CLINICAL CONSULTATION Axitinib
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C L I N I C A L C O N S U LTAT I O N
Layar
Common questions regarding clinical use of axitinib in advanced renal cell carcinoma Diane L. Borst, Lillian S. Arruda, Elizabeth MacLean, Yazdi K. Pithavala, and James E. Morgado
A
xitinib (Inlyta, Pfizer) was approved by the Food and Drug Administration (FDA) on January 27, 2012, for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy. The recommended starting dosage is 5 mg orally twice daily.1 The approval was based on the Phase III AXIS trial,2 which compared axitinib to sorafenib in patients with metastatic RCC after prior treatment with one of several approved firstline therapies for advanced RCC.1,2 Several articles, reviews, and commentaries on the efficacy of axitinib have been published, as well as descriptions of associated adverse reactions.3-6 As the number of approved oral anticancer agents increases, it becomes more important to provide the most up-to-date and accurate information on appropriate administration of these agents to ensure optimal outcomes.7 Since FDA’s approval of axitinib, many of the inquiries that have been submitted by pharmacists and other health care professionals to Pfizer Medical Information were related to
Purpose. An overview of the responses to some of the most frequently asked questions regarding axitinib administration and dosage modifications used in clinical practice are presented. Summary. Axitinib was approved for second-line treatment of advanced renal cell carcinoma by the Food and Drug Administration on January 27, 2012. Inquiries received over the first six months after the approval date were reviewed. A large number of questions were related to administration of axitinib in different patient populations or in patients with various comorbidities, such as its (1) use in patients unable to swallow oral medication or administration of axitinib via a nasogastric tube, (2) use in patients with renal or hepatic impairment, (3) central nervous system penetration and use in patients with brain metastases, (4) drug interactions, particularly with anticoagulants, and (5) dosage modifications. Responses to
administration of the drug in different patient populations or its use in patients with varying comorbidities. Although enrollment of patients representing such diverse populations in clinical trials was limited, a review of
Diane L. Borst, Pharm.D., is Director, Regional Medical Research Specialists, U.S. Medical Affairs, Pfizer, New York, NY. Lillian S. Arruda, Ph.D., is Associate Director, Oncology Medical Information, Pfizer, Collegeville, PA. E lizabeth Mac L ean , P harm .D., is Director, U.S. Health Economics and Outcomes ResearchOncology, Pfizer, New York, NY. Yazdi K. Pithavala, Ph.D., is Senior Director, Clinical Pharmacology, Pfizer, San Diego, CA. James E. Morgado, B.Sc., is Principal Scientist, Chemistry-Analytics, Pfizer, Groton, CT.
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these inquiries were provided based on the published literature or from data on file from the manufacturer. The dosage of axitinib can be adjusted for use in patients with hepatic impairment or in patients who cannot otherwise tolerate the usual regimen. Patients taking concomitant warfarin can also take axitinib, and patients who cannot swallow oral medications can receive a liquid formulation of the drug, though its efficacy and comparability to the tablet formulation has not been tested. Conclusion. Based on the published literature and company data on file, the axitinib dosage may be modified to accommodate patients with renal or hepatic impairment, who cannot swallow oral medication, are receiving concomitant warfarin, or who cannot otherwise tolerate the standard dosage regimen. For patients who cannot swallow, an oral suspension can be prepared because crushing axitinib is not recommended. Am J Health-Syst Pharm. 2014; 71:1092-6
the published literature and internal data was conducted to provide guidance in answering these questions. All axitinib-related medical information requests received between January 27, 2012, (approval date),
Address correspondence to Dr. Borst ([email protected]). Sponsored by Pfizer. Editorial support was provided by Mariko Nagashima, Ph.D., of Engage Scientific Solutions, Southport, CT, and funded by Pfizer. The authors are employees of and own stock in Pfizer. Copyright © 2014, American Society of Health-System Pharmacists, Inc. All rights reserved. 1079-2082/14/0701-1092$06.00. DOI 10.2146/ajhp130581
CLINICAL CONSULTATION Axitinib
The Clinical Consultation section features articles that provide brief advice on how to handle specific drug therapy problems. All articles are based on a systematic review of the literature. The assistance of ASHP’s Section of Clinical Specialists and Scientists in soliciting Clinical Consultation submissions is acknowledged. Unsolicited submissions are also welcome.
and July 31, 2012, were reviewed and categorized. While many of these inquiries were regarding efficacy and safety, there were many requests for information regarding drug administration. These included (1) use in patients unable to swallow oral medications or administration of axitinib via a nasogastric tube, (2) use in patients with renal or hepatic impairment, (3) central nervous system (CNS) penetration and use in patients with brain metastases, (4) drug interactions, particularly with anticoagulants (e.g., warfarin), and (5) dosage modifications. This report provides an overview of the responses to some of the most frequently asked questions regarding axitinib administration and an estimate of dosage modifications used in clinical practice. Use in patients unable to swallow Pharmacists and nurses may frequently encounter the issue of axitinib administration to patients with a nasogastric tube or to those unable to swallow oral medications for other reasons. To date, no formal clinical studies have been conducted to demonstrate that delivery of axitinib via a nasogastric tube or other similar method will result in comparable safety and efficacy outcomes as observed with the oral administration of the intact commercially available axitinib tablet formulation. Hence, no conclusions can be made about the effectiveness of axitinib delivered by a nasogastric tube. Although it is recommended that axitinib tablets be swallowed whole with a glass of water, a method for preparation of
an axitinib oral suspension for nasogastric tube administration was established to address the needs of a few patients in clinical trials who were unable to swallow the axitinib tablets.8 This was created for doses of 2–10 mg of axitinib from a clinical study supply. Key axitinib characteristics taken into account during the development of this administration method included the lack of scoring on the tablet and other factors, such as the photolability of the axitinib drug substance, which needs to be protected from light. In addition, axitinib aqueous solubility is pH dependent, with increasing pH resulting in lower solubility. Another factor to consider is the safe handling of axitinib tablets. Crushing these tablets is not recommended, as there is limited guidance on crushing oral antineoplastics, and pharmacists and nurses would require protection from inadvertent exposure.7,9.10 Further details on the preparation of the oral suspension for use in patients with a nasogastric tube can be accessed online (www.PfizerMedInfo.com) or by contacting Pfizer Medical Information. Briefly, without crushing the axitinib tablet, the suspension is prepared by placing the tablet in an amber oral syringe with 15 mL of United States Pharmacopeia (USP)grade water and waiting 10 minutes for the tablet to disintegrate. When developing the methodology for preparation of the oral suspension, USP grade water was used since it would provide consistent pH control and minimize potential interactions with impurities in tap water. The suspension is to be kept away from light and administered via nasogastric tube within 15 minutes of preparation. After administration, the nasogastric tube should be flushed with at least 15 mL of USP-grade water. Use in patients with renal or hepatic impairment Guidance for adjusting the dos-
ages of axitinib for patients with renal or hepatic impairment is addressed in the approved labeling and the axitinib clinical pharmacology review.1,3 When considering the administration of axitinib to such patients, it is important to note that axitinib is primarily eliminated via hepatobiliary elimination. The two major circulating plasma metabolites (sulfoxide and N-glucuronide) are ≥400-fold less potent in vitro against vascular endothelial growth factor receptor-2 compared with axitinib and are therefore considered pharmacologically inactive. After oral administration of a 5-mg dose of axitinib containing a trace amount of radioactive drug, approximately 41% of the radioactivity was recovered in the feces and approximately 23% was recovered in the urine. Unchanged axitinib, accounting for 12% of the administered dose, was the major component identified in the feces, whereas no unchanged axitinib was detected in the urine. A formal clinical study has not been conducted to evaluate the pharmacokinetics of axitinib in patients with renal impairment. However, population pharmacokinetic modeling was performed using data from 590 axitinib-treated subjects (383 healthy volunteers and 207 patients with solid tumors, including metastatic RCC) across 17 clinical studies.3 Data varied in terms of axitinib formulation, route of administration, fed state versus fasted state, and subject population (healthy volunteers versus patients with cancer). The analysis resulted in a model that describes axitinib plasma pharmacokinetics in subjects enrolled in Phase I and II studies and identified potential factors that may affect variability in axitinib disposition and elimination. Renal function was assessed by creatinine clearance (CLcr). Patients with normal renal function (CLcr, ≥90 mL/min; n = 338); mild (CLcr, 60−89 mL/min; n = 143), moderate (CLcr, 30−59 mL/min; n = 97), or
Am J Health-Syst Pharm—Vol 71 Jul 1, 2014
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severe (CLcr, 15−29 mL/min; n = 11) renal impairment; or end-stage renal disease (ESRD)(CLcr,
ar
C L I N I C A L C O N S U LTAT I O N
Layar
Common questions regarding clinical use of axitinib in advanced renal cell carcinoma Diane L. Borst, Lillian S. Arruda, Elizabeth MacLean, Yazdi K. Pithavala, and James E. Morgado
A
xitinib (Inlyta, Pfizer) was approved by the Food and Drug Administration (FDA) on January 27, 2012, for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy. The recommended starting dosage is 5 mg orally twice daily.1 The approval was based on the Phase III AXIS trial,2 which compared axitinib to sorafenib in patients with metastatic RCC after prior treatment with one of several approved firstline therapies for advanced RCC.1,2 Several articles, reviews, and commentaries on the efficacy of axitinib have been published, as well as descriptions of associated adverse reactions.3-6 As the number of approved oral anticancer agents increases, it becomes more important to provide the most up-to-date and accurate information on appropriate administration of these agents to ensure optimal outcomes.7 Since FDA’s approval of axitinib, many of the inquiries that have been submitted by pharmacists and other health care professionals to Pfizer Medical Information were related to
Purpose. An overview of the responses to some of the most frequently asked questions regarding axitinib administration and dosage modifications used in clinical practice are presented. Summary. Axitinib was approved for second-line treatment of advanced renal cell carcinoma by the Food and Drug Administration on January 27, 2012. Inquiries received over the first six months after the approval date were reviewed. A large number of questions were related to administration of axitinib in different patient populations or in patients with various comorbidities, such as its (1) use in patients unable to swallow oral medication or administration of axitinib via a nasogastric tube, (2) use in patients with renal or hepatic impairment, (3) central nervous system penetration and use in patients with brain metastases, (4) drug interactions, particularly with anticoagulants, and (5) dosage modifications. Responses to
administration of the drug in different patient populations or its use in patients with varying comorbidities. Although enrollment of patients representing such diverse populations in clinical trials was limited, a review of
Diane L. Borst, Pharm.D., is Director, Regional Medical Research Specialists, U.S. Medical Affairs, Pfizer, New York, NY. Lillian S. Arruda, Ph.D., is Associate Director, Oncology Medical Information, Pfizer, Collegeville, PA. E lizabeth Mac L ean , P harm .D., is Director, U.S. Health Economics and Outcomes ResearchOncology, Pfizer, New York, NY. Yazdi K. Pithavala, Ph.D., is Senior Director, Clinical Pharmacology, Pfizer, San Diego, CA. James E. Morgado, B.Sc., is Principal Scientist, Chemistry-Analytics, Pfizer, Groton, CT.
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these inquiries were provided based on the published literature or from data on file from the manufacturer. The dosage of axitinib can be adjusted for use in patients with hepatic impairment or in patients who cannot otherwise tolerate the usual regimen. Patients taking concomitant warfarin can also take axitinib, and patients who cannot swallow oral medications can receive a liquid formulation of the drug, though its efficacy and comparability to the tablet formulation has not been tested. Conclusion. Based on the published literature and company data on file, the axitinib dosage may be modified to accommodate patients with renal or hepatic impairment, who cannot swallow oral medication, are receiving concomitant warfarin, or who cannot otherwise tolerate the standard dosage regimen. For patients who cannot swallow, an oral suspension can be prepared because crushing axitinib is not recommended. Am J Health-Syst Pharm. 2014; 71:1092-6
the published literature and internal data was conducted to provide guidance in answering these questions. All axitinib-related medical information requests received between January 27, 2012, (approval date),
Address correspondence to Dr. Borst ([email protected]). Sponsored by Pfizer. Editorial support was provided by Mariko Nagashima, Ph.D., of Engage Scientific Solutions, Southport, CT, and funded by Pfizer. The authors are employees of and own stock in Pfizer. Copyright © 2014, American Society of Health-System Pharmacists, Inc. All rights reserved. 1079-2082/14/0701-1092$06.00. DOI 10.2146/ajhp130581
CLINICAL CONSULTATION Axitinib
The Clinical Consultation section features articles that provide brief advice on how to handle specific drug therapy problems. All articles are based on a systematic review of the literature. The assistance of ASHP’s Section of Clinical Specialists and Scientists in soliciting Clinical Consultation submissions is acknowledged. Unsolicited submissions are also welcome.
and July 31, 2012, were reviewed and categorized. While many of these inquiries were regarding efficacy and safety, there were many requests for information regarding drug administration. These included (1) use in patients unable to swallow oral medications or administration of axitinib via a nasogastric tube, (2) use in patients with renal or hepatic impairment, (3) central nervous system (CNS) penetration and use in patients with brain metastases, (4) drug interactions, particularly with anticoagulants (e.g., warfarin), and (5) dosage modifications. This report provides an overview of the responses to some of the most frequently asked questions regarding axitinib administration and an estimate of dosage modifications used in clinical practice. Use in patients unable to swallow Pharmacists and nurses may frequently encounter the issue of axitinib administration to patients with a nasogastric tube or to those unable to swallow oral medications for other reasons. To date, no formal clinical studies have been conducted to demonstrate that delivery of axitinib via a nasogastric tube or other similar method will result in comparable safety and efficacy outcomes as observed with the oral administration of the intact commercially available axitinib tablet formulation. Hence, no conclusions can be made about the effectiveness of axitinib delivered by a nasogastric tube. Although it is recommended that axitinib tablets be swallowed whole with a glass of water, a method for preparation of
an axitinib oral suspension for nasogastric tube administration was established to address the needs of a few patients in clinical trials who were unable to swallow the axitinib tablets.8 This was created for doses of 2–10 mg of axitinib from a clinical study supply. Key axitinib characteristics taken into account during the development of this administration method included the lack of scoring on the tablet and other factors, such as the photolability of the axitinib drug substance, which needs to be protected from light. In addition, axitinib aqueous solubility is pH dependent, with increasing pH resulting in lower solubility. Another factor to consider is the safe handling of axitinib tablets. Crushing these tablets is not recommended, as there is limited guidance on crushing oral antineoplastics, and pharmacists and nurses would require protection from inadvertent exposure.7,9.10 Further details on the preparation of the oral suspension for use in patients with a nasogastric tube can be accessed online (www.PfizerMedInfo.com) or by contacting Pfizer Medical Information. Briefly, without crushing the axitinib tablet, the suspension is prepared by placing the tablet in an amber oral syringe with 15 mL of United States Pharmacopeia (USP)grade water and waiting 10 minutes for the tablet to disintegrate. When developing the methodology for preparation of the oral suspension, USP grade water was used since it would provide consistent pH control and minimize potential interactions with impurities in tap water. The suspension is to be kept away from light and administered via nasogastric tube within 15 minutes of preparation. After administration, the nasogastric tube should be flushed with at least 15 mL of USP-grade water. Use in patients with renal or hepatic impairment Guidance for adjusting the dos-
ages of axitinib for patients with renal or hepatic impairment is addressed in the approved labeling and the axitinib clinical pharmacology review.1,3 When considering the administration of axitinib to such patients, it is important to note that axitinib is primarily eliminated via hepatobiliary elimination. The two major circulating plasma metabolites (sulfoxide and N-glucuronide) are ≥400-fold less potent in vitro against vascular endothelial growth factor receptor-2 compared with axitinib and are therefore considered pharmacologically inactive. After oral administration of a 5-mg dose of axitinib containing a trace amount of radioactive drug, approximately 41% of the radioactivity was recovered in the feces and approximately 23% was recovered in the urine. Unchanged axitinib, accounting for 12% of the administered dose, was the major component identified in the feces, whereas no unchanged axitinib was detected in the urine. A formal clinical study has not been conducted to evaluate the pharmacokinetics of axitinib in patients with renal impairment. However, population pharmacokinetic modeling was performed using data from 590 axitinib-treated subjects (383 healthy volunteers and 207 patients with solid tumors, including metastatic RCC) across 17 clinical studies.3 Data varied in terms of axitinib formulation, route of administration, fed state versus fasted state, and subject population (healthy volunteers versus patients with cancer). The analysis resulted in a model that describes axitinib plasma pharmacokinetics in subjects enrolled in Phase I and II studies and identified potential factors that may affect variability in axitinib disposition and elimination. Renal function was assessed by creatinine clearance (CLcr). Patients with normal renal function (CLcr, ≥90 mL/min; n = 338); mild (CLcr, 60−89 mL/min; n = 143), moderate (CLcr, 30−59 mL/min; n = 97), or
Am J Health-Syst Pharm—Vol 71 Jul 1, 2014
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CLINICAL CONSULTATION Axitinib
severe (CLcr, 15−29 mL/min; n = 11) renal impairment; or end-stage renal disease (ESRD)(CLcr,
