profile of the all-oral anti-hepatitis C
virus regimen of paritaprevir/ritonavir, ombitasvir, and
1. Thompson JR. Emerging therapeutic options for the manage- dasabuvir. J Hepatol. 2015;63(1):20–9. doi :10.1016/
ment of hepatitis C infection. World J Gastroenterol. j.jhep.2015.01.026.
2014;20(23):7079–88. doi:10.3748/wjg.v20.i23.7079. 20. Khatri A, Menon RM, Marbury TC, Lawitz EJ, Podsadecki TJ,
2. Andreone P, Colombo MG, Enejosa JV, Koksal I, Ferenci P, Mullally VM, et al. Pharmacokinetics and safety of co-
Maieron A, et al. ABT-450, ritonavir, ombitasvir, and dasabuvir administered paritaprevir plus ritonavir, ombitasvir, and
achieves 97% and 100% sustained virologic response with or dasabuvir in hepatic impairment. J Hepatol. 2015;63(4):805–12.
without ribavirin in treatment-experienced patients with HCV doi:10.1016/j.jhep.2015.05.029.
genotype 1b infection. Gastroenterology. 2014;147(2):359–65. 21. Badri PS, King JR, Polepally AR, McGovern BH, Dutta S,
doi:10.1053/j.gastro.2014.04.045. e1. Menon RM. Dosing recommendations for concomitant medica-
3. Ferenci P, Bernstein D, Lalezari J, Cohen D, Luo Y, Cooper C, tions during 3D anti-HCV therapy. Clin Pharmacokinet.
et al. ABT-450/r-ombitasvir and dasabuvir with or without 2015. doi:10.1007/s40262-015-0317-8.
ribavirin for HCV. N Engl J Med. 2014;370(21):1983–92. 22. Badri PS, Dutta S, Wang H, Podsadecki TJ, Polepally AR,
doi:10.1056/NEJMoa1402338. Khatri A, et al. Drug interactions with the direct-acting antiviral
4. Poordad F, Hezode C, Trinh R, Kowdley KV, Zeuzem S, combination of ombitasvir and paritaprevir/ritonavir (2D regi-
Agarwal K, et al. ABT-450/r-ombitasvir and dasabuvir with men). Antimicrob Agents Chemother. 2015. doi:10.1128/
ribavirin for hepatitis C with cirrhosis. N Engl J Med. AAC.01778-1 .
2014;370(21):1973–82. doi:10.1056/NEJMoa1402869. 23. Polepally AR, King JR, Ding B, Shuster DL, Dumas EO, Khatri
5. Feld JJ, Kowdley KV, Coakley E, Sigal S, Nelson DR, Crawford A, et al. Drug-drug interactions of commonly used medications
D, et al. Treatment of HCV with ABT-450/r-ombitasvir and with direct acting antiviral HCV combination therapy of
dasabuvir with ribavirin. N Engl J Med. 2014;370(17):1594–603. paritaprevir/r, ombitasvir and dasabuvir. Presented at the 16th
doi:10.1056/NEJMoa1315722. International Workshop on Clinical Pharmacology of HIV and
6. Zeuzem S, Jacobson IM, Baykal T, Marinho RT, Poordad F, Hepatitis Therapy, Washington, DC, 26–28 May 2015.
Bourliere M, et al. Retreatment of HCV with ABT-450/r- 24. Viekirax 12.5 mg/75 mg/50 mg film-coated tablets [Summary of
ombitasvir and dasabuvir with ribavirin. N Engl J Med. product characteristics]. Berkshire, United Kingdom: AbbVie
2014;370(17):1604–14. doi:10.1056/NEJMoa1401561. Limited; 2015.
7. Kwo PY, Mantry PS, Coakley E, Te HS, Vargas HE, Brown Jr R, 25. Feld JJ, Moreno C, Trinh R, Tam E, Bourgeois S, Horsmans Y,
et al. An interferon-free antiviral regimen for HCV after liver et al. Sustained virologic response of 100% in HCV genotype 1b
transplantation. N Engl J Med. 2014;371(25):2375–82. patients with cirrhosis receiving ombitasvir/paritaprevir/r and
doi:10.1056/NEJMoa1408921. dasabuvir for 12 weeks. J Hepatol. 2015. doi:10.1016/
8. Eron JJ, Lalezari J, Slim J, Gathe J, Ruane PJ, Wang C, et al. j.jhep.2015.10.005.
Safety and efficacy of ombitasvir - 450/r and dasabuvir and 26. Wade JR, Snoeck E, Duff F, Lamb M, Jorga K. Pharmacokinet-
ribavirin in HCV/HIV-1 co-infected patients receiving atazanavir ics of ribavirin in patients with hepatitis C virus. Br J Clin
or raltegravir ART regimens. J Int AIDS Soc. 2014;17(4 Suppl P h a rm ac o l . 2 00 6; 62 (6 ) :7 10 –4 . d o i :10. 1111 /j .1 36 5-
3):19500. doi:10.7448/IAS.17.4.19500. 2125.2006.02704.x.
9. Hezode C, Asselah T, Reddy KR, Hassanein T, Berenguer M, 27. Jin R, Fossler MJ, McHutchison JG, Howell CD, Dowling TC.
Fleischer-Stepniewska K, et al. Ombitasvir plus paritaprevir plus Population pharmacokinetics and pharmacodynamics of ribavirin
ritonavir with or without ribavirin in treatment-naive and in patients with chronic hepatitis C genotype 1 infection. AAPS
treatment-experienced patients with genotype 4 chronic hepatitis J. 2012;14(3):571–80. doi:10.1208/s12248-012-9368-z.
C virus infection (PEARL-I): a randomised, open-label trial. 28. Gupta SK, Kantesaria B, Glue P. Pharmacokinetics and safety of
Lancet. 2015. doi:10.1016/S0140-6736(15)60159-3. single-dose ribavirin in patients with chronic renal impairment.
10. Sullivan GJ, Rodrigues-Torres M, Lawitz E, Poordad F, Kapoor Drug Discov Ther. 2013;7(4):158–63.
M, Campbell A, et al. ABT-267 combined with pegylated 29. Brennan BJ, Wang K, Blotner S, Magnusson MO, Wilkins JJ,
interferon alpha-2a/ribavirin in genotype 1 (GT1) HCV-infected Martin P, et al. Safety, tolerability, and pharmacokinetics of
treatment-naive subjects: 12 week antiviral and safety analysis. J ribavirin in hepatitis C virus-infected patients with various
Hepatol. 2012;56 Suppl 2:S480. degrees of renal impairment. Antimicrob Agents Chemother.
11. Poordad F, Lawitz E, Kowdley KV, Cohen DE, Podsadecki T, 2013;57(12):6097–105. doi:10.1128/AAC.00608-13.
Siggelkow S, et al. Exploratory study of oral combination 30. Gupta SK, Kantesaria B, Glue P. Exploring the influence of renal
antiviral therapy for hepatitis C. N Engl J Med. 2013;368(1):45– dysfunction on the pharmacokinetics of ribavirin after oral and
53. doi:10.1056/NEJMoa1208809. intravenous dosing. Drug Discov Ther. 2014;8(2):89–95.
12. Kowdley KV, Lawitz E, Poordad F, Cohen DE, Nelson DR, 31. Thompson AJ, Muir AJ, Sulkowski MS, Ge D, Fellay J,
Zeuzem S, et al. Phase 2b trial of interferon-free therapy for Shianna KV, et al. Interleukin-28B polymorphism improves
hepatitis C virus genotype 1. N Engl J Med. 2014;370(3):222–32. viral kinetics and is the strongest pretreatment predictor of
doi:10.1056/NEJMoa1306227. sustained virologic response in genotype 1 hepatitis C virus.
13. Krishnan P, Beyer J, Mistry N, Koev G, Reisch T, DeGoey D, et al. G a s t r o e n t e r o l o g y. 2 0 1 0 ; 1 3 9 ( 1 ) : 1 2 0 – 9 . d o i : 1 0 . 1 0 5 3 /
In vitro and in vivo antiviral activity and resistance profile of j.gastro.2010.04.013. e18.
ombitasvir, an inhibitor of hepatitis C virus NS5A. Antimicrob 32. Khatri A, Dutta S, Marbury T, Preston RA, Rodrigues L, Wang
Agents Chemother. 2015;59(2):979–87. doi:10.1128/AAC.04226-14. H, et al. The pharmacokinetics and safety of the direct acting
14. Polepally A, Mensing S, Khatri A, Liu W, Awni W, Menon R, antiviral regimen of ABT-450/r, ombitasvir with/without
et al. Dose- and formulation-dependent non-linear pharmacoki- dasabuvir in subjects with mild, moderate and severe renal
netic model of ABT-450, a protease inhibitor for the treatment of impairment compared to subjects with normal renal function.
HCV: combined analyses from 12 phase 1 studies. J Boston: 65th Annual Meeting of the American Association for
Pharmacokinet Pharmacodyn. 2014;41(Suppl):S7–S101. the Study of Liver Diseases; 2014.