Oncologist. The. Clinical Pharmacology: Concise Drug Reviews. Imatinib INTRODUCTION MECHANISM OF ACTION CLINICAL USE

Transcription

1 The Oncologist Clinical Pharmacology: Concise Drug Reviews Imatinib CHRISTINE E. DE KOGEL, a JAN H. M. SCHELLENS a,b a Utrecht University, Faculty of Science, Department of Pharmaceutical Sciences, Section of Biomedical Analysis, Division of Drug Toxicology, Utrecht, The Netherlands; b Division of Clinical Pharmacology, Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands Disclosure: No potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article. LEARNING OBJECTIVES After completing this course, the reader will be able to: 1. Identify the current indications for imatinib. 2. Describe the pharmacokinetics of imatinib. 3. Discuss the mechanisms involved in imatinib resistance. CME INTRODUCTION Access and take the CME test online and receive 1 AMA PRA Category 1 Credit at CME.TheOncologist.com Imatinib (Fig. 1) is currently registered in adults for two indications: (a) monotherapy in chronic myeloid leukemia (CML) and (b) monotherapy in c-kit (CD117)-positive unresectable or metastatic gastrointestinal stromal tumors (GISTs) [1, 2]. Clinical trials showed that the activity of imatinib in other malignancies, such as small cell lung cancer, acute myeloid leukemia, and prostate cancer, is negligible. In combination with hydroxyurea, imatinib has activity in glioblastoma multiforme [3]. In children, the use of imatinib mesylate is registered for patients with Philadelphia chromosome positive (Ph ) chronic CML that is resistant to interferon- therapy or recurrent after bone marrow transplantation. both indications. In GIST, most patients are started on a single dose of 400 mg daily, with dose escalation to a single dose of 600 mg daily or 400 mg twice daily if disease progression occurs during treatment. GIST patients with a mutation in exon 9 are commonly started on a single dose of 600 mg daily, because of a longer progression-free survival time in clinical trials for this dose. Patients with CML in the chronic phase are started on a single dose of 400 mg daily as well. CML patients in the acceleration phase or in blast crisis are started on 600 mg daily as a single dose. Dose escalations to a maximum of 400 mg twice daily are started if progression occurs. In children with chronic phase Ph CML, the standard starting dose is 260 mg/m 2 per day, preferentially administered as a single dose. CLINICAL USE Imatinib is available as oral tablets of 100 and 400 mg strength. The recommended dose ranges between 400 and 800 mg daily in MECHANISM OF ACTION Imatinib is a tyrosine kinase inhibitor. Binding studies are compatible with competitive inhibition of ATP binding [1, 4]. It in- Correspondence: Jan H.M. Schellens, M.D., Ph.D., Department of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. Telephone: ; Fax: ; jhm@nki.nl Received May 14, 2007; accepted for publication October 22, AlphaMed Press /2007/$30.00/0 doi: /theoncologist The Oncologist 2007;12:

2 de Kogel, Schellens 1391 SUMMARY TABLE Generic name(s) Imatinib mesylate Commercial name(s) Gleevec /Glivec Molecular weight g/mol Mechanism of action Inhibition of tyrosine kinase activity by competitive inhibition of ATP binding to Bcr-Abl, CD117 (c-kit), and the PDGF receptor Cell-cycle specificity G 1 phase [13] Route of Oral; bioavailability nearly complete, unaffected by food administration Protein binding (%) 95% Metabolism Metabolism to the active metabolite N-demethylated piperazine by the CYP3A4 isoenzyme; further metabolized by N-oxidation of the 4-nitrogen of the piperazine and N-oxidation of the pyridine nitrogen Elimination Terminal half-life Main toxicities Pharmacogenetics Resistance Unique features Main drug interactions Biotransformation approximately 75%; renal elimination, 13%; fecal elimination (via bile), 68%, of which, parent drug, 20% 19 hours (active parent compound) (range, hours) 40 h (active metabolite) (range h) Mild nausea, vomiting, edema, muscle cramps, liver dysfunction, and bone marrow toxicity No known effect of CYP3A4 polymorphisms on pharmacokinetics; the relevance of polymorphisms in ABCB1 and ABCG2 is being studied Will develop as a result of overexpression of the tyrosine kinase, genomic amplification of the kinase, clonal selection of resistant cells, and resistanceinducing mutations; important mutations in CML include E255K/V, Y253F/H (Ploop), T315I (binding pocket) and M351T (activation loop). Important mutations in GIST include exon 13 V654A and exon 14 T670I (binding pocket), and exon 17 C809G, D816H, D820A/E/G, N822K/H, and Y823D (activation loop); pharmacokinetic resistance may also play a role, but needs clinical confirmation Practical because of oral therapy CYP3A4 inhibitors such as ketoconazole and erythromycin and CYP3A4 inducers such as rifampicin and the herb St. John s Wort; CYP3A4 substrates such as cyclosporine and simvastatin Abbreviations: ABC, ATP-binding cassette; Bcr-Abl, breakpoint cluster region/abelson; CML, chronic myelogenous leukemia; CYP3A4, cytochrome P450 3A4 isoenzyme; GIST, gastrointestinal stromal tumor; PDGF, platelet-derived growth factor. hibits the Abelson (Abl) tyrosine kinase with high selectivity. Concentrations above 0.3 mol/l were sufficient to inhibit Abl in in vitro studies. In in vivo studies, concentrations 1 M were needed for normalization of hematological parameters [5]. It also inhibits CD117 and platelet-derived growth factor (PDGF)- and PDGF- at concentrations of approximately 0.5 mol/l in vitro [1, 2]. These tyrosine kinases play a significant role in the growth and proliferation of malignant cells in CML, GIST, and the rare disease dermatofibrosarcoma protuberans. BIOANALYSIS Figure 1. Chemical structure of imatinib mesylate. Bioanalysis of imatinib and its metabolites can be performed by liquid chromatography mass spectrometry or liquid chromatography tandem mass spectrometry [6].

3 1392 Imatinib PHARMACOKINETICS Absorption After oral intake, imatinib is rapidly absorbed from the gut, because of its rapid dissolution at acidic ph [5]. Imatinib should be taken with a meal and water to reduce gastrointestinal side effects. However, a high fat meal can prolong the uptake and therefore the time to reach a maximum plasma concentration (t max ). Under normal conditions, the maximal plasma concentration of approximately 1.9 g/ml is reached after 2 4 hours [5]. After repeated administration of 400 mg of imatinib per day, the mean plasma concentration in steady state is 1 mol/l after 24 hours. Absolute bioavailability is estimated to be almost complete, but can be significantly lower in some cases as a result of limited absorption. Bioavailability is unaffected by food [5]. Protein Binding Imatinib is highly protein bound. It binds mostly to albumin. Protein binding is approximately 95% [5]. Imatinib also binds to 1-acid-glycoprotein in vitro and in vivo. 1- Acid-glycoprotein levels are elevated in patients with CML and GIST. However, it is thought that at clinically relevant doses, 1-acid-glycoprotein binding does not influence the activity of imatinib. Metabolism Imatinib is metabolized by the cytochrome P450 (CYP) isoenzymes in the gut wall and liver. The metabolism is mainly mediated by CYP3A4 and CYP3A5, but other CYP isoenzymes such as CYP1A2, CYP2D6, CYP2C9, and CYP2C19 also play minor roles. The main metabolite is the N-demethylated piperazine derivate (Fig. 2). Based on in vitro data, this metabolite has potency comparable to that of the parent compound [5]. The exposure measured as a percentage of the area under the concentration time curve in plasma of the N-demethylated piperazine derivate is approximately 10% 15% of that of imatinib. In addition, imatinib and its N-demethylated piperazine derivate are N-oxidized in the liver [5]. Elimination On average, 75% of the dose of imatinib undergoes biotransformation. Imatinib has a terminal half-life of 19 hours (range, hours), while its main metabolite has a terminal half-life of 40 hours (range, hours) [5]. Excretion takes place mainly via the bile, 68% as metabolites and 20% as parent compound. Renal excretion is low, as only 13% of the metabolites and 5% of the parent compound are excreted via the kidneys [5]. Figure 2. Chemical structure of the N-demethylated piperazine derivate. Drug Interactions The metabolism of imatinib is largely dependent on CYP3A4. Therefore, caution should be undertaken when patients are treated with inducers and/or inhibitors of CYP3A4 during imatinib therapy. Inhibitors, such as ketoconazole and erythromycin, led to higher plasma concentrations of imatinib in clinical trials [5]. Inducers, such as rifampicin and the herb St. John s Wort, can lower the terminal half-life of imatinib twoto fourfold. This is relevant because patients could fail to respond to treatment as a result of the greater clearance of the drug [5]. As imatinib itself is also an inhibitor of CYP3A4, competitive inhibition of certain drugs, such as simvastatin and cyclosporine, can occur. This can increase drug exposure to both compounds [5]. Alterations with Disease or Age According to clinical trials, age has no significant influence on the pharmacokinetics of imatinib, although the volume of distribution increases with age [5]. Pharmacokinetic parameters in pediatric patients were comparable to those found in adults. Information on the effect of diminished liver or kidney function on the pharmacokinetics of imatinib is limited. Although metabolism is highly dependent on liver enzymes, patients with liver dysfunction seem to tolerate the standard dosage of imatinib well [5]. Although renal clearance of imatinib is low, it was shown in a clinical trial that imatinib clearance is slower in patients with renal dysfunction (creatinine clearance, 40 ml/minute). The implications of this slower clearance for clinical safety are as yet unknown [5]. PHARMACOGENETICS As metabolism of imatinib occurs mainly via the CYP isoenzymes, polymorphisms in these isoenzymes might in-

4 de Kogel, Schellens 1393 fluence the pharmacokinetic parameters and thus drug exposure in vivo. A study by Gardner et al. [7] in patients with GIST and in human embryo kidney cells showed no significant effect of polymorphisms in CYP3A4 and CYP3A5 on the pharmacokinetic parameters of imatinib. This is probably a result of the already large variability in the activity and expression of CYP3A4 and CYP3A5 in cancer patients and the relatively low allelic frequencies. Polymorphisms in CYP2C9, CYP2C19, and CYP2D6 were also of no significant relevance in explaining the large interpatient variability in the pharmacokinetics of imatinib. However, an oral clearance higher than the mean value was shown to be more common in patients with wild-type CYP2D6 alleles as compared with patients with a CYP2D6*4 polymorphism [7]. Excretion of imatinib occurs mainly via the bile. It was shown that imatinib is a substrate for the ATP-binding cassette (ABC) transporters ABCB1 (P-glycoprotein) and ABCG2 (breast cancer resistance protein), and these biliary pumps probably mediate substantial elimination of imatinib. Further investigation on the influence of ABCB1 and ABCG2 polymorphisms on imatinib pharmacokinetics is ongoing [8]. DRUG RESISTANCE Although imatinib is an effective drug, resistance develops over time in almost all patients. In CML this drug resistance has been most elaborately studied. Resistance can be caused by several different mechanisms. First, in some patients, a two- to tenfold genomic amplification of the breakpoint cluster region Abelson gene (bcr-abl) is found. Secondly, in some patients, overexpression of bcr-abl is observed [9]. In these first two groups of patients, dose escalations might at least temporarily overcome resistance [2]. Finally, in CML patients, various mutations have been found in the bcr-abl gene. These mutations reduce the affinity of imatinib for the tyrosine kinase and therefore induce resistance. [2, 9] The most frequently seen mutations are E255K, E255V, Y253F, and Y253H in the P-loop of the Bcr-Abl protein and mutations at T315, M351, and E355. Resistance mutations have two main effects: they impair binding of imatinib to Bcr-Abl and they induce stable activation of Bcr-Abl that is insensitive to imatinib [9, 10]. In patients with GISTs, resistance is common as well. In rare cases, overexpression of CD117 or gene amplification has been found. Dose escalations might prove effective in this group of patients. However, this type of resistance seems of minor importance in GIST. Secondary mutations are the primary cause of resistance in GIST patients. Secondary mutations occur commonly in patients with primary exon 11 mutations and are rare in other CD117 mutations. Two separate types of mutations occur: (a) mutations that induce structural changes to the ATP-binding pocket and (b) mutations to the activation loop at exon 17, that activate CD117 in an imatinib-insensitive manor. In the first group, mutations V654A at exon 13 and T670I at exon 14 are most common. In the second group, several mutations have been found, including C809G, D816H, D820A/E/G, N822K/H, and Y823D [11]. A small group of GIST patients show mutations in PDGF receptor (PDGFR)- instead of CD117 activation. These patients show primary resistance if a D842V mutation at exon 18 is found. This mutation can also cause secondary resistance in patients with another primary PDGFR- mutation, such as V561D at exon 12 [11]. Besides these specific causes of resistance to imatinib, it is thought that pharmacokinetic resistance also may play a role. Several possible mechanisms have been described including (a) upregulation of liver enzymes, causing increased clearance of imatinib and (b) upregulation of drug transporters such as ABCB1 and ABCG2. Clinical studies are warranted to determine whether these supposed mechanisms play a relevant role in dosing of patients, because dose escalation should be effective in these forms of resistance [9 11]. PHARMACODYNAMICS The pharmacokinetic pharmacodynamic relationships of imatinib have not been extensively studied. However, there seems to be a relationship between dose and likelihood of tumor response. In CML, patients treated at a dose 400 mg/day showed a significantly lower cytogenic response than patients treated with a higher dose [2, 4]. Early trials showed no significant positive effect of a starting dose 400 mg/day in most patients if adverse effects are considered. Therefore, it was concluded that a 400-mg/day dose would be optimal in most patients [5]. However, in patients with an unsatisfactory response to the 400-mg/day dose, dose escalation to 600 mg/day or 800 mg/day can be effective without resulting in greater adverse effects. At a dose 800 mg/day, toxic effects are significantly greater without greater activity. In patients with CML, the overall survival rate after 60 months is estimated to be approximately 89% after treatment with imatinib. The progression-free survival rate at 60 months was approximately 83% (95% confidence interval, 79% 87%) in the same study [1]. In patients with GISTs, the progression-free survival duration after treatment with imatinib is estimated to be approximately 2 years. A European trial in GIST patients showed that the progression-free survival rate was signifi-

5 1394 Imatinib cantly higher in patients who started on 400 mg twice daily than in patients treated with 400 mg daily (56% versus 50%) [12]. PATIENT INSTRUCTIONS AND RECOMMENDATIONS FOR SUPPORTIVE CARE The tablets should be taken with a meal and a large glass of water to prevent gastrointestinal side effects. Tablets should be stored at room temperature. Liver function parameters (transaminases, alkaline phosphatase, bilirubin) should be monitored prior to start of therapy and as clinically indicated, initially monthly is advised. To monitor myelosuppression, it is advised that a CBC is performed weekly during the first month of treatment, biweekly during the second month, and once every 2 3 months thereafter. REFERENCES 1 Druker BJ, Guilhot F, O Brien SG et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 2006;355: Capdeville R, Buchdunger E, Zimmerman J et al. Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug. Nat Rev Drug Discov 2002;1: Desjardins A, Quinn JA, Vredenburgh JJ et al. Phase II study of imatinib mesylate and hydroxyurea for recurrent grade III malignant gliomas. J Neurooncol 2007;83: Deininger M, Buchdunger E, Druker BJ. The development of imatinib as a therapeutic agent for chronic myeloid leukaemia. Blood 2005;105: Peng B, Lloyd P, Schran H. Clinical pharmacokinetics of imatinib. Clin Pharmacokinet 2005;44: Titier K, Picard S, Ducint D et al. Quantification of imatinib in human plasma by high-performance liquid chromatography-tandem mass spectrometry. Ther Drug Monit 2005;27: Gardner ER, Burger H, van Schaik RH et al. Association of enzyme and transporter genotypes with the pharmacokinetics of imatinib. Clin Pharmacol Ther 2006;80: Gurney H, Wong M, Balleine RL et al. Imatinib disposition and ABCB1 (MDR-1, P-glycoprotein) genotype. Clin Pharmacol Ther 2007;82: Hochhaus A, Kreil S, Corbin AS et al. Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia 2002;16: Villuendas R, Steegmann JL, Pollàn M et al. Identification of genes involved in imatinib resistance in CML: A gene-expression profiling approach. Leukemia 2006;20: Heinrich MC, Corless CL, Blanke CD et al. Molecular correlates of imatinib resistance in gastrointestinal stromal tumors. J Clin Oncol 2006;24: Verweij J, Casali PG, Zalcberg J et al. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: Randomised trial. Lancet 2004;364: Massagué J. G1 cell-cycle control and cancer. Nature 2004;432: