- Email: [email protected]
Potential drug—Drug interaction between interferon alfa-2b and gemfibrozil in a patient with malignant melanoma
Case Report
Potential Drug-Drug Interaction Between Interferon Alfa-2b and Gemfibrozil in a Patient with Malignant Melanoma Siu-Fun Wong, PharmD1;James G. Jakowatz, MD2; and RezaTaheri, PharmD3. l Western University College of Pharmacy, Pomona,
California;2Department of Surgical Oncology,
University of California Irvine Medical Center, Orange, California; and 3Western University College of Pkarmacy, Pomona, California ABSTRACT
Background: In the United States, patients with high-risk stage II or III melanoma are often treated with adjuvant interferon (IFN) therapy for 1 year after surgery. Adverse events associated with IFN alfa-2b use are primarily constitutional symptoms. However, hypertriglyceridemia requiring treatment has been reported. Objective: The aim of this report was to describe a potential drug-drug interaction between IFN alfa-2b and gemfibrozil in a patient with malignant melanoma. The possible mechanism of this potential interaction was examined. Methods: This report presents the case of a 43-yearold male patient weighing 101 kg with newly diagnosed stage III melanoma of the left arm, with metastasis to the supraclavicular node. The patient presented to the University of California Irvine Medical Center, Orange, California with severe gastrointestinal (GI) symptoms and elevated hepatic enzyme concentrations at week 48 of 104 of adjuvant treatment of malignant melanoma (IFN alfa 11 MU SC TIW in combination with the investigational melanoma vaccine melanoma theraccine 1.25 mL [1 mL lysate + 0.25 mL vaccine adjuvant] given SC at weeks 1, 2, 3, 4, 8, 16, 24, 32, 40, and 48 and then every 8 weeks until week 104), and IFNinduced hypertriglyceridemia (gemfibrozil 600 mg PO BID). The patient had no history of cardiovascular or GI disease and was not receiving any concomitant medication. The possible mechanism of this potential IFN alfa-gemfibrozil interaction as related to the cytochrome P450 (CYP) enzyme system was assessed. Results: In this case of a possible drug-drug interaction between IFN alfa 11 MU TIW and gemfibrozil 600 mg BID in a patient undergoing treatment for IFN-induced hypertriglyceridemia, the Naranjo Ad-
verse Drug Reactions (ADR) Probability Scale score was 7 (ie, ADR possibly related to treatment). Conclusions: Both IFN and gemfibrozil inhibit the activity of the hepatic enzymes CYPIA2 and CYP2C19. A possible drug-drug interaction between IFN alfa 11 MU TIW and gemfibrozil 600 mg BID was reported in a patient undergoing treatment for IFN-induced hypertriglyceridemia. (Clin Ther. 2005; 27:1942-1948) Copyright © 2005 Excerpta Medica, Inc. Key words: interferon alfa, gemfibrozil, drug interaction, hypertriglyceridemia, malignant melanoma, cytochrome P450.
INTRODUCTION
In the United States, patients with melanoma are primarily treated with surgical resection. 1 However, some patients require additional adjuvant systemic therapy after surgery. 1-3 The current standard adjuvant therapy for high-risk stage II or III melanoma is I year of interferon (IFN) alfa at 20 MU/m 2 IV 5 times per week for 4 weeks, followed by 10 MU/m 2 SC TIW for 48 weeks. 1-3 Additional IFN alfa-based treatment options are being investigated to improve the therapeutic outcome of this disease. Reported adverse events (AEs) associated with IFN include constitutional symptoms (eg, flulike symptoms); *Current affiliation: Loma Linda University School of Pharmacy, Loma Linda, California
Accepted for publication September 20, 2005. doi:l 0.1016/j.clinthera.2005.12.002 0149-2918/05/$19.00 Printed in the USA. Reproduction in whole or part is not permitted. Copyright © 2005 Excerpta Medica, Inc.
and neurologic, hematologic, endocrine, and hepatic disorders. 4 An uncommon AE associated with IFN therapy is hypertriglyceridemia with reduced or unchanged total cholesterol (TC) levels, s,6 This AE has been reported in patients diagnosed with hepatitis C and those with malignancy treated with IFN alfa. s-9 Two cases of acute pancreatitis associated with hypertriglyceridemia secondary to the use of high-dose IFN (20 MU/m 2 IV 5 times per week for 4 weeks, followed by 10 MU/m 2 SC TIW for 48 weeks) have been reported in patients with melanoma.l°a I Due to the potential impact of this AE, treatment with an antidyslipidemic drug, in combination with lifestyle modifications, such as exercise, a low-carbohydrate diet, and/or high consumption of fatty fish, is warrantedJ 2 A search of published literature concerning gemfibrozil used to treat IFN-induced hypertriglyceridemia, s,6 identified using PubMed (key terms: interferon-alfa, Intron-A, gemfibrozil, Lopid, drug interactions, and cytochrome enzymes; years: 1965-2004), did not yield any reports of potential drug-drug interactions associated with the use of IFN and gemfibrozil. The aim of this article was to report the case of a patient who experienced severe gastrointestinal (GI) symptoms and elevated hepatic enzyme concentrations while receiving adjuvant therapy for malignant melanoma (IFN alfa-2b and vaccine) and IFN alfainduced hypertriglyceridemia (gemfibrozil). The possible mechanism of the potential interaction between these 2 drugs as related to the cytochrome P450 (CYP) enzyme system was examined. CASE S U M M A R Y
A 43-year-old white male patient weighing 101 kg was diagnosed in 2000 with stage III melanoma of the left arm, with metastasis to the supraclavicular node. The patient's laboratory values and description of events are summarized in the table. On March 6, 2000, 2-year adjuvant treatment was initiated and consisted of IFN alfa 11 MU SC TIW and melanoma theraccine, an investigational vaccine for melanoma. Melanoma theraccine 1.25 mL (1 mL lysate ÷ 0.25 mL vaccine adjuvant*) was given SC at weeks 1, 2, 3, 4, 8, 16, 24, 32, 40, and 48 and then every 8 weeks until week 104. The patient had no history of cardiovascular or GI disease and was not receiving any concomitant medi*Trademark: DetoxT M PC (GlaxoSmithKline, Research Triangle Park, North Carolina).
cation at the time of initiation of his melanoma treatment. His baseline laboratory test results were within normal ranges. On March 21, 2000, the patient had a serum TC concentration of 170 mg/dL, and a serum triglyceride (TG) concentration of 256 mg/dL. Seven months after the initiation of IFN alfa treatment, a fasting lipid panel (FLP) revealed a serum TG concentration of 653 mg/dL. On December 19, 2000, treatment with gemfibrozil 600 mg PO BID was initiated, and -1 month later, the patient presented to the University of California Irvine Medical Center, Orange, California, with severe GI distress consisting of nausea and decreased appetite. Weight loss of 3.2 kg was also noted. An FLP that day revealed a serum TG concentration of 177 mg/dL, but the patient also had alanine and aspartate aminotransferase (ALT and AST, respectively) concentrations of 693 and 470 IU/L, respectively. After the use of IFN alfa and melanoma vaccine, as well as possible progression of melanoma, were ruled out (using radiography) as causes of the GI AEs and the elevated hepatic enzyme concentrations, the dose of gemfibrozil was reduced to 300 mg PO QD. The IFN regimen was continued, and melanoma theraccine was given every 8 weeks. Three weeks after the gemfibrozil dose was reduced, the patient's hepatic enzyme levels were significantly improved (ALT, 148 IU/L; AST, 103 IU/L), and his TG continued to be well controlled, at 151 mg/dL. The patient had complete resolution of nausea and improvement of appetite. On March 24, 2001, a repeat FLP found a TC concentration of 171 mg/dL and TG concentration of 161 mg/dL. One month later, the patient's TG concentration increased to 215 mg/dL, and on June 9, 2001, it was further increased, to 320 mg/dL. The patient was found to have self-discontinued his gemfibrozil treatment at the beginning of March 2001. On June 9, 2001, the patient was advised to restart the gemfibrozil treatment at 300 mg PO QD. One month later, the TC concentration was 159 mg/dL, and the TG concentration was 193 mg/dL. The patient continued to receive this gemfibrozil regimen, with stabilization of the TC at 173 mg/dL, TG at 182 mg/dL, ALT at 72 IU/L, and AST at 45 IU/L until the completion of IFN treatment. The Naranjo Adverse Drug Reactions (ADR) Probability Scale score of this case was 7 (ie, ADR possibly related to treatment). 13 DISCUSSION In patients receiving IFN alfa for the treatment of malignant melanoma in whom hypertriglyceridemia de-
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velops, therapeutic management should be considered due to its potential severe complications and the duration of IFN treatment, s,6 Although lifestyle modifications may be considered as first-line treatment, patients might also require concurrent antihypertriglyceridemic drug therapy) 2 Gemfibrozil has been used to treat hypertriglyceridemia that developed during IFN treatment. s,6 Although AEs were not reported in those articles, the doses of gemfibrozil used ranged from 600 mg TIW s to 600 mg QD, 6 both of which were lower compared with the dose used in the patient reported here. The present patient was administered gemfibrozil 600 mg PO BID for 4 weeks, at which time severe GI distress and elevated hepatic enzyme concentrations developed. Although these 2 AEs are documented toxicities of both IFN alfa 2~ and gemfibrozil, 14 this patient had been receiving the same dose of IFN alfa for at least 6 months without experiencing any AEs until the initiation of gemfibrozil treatment. This finding led the authors to suspect that these AEs were primary gemfibrozil toxicities or drug interactions. However, the first suspicion was unlikely because the patient did not have any degree of renal insufficiency that may have led to the accumulation of and toxicity from gemfibrozil use (serum creatinine, 1.0-1.1 mg/dL; blood urea nitrogen, 13-14 mg/dL). Another possibility was that the AEs might have been the result of a drug-drug interaction between IFN alfa and gemfibrozil or melanoma theraccine and gemfibrozil. To assess the plausible mechanism of this potential drug-drug interaction, the pharmacologic properties, especially the pharmacokinetic properties, of all of the drugs involved were examined. According to the product information for melanoma theraccine, ~s standard pharmacokinetic studies of melanoma theraccine in animals have not been performed because of the extremely small quantities of melanoma theraccine and its components present in the blood after administration. These small quantities do not allow for adequate testing by available assays. It has been found that the oil component of melanoma theraccine remains localized after administration, with no evidence of systemic distribution) s The potential role of the vaccine in this AE would not be absolutely ruled out. Based on the literature search, the pharmacokinetic properties of IFN alfa have not been well studied. It appears to be metabolized principally in the kidney, with a tl/2 of -2 to 3 hours, and cannot be detected in urine) 6 The effect of IFN alfa-2b on the CYP system was
studied prospectively by Islam et a117 in 17 patients with high-risk resected melanoma treated with adjuvant IFN alfa-2b. The CYP activity was estimated in vivo with electrochemiluminescence immunoassay throughout 1-year treatment using the "Pittsburgh cocktail" approach, 18 in which 5 oral probe drugs with well-characterized metabolism information were simultaneously administered to the patients during each visit. Multiple blood and urine samples were collected at predefined time points to measure the concentration of the probe drugs and/or their metabolites. Significant inhibition of isozyme CYPIA2 immediately after the administration of the first dose of IFN alfa-2b on days 26 and 52 (both, P < 0.005), and of CYP2D6 immediately after the first dose and on days 26 and 52 (P < 0.001 and 0.005) were observed. Onset of suppression of CYP2C19 was slower compared with 1A2 and 2D6 and reached its maximum effect on days 26 and 52 (P < 0.001). Becquemont et a119 assessed 14 patients with chronic hepatitis C virus infection receiving low-dose IFN alfa (3 MU SC TIW) plus ribavirin (1000-2000 rag/d) found that the activity of CYP3A4 and CYP2D6 did not change significantly after 1 month of IFN treatment. The reason for the contrasting findings of CYP2D6 activity in those 2 studies is unclear. Islam et a117proposed that the inhibition of the activity of the CYP isozymes by IFN might alter the metabolism of the cytokines, neurotransmitters, and hormones associated with IFN alfa toxicity. These findings might allow clinicians to better prevent and manage these toxicities by assessing the activity of CYP isozymes in each individual patient. 17 Gemfibrozil undergoes oxidation to form hydroxymethyl and carboxyl metabolites. 14 Enterohepatic circulation and reabsorption in the GI tract occur, which contribute to the longer biologic tl/2 of gemfibrozil. Approximately 70% of the drug is excreted in the urine predominately as the glucuronide conjugate, and 6% is excreted fecally. 14 An in vitro study by Wen et al 2° reported that gemfibrozil inhibited CYP2C9 activity competitively and exhibited an inhibitory effect on CYPIA2 and CYP2C19 isozyme activity. The investigators used the theory that drug interactions based on the inhibition of hepatic metabolism can be predicted by the apparent inhibitory constant and the concentration of inhibitor around the metabolic enzyme in the liver. Based on the hypothesis that only the unbound concentration of a drug in plasma is available for diffusion to intrahepatic sites of metabol-
ic activity, the unbound plasma concentration of an inhibitor can be used to predict in vivo drug-drug interactions. The investigators used this method and reported 24%, 7%, and 2% inhibition of clearance of CYP2C9, CYP2C19, and CYPIA2 substrates, respectively, with gemfibrozil use. Clinical trials have found significant drug-drug interactions with gemfibrozil used concurrently with warfarin 21,22 and glyburide23 (severe hypoprothrombinemia/bleeding and hypoglycemia, respectively). The investigators proposed that the mechanisms of these interactions were inhibition of CYP2C9 activity by gemfibrozil, and minor inhibition of the CYPiA2-mediated interaction. Because inhibitors or inducers of the CYP system often act as substrates being affected by the same enzymes, inhibition of CYPlA2 and CYP2C19 activity could represent a plausible mechanism for the potential drugdrug interaction between IFN alfa and gemfibrozil that was observed in the present case. Unfortunately, the enzymatic inhibitory effect and the plasma concentrations of IFN and gemfibrozil were not measured in the patient to confirm the possible mechanism of the potential drug-drug interaction. Further study is warranted to measure the enzymatic inhibitory effect and the plasma concentrations of the drugs involved to better assess the mechanism of action of this potential drug-drug interaction. CONCLUSIONS
Both IFN and gemfibrozil inhibit the activity of the hepatic enzymes CYP1A2 and CYP2C19. A possible drugdrug interaction between IFN alfa 11 MU TIW and gemfibrozi1600 mg BID was reported in a patient undergoing treatment for IFN-induced hypertriglyceridemia.
4. 5.
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ACKNOWLEDGMENT The authors acknowledge Sompon Wanwimolruk, PhD, School of Pharmacy, Loma Linda University, Loma Linda, California, for his review of the manuscript. 15.
REFERENCES 1. Houghton A, Coit D. Practice Guidelines in Oncology: Melanoma. National Comprehensive Cancer Network. JNCCN. 2004;2:46-60. 2. Kirkwood JM, Strawderman MH, Ernstoff MS, et al. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: The Eastern Cooperative Oncology Group Trial EST 1684.J Clin Oncol. 1996;14:7-17. 3. Kirkwood JM, Ibrahim JG, Sosman JA, et al. High-dose interferon alfa-2b significantly prolongs relapse-free and
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overall survival compared with the GM2-KLH/QS-21 vaccine in patients with resected stage liB-Ill melanoma: Results of intergroup trial E1694/$9512/C509801. J Clin Oncol. 2001 ;19:2370-2380. Weiss K. Safety profile of interferon-alpha therapy. Semin Oncol. 1998;25(SuppI 1):9-13. Berruti A, Gorzegno G, Vitetta G, et al. Hypertriglyceridemia during long-term interferon-alpha therapy: Efficacy of diet and gemfibrosil treatment. A case report. Tumori. 1992;78:353-355. Sgarabotto D, Vianello F, Stefani PM, et al. Hypertriglyceridemia during long-term interferon-alpha therapy in a series of hematologic patients. J Interferon Cytokine Res. 1997;17:241-244. Ruiz-Moreno M, Carreno V, Rua MJ, et al. Increase in triglycerides during alpha-interferon treatment of chronic viral hepadds.J Hepatol. 1992;16:384. Letter. Shinohara E, Yamashita S, Kihara S, et al. Interferon alpha induces disorder of lipid metabolism by lowering postheparin lipases and cholesteryl ester transfer protein activities in patients with chronic hepatitis C. Hepatology. 1997;25: 1502-1506. Penarrubia MJ, Steegmann JL, Lavilla E, et al. Hypertriglyceridemia may be severe in CML patients treated with interferon-alpha. AmJ Hematol. 1995;49:240-241. Keung YK, Rizk R, Wu XY, Cobos E. Drug-induced hypertriglyceridemia with and without pancreatitis. South MedJ. 1999;92:912-914. Roguedas AM, LonceintJ, Sassolas B, et al. Acute pancreatitis after high-dose interferon therapy in a patient with melanoma [in French]. PresseMed. 2001 ;30:1105. Letter. Wong SF, Jakowatz J, Jaheri R. Management of hypertriglyceridemia in patients receiving interferon for malignant melanoma. Ann Pharmacother. 2004;38:1655-1659. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Cfin Pharmacol Ther. 1981 ;30:239-245. Witztum J. Drugs used in the treatment of hyperlipoproteinemias. In: Hardman J, Limbird L, Molinoff R, et al, eds. Goodman C~" Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill; 1996: 875-897. Melacine Melanoma Theraccine Investigator Drug [product information]. Hamilton, Montana: Ribi ImmunoChem Research; 1995. Hayden F. Antimicrobial agents: Antiviral agents. In: Hardman J, Limbird L, Molinoff R, et al, eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill; 1996:1191-1223. Islam M, Frye RF, Richards TJ, et al. Differential effect of IFNalpha-2b on the cytochrome P450 enzyme system: A potential basis oflFN toxicity and its modulation by other drugs. Clin Cancer Res. 2002;8:2480-2487.
18. Frye R, Matzke G, Adedoyin A, et al. Validation of the five-drug "Pittsburgh cocktail" approach for assessment of selective regulation of drug-metabolizing enzymes. Clin Pkarmacol Ther. 1997;62:365-376. 19. Becquemont L, Chazouilleres O, Serfaty L, et al. Effect of interferon alpha-ribavirin bitherapy on cytochrome P450 1A2 and 2D6 and
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N-acetyltransferase-2 activities in patients with chronic active hepatitis C. Clin PkarmacolTker. 2002;71:488-495. Wen X, WangJS, Backman JT, et al. Gemfibrozil is a potent inhibitor of human cytochrome P450 2C9. Drug Metab Dispos. 2001 ;29:1359-1361. Ahmad S. Gemfibrozil interaction with warfarin sodium (Coumadin). Chest. 1990;98:1041-1042. Rindone JP, Keng HC. Gemfibrozilwarfarin drug interaction resulting in profound hypoprothrombinemia. Chest. 1998;114:641-642. Ahmad S. Gemfibrozil: Interaction with glyburide. South MedJ. 1991 ;84: 102.
Address correspondence to: Siu-Fun Wong, PharmD, Western University College of Pharmacy, 309 East Second Street, Pomona, CA 91766-1854. E-maih [email protected]
Potential Drug-Drug Interaction Between Interferon Alfa-2b and Gemfibrozil in a Patient with Malignant Melanoma Siu-Fun Wong, PharmD1;James G. Jakowatz, MD2; and RezaTaheri, PharmD3. l Western University College of Pharmacy, Pomona,
California;2Department of Surgical Oncology,
University of California Irvine Medical Center, Orange, California; and 3Western University College of Pkarmacy, Pomona, California ABSTRACT
Background: In the United States, patients with high-risk stage II or III melanoma are often treated with adjuvant interferon (IFN) therapy for 1 year after surgery. Adverse events associated with IFN alfa-2b use are primarily constitutional symptoms. However, hypertriglyceridemia requiring treatment has been reported. Objective: The aim of this report was to describe a potential drug-drug interaction between IFN alfa-2b and gemfibrozil in a patient with malignant melanoma. The possible mechanism of this potential interaction was examined. Methods: This report presents the case of a 43-yearold male patient weighing 101 kg with newly diagnosed stage III melanoma of the left arm, with metastasis to the supraclavicular node. The patient presented to the University of California Irvine Medical Center, Orange, California with severe gastrointestinal (GI) symptoms and elevated hepatic enzyme concentrations at week 48 of 104 of adjuvant treatment of malignant melanoma (IFN alfa 11 MU SC TIW in combination with the investigational melanoma vaccine melanoma theraccine 1.25 mL [1 mL lysate + 0.25 mL vaccine adjuvant] given SC at weeks 1, 2, 3, 4, 8, 16, 24, 32, 40, and 48 and then every 8 weeks until week 104), and IFNinduced hypertriglyceridemia (gemfibrozil 600 mg PO BID). The patient had no history of cardiovascular or GI disease and was not receiving any concomitant medication. The possible mechanism of this potential IFN alfa-gemfibrozil interaction as related to the cytochrome P450 (CYP) enzyme system was assessed. Results: In this case of a possible drug-drug interaction between IFN alfa 11 MU TIW and gemfibrozil 600 mg BID in a patient undergoing treatment for IFN-induced hypertriglyceridemia, the Naranjo Ad-
verse Drug Reactions (ADR) Probability Scale score was 7 (ie, ADR possibly related to treatment). Conclusions: Both IFN and gemfibrozil inhibit the activity of the hepatic enzymes CYPIA2 and CYP2C19. A possible drug-drug interaction between IFN alfa 11 MU TIW and gemfibrozil 600 mg BID was reported in a patient undergoing treatment for IFN-induced hypertriglyceridemia. (Clin Ther. 2005; 27:1942-1948) Copyright © 2005 Excerpta Medica, Inc. Key words: interferon alfa, gemfibrozil, drug interaction, hypertriglyceridemia, malignant melanoma, cytochrome P450.
INTRODUCTION
In the United States, patients with melanoma are primarily treated with surgical resection. 1 However, some patients require additional adjuvant systemic therapy after surgery. 1-3 The current standard adjuvant therapy for high-risk stage II or III melanoma is I year of interferon (IFN) alfa at 20 MU/m 2 IV 5 times per week for 4 weeks, followed by 10 MU/m 2 SC TIW for 48 weeks. 1-3 Additional IFN alfa-based treatment options are being investigated to improve the therapeutic outcome of this disease. Reported adverse events (AEs) associated with IFN include constitutional symptoms (eg, flulike symptoms); *Current affiliation: Loma Linda University School of Pharmacy, Loma Linda, California
Accepted for publication September 20, 2005. doi:l 0.1016/j.clinthera.2005.12.002 0149-2918/05/$19.00 Printed in the USA. Reproduction in whole or part is not permitted. Copyright © 2005 Excerpta Medica, Inc.
and neurologic, hematologic, endocrine, and hepatic disorders. 4 An uncommon AE associated with IFN therapy is hypertriglyceridemia with reduced or unchanged total cholesterol (TC) levels, s,6 This AE has been reported in patients diagnosed with hepatitis C and those with malignancy treated with IFN alfa. s-9 Two cases of acute pancreatitis associated with hypertriglyceridemia secondary to the use of high-dose IFN (20 MU/m 2 IV 5 times per week for 4 weeks, followed by 10 MU/m 2 SC TIW for 48 weeks) have been reported in patients with melanoma.l°a I Due to the potential impact of this AE, treatment with an antidyslipidemic drug, in combination with lifestyle modifications, such as exercise, a low-carbohydrate diet, and/or high consumption of fatty fish, is warrantedJ 2 A search of published literature concerning gemfibrozil used to treat IFN-induced hypertriglyceridemia, s,6 identified using PubMed (key terms: interferon-alfa, Intron-A, gemfibrozil, Lopid, drug interactions, and cytochrome enzymes; years: 1965-2004), did not yield any reports of potential drug-drug interactions associated with the use of IFN and gemfibrozil. The aim of this article was to report the case of a patient who experienced severe gastrointestinal (GI) symptoms and elevated hepatic enzyme concentrations while receiving adjuvant therapy for malignant melanoma (IFN alfa-2b and vaccine) and IFN alfainduced hypertriglyceridemia (gemfibrozil). The possible mechanism of the potential interaction between these 2 drugs as related to the cytochrome P450 (CYP) enzyme system was examined. CASE S U M M A R Y
A 43-year-old white male patient weighing 101 kg was diagnosed in 2000 with stage III melanoma of the left arm, with metastasis to the supraclavicular node. The patient's laboratory values and description of events are summarized in the table. On March 6, 2000, 2-year adjuvant treatment was initiated and consisted of IFN alfa 11 MU SC TIW and melanoma theraccine, an investigational vaccine for melanoma. Melanoma theraccine 1.25 mL (1 mL lysate ÷ 0.25 mL vaccine adjuvant*) was given SC at weeks 1, 2, 3, 4, 8, 16, 24, 32, 40, and 48 and then every 8 weeks until week 104. The patient had no history of cardiovascular or GI disease and was not receiving any concomitant medi*Trademark: DetoxT M PC (GlaxoSmithKline, Research Triangle Park, North Carolina).
cation at the time of initiation of his melanoma treatment. His baseline laboratory test results were within normal ranges. On March 21, 2000, the patient had a serum TC concentration of 170 mg/dL, and a serum triglyceride (TG) concentration of 256 mg/dL. Seven months after the initiation of IFN alfa treatment, a fasting lipid panel (FLP) revealed a serum TG concentration of 653 mg/dL. On December 19, 2000, treatment with gemfibrozil 600 mg PO BID was initiated, and -1 month later, the patient presented to the University of California Irvine Medical Center, Orange, California, with severe GI distress consisting of nausea and decreased appetite. Weight loss of 3.2 kg was also noted. An FLP that day revealed a serum TG concentration of 177 mg/dL, but the patient also had alanine and aspartate aminotransferase (ALT and AST, respectively) concentrations of 693 and 470 IU/L, respectively. After the use of IFN alfa and melanoma vaccine, as well as possible progression of melanoma, were ruled out (using radiography) as causes of the GI AEs and the elevated hepatic enzyme concentrations, the dose of gemfibrozil was reduced to 300 mg PO QD. The IFN regimen was continued, and melanoma theraccine was given every 8 weeks. Three weeks after the gemfibrozil dose was reduced, the patient's hepatic enzyme levels were significantly improved (ALT, 148 IU/L; AST, 103 IU/L), and his TG continued to be well controlled, at 151 mg/dL. The patient had complete resolution of nausea and improvement of appetite. On March 24, 2001, a repeat FLP found a TC concentration of 171 mg/dL and TG concentration of 161 mg/dL. One month later, the patient's TG concentration increased to 215 mg/dL, and on June 9, 2001, it was further increased, to 320 mg/dL. The patient was found to have self-discontinued his gemfibrozil treatment at the beginning of March 2001. On June 9, 2001, the patient was advised to restart the gemfibrozil treatment at 300 mg PO QD. One month later, the TC concentration was 159 mg/dL, and the TG concentration was 193 mg/dL. The patient continued to receive this gemfibrozil regimen, with stabilization of the TC at 173 mg/dL, TG at 182 mg/dL, ALT at 72 IU/L, and AST at 45 IU/L until the completion of IFN treatment. The Naranjo Adverse Drug Reactions (ADR) Probability Scale score of this case was 7 (ie, ADR possibly related to treatment). 13 DISCUSSION In patients receiving IFN alfa for the treatment of malignant melanoma in whom hypertriglyceridemia de-
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velops, therapeutic management should be considered due to its potential severe complications and the duration of IFN treatment, s,6 Although lifestyle modifications may be considered as first-line treatment, patients might also require concurrent antihypertriglyceridemic drug therapy) 2 Gemfibrozil has been used to treat hypertriglyceridemia that developed during IFN treatment. s,6 Although AEs were not reported in those articles, the doses of gemfibrozil used ranged from 600 mg TIW s to 600 mg QD, 6 both of which were lower compared with the dose used in the patient reported here. The present patient was administered gemfibrozil 600 mg PO BID for 4 weeks, at which time severe GI distress and elevated hepatic enzyme concentrations developed. Although these 2 AEs are documented toxicities of both IFN alfa 2~ and gemfibrozil, 14 this patient had been receiving the same dose of IFN alfa for at least 6 months without experiencing any AEs until the initiation of gemfibrozil treatment. This finding led the authors to suspect that these AEs were primary gemfibrozil toxicities or drug interactions. However, the first suspicion was unlikely because the patient did not have any degree of renal insufficiency that may have led to the accumulation of and toxicity from gemfibrozil use (serum creatinine, 1.0-1.1 mg/dL; blood urea nitrogen, 13-14 mg/dL). Another possibility was that the AEs might have been the result of a drug-drug interaction between IFN alfa and gemfibrozil or melanoma theraccine and gemfibrozil. To assess the plausible mechanism of this potential drug-drug interaction, the pharmacologic properties, especially the pharmacokinetic properties, of all of the drugs involved were examined. According to the product information for melanoma theraccine, ~s standard pharmacokinetic studies of melanoma theraccine in animals have not been performed because of the extremely small quantities of melanoma theraccine and its components present in the blood after administration. These small quantities do not allow for adequate testing by available assays. It has been found that the oil component of melanoma theraccine remains localized after administration, with no evidence of systemic distribution) s The potential role of the vaccine in this AE would not be absolutely ruled out. Based on the literature search, the pharmacokinetic properties of IFN alfa have not been well studied. It appears to be metabolized principally in the kidney, with a tl/2 of -2 to 3 hours, and cannot be detected in urine) 6 The effect of IFN alfa-2b on the CYP system was
studied prospectively by Islam et a117 in 17 patients with high-risk resected melanoma treated with adjuvant IFN alfa-2b. The CYP activity was estimated in vivo with electrochemiluminescence immunoassay throughout 1-year treatment using the "Pittsburgh cocktail" approach, 18 in which 5 oral probe drugs with well-characterized metabolism information were simultaneously administered to the patients during each visit. Multiple blood and urine samples were collected at predefined time points to measure the concentration of the probe drugs and/or their metabolites. Significant inhibition of isozyme CYPIA2 immediately after the administration of the first dose of IFN alfa-2b on days 26 and 52 (both, P < 0.005), and of CYP2D6 immediately after the first dose and on days 26 and 52 (P < 0.001 and 0.005) were observed. Onset of suppression of CYP2C19 was slower compared with 1A2 and 2D6 and reached its maximum effect on days 26 and 52 (P < 0.001). Becquemont et a119 assessed 14 patients with chronic hepatitis C virus infection receiving low-dose IFN alfa (3 MU SC TIW) plus ribavirin (1000-2000 rag/d) found that the activity of CYP3A4 and CYP2D6 did not change significantly after 1 month of IFN treatment. The reason for the contrasting findings of CYP2D6 activity in those 2 studies is unclear. Islam et a117proposed that the inhibition of the activity of the CYP isozymes by IFN might alter the metabolism of the cytokines, neurotransmitters, and hormones associated with IFN alfa toxicity. These findings might allow clinicians to better prevent and manage these toxicities by assessing the activity of CYP isozymes in each individual patient. 17 Gemfibrozil undergoes oxidation to form hydroxymethyl and carboxyl metabolites. 14 Enterohepatic circulation and reabsorption in the GI tract occur, which contribute to the longer biologic tl/2 of gemfibrozil. Approximately 70% of the drug is excreted in the urine predominately as the glucuronide conjugate, and 6% is excreted fecally. 14 An in vitro study by Wen et al 2° reported that gemfibrozil inhibited CYP2C9 activity competitively and exhibited an inhibitory effect on CYPIA2 and CYP2C19 isozyme activity. The investigators used the theory that drug interactions based on the inhibition of hepatic metabolism can be predicted by the apparent inhibitory constant and the concentration of inhibitor around the metabolic enzyme in the liver. Based on the hypothesis that only the unbound concentration of a drug in plasma is available for diffusion to intrahepatic sites of metabol-
ic activity, the unbound plasma concentration of an inhibitor can be used to predict in vivo drug-drug interactions. The investigators used this method and reported 24%, 7%, and 2% inhibition of clearance of CYP2C9, CYP2C19, and CYPIA2 substrates, respectively, with gemfibrozil use. Clinical trials have found significant drug-drug interactions with gemfibrozil used concurrently with warfarin 21,22 and glyburide23 (severe hypoprothrombinemia/bleeding and hypoglycemia, respectively). The investigators proposed that the mechanisms of these interactions were inhibition of CYP2C9 activity by gemfibrozil, and minor inhibition of the CYPiA2-mediated interaction. Because inhibitors or inducers of the CYP system often act as substrates being affected by the same enzymes, inhibition of CYPlA2 and CYP2C19 activity could represent a plausible mechanism for the potential drugdrug interaction between IFN alfa and gemfibrozil that was observed in the present case. Unfortunately, the enzymatic inhibitory effect and the plasma concentrations of IFN and gemfibrozil were not measured in the patient to confirm the possible mechanism of the potential drug-drug interaction. Further study is warranted to measure the enzymatic inhibitory effect and the plasma concentrations of the drugs involved to better assess the mechanism of action of this potential drug-drug interaction. CONCLUSIONS
Both IFN and gemfibrozil inhibit the activity of the hepatic enzymes CYP1A2 and CYP2C19. A possible drugdrug interaction between IFN alfa 11 MU TIW and gemfibrozi1600 mg BID was reported in a patient undergoing treatment for IFN-induced hypertriglyceridemia.
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ACKNOWLEDGMENT The authors acknowledge Sompon Wanwimolruk, PhD, School of Pharmacy, Loma Linda University, Loma Linda, California, for his review of the manuscript. 15.
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Address correspondence to: Siu-Fun Wong, PharmD, Western University College of Pharmacy, 309 East Second Street, Pomona, CA 91766-1854. E-maih [email protected]