1. 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 1

2. Healthy volunteers (control)
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
Participants 1
Child-Pugh Class A 2
Child-Pugh Class B 3
Healthy volunteers (control)
PK=pharmacokinetic.
Adapted from Lettieri J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL. 2 2 2

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. Patient Demographics Characteristic 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)
12 (80.0)
40 (88.9)
Black, n (%)
1 (6.7)
4 (8.9)
Asian, n (%)
0 (0.0)
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)
SD=standard deviation.
Adapted from Lettieri J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

9. Pharmacokinetics
PK Assessment of Sorafenib 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
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%)
* n=14.
CV=coefficient of variation.
Adapted from Lettieri J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

10. 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%)
tmax, hours†
3 (3-12)
5 (2-24)
3 (2-5 )
* n=14; †median (range).
Adapted from Lettieri J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

11. 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%)
t½, hours
33.9 (78%)
26.9 (38%)
25.8 (53%)
tmax, hours*
12 (3-24)
16 (3-24)
9 (3-24)
* Median (range).
Adapted from Lettieri J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

12. Pharmacokinetics (cont’d)
Plasma Concentrations of Sorafenib (geometric means) Following a Single 400-mg Dose 10
Child-Pugh A
Child-Pugh B
Healthy
Plasma Concentration (mg/L) 1
0.1 20 40 60 80
100
120
140
Time (hours)
Adapted from Lettieri J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

13. Pharmacokinetics (cont’d)
Results of Statistical Analysis of AUC and Cmax Ratios Between Different Participant Groups
Participant Groups
Estimated Ratio
90% Confidence Interval
A/C
AUC
1.22
( )
Cmax
1.32
( )
B/C
1.06
( )
1.09
( )
B/A
0.86
( )
0.83
( )
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.

14. 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 protocol- specified 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.