Pharmacokinetics of TMC435 in subjects with moderate hepatic impairment
Reported by Jules Levin
46th Annual Meeting of
the European Association for the Study of the Liver
(EASL) 30 March - 3 April, 2011·Berlin, Germany
Vanitha Sekar,1 Alexandru Simion,2 Monika Peeters,3 Kurt Spittaels,2 Eric Lawitz,4 Thomas C Marbury,5 Goedele De Smedt2
1Department of Pharmacokinetics and Pharmacodynamics, Tibotec Inc., Titusville, NJ, USA; 2Department of Clinical Development; 3Department of Statistics, Tibotec, Beerse, Belgium;
4Department of Gastroenterology, Alamo Medical Research, San Antonio, TX, USA; 5Orlando Clinical Research Center, Orlando, FL, USA
TMC435 exposure in HCV-infected patients with moderate
hepatic impairment (Child-Pugh B) is comparable to that
observed in HCV-infected patients with mild hepatic
impairment (Child-Pugh A), who participated in OPERA-1.
Treatment with TMC435 150 mg QD for 7 days was generally
well tolerated in all subjects, and there were no clinically
relevant changes in any hepatic parameters during the
TMC435 treatment period.
These findings suggest that no TMC435 dose adjustment
is necessary for HCV-infected patients with moderate
liver impairment, and routine clinical monitoring may be
This study is ongoing in panel B.
I N T R O D U C T I O N
· TMC435 is a once daily (QD) oral NS3/4A protease inhibitor
currently in Phase III clinical development for the treatment of
hepatitis C virus (HCV) infection.
· TMC435 is an investigational potent and selective inhibitor of NS3/4A
in vitro, with median effective concentrations (EC50) ranging from 8
to 28 nM across different genotype 1a and 1b replicon cell lines.1,2
· Findings from Phase I and II studies have shown that TMC435
is well tolerated at doses ranging from 25-200 mg QD, with a
pharmacokinetic (PK) profile that supports a QD dosing regimen.2-7
· As many HCV-infected patients requiring antiviral therapy will have
impaired hepatic function, it is necessary to evaluate the impact of
hepatic impairment on the PK and safety of TMC435.
· Here, we describe findings from a Phase I, open-label study
(TMC435-C113; NCT01046058) which investigated the steady-state
PK and short-term safety/tolerability profile of TMC435 in
HCV-negative volunteers with moderate hepatic impairment
Study Design and Treatment
· This was a Phase I, open-label, study. Panel A included
16 subjects: 8 with moderate hepatic impairment and 8 healthy
controls (subjects in Panel B are not yet fully recruited, so are not
· Eligible subjects were males or females, aged 18-65 years old, with
a body mass index (BMI) of 18-35 kg/m2, and were non-smokers or
smoking <10 cigarettes, 2 cigars, or 2 pipes for >3 months prior
· Subjects with hepatic impairment were also required to have
a documented history of cirrhosis diagnosed by liver biopsy,
ultrasound, computed tomography (CT) scan, or magnetic
resonance imaging (MRI); Child-Pugh score of 7-9 indicative of
moderate hepatic impairment (i.e. Child-Pugh B); and stable hepatic
function for >3 months, as determined by clinical and/or laboratory
parameters (i.e. stable albumin, bilirubin, international normalised
ratio [INR], and platelet counts).8
· Control subjects with normal hepatic function were matched
to those with hepatic impairment according to sex, race, age
(± 5 years), BMI (± 15%) and smoking status.
· Subjects with HIV type 1 or 2, or hepatitis A, B or C infection at
screening were excluded.
· All subjects received TMC435 150 mg QD from Day 1 to Day 7,
taken between 07:30 am and 10:00 am with approximately 240 mL
of water after breakfast; all drug intakes were supervised.
· Full PK profiles for TMC435 were determined on Day 7 up to
48 hours post-dose. Plasma concentrations of TMC435 were
determined using validated liquid chromatographic - mass
spectrometry/mass spectrometry (LC-MS/MS) methods with a lower
limit of quantification of 2.0 ng/mL for TMC435.
· PK analysis was performed using non-compartmental methods
using the WinNonlin ProfessionalTM (Version 4.1; Pharsight
Corporation, Mountain View, California, USA), Microsoft ExcelŽ
(Microsoft Redmond, Washington, USA) and/or SAS 9.1
(SAS Institute Inc., Cary, NC, USA).
· Calculated TMC435 PK parameters included pre-dose plasma
concentration (C0h), maximum plasma concentration (Cmax), minimum
plasma concentration (Cmin), time to reach the maximum plasma
concentration (tmax), area under the concentration-time curve (AUC)
from time of administration up to 24 hours post-dosing (AUC24h).
· TMC435 PK parameters were summarised using descriptive
statistics. PK parameters on Day 7 for subjects with moderate
hepatic impairment were compared with those obtained on Day 7
for the healthy matched controls in this study.
· Steady-state PK for TMC435 is achieved by Day 7. PK parameters on
Day 7 for subjects with moderate hepatic impairment were also
compared with those obtained on Day 28 for the subgroup of
HCV-infected patients with mild hepatic impairment (Child-Pugh A)
included in study TMC435-C201 (OPERA-1; NCT00561353) who
received four weeks of treatment with the same dose of TMC435 as in
this study (i.e. 150 mg QD) in combination with pegylated (Peg)
interferon (IFN)a-2a and ribavirin (RBV) (n=8 patients for whom we
had PK data).9
· Safety was assessed at screening, throughout the TMC435
treatment period, and at 10-14 days and 30-35 days after last
intake of TMC435 or study withdrawal. Adverse events (AEs) were
coded according to the Medical Dictionary for Regulatory Activities
(MedDRA) preferred term, and graded according to the World
Health Organization (WHO) toxicity grading scale. The severity of all
reported AEs and their relationship to study drug was tabulated.
· Vital signs, electrocardiogram (ECG) recordings and clinical laboratory
tests were also performed at screening, on Day 7, and at 10-14 days
and 30-35 days after last intake of TMC435 or study withdrawal.
· Subject demographics were well balanced between treatment
groups in terms of sex, race, age, BMI (Table 1) and smoking status.
· Subject demographics were similar to those of patients infected
with HCV who participated in the OPERA-1 trial.
Pharmacokinetics of TMC435
· Steady-state conditions were reached by Day 7 for TMC435 both
in subjects with moderate hepatic impairment and in healthy
· TMC435 PK parameters on Day 7 for subjects with moderate
hepatic impairment were higher than those for healthy matched
controls (Table 2, Figure 1).
- The median (range) ratios for TMC435 exposure (AUC24h) and Cmax
at Day 7 for subjects with moderate hepatic impairment relative
to healthy matched controls were 2.62 (1.04-7.48) and 1.76
AUC24h, area under the concentration-time curve from time of administration up to 24 hours postdosing;
C0h, pre-dose plasma concentration; Cmax, maximum plasma concentration; Cmin, minimum
plasma concentration; tmax, time to reach the maximum plasma concentration
· TMC435 PK parameters on Day 7 for subjects with moderate
hepatic impairment were comparable to those reported on Day 28
for HCV-infected patients with mild hepatic impairment in study
TMC435-C201 (Table 2).9
· In this study, there were no relevant differences in unbound
TMC435 between treatment groups (data not shown).
· A summary of all AEs reported during the TMC435 treatment
period is shown in Table 3. The most common AE, reported by three
subjects, was headache.
· Most AEs were Grade 1-2. One serious AE (Grade 4 pneumonia),
which was not considered treatment-related, was reported.
· There were no discontinuations due to AEs.
· Mean baseline to Day 8 levels of total, direct, and indirect bilirubin;
alkaline phosphatase (ALP); aspartate aminotransferase (AST) and
alanine aminotransferase (ALT) are shown in Figure 2.
· Subjects with moderate hepatic impairment (Child-Pugh B) had
transiently higher levels of serum bilirubin (total, direct and
indirect), ALP and AST from baseline to Day 8, compared with
healthy matched controls.
· In both groups, no clinically relevant changes in hepatic parameters
were observed during the TMC435 treatment period.
- One subject with hepatic impairment experienced a transient
total bilirubin increase from Grade 2 at baseline to Grade 3
at Day 7 and Day 8 (increase from 51 to 53 and 63 umol/L,
respectively). This hyperbilirubinemia was not associated with an
increase in other hepatic parameters.
· There were no clinically relevant changes in any other laboratory
parameters, and no clinically significant findings in terms of vital
signs or ECG recordings during the study.
1. Lin TI et al. Antimicrob Agents Chemother 2009; 53: 1377-1385.
2. Reesink HW et al. Gastroenterology 2010; 138: 913-921.
3. Reesink H et al. Poster presented at the 60th American Association for the Study of
Liver Diseases (AASLD) meeting, Boston, MA, USA, October 30 - November 3, 2009.
4. Marcellin P et al. Poster presented at the 44th Annual Meeting of European Association
for the Study of the Liver (EASL), Copenhagen, Denmark, 22-26 April, 2009.
5. Manns M et al. Presented at the 44th Annual Meeting of European Association for
the Study of the Liver (EASL), Copenhagen, Denmark, 22-26 April, 2009.
6. Sekar V et al. Poster presented at the 45th Annual Meeting of European Association
for the Study of the Liver (EASL), Vienna, Austria, 14-18 April, 2010.
7. Fried MW, et al. Presented at the 61st AASLD Meeting, Boston, MA, USA, October 29
- November 2, 2010.
8. US FDA Guidance for industry. Pharmacokinetics in Patients with Impaired Hepatic
Function: Study Design, Data Analysis, and Impact on Dosing and Labeling. May 2003.
9. Data on File, Tibotec Inc. 2011.