Effect of Hepatic Impairment
on Sorafenib Pharmacokinetics:
Results of a Multicenter,
Open-Label, Single-Dose,
Phase I Trial
J Lettieri, A Mazzu,
L Huang, and C Lathia
Bayer HealthCare Pharmaceuticals, Montville, NJ
Study Design
Multicenter, open-label, nonrandomized, Phase I study to evaluate
the PK profile and safety of oral sorafenib in noncancer
participants with hepatic impairment and in healthy volunteers
as a control group. All participants were treated with a single
400-mg dose of sorafenib
There were 3 cohorts of participants in the study, each with
15 members:
Cohort
1
2
3
Participants
Child-Pugh Class A
Child-Pugh Class B
Healthy volunteers (control)
PK=pharmacokinetic.
Adapted from Lettieri J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
Study Design (cont’d)
Blood samples for the determination of plasma
concentrations of sorafenib and metabolites were
collected following study drug administration on
Day 1
Blood samples were collected at 0 hour (pre-dose), and
at 1, 2, 3, 5, 7, 9, 12, 16, 24, 48, 72, 96, and 120 hours
post-dose. The following PK parameters were
derived: AUC, Cmax, tmax, and t½
Safety evaluations included results of physical
examination, electrocardiographic evaluation, vital
sign assessment, adverse events monitoring,
laboratory tests, and use of concomitant medications
AUC=area under curve; Cmax=peak concentration; tmax=time to peak concentration; t½=half-life.
Adapted from Lettieri J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
Inclusion Criteria
All participants
Aged 50 to 75 years
Body mass index (BMI) >20 and ≤35
Patients with liver disease*
Child-Pugh Class A or B
Control participants
Healthy volunteers with normal liver function were matched to
participants with liver disease with regard to age, weight,
gender, and ethnicity
* Liver disease was primarily due to hepatitis C (93% of Child-Pugh A patients and
100% of Child-Pugh B patients).
Adapted from Lettieri J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
Exclusion Criteria
All Participants
Malignancy other than squamous- or basal-cell carcinoma in situ or other
malignancies not considered cured according to the criteria of the American
Cancer Society
Uncontrolled blood pressure (defined as systolic BP ≥160 mm Hg and diastolic BP
≥90 mm Hg)
Creatine kinase levels >3 times the upper limit of normal at screening
Hematocrit <32% at screening
Serum creatinine level >2.0 mg/dL at screening
Other abnormal laboratory parameters determined to be clinically significant (in the
opinion of the investigator and the sponsor); laboratory values that were slightly
outside the normal ranges may have been allowed
Major surgery, open biopsy, or significant trauma within 4 weeks of Day 1
BP=blood pressure.
Adapted from Lettieri J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
Exclusion Criteria (cont’d)
Patients With Liver Disease
Failure of a major organ system other than the liver
Elevation of AST, ALT, LDH, bilirubin, and/or all other
laboratory parameters related to liver function to
levels beyond what would be considered consistent
with the diagnosis of liver disease at screening
Inability to completely abstain from alcohol consumption
for 24 hours before the start of the study (Day 1) and
during the study
ALT=alanine aminotransferase; AST=aspartate aminotransferase; LDH=lactate dehydrogenase.
Adapted from Lettieri J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
Exclusion Criteria (cont’d)
Control Participants
Failure of a major organ system or presence of a medical
disorder that would impair the participant’s ability to
complete the study
AST, ALT, and/or LDH >1.2 times the upper limit of normal
at screening
History of drug or alcohol abuse
Positive test for human immunodeficiency virus,
hepatitis B virus, or hepatitis C virus
Adapted from Lettieri J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
Patient Demographics
Child-Pugh
Class A
(n=15)
Child-Pugh
Class B
(n=15)
Healthy
Volunteers
(n=15)
Total (N=45)
Male, n (%)
10 (66.7)
13 (86.7)
11 (73.3)
34 (75.6)
Female, n (%)
5 (33.3)
2 (13.3)
4 (26.7)
11 (24.4)
White, n (%)
14 (93.3)
14 (93.3)
12 (80.0)
40 (88.9)
Black, n (%)
1 (6.7)
1 (6.7)
2 (13.3)
4 (8.9)
Asian, n (%)
0 (0.0)
0 (0.0)
1 (6.7)
1 (2.2)
Mean age, years
(range)
54.4 (50-58)
57.8 (50-67)
55.8 (51-61)
56.0 (50-67)
Weight, kg,
(mean+SD)
84.1 (16.9)
78.5 (14.1)
82.8 (6.56)
81.8 (13.2)
Height, cm
(mean+SD)
171 (7.6)
172 (9.7)
172 (6.0)
172 (7.8)
Characteristic
SD=standard deviation.
Adapted from Lettieri J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
Pharmacokinetics
PK Assessment of Sorafenib Following a Single 400-mg Dose
(geometric mean, % CV)
Child-Pugh
Class A
(n=15)
Child-Pugh
Class B
(n=15)
Healthy Volunteers
(n=15)
AUC, mg-h/L
124 (57%)
107 (75%)*
102 (67%)
Cmax, mg/L
4.01 (67%)
3.31 (50%)
3.03 (59%)
t½, hours
27.5 (38%)
27.9 (37%)
27.0 (33%)
PK Parameter
*
n=14.
CV=coefficient of variation.
Adapted from Lettieri J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
Pharmacokinetics
(cont’d)
PK Assessment of Metabolite M2 Following a Single 400-mg Dose
(geometric mean, % CV)
PK Parameter
Child-Pugh
Class A
(n=15)
Child-Pugh
Class B
(n=15)
Healthy Volunteers
(n=15)
AUC, mg-h/L
23.5 (88%)*
30.0 (121%)*
21.1 (72%)
Cmax, mg/L
0.89 (84%)
0.97 (87%)
0.78 (59%)
t½, hours
27.0 (31%)
25.6 (38%)
27.3 (33%)
3 (3-12)
5 (2-24)
3 (2-5 )
tmax, hours†
*
n=14; †median (range).
Adapted from Lettieri J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
Pharmacokinetics
(cont’d)
PK Assessment of Metabolite M4 (demethylated sorafenib)
Following a Single 400-mg Dose of Sorafenib
(geometric mean, % CV)
PK Parameter
Child-Pugh
Class A
(n=15)
Child-Pugh
Class B
(n=15)
Healthy Volunteers
(n=15)
AUC0-tn, mg-h/L
2.29 (217%)
1.68 (1081%)
1.33 (239%)
Cmax, mg/L
0.076 (129%)
0.079 (184%)
0.053 (77%)
33.9 (78%)
26.9 (38%)
25.8 (53%)
12 (3-24)
16 (3-24)
9 (3-24)
t½, hours
tmax, hours*
*
Median (range).
Adapted from Lettieri J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
Pharmacokinetics
(cont’d)
Plasma Concentrations of Sorafenib
(geometric means) Following a Single 400-mg Dose
Plasma Concentration (mg/L)
10
Child-Pugh A
Child-Pugh B
Healthy
1
0.1
0
20
40
60
80
100
Time (hours)
Adapted from Lettieri J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
120
140
Pharmacokinetics
(cont’d)
Results of Statistical Analysis of AUC and Cmax Ratios
Between Different Participant Groups
Participant Groups
Estimated Ratio
90% Confidence Interval
AUC
1.22
(0.84-1.77)
Cmax
1.32
(0.95-1.85)
AUC
1.06
(0.73-1.54)
Cmax
1.09
(0.78-1.53)
AUC
0.86
(0.59-1.26)
Cmax
0.83
(0.59-1.16)
A/C
B/C
B/A
A=Child Pugh A; B=Child Pugh B; C=Healthy.
Adapted from Lettieri J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
Conclusions
No evidence for any clinically relevant or statistically significant differences in
PK between the 3 participant cohorts (CPA and CPB, and
a matched healthy control group) was found in this study, with respect to
either sorafenib or its most significant metabolites
For unchanged sorafenib, which is the principal drug-related moiety in plasma,
slight increases in AUC and Cmax were seen in CPA patients but were not
seen in CPB patients, suggesting that these effects are not related directly
to hepatic function
The 400-mg dose of sorafenib given to the CPA and CPB liver disease patients
and to the matched control group of healthy volunteers appeared to be
safe and well tolerated based on the review of typically standard protocolspecified safety variables collected and/or monitored in this study. No new
or unexpected adverse events were reported
Based on these data, no adjustment of sorafenib dose is required in
patients with mild to moderate hepatic impairment
CPA=Child-Pugh A; CPB=Child-Pugh B.
Adapted from Lettieri J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.