- Email: [email protected]
A Drug Interaction Between Cabozantinib and Warfarin in a Patient With Renal Cell Carcinoma
Accepted Manuscript A drug interaction between cabozantinib and warfarin in a patient with renal cell carcinoma William Travis Foxx-Lupo, PharmD, Sarah Sing, PharmD, Laura Alwan, PharmD, Scott S. Tykodi, MD, PhD PII:
S1558-7673(15)00256-6
DOI:
10.1016/j.clgc.2015.09.015
Reference:
CLGC 477
To appear in:
Clinical Genitourinary Cancer
Received Date: 18 June 2015 Revised Date:
9 September 2015
Accepted Date: 25 September 2015
Please cite this article as: Foxx-Lupo WT, Sing S, Alwan L, Tykodi SS, A drug interaction between cabozantinib and warfarin in a patient with renal cell carcinoma, Clinical Genitourinary Cancer (2015), doi: 10.1016/j.clgc.2015.09.015. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
RI PT
ACCEPTED MANUSCRIPT
Authors: William Travis Foxx-Lupo, PharmDa Sarah Sing, PharmDa Laura Alwan, PharmDa Scott S. Tykodi, MD, PhDb,c
M AN U
SC
Title: A drug interaction between cabozantinib and warfarin in a patient with renal cell carcinoma
EP
TE D
Affiliations: a) Department of Pharmacy, University of Washington Medical Center, Seattle, WA UWMCs address it is 1959 NE Pacific St. Seattle, WA, US. 98195 b) Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA 825 Eastlake Ave E., Seattle, WA, US. 98109 c) Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 1100 Fairview Ave. N., Seattle, WA, US 98109
AC C
Address for Correspondence: William Travis Foxx-Lupo, PharmD Seattle Cancer Care Alliance – Northwest Hospital 1560 N 115th St, Suite G-16. Seattle, WA 98133 P: (206)368-5802, F: (206)368-1403 [email protected]
1
ACCEPTED MANUSCRIPT
Conflict of Interest Page
AC C
EP
TE D
M AN U
SC
RI PT
Financial Disclosure/Acknowledgements: WTF, SS and LA have no disclosures. SST has received funding for a clinical trial on behalf of his institution from Exelixis, Inc.
2
ACCEPTED MANUSCRIPT
Clinical Practice Points • Tyrosine Kinase Inhibitors (TKIs) are frequently associated with clinically relevant drug-drug interactions. We present here evidence for a novel drug interaction between the oral TKI cabozantinib and warfarin resulting in extreme elevation of INR values. A pharmacokinetic drug interaction via CYP enzyme activity is the likely cause for the observed INR modulation.
•
This case should give caution to practitioners in combining these two agents.
•
Clinicians need to be cognizant of the potential for drug interactions beyond the information provided by commonly utilized drug reference sources.
AC C
EP
TE D
M AN U
SC
RI PT
•
Keywords: warfarin, cabozantinib, tyrosine kinase inhibitor, renal cell carcinoma, drug interaction 3
ACCEPTED MANUSCRIPT
Introduction
RI PT
The oncology patient is vulnerable to complications of care including both expected and unexpected effects of cancer therapies. Unanticipated effects, such as clinically significant drug-drug interactions, have the potential to be unrecognized in the early phases of clinical use of novel therapeutic agents due to small study recruitment numbers and the limited associated spectrum of interacting medications that may be encountered during clinical research. Previous reports have estimated as many as 63% of cancer patients may be exposed to drug-drug interactions with the majority of these interactions being classified as moderate to severe. 1
M AN U
SC
Cabozantinib is an oral, small molecule tyrosine kinase inhibitor (TKI) targeting the ret proto-oncogene (RET), the hepatocyte growth factor receptor (MET), and vascular endothelial growth factor receptor 2 (VEGFR2) that was approved for the treatment of metastatic medullary thyroid cancer (MTC) in 2012. 2 This agent has also demonstrated substantial anti-tumor activity in heavily pretreated patients with metastatic renal cell carcinoma (RCC) in a phase I study with a response rate of 28% and median progression free survival of 12.9 months. 3 A randomized, phase III study of cabozantinib versus the mammalian target of rapamycin (mTOR)-inhibitor everolimus for previously treated RCC patients is currently ongoing. 4
Case Report
TE D
We report here a case of extremely elevated international normalized ratio (INR) values in a patient previously stable on warfarin. This occurred shortly after the initiation of cabozantinib for treatment of metastatic RCC suggesting a clinically relevant drug interaction between cabozantinib and warfarin. However, the approved product labeling for cabozantinib and pharmacology resources do not identify any interactions between cabozantinib and warfarin. 5,6,7,8
EP
A 64 year old Caucasian man without significant past medical history was diagnosed with metastatic RCC involving the lungs and mediastinum in 2012. He underwent a cytoreductive right nephrectomy. Pathology confirmed clear cell RCC with one positive lymph node and negative margins (stage pT3A N1 M1). In the immediate post-operative period, he was diagnosed with a pulmonary embolus treated with low molecular weight heparin. On recovery from his surgery, he was transitioned to warfarin with a plan for long term anticoagulation in the setting of metastatic cancer.
AC C
For his metastatic RCC, he was treated initially with pazopanib for four months. For progressing disease, he then received palliative radiation therapy targeting new bony metastases in the sacrum and pelvis followed by second-line everolimus for eight months. Throughout this time the patient continued on warfarin. Additional medications included oxycodone, monthly zoledronic acid, and as needed zolpidem and ondansetron. For further disease progression involving the mediastinum, liver, adrenals, and retroperitoneum, the patient initiated third line treatment with cabozantinib at 140 mg daily; the FDA-approved dose for MTC that had also been tested in a phase I study with heavily pretreated RCC patients. 3 Of note, no other medications were added to this patient’s regimen at this time. The patient’s INR was being actively monitored by a pharmacist-managed anticoagulation clinic under a collaborative practice agreement. Prior to initiation of cabozantinib, the patient’s INR had remained stable in the therapeutic range (2.2 3.1) for greater than three months (Figure). The patient had been on stable doses of warfarin of 35-37.5 4
ACCEPTED MANUSCRIPT
RI PT
mg per week and was managed with monthly INR evaluations and clinic visits. No warfarin dose adjustments were made before initiation of cabozantinib. Two weeks following the initiation of cabozantinib, the patient presented for a routine INR assessment and was found to have an INR of 9.7 with no concomitant signs of bleeding (Figure). The patient was instructed to take 1.25 mg of vitamin K orally and to hold warfarin. A follow-up INR drawn two days later was 3.4, demonstrating a response to the INR reversal intervention. Following one additional held dose of warfarin, the patient was instructed to restart his warfarin at a lower dose of 27.5 mg per week.
M AN U
SC
Six days after restarting warfarin, the patient was found to have an INR of 18. The patient reported scant nose bleeds, however, no other bleeding symptoms were present. Due to his elevated INR the patient was instructed to take 5 mg of oral vitamin K and to hold warfarin until further notice. The patient presented the following day for repeat INR evaluation documenting no change in the patient’s INR after 24 hours. He was then given an additional 5 mg of oral vitamin K as well as four units of fresh frozen plasma (Figure). Cabozantinib was also discontinued at this time. Following these interventions, the patient’s INR corrected to a value of 2 within seven days (Figure) at which time he restarted warfarin at the previously stable dose of 37.5 mg per week. Beginning two weeks after the start of cabozantinib therapy, the patient also reported side effects related to cabozantinib including mouth sensitivity, nausea, anorexia, an acneiform skin rash and escalating fatigue. Additionally, the patient’s total bilirubin was measured at 3.1 mg/dL which was newly elevated. Liver-function tests before the start of cabozantinib had been entirely within normal limits. Two weeks after stopping cabozantinib, repeat LFTs demonstrated total bilirubin within normal limits (1.3 mg/dL) with slightly elevated direct bilirubin (0.7 mg/dL). The patient’s albumin was low before cabozantinib initiation, but remained stable between 3.1-3.3 g/dL.
Discussion
TE D
Following the discontinuation of cabozantinib, the patient opted to receive no further systemic therapy for his RCC. Six weeks later, the patient was referred for home Hospice care.
AC C
EP
Oral TKIs have become a significant focus of research in both solid and hematologic malignancies due to their generally favorable tolerability profile compared to other chemotherapeutics and ease of oral administration. Nevertheless, many TKI therapies are affected by and contribute to numerous drug interactions such as pH related absorption limitations, cytochrome P450 inhibition and induction, or QTc prolongation.9 Recognition of these potential complications is becoming paramount to ensuring the safe and effective management of patients treated with a TKI. Clinically significant effects on the pharmacokinetics of warfarin have been demonstrated with a broad variety of medications including antibiotics, antifungals, antiepileptics, antidepressants, antiretrovirals, and chemotherapeutic agents including TKIs. Although potential pharmacokinetic drug interactions with warfarin are becoming easier to identify prospectively, the therapeutic significance of many potential interactions remains uncertain. Our case suggests a previously unreported drug interaction occurring between the TKI cabozantinib and warfarin. The clinical trial the patient’s regimen was based on did not allow for warfarin co-administration3, however we are unaware of published data describing interaction effects. Modulation of cytochrome P450 kinetics likely represents the most significant contribution to this interaction effect. Warfarin, specifically its enantiomer S-warfarin, undergoes metabolism primarily through CYP2C9 and to a lesser extent through CYP2C19, 3A4, 2C8, 2C18, and 1A2. 5,10 As described in the product information, cabozantinib is a mixed inhibitor of CYP2C9 and 2C19 as well as a 5
ACCEPTED MANUSCRIPT
RI PT
noncompetitive inhibitor of 2C8 and a minor competitive inhibitor of 3A4. 8 These pharmacokinetic effects likely delayed the clearance of warfarin resulting in excessive inactivation of clotting factors and a subsequent dramatic increase in INR. Many medications that are associated with significant interactions with warfarin have been assumed to affect warfarin kinetics by inhibition of CYP2C9 including triazole antifungals (fluconazole, voriconazole), sulfamethaxazole, and metronidazole. On review of the patient’s other medications, none were found to interact with warfarin.
M AN U
SC
Other confounding factors including the presence of liver metastases, an increase in bilirubin which may have indicated liver dysfunction and decreased warfarin clearance, and decreased dietary vitamin K intake due to symptoms caused by cabozantinib were judged unlikely to have substantially contributed to the extreme INR elevations seen in this case. Normal liver function tests recorded immediately preceding the start of cabozantinib argues against overt liver dysfunction present during the time interval of cabozantinib and warfarin co-administration. Also, although the patient had minor elevations in LFTs after initiation of cabazantinib, these were not deemed significant enough to affect warfarin drug metabolism and clearance. The patient did not have any history of cirrhosis, active hepatitis, or other underlying liver abnormalities and the patient had consistently denied any alcohol use while on warfarin. Additionally, cabozantinib itself can cause transient elevations in aminotransferase and bilirubin without causing overt liver dysfunction. Lastly, the patient did not self-report major changes in oral intake of foods containing oral vitamin K to anticoagulation clinic providers despite acknowledging cabozantinib-associated GI symptoms. Conclusion
AC C
EP
TE D
Taken together, the close association of extreme changes in INR values with cabozantinib and warfarin co-administration, the modulation of INR values by withdrawal of warfarin, and subsequently by the withdrawal of cabozantinib, and the plausible mechanism for a pharmacokinetic drug interaction via CYP enzyme activity strongly support the conclusion that a cabozantinib-warfarin drug interaction was the primary cause for the extremely elevated INR values recorded for our patient. This case should give caution to practitioners in combining these two agents and exemplifies the need for clinicians to be cognizant of potential drug interactions beyond the information provided by commonly utilized drug reference resources.
6
ACCEPTED MANUSCRIPT
References
AC C
EP
TE D
M AN U
SC
RI PT
1. Riechelmann RP, Del Giglio A. Drug interactions in oncology: how common are they? Ann Oncol 2009;20:1907-1912. 2. Kurzrock R, Sherman S, Ball D, et al. Activity of XL184 (cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer. J Clin Oncol 2011;29:2660-6. 3. Choueiri T, Kumar Pal S, McDermott D. et al. A phase I study of cabozantinib (XL184) in patients with renal cell cancer. Ann Oncol 2014;25:1603-8. 4. https://clinicaltrials.gov/ct2/show/NCT01865747?term=cabozantinib&rank=32 5. Facts & Comparisons eAnswers. Drug Facts and Comparisons. Indianapolis, IN: Wolters Kluwer Health; 2013. http://online.factsandcomparisons.com/. Accessed April 5, 2014. 6. Micromedex Healthcare Series. DRUGDEX System. Greenwood Village, CO: Truven Health Analytics, 2013. http://www.thomsonhc.com/. Accessed April 5, 2014. 7. Natural Medicines Comprehensive Database. Stockton, CA: Therapeutic Research Faculty; 2010. http://naturaldatabase.therapeuticresearch.com/. Accessed April 5, 2014. 8. Cometriq(R) [package insert]. San Francisco, CA: Exelixis Inc; 2012. 9. van Leeuwen RWF, van Gelder T, Mathijssen RHJ, et al. Drug-drug interactions with tyrosine kinase inhibitors: a clinical perspective. Lancet Oncol 2014;15:e315-26. 10. Whirl-Carrillo M, McDonagh E, Hebert J, et al. Pharmacogenomics Knowledge for Personalized Medicine. Clin Pharmacol Ther 2012;92:414-417.
7
ACCEPTED MANUSCRIPT
Figure Legend
AC C
EP
TE D
M AN U
SC
RI PT
Measured INR values (black circles with solid black line) are shown for an RCC patient receiving warfarin therapy. Average daily dose of warfarin (gray circles with dotted gray line) are also shown. Arrows denote treatment changes along the time period shown. C = cabozantinib, W = warfarin,
8
ACCEPTED MANUSCRIPT
Figure. INR values observed on warfarin therapy with and without cabozantinb co-administration.
20
RI PT
20 W held, Stop C,
18
18
16
16
14
14
12
12
10
10
SC
W held
INR
8
8
C initiated
6
6 4
2
M AN U
4 W resumed
0 -140
-120
-100
-80
-60
-40
-20
0
20
40
2
AVG DAILY WARFAIN D OSE (mg)
0
60
AC C
EP
TE D
Time (days)
9
S1558-7673(15)00256-6
DOI:
10.1016/j.clgc.2015.09.015
Reference:
CLGC 477
To appear in:
Clinical Genitourinary Cancer
Received Date: 18 June 2015 Revised Date:
9 September 2015
Accepted Date: 25 September 2015
Please cite this article as: Foxx-Lupo WT, Sing S, Alwan L, Tykodi SS, A drug interaction between cabozantinib and warfarin in a patient with renal cell carcinoma, Clinical Genitourinary Cancer (2015), doi: 10.1016/j.clgc.2015.09.015. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
RI PT
ACCEPTED MANUSCRIPT
Authors: William Travis Foxx-Lupo, PharmDa Sarah Sing, PharmDa Laura Alwan, PharmDa Scott S. Tykodi, MD, PhDb,c
M AN U
SC
Title: A drug interaction between cabozantinib and warfarin in a patient with renal cell carcinoma
EP
TE D
Affiliations: a) Department of Pharmacy, University of Washington Medical Center, Seattle, WA UWMCs address it is 1959 NE Pacific St. Seattle, WA, US. 98195 b) Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA 825 Eastlake Ave E., Seattle, WA, US. 98109 c) Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 1100 Fairview Ave. N., Seattle, WA, US 98109
AC C
Address for Correspondence: William Travis Foxx-Lupo, PharmD Seattle Cancer Care Alliance – Northwest Hospital 1560 N 115th St, Suite G-16. Seattle, WA 98133 P: (206)368-5802, F: (206)368-1403 [email protected]
1
ACCEPTED MANUSCRIPT
Conflict of Interest Page
AC C
EP
TE D
M AN U
SC
RI PT
Financial Disclosure/Acknowledgements: WTF, SS and LA have no disclosures. SST has received funding for a clinical trial on behalf of his institution from Exelixis, Inc.
2
ACCEPTED MANUSCRIPT
Clinical Practice Points • Tyrosine Kinase Inhibitors (TKIs) are frequently associated with clinically relevant drug-drug interactions. We present here evidence for a novel drug interaction between the oral TKI cabozantinib and warfarin resulting in extreme elevation of INR values. A pharmacokinetic drug interaction via CYP enzyme activity is the likely cause for the observed INR modulation.
•
This case should give caution to practitioners in combining these two agents.
•
Clinicians need to be cognizant of the potential for drug interactions beyond the information provided by commonly utilized drug reference sources.
AC C
EP
TE D
M AN U
SC
RI PT
•
Keywords: warfarin, cabozantinib, tyrosine kinase inhibitor, renal cell carcinoma, drug interaction 3
ACCEPTED MANUSCRIPT
Introduction
RI PT
The oncology patient is vulnerable to complications of care including both expected and unexpected effects of cancer therapies. Unanticipated effects, such as clinically significant drug-drug interactions, have the potential to be unrecognized in the early phases of clinical use of novel therapeutic agents due to small study recruitment numbers and the limited associated spectrum of interacting medications that may be encountered during clinical research. Previous reports have estimated as many as 63% of cancer patients may be exposed to drug-drug interactions with the majority of these interactions being classified as moderate to severe. 1
M AN U
SC
Cabozantinib is an oral, small molecule tyrosine kinase inhibitor (TKI) targeting the ret proto-oncogene (RET), the hepatocyte growth factor receptor (MET), and vascular endothelial growth factor receptor 2 (VEGFR2) that was approved for the treatment of metastatic medullary thyroid cancer (MTC) in 2012. 2 This agent has also demonstrated substantial anti-tumor activity in heavily pretreated patients with metastatic renal cell carcinoma (RCC) in a phase I study with a response rate of 28% and median progression free survival of 12.9 months. 3 A randomized, phase III study of cabozantinib versus the mammalian target of rapamycin (mTOR)-inhibitor everolimus for previously treated RCC patients is currently ongoing. 4
Case Report
TE D
We report here a case of extremely elevated international normalized ratio (INR) values in a patient previously stable on warfarin. This occurred shortly after the initiation of cabozantinib for treatment of metastatic RCC suggesting a clinically relevant drug interaction between cabozantinib and warfarin. However, the approved product labeling for cabozantinib and pharmacology resources do not identify any interactions between cabozantinib and warfarin. 5,6,7,8
EP
A 64 year old Caucasian man without significant past medical history was diagnosed with metastatic RCC involving the lungs and mediastinum in 2012. He underwent a cytoreductive right nephrectomy. Pathology confirmed clear cell RCC with one positive lymph node and negative margins (stage pT3A N1 M1). In the immediate post-operative period, he was diagnosed with a pulmonary embolus treated with low molecular weight heparin. On recovery from his surgery, he was transitioned to warfarin with a plan for long term anticoagulation in the setting of metastatic cancer.
AC C
For his metastatic RCC, he was treated initially with pazopanib for four months. For progressing disease, he then received palliative radiation therapy targeting new bony metastases in the sacrum and pelvis followed by second-line everolimus for eight months. Throughout this time the patient continued on warfarin. Additional medications included oxycodone, monthly zoledronic acid, and as needed zolpidem and ondansetron. For further disease progression involving the mediastinum, liver, adrenals, and retroperitoneum, the patient initiated third line treatment with cabozantinib at 140 mg daily; the FDA-approved dose for MTC that had also been tested in a phase I study with heavily pretreated RCC patients. 3 Of note, no other medications were added to this patient’s regimen at this time. The patient’s INR was being actively monitored by a pharmacist-managed anticoagulation clinic under a collaborative practice agreement. Prior to initiation of cabozantinib, the patient’s INR had remained stable in the therapeutic range (2.2 3.1) for greater than three months (Figure). The patient had been on stable doses of warfarin of 35-37.5 4
ACCEPTED MANUSCRIPT
RI PT
mg per week and was managed with monthly INR evaluations and clinic visits. No warfarin dose adjustments were made before initiation of cabozantinib. Two weeks following the initiation of cabozantinib, the patient presented for a routine INR assessment and was found to have an INR of 9.7 with no concomitant signs of bleeding (Figure). The patient was instructed to take 1.25 mg of vitamin K orally and to hold warfarin. A follow-up INR drawn two days later was 3.4, demonstrating a response to the INR reversal intervention. Following one additional held dose of warfarin, the patient was instructed to restart his warfarin at a lower dose of 27.5 mg per week.
M AN U
SC
Six days after restarting warfarin, the patient was found to have an INR of 18. The patient reported scant nose bleeds, however, no other bleeding symptoms were present. Due to his elevated INR the patient was instructed to take 5 mg of oral vitamin K and to hold warfarin until further notice. The patient presented the following day for repeat INR evaluation documenting no change in the patient’s INR after 24 hours. He was then given an additional 5 mg of oral vitamin K as well as four units of fresh frozen plasma (Figure). Cabozantinib was also discontinued at this time. Following these interventions, the patient’s INR corrected to a value of 2 within seven days (Figure) at which time he restarted warfarin at the previously stable dose of 37.5 mg per week. Beginning two weeks after the start of cabozantinib therapy, the patient also reported side effects related to cabozantinib including mouth sensitivity, nausea, anorexia, an acneiform skin rash and escalating fatigue. Additionally, the patient’s total bilirubin was measured at 3.1 mg/dL which was newly elevated. Liver-function tests before the start of cabozantinib had been entirely within normal limits. Two weeks after stopping cabozantinib, repeat LFTs demonstrated total bilirubin within normal limits (1.3 mg/dL) with slightly elevated direct bilirubin (0.7 mg/dL). The patient’s albumin was low before cabozantinib initiation, but remained stable between 3.1-3.3 g/dL.
Discussion
TE D
Following the discontinuation of cabozantinib, the patient opted to receive no further systemic therapy for his RCC. Six weeks later, the patient was referred for home Hospice care.
AC C
EP
Oral TKIs have become a significant focus of research in both solid and hematologic malignancies due to their generally favorable tolerability profile compared to other chemotherapeutics and ease of oral administration. Nevertheless, many TKI therapies are affected by and contribute to numerous drug interactions such as pH related absorption limitations, cytochrome P450 inhibition and induction, or QTc prolongation.9 Recognition of these potential complications is becoming paramount to ensuring the safe and effective management of patients treated with a TKI. Clinically significant effects on the pharmacokinetics of warfarin have been demonstrated with a broad variety of medications including antibiotics, antifungals, antiepileptics, antidepressants, antiretrovirals, and chemotherapeutic agents including TKIs. Although potential pharmacokinetic drug interactions with warfarin are becoming easier to identify prospectively, the therapeutic significance of many potential interactions remains uncertain. Our case suggests a previously unreported drug interaction occurring between the TKI cabozantinib and warfarin. The clinical trial the patient’s regimen was based on did not allow for warfarin co-administration3, however we are unaware of published data describing interaction effects. Modulation of cytochrome P450 kinetics likely represents the most significant contribution to this interaction effect. Warfarin, specifically its enantiomer S-warfarin, undergoes metabolism primarily through CYP2C9 and to a lesser extent through CYP2C19, 3A4, 2C8, 2C18, and 1A2. 5,10 As described in the product information, cabozantinib is a mixed inhibitor of CYP2C9 and 2C19 as well as a 5
ACCEPTED MANUSCRIPT
RI PT
noncompetitive inhibitor of 2C8 and a minor competitive inhibitor of 3A4. 8 These pharmacokinetic effects likely delayed the clearance of warfarin resulting in excessive inactivation of clotting factors and a subsequent dramatic increase in INR. Many medications that are associated with significant interactions with warfarin have been assumed to affect warfarin kinetics by inhibition of CYP2C9 including triazole antifungals (fluconazole, voriconazole), sulfamethaxazole, and metronidazole. On review of the patient’s other medications, none were found to interact with warfarin.
M AN U
SC
Other confounding factors including the presence of liver metastases, an increase in bilirubin which may have indicated liver dysfunction and decreased warfarin clearance, and decreased dietary vitamin K intake due to symptoms caused by cabozantinib were judged unlikely to have substantially contributed to the extreme INR elevations seen in this case. Normal liver function tests recorded immediately preceding the start of cabozantinib argues against overt liver dysfunction present during the time interval of cabozantinib and warfarin co-administration. Also, although the patient had minor elevations in LFTs after initiation of cabazantinib, these were not deemed significant enough to affect warfarin drug metabolism and clearance. The patient did not have any history of cirrhosis, active hepatitis, or other underlying liver abnormalities and the patient had consistently denied any alcohol use while on warfarin. Additionally, cabozantinib itself can cause transient elevations in aminotransferase and bilirubin without causing overt liver dysfunction. Lastly, the patient did not self-report major changes in oral intake of foods containing oral vitamin K to anticoagulation clinic providers despite acknowledging cabozantinib-associated GI symptoms. Conclusion
AC C
EP
TE D
Taken together, the close association of extreme changes in INR values with cabozantinib and warfarin co-administration, the modulation of INR values by withdrawal of warfarin, and subsequently by the withdrawal of cabozantinib, and the plausible mechanism for a pharmacokinetic drug interaction via CYP enzyme activity strongly support the conclusion that a cabozantinib-warfarin drug interaction was the primary cause for the extremely elevated INR values recorded for our patient. This case should give caution to practitioners in combining these two agents and exemplifies the need for clinicians to be cognizant of potential drug interactions beyond the information provided by commonly utilized drug reference resources.
6
ACCEPTED MANUSCRIPT
References
AC C
EP
TE D
M AN U
SC
RI PT
1. Riechelmann RP, Del Giglio A. Drug interactions in oncology: how common are they? Ann Oncol 2009;20:1907-1912. 2. Kurzrock R, Sherman S, Ball D, et al. Activity of XL184 (cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer. J Clin Oncol 2011;29:2660-6. 3. Choueiri T, Kumar Pal S, McDermott D. et al. A phase I study of cabozantinib (XL184) in patients with renal cell cancer. Ann Oncol 2014;25:1603-8. 4. https://clinicaltrials.gov/ct2/show/NCT01865747?term=cabozantinib&rank=32 5. Facts & Comparisons eAnswers. Drug Facts and Comparisons. Indianapolis, IN: Wolters Kluwer Health; 2013. http://online.factsandcomparisons.com/. Accessed April 5, 2014. 6. Micromedex Healthcare Series. DRUGDEX System. Greenwood Village, CO: Truven Health Analytics, 2013. http://www.thomsonhc.com/. Accessed April 5, 2014. 7. Natural Medicines Comprehensive Database. Stockton, CA: Therapeutic Research Faculty; 2010. http://naturaldatabase.therapeuticresearch.com/. Accessed April 5, 2014. 8. Cometriq(R) [package insert]. San Francisco, CA: Exelixis Inc; 2012. 9. van Leeuwen RWF, van Gelder T, Mathijssen RHJ, et al. Drug-drug interactions with tyrosine kinase inhibitors: a clinical perspective. Lancet Oncol 2014;15:e315-26. 10. Whirl-Carrillo M, McDonagh E, Hebert J, et al. Pharmacogenomics Knowledge for Personalized Medicine. Clin Pharmacol Ther 2012;92:414-417.
7
ACCEPTED MANUSCRIPT
Figure Legend
AC C
EP
TE D
M AN U
SC
RI PT
Measured INR values (black circles with solid black line) are shown for an RCC patient receiving warfarin therapy. Average daily dose of warfarin (gray circles with dotted gray line) are also shown. Arrows denote treatment changes along the time period shown. C = cabozantinib, W = warfarin,
8
ACCEPTED MANUSCRIPT
Figure. INR values observed on warfarin therapy with and without cabozantinb co-administration.
20
RI PT
20 W held, Stop C,
18
18
16
16
14
14
12
12
10
10
SC
W held
INR
8
8
C initiated
6
6 4
2
M AN U
4 W resumed
0 -140
-120
-100
-80
-60
-40
-20
0
20
40
2
AVG DAILY WARFAIN D OSE (mg)
0
60
AC C
EP
TE D
Time (days)
9