FDA Evaluation of HepatotoxicityRelated to Tyrosine Kinase Inhibitors

1Division of Drug Oncology Products; 2Office of Surveillance and Epidemiology;

3Office of Clinical Pharmacology; 4Office of Oncology Drug Products

J Chang,1 M Rand,2 G Blumenthal,1 P Cortazar,1 C Kulick,2 E Hausman,2 S Chang,2 R Pratt,2 B Habtemariam,3 Y Chen,3

J Bullock,3 RC Orbach,3 I Zineh,3 R Justice,1 R Pazdur4

Background

Tyrosine kinase inhibitors (TKIs) interfere with several critical signal transduction pathways in cancer

As of March 2010, FDA had approved 9 TKIs (imatinib, dasatinib, nilotinib, erlotinib, gefitinib, lapatinib, sorafenib, sunitinib, and pazopanib) to treat a variety of malignancies

All TKIs are associated with severe liver injury (SLI) and have different categories for liver injury, ranging from boxed warnings for fatal hepatotoxicity to adverse reactions for elevated LFTs

LFTs=liver function tests.Adapted from Chang J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

Methods

Analyses included a literature review and an evaluation of postmarketing reports of SLI associated with TKIs from FDA’s Adverse Event Reporting System* (AERS) from various dates of marketing approval until March 15, 2010. SLI is defined as acute liver injury (elevated LFTs, bilirubinemia, or jaundice) in combination with 1 of the following events: death, liver transplantation or placement on liver transplant list, hepatic encepholopathy, coagulopathy, or renal impairment

Drug utilization data were reviewed for comparison across TKIs. The estimated number of nationally projected dispensed prescriptions from mail order/specialty pharmacy and outpatient retail pharmacy settings was obtained from Wolters Kluwer Source PHAST Prescription Monthly™ from 2006 through 2009

For a mechanistic explanation, laboratory and exposure data were reviewed from 8 new drug application (NDA) submissions. Gefitinib data are excluded because it is no longer marketed in the United States. Exposure-response properties of TKI-induced liver enzyme and bilirubin elevations were evaluated

* Limitations of AERS data include: underreporting, stimulated reporting, biased reporting, variable quality and content, and no certainty that the reported event is due to the product.

Adapted from Chang J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

Results

Literature search: As of April 2010, there were 19 case reports of liver injury with imatinib, 7 with erlotinib, 5 with sorafenib, 4 with sunitinib, and 2 with gefitinib. 15 of these reports were captured in AERS

Drug utilization results: Total oral TKI market increased from approximately 313,000 prescriptions in 2006 to 348,000 prescriptions in 2009. Imatinib had the largest proportion of dispensed prescriptions

Adapted from Chang J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

Results (cont’d)

TKI FDA Approval YearTotal Prescriptions

2006-2009, NMarket Share2006-2009, %

Imatinib 2001 652,997 45.1

Erlotinib 2004 479,114 33.1

Sunitinib 2006 148,864 10.3

Lapatinib 2007 66,008 4.6

Dasatinib 2006 47,353 3.3

Gefitinib 2003 17,325 1.2

Sorafenib 2005 25,726 1.8

Nilotinib 2007 9,671 0.7

Pazopanib 2009 105 0

TOTAL 1,447,163 100

Adapted from Chang J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

Source: Wolters Kluwer SOURCE PHAST Prescription, 2005-2009.

Total Number of Nationally Projected Dispensed Prescriptions for TKIs in US Mail-Order and Outpatient Retail Pharmacies, 2006-2009

Postmarketing Cases

Of the 497 cases evaluated for SLI, 55 were categorized as possibly or likely associated with a drug

The majority of SLI cases were associated with sunitinib (22) and imatinib (13)

Most common event terms were hepatic failure, hepatic necrosis, hepatic coma or encephalopathy, and hepatorenal failure

67% of postmarketing cases were from foreign sources, and 45% of cases involved patients enrolled in clinical trials

No dasatinib cases were classified as possibly or likely associated with a drug

Adapted from Chang J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

Postmarketing TKI Cases of SLI*

* Limitations of AERS data include: underreporting, stimulated reporting, biased reporting, variable quality and content, and no certainty that the reported event is due to the product.

† Gefitinib is no longer marketed in the United States.

CML=chronic myelogenous leukemia; GIST=gastrointestinal stromal tumor; NSCLC=non–small cell lung cancer; RCC=renal cell carcinoma.

Adapted from Chang J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

Sunitinibn=22

Imatinibn=13

Gefitinib†

n=7Erlotinib

n=6Sorafenib

n=2Nilotinib

n=2Lapatinib

n=1Pazopanib

n=2

Demographics

Age (years)MedianRange

6445-83

504-78

7248-88

6753-77

5656

3822-53

5454

2921-37

GenderMaleFemaleUnknown

1481

103

4 3

33

1

1

20

01

02

Cancer typeRCC 16GIST 2Other 4

CML 8GIST 3Other 2

NSCLC 6Pancreatic 1

NSCLC 5Other 1

Thyroid 1RCC 1

CML 1GIST 1 Breast 1 Synovial

sarcoma 2

Postmarketing TKI Cases of SLI* (cont’d)

* Limitations of AERS data include: underreporting, stimulated reporting, biased reporting, variable quality andcontent, and no certainty that the reported event is due to the product. † Gefitinib is no longer marketed in the United States.‡ 2 Patients required liver transplant.§ Other includes: hepatitis fulminant (2), liver disorder (1), hepatitis (1), hepatic cirrhosis (1).

Adapted from Chang J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

Sunitinibn=22

Imatinibn=13

Gefitinib†

n=7Erlotinib

n=6Sorafenib

n=2Nilotinib

n=2Lapatinib

n=1Pazopanib

n=2

Reported Adverse Event and Event Characteristics

Hepatic failureHepatic necrosisHepatic coma or encephalopathyHepatorenal failureOther§

1622

02

10‡

10

11

401

02

500

10

101

00

200

00

100

00

200

00

Dose (mg)MedianRange

5025-50

400200-400

250None

150100-150

800None

800None

1500None

800None

Time to event (days)MedianRange

277-314

1508-312

224-180

2812-71

6856-80

636-120

126126

4534-55

OutcomeDeathHospitalizationLife-threateningOther

16420

8508

6100

5100

1001

2000

0100

2000

(+) dechallenge(+) rechallenge

50

10

02

10

10

00

10

00

Pharmacogenomics

HLA=human leukocyte antigen.Adapted from Chang J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

This is being explored as a potential tool to understand the mechanistic basis of drug-induced liver injury (DILI) and manage its clinical risks

Susceptibility to idiosycratic DILI is currently attributed to the complex interaction of multiple factors such as genetic, environmental, and drug-related factors

Genetic susceptibility to DILI is mostly associated with variations in immune response and/or drug metabolism and transport genes

Lapatinib-induced hepatotoxicity has recently been linked to a HLA allele

Examples of Genotypic Associations for DILI

Drug Therapeutic Class HLA Allele Reference (PMID)

Flucloxacillin Antibiotic HLA-B*5701 Daly et al. 2009[19483685]

Ximelagatran Thrombin inhibitor HLA-DRB1*07 and HLA-DQA1*02

Kindmark et al. 2008[17505501]

Lumiracoxib NSAID HLA-DQA1*0102 Singer et al. 2010[20639878]

Lapatinib Antineoplastic HLA-DQA1*0201 Spraggs et al. 2011[21245432]

NSAID=nonsteroidal anti-inflammatory drug; PMID=PubMed identifier.

Adapted from Chang J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

Clinical Pharmacology

Adapted from Chang J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

Preliminary review of the data from NDA submissions suggests that TKIs inhibit bilirubin clearance. As shown below, sorafenib (sor), nilotinib (Nil), and pazopanib (pazo) exhibit concentration-dependent inhibition of the hepatic UGT1A1 enzyme in vitro. Inhibition of UGT1A1 is expected to increase total bilirubin in vivo.

% In

hib

itio

n

0

100

0.5 1.0 10.05.0

Drug Concentration (M)

80

40

60

20

sor:estradiolsor:SN-38Nil:bilirubinNil:estradiolpazo:HFC

0.1 50.0 100.0

Clinical Pharmacology (cont’d)

ALT=alanine aminotransferese; CI=confidence interval; ULN=upper limit of normal.

Adapted from Chang J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

With increasing trough concentrations of pazopanib, the probability of ALT >3 x ULN increases with increasing pazopanib plasma concentrations

No concentration-dependent increase in total bilirubin >2 x ULN is observed

Probability of ALT >3 x ULN WithIncreasing Pazopanib Concentrations

Logistic regressionObserved proportion (95% CI)

Probability of bilirubin >2 x ULN WithIncreasing Pazopanib Concentrations

Pro

bab

ilit

y o

fA

LT

>3

x U

LN

(%

)

0

40

60

80

100

0 20 60

20

80400

40

60

80

0 20 60

20

8040P

rob

abil

ity

of

AL

T >

3 x

UL

N (

%)

Steady State Trough Concentration (g/mL)

Steady State Trough Concentration (g/mL)

Logistic regressionObserved proportion (95% CI)

16/6317/63

11/638/64

1/64

3/632/63

4/63

Conclusions

* Limitations of AERS data include: underreporting, stimulated reporting, biased reporting, variable quality and content, and no certainty that the reported event is due to the product.Adapted from Chang J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

The pharmacogenomics data for lapatinib thus far suggest a genetic association for DILI. More research into the predictive value, sensitivity, and specificity of these biomarkers is needed to understand their clinical utility for predicting patients who are susceptible

These associations may be used in the future to identify individuals at greater risk of developing liver injury

Consideration of both genetic and nongenetic factors in DILI may help to identify these patients and improve therapy management. Investigations of the exposure response analysis for other TKIs are ongoing

Review of postmarketing and clinical pharmacology data suggests a role for TKIs in causing hepatotoxicity. However, review of postmarketing AERS data* precludes class labeling for SLI for all TKIs

Greater numbers of cases for imatinib and sunitinib may relate to greater national market share of TKIs

TKI Labeling for Hepatotoxicity

* Imatinib and sorafenib prescribing information updated in italics.† Gefitinib is no longer marketed in the United States.

Adapted from Chang J et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.

DrugBoxed

WarningWarnings andPrecautions

AdverseReactions

Additional Data From Clinical Trials or

Postmarketing Experience

Imatinib*

Fatal Hepatotoxicity, Severe Liver Injury (requiring liver

transplant), Acute Liver Failure,

Elevated LFTs

Elevated LFTsHepatitis, Hepatic Failure,

and Hepatic Necrosis (including some fatalities)

Dasatinib Elevated LFTs Hepatitis

Nilotinib Elevated LFTs Elevated LFTs Hepatitis, Hepatotoxicity

Erlotinib Hepatic Failure and Hepatorenal Syndrome (including fatalities) Elevated LFTs

Gefitinib† Elevated LFTs(Precautions section)

Lapatinib Fatal Hepatotoxicity Fatal Hepatotoxicity Hepatotoxicity

Sunitinib Fatal Hepatotoxicity Fatal Hepatotoxicity Hepatotoxicity

Sorafenib* Liver DysfunctionDrug-induced hepatitis,

including reports of hepatic failure and death

Pazopanib Fatal Hepatotoxicity Fatal Hepatotoxicity Elevated LFTs

Updated changes are in bold and italics