The inhibition by imatinib of the cytochrome P450 3A4 isoenzyme may reduce the CYP3A4-mediated metabolic clearance of clinically important coadministered drugs. The main purpose of this study was to evaluate the effect of the coadministration of imatinib on the pharmacokinetics of simvastatin, a probe CYP3A4 substrate. In total, 20 patients with chronic myeloid leukaemia received an oral dose of 40 mg of simvastatin on study day 1. On study days 2–7, each patient received 400 mg of imatinib once daily orally and on study day 8, 400 mg imatinib together with 40 mg of simvastatin was given. Blood levels of simvastatin were measured predose and for 24 h postdose on study days 1 and 8. Two additional blood samples were taken for imatinib pharmacokinetic (PK) assessment on day 8 before, and 24 h after, imatinib administration. Imatinib increased the mean maximum concentration (Cmax) value of simvastatin two-fold and the area under concentration–time curve (AUC (0–inf)) value 3.5-fold (P<0.001) compared with simvastatin alone. There was a statistically significant decrease in total-body clearance of drug from the plasma (CL/F) with a mean reduction of 70% for simvastatin (P<0.001): the mean half-life of simvastatin was prolonged from 1.4–2.7 h when given together with imatinib. No changes in imatinib PK parameters were found when given concomitantly with simvastatin. In conclusion, the coadministration of imatinib at steady state with 40 mg simvastatin increases the exposure (Cmax and AUCs) of simvastatin significantly (P<0.001) by two-three-fold. Caution is therefore required when administering imatinib with CYP3A4 substrates with a narrow therapeutic window. The coadministration of simvastatin with imatinib (400 mg) was well tolerated and no major safety findings were reported in this study.
Imatinib mesylate (STI571, Glivec®, Gleevec® – Novartis, Basel, Switzerland) is a potent competitive inhibitor of the tyrosine kinases associated with ABL (Buchdunger et al, 1996; Druker et al, 1996), KIT (Buchdunger et al, 2000; Heinrich et al, 2000), PDGFr (Buchdunger et al, 1996, 2000) and ARG (Okuda et al, 2001), which impedes the interaction of ATP with the SH1 domain of these proteins (Schindler et al, 2000), thereby inhibiting the phosphorylation of downstream target proteins. Imatinib is a phenylaminopyrimidine derivative and represents the first of a new class of drugs known as signal transduction inhibitors. Following initial phase I/II dose-escalation studies with imatinib (Druker et al, 2001a, 2001b), subsequent studies have demonstrated remarkable efficacy with minimal side effects mostly in Philadelphia-positive leukaemias (Kantarjian et al, 2002; Ottmann et al, 2002; Sawyers et al, 2002; Talpaz et al, 2002; O'Brien et al, 2003) but also in solid tumours (Joensuu et al, 2001). Currently, clinical trials using imatinib with and without concomitant chemotherapy are being conducted in a number of c-kit and PDGF-R-positive malignancies(Apperley et al, 2001; Fischer et al, 2001; Johnson et al, 2002).
Imatinib is a competitive inhibitor of CYP3A4, CYP2D6 cytochrome P450 isoenzymes as well as CYP2C9, CYP3A5 and CYP4A to a lesser extent (Novartis, unpublished data). Coadministration of inhibitors of CYP3A4 with drugs known to be substrates of this enzyme could potentially affect the pharmacokinetic parameters of the substrate drug, and could be also responsible for considerably increasing its side effects (Desager and Horsmans, 1996). Simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, is used as a lipid-lowering agent. It is uniquely metabolised by CYP3A4, is well tolerated and is therefore commonly recommended as the model drug for testing drug interactions involving CYP3A4 substrates (US Department of Health and Human Services, 1999). Drug interactions between CYP3A4 substrates such as simvastatin and CYP3A4 inhibitors are potentially clinically important and have been reported to potentially enhance the risk of myopathy and rhabdomyolysis (Walker, 1989; Todd and Goa, 1990; Berland et al, 1991; Smith et al, 1991; Garnett, 1995; Meier et al, 1995; Goodman & Gilman's, The Pharmacological Basis of Therapeutics, 2000). Accordingly, the prescription instructions for HMG-CoA reductase inhibitors often suggest caution regarding the potential of occurrence of drug interactions with substrates, inhibitors and inducers of CYP3A compounds (Walker, 1989).
We therefore hypothesised that coadministration of imatinib, as an inhibitor of the microsomal CYP3A4 enzyme system, could affect the elimination rate of simvastatin. The present study was undertaken to assess this potential pharmacokinetic interaction by evaluation of the simvastatin plasma concentration vs time profiles after coadministration with imatinib (US Department of Health and Human Services, 1999) and its effects on safety and tolerability in patients with chronic myeloid leukaemia (CML).
Materials and methods
In an open-label, nonrandomised, one-sequence study, 20 adult patients with CML who were haematologically or cytogenetically resistant or refractory to interferon-α, or intolerant of interferon-α were enrolled. There were 10 male and 10 female patients the mean age (±s.d.) was 50.5 years (±13.4 years), weight ranged from 53 to 111 kg, and height from 158 to 192 cm. None of the patients had any past or present medical conditions that could affect the study results. Each patient gave written informed consent before taking part of the study, which was approved by the ethics committee of the Landesärztekammer Rheinland-Pfalz, Mainz (Germany) and of the University of Newcastle/Royal Victoria Infirmary (UK). The study was conducted in agreement with the declaration of Helsinki, as amended in Tokyo, Venice, Hong-Kong and Somerset West. Drug interaction studies performed in healthy volunteers commonly use a crossover design. However, one of the requirements of the present study was to test interactions with simvastatin at steady-state levels of imatinib. As it usually requires approximately 7 days to reach serum steady-state levels of imatinib, it was considered unethical to perform the study in healthy volunteers and therefore the study was conducted in patients with CML. As a corollary of this restriction, practical and ethical issues (e.g., wash-out phase) prevented the study being performed as a crossover design. The use of concomitant medications that could potentially alter the integrity of the PK analysis (e.g., altered absorption, distribution) was forbidden. The patients were asked to refrain from strenuous physical exercise (e.g., weight training, aerobics, football) for 7 days before dosing until after the study completion evaluation, from alcohol for 72 h before dosing until after the study completion evaluation and from intake of xanthine (e.g., caffeine) or grapefruit (known as a CYP3A4 inhibitor (Schmiedlin-Ren et al, 1997; Lilja et al, 1998; Kane and Lipsky, 2000))-containing food or beverages 48 h before dosing and during the whole study.
On study days 1 and 8, patients reported to the study site around 1 h prior to dosing for baseline evaluations and were kept at the centre until 12 h postdosing (Table 1). At 24 h after dosing, the patients reported again to the study site for the 24 h blood sampling (study days 2 and 8) and study completion evaluations (study day 9). Blood samples for determination of simvastatin plasma concentrations were taken up to 24 h after dosing on study days 1 and 8. Imatinib was administered daily starting at day 2 at a dose of 400 mg (supplied as 100 mg hard gelatine capsules). Simvastatin (40 mg tablets of Denan® – Boehringer Ingelheim) for both centres was purchased by the pharmacist of the University of Mainz's Hospital. On study days 1 and 8, 40 mg of oral simvastatin was administered immediately after a low fat breakfast (on day 8, simvastatin and imatinib were given at the same time). No fluid intake apart from the fluid given at the time of drug intake was allowed until 2 h after dosing. Owing to the inherent risk of either reduced activity or enhanced toxicity of the concomitant medication and/or imatinib, drugs known to be metabolised by the same CYP450 isoenzymes as imatinib, were forbidden. Allopurinol 300 mg daily (an inhibitor of CYP2C9/10 (Yokochi et al, 1982; Veronese et al, 1991; Kane and Lipsky, 2000)) was recommended for patients with WBC 20.0 × 109 l−1. Following the PK study, patients continued with therapeutic imatinib at the standard dose.
All blood samples were taken by either direct venepuncture or an indwelling cannula inserted in a forearm vein at predose (0 h), 0.5, 1, 2, 3, 4, 6, 10, 12 and 24 h after dosing on days 1 and 8 (Table 1). Immediately after the blood was drawn, each tube was inverted gently several times to ensure the mixing of tube contents (e.g., anticoagulant) and prolonged sample contact with the rubber stopper was avoided. The upright tube was kept on ice, and within 30 min the sample was centrifuged at 3 and 5°C for 10 min at approximately 1500 g. Immediately after centrifugation, at least 2 ml plasma was transferred to a polypropylene screw-cap tube put on dry ice. The tubes were kept frozen at ⩽−18°C pending analysis.
Simvastatin and simvastatin hydroxy acid with lovastatin as internal standard were determined in plasma by LC/MS/MS. The LC/MS/MS analyses were carried out on a Sciex API3000 mass spectrometer. The instrument was operated in the ESI mode (positive ion for drug, negative ion for metabolite) with selected reaction monitoring. LC was performed on a Shimadzu LC system operated in isocratic mode with a 2.0 × 50 mm2 C-18 column. Samples were prepared using a solid-phase extraction procedure. All concentrations are reported in terms of the free acid form of simvastatin and simvastatin hydroxy acid.
All completed patients were included in the pharmacokinetic data analysis. For plasma concentrations of simvastatin the following parameters were determined: AUC(0–t) (area under the concentration–time curve from time zero to t), AUC(0–∞) (area under the concentration–time curve from time zero to infinity), Cmax (maximum plasma drug concentration), tmax (time to reach maximum concentration following drug administration), t1/2 (elimination half-life associated with terminal slope of a semilogarithmic concentration–time curve), Vz/f (apparent volume of distribution based on terminal phase of plasma concentration–time curves) and CL/F (total body clearance of drug from the plasma), in order to assess the effects of imatinib on the PK of simvastatin.
The following pharmacokinetic parameters were used to assess an interaction of imatinib on simvastatin: AUCinf, AUCall, Cmax, Vz/f, CL/f, t1/2 and tmax. With the exception of t1/2 and tmax, parameters were ln-transformed prior to analysis. Treatment differences were assessed by t-tests. The means of differences of ln-transformed data together with 90% confidence intervals were then antilogged in order to get confidence intervals for the ratio ‘simvastatin+imatinib/simvastatin’. An interaction of imatinib with simvastatin was assumed, if these confidence intervals were not included in the ‘no-effect’ interval (0.80, 1.25). Tmax was analysed nonparametrically. The alpha-level was set to 0.05 and no alpha-adjustment was made for multiple testing.
Drug safety and tolerability
In total, 14 (70%) of the 20 recruited patients reported a total of 30 adverse events. All but one adverse events were rated by the investigators as mild (grade 1) to moderate (grade 2). Of these, 12 patients had at least one adverse event grade 1, and four patients at least grade 2. Only one patient experienced a grade 3 left leg cellulitis, but this was assessed as not related to the study drugs. No deaths occurred during the course of the study and none of the adverse events resulted in discontinuation from the study. The most common adverse events reported were neurological symptoms (headache, insomnia), gastrointestinal symptoms (nausea, loose stool), and musculoskeletal symptoms (myalgia, muscle cramps cramping, pain in limb).
Pharmacokinetics of simvastatin
The main pharmacokinetic parameters of simvastatin and its hydroxy acid metabolite, for the 20 CML patients determined by noncompartmental model analyses, are listed in Tables 2 and 3. The mean and standard deviation for each parameter are given for the two treatment periods in which simvastatin was administered. Figures 1 and 2 show the mean plasma concentrations of simvastatin and its metabolite (simvastatin hydroxy acid), respectively, following either oral administration of simvastatin alone or combined with oral administration of imatinib. Figure 3 shows the comparison of plasma AUC(0–∞) of simvastatin following oral administration of simvastatin alone and combined with oral administration of imatinib in 20 subjects. Following imatinib coadministration, the mean simvastatin Cmax, AUC(0–all) and AUC(0–∞) increased significantly by two-to-three-fold (P<0.001). There was a statistically significant decrease in CL/F with a mean reduction of 70% (P<0.001). With regard to metabolites, the mean Cmax and AUCs of simvastatin hydroxy acid also increased significantly by two-to-three-fold (P<0.001) after imatinib treatment (Table 3 and Figure 2). The coefficient of variation (CV) for Cmax and AUCs showed considerable interpatient variation. The mechanism for this variability is not clear yet but could be attributed to interpatient variations in CYP3A4 activity. Compliance to imatinib treatment and plasma concentration at steady state were checked by the analysis of the plasma samples taken on study days 8 and 9 in the morning prior to administration. The mean plasma imatinib trough concentrations were similar on day 8 (1268 ng ml−1) and day 9 (1182 ng ml−1) indicating that PK steady state for imatinib was reached in those patients after 6-day oral doses.
This study was performed to determine whether imatinib could alter the pharmacokinetics of a single dose of simvastatin when given concomitantly in patients with chronic myeloid leukaemia. This has important implications because of potential interactions of imatinib with commonly prescribed drugs in the clinic.
The major route of degradation of simvastatin within the body is by cytochrome P450 3A4-mediated biotransformation (Vickers et al, 1990; Prueksaritanont et al, 1997) although the drug can be converted reversibly to simvastatin hydroxy acid by esterases. From in vitro drug interaction studies, CYP3A4 was also found to be the major human P450 enzyme involved in the microsomal biotransformation of imatinib (data not shown). Simvastatin inhibits HMG-CoA reductase causing decreases in intrahepatic cholesterol and upregulation of LDL-receptors with enhanced clearance of LDL and other apolipoprotein B containing lipoproteins from the circulation. It appears that these interactions do not have a relevant clinical effect on the efficacy of the HMG-CoA reductase inhibitors to reduce the cLDL from the plasma, but the concomitant administration of HMG-CoA reductase inhibitors and cyclosporine, fibrate or nicotinic acid may enhance the risk of myopathy or rhabdomyolysis (Berland et al, 1991; Smith et al, 1991; Meier et al, 1995).
The coadministration of simvastatin with imatinib (400 mg) was well-tolerated and no major safety concerns were reported in this study. No clinically significant abnormalities in laboratory values, vital signs or ECGs were reported. The majority of the adverse events were assessed as grade 1/2 and no myopathy or rhabdomyolysis occurred. Only one grade 3 left leg cellulitis (which required hospitalisation) was reported but was not related to the study drugs. This study shows that coadministration of imatinib increased the mean Cmax value of simvastatin two-fold and the AUC(0–∞) value three-fold compared with simvastatin alone and the mean half-life of simvastatin was prolonged from 1.4 to 2.7 h when given together with imatinib. This indicates an inhibition of CYP3A4 by which the oxidative biotransformation of simvastatin to other metabolites is primarily mediated. It was also observed that the formation of simvastatin hydroxy acid from simvastatin by esterases is not prevented by imatinib, which explains the increases in both simvastatin and simvastatin hydroxy acid concentrations. This would suggest that in the presence of imatinib, plasma levels of standard doses of drugs which are degraded by the CYP3A4 system (Table 4 and see also: http://medicine.iupui.edu/flockhart/) may be increased. For example, one might predict that the effects of warfarin, digoxin, certain antihypertensive agents (e.g., diltiazem, nifedipine, verapamil), steroids, benzodiazepines and other drugs commonly used in the practice of haematology (e.g., busulphan, cyclosporine, cyclophosphamide, doxorubicin etoposide, vincristine) could be enhanced and appropriate vigilance to avoid undesirable effects should be exercised. In addition, concomitant use of simvastatin or other HMG-CoA reductase inhibitors with imatinib may increase the risk of myopathy or rhabdomyolysis and again caution is required.
The design of the study allows only limited interpretation of the effects of simvastatin on plasma levels, and perhaps therefore efficacy, of imatinib. However there were no apparent effects of simvastatin on the PK of imatinib in these 20 patients, although more detailed PK studies would be required to resolve this issue definitively. Although this study was not designed to assess the potential relationships between the efficacy of imatinib and pharmacokinetics parameters, this important question is being addressed by ongoing population PK/PD modelling analyses within the context of ongoing phase II and phase III studies.
In conclusion, the coadministration of imatinib (400 mg) at steady state with 40 mg simvastatin significantly (P<0.001) increases the exposure (Cmax and AUCs) to simvastatin by two-to-three-fold. This effect is most likely the result of the inhibition of CYP3A4-mediated metabolism of simvastatin in the liver and has implications for the monitoring of concomitant therapies in patients being treated with imatinib. Caution is therefore required when administering imatinib with CYP3A4 substrates with a narrow therapeutic window.
Apperley JF, Schultheis B, Chase A, Steer J, Bain B, Dimitrijevic S, Martin D, Olavarria E, Cross NCP, Russell-Jones R, Melo J, Goldman JM (2001) Chronic myeloproliferative diseases with t(5;12) and a PDGFRB fusion gene: complete cytogenetic remissions on STI571. Blood 98: 726a
Berland Y, Vacher Coponat H, Durand C, Baz M, Laugier R, Musso JL (1991) Rhabdomyolysis with simvastatin use. Nephron 57: 365–366
Buchdunger E, Cioffi CL, Law N, Stover D, Ohno-Jones S, Druker BJ, Lydon NB (2000) Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-kit and platelet-derived growth factor receptors. J Pharmacol Exp Ther 295: 139–145
Buchdunger E, Zimmerman J, Mett H, Meyer T, Muller M, Druker BJ, Lydon NB (1996) Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative. Cancer Res 56: 100–104
Desager JP, Horsmans Y (1996) Clinical pharmacokinetics of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors. Clin Pharmacokinet 31: 348–371
Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Fernandes Reese S, Ford JM, Capdeville R, Talpaz M (2001a) Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 344: 1038–1042
Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, Lydon NB, Kantarjian H, Capdeville R, Ohno-Jones S, Sawyers CL (2001b) Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 344: 1031–1037
Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S, Zimmermann J, Lydon NB (1996) Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med 2: 561–566
Fischer T, Gamm H, Beck J, Gschaidmeier H, Theobald M, Huber C (2001) Complete remission after administration of the c-kit inhibitor STI-571 (GleevecTM) in a patient with acute myeloid leukemia refractory to chemotherapy. Blood 98: 588a
Garnett WR (1995) Interactions with hydroxymethylglutaryl-coenzyme A reductase inhibitors. Am J Health Syst Pharm 52: 1639–1645
Goodman & Gilman's, The Pharmacological Basis of Therapeutics (2000) Swiss Drug Compendium (Schweizer Arzneimittelcompendium)
Heinrich MC, Griffith DJ, Druker BJ, Wait CL, Ott KA, Zigler AJ (2000) Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. Blood 96: 925–932
Joensuu H, Roberts PJ, Sarlomo-Rikala M, Andersson LC, Tervahartiala P, Tuveson D, Silberman S, Capdeville R, Dimitrijevic S, Druker B, Demetri GD (2001) Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med 344: 1052–1056
Johnson BE, Fischer B, Fischer T, Dunlop D, Rischin D, MacCallum P, Silberman S, Kowalski M, Sayles D, Fletcher C, Salgia R, Delbaldo C (2002) Phase II Study of STI571 (Gleevec) for Patients with Small Cell Lung Cancer. Orlando, FL: American Society of Clinical Oncology
Kane GC, Lipsky JJ (2000) Drug–grapefruit juice interactions. Mayo Clin Proc 75: 933–942
Kantarjian H, Sawyers CL, Hochhaus A, Guilhot F, Schiffer C, Gambacorti-Passerini C, Niederwieser D, Stone R, Goldman JM, Fischer T, Cony-Makhoul P, O'Brien SG, Miller C, Tallman M, Brown R, Schuster M, Gratwohl A, Loughran T, Mandelli F, Saglio G, Ottmann OG, Lazzarino M, Russo D, Tura S, Facon T, Morra E, Russell N, Zoellner U, Resta R, Capdeville R, Talpaz M, Druker BJ (2002) Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 346: 645–652
Lilja JJ, Kivisto KT, Neuvonen PJ (1998) Grapefruit juice–simvastatin interaction: effect on serum concentrations of simvastatin, simvastatin acid, and HMG-CoA reductase inhibitors. Clin Pharmacol Ther 64: 477–483
Meier C, Stey C, Brack T, Maggiorini M, Risti B, Krahenbuhl S (1995) Rhabdomyolysis in patients treated with simvastatin and cyclosporin: role of the hepatic cytochrome P450 enzyme system activity. Schweiz Med Wochenschr 125: 1342–1346
O'Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F, Cornelissen JJ, Fischer T, Hochhaus A, Hughes T, Lechner K, Nielsen JL, Rousselot P, Reiffers J, Saglio G, Shepherd J, Simonsson B, Gratwohl A, Goldman JM, Kantarjian H, Taylor K, Verhoef G, Bolton AE, Capdeville R, Druker BJ (2003) Imatinib compared with interferon and low-dose cytarbine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 348: 994–1004
Okuda K, Weisberg E, Gilliland DG, Griffin JD (2001) ARG tyrosine kinase activity is inhibited by STI571. Blood 97: 2440–2448
Ottmann OG, Druker BJ, Sawyers CL, Goldman JM, Mahon FX, Silver RT, Tura S, Fischer T, Deininger M, Schiffer CA, Baccarani M, Gratwohl A, Hochhaus A, Hoelzer D, Fernandes-Reese S, Gathmann I, Capdeville R, O'Brien SG (2002) Glivec (imatinib mesylate) induces hematologic and cytogenetic responses in patients with relapsed or refractory Philadelphia chromosome-positive acute leukemias: results of a phase II study. Blood 100: 1965–1971
Prueksaritanont T, Gorham LM, Ma B, Liu L, Yu X, Zhao JJ, Slaughter DE, Arison BH, Vyas KP (1997) In vitro metabolism of simvastatin in humans [SBT]identification of metabolizing enzymes and effect of the drug on hepatic P450s. Drug Metab Dispos 25: 1191–1199
Sawyers CL, Hochaus A, Feldman E, Goldman JM, Miller CM, Ottman OG, Schiffer CA, Talpaz M, Guilhot F, Deininger MWN, Fischer T, O'Brien SG, Stone R, Gambacorti-Passerini C, Russel N, Reiffers J, Shea T, Chapuis B, Coutre S, Tura S, Morra E, Larson RA, Saven A, Peschel C, Gratwohl A, Mandelli F, Ben-Am M, Ganthmann I, Capdeville R, Paquette RL, Druker BJ (2002) Glivec (imatinib mesylate) induces hematologic and cytogenetic responses in patients with chronic myeloid leukemia in myeloid blast crisis: results of a phase II study. Blood 99: 3530–3539
Schindler T, Bornmann W, Pellicena P, Miller WT, Clarkson B, Kuriyan J (2000) Structural mechanism for STI-571 inhibition of abelson tyrosine kinase. Science 289: 1938–1942
Schmiedlin-Ren P, Edwards DJ, Fitzsimmons ME, He K, Lown KS, Woster PM, Rahman A, Thummel KE, Fisher JM, Hollenberg PF, Watkins PB (1997) Mechanisms of enhanced oral availability of CYP3A4 substrates by grapefruit constituents. Decreased enterocyte CYP3A4 concentration and mechanism-based inactivation by furanocoumarins. Drug Metab Dispos 25: 1228–1233
Smith PF, Eydelloth RS, Grossman SJ, Stubbs RJ, Schwartz MS, Germershausen JI, Vyas KP, Kari PH, MacDonald JS (1991) HMG-CoA reductase inhibitor-induced myopathy in the rat: cyclosporine A interaction and mechanism studies. J Pharmacol Exp Ther 257: 1225–1235
Talpaz M, Silver RT, Druker BJ, Goldman JM, Gambacorti-Passerini C, Guilhot F, Schiffer CA, Fischer T, Deininger MW, Lennard AL, Hochhaus A, Ottmann OG, Gratwohl A, Baccarani M, Stone R, Tura S, Mahon FX, Fernandes-Reese S, Gathmann I, Capdeville R, Kantarjian HM, Sawyers CL (2002) Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study. Blood 99: 1928–1937
Todd PA, Goa KL (1990) Simvastatin. A review of its pharmacological properties and therapeutic potential in hypercholesterolaemia. Drugs 40: 583–607
US Department of Health and Human Services, F.a.D.A. (1999) Guidance for Industry: in vivo Drug Metabolism/Drug Interaction Studies – Study Design, Data Analysis, and Recommendations for Dosing and Labeling
Veronese ME, Mackenzie PI, Doecke CJ, McManus ME, Miners JO, Birkett DJ (1991) Tolbutamide and phenytoin hydroxylations by cDNA-expressed human liver cytochrome P4502C9. Biochem Biophys Res Commun 175: 1112–1118
Vickers S, Duncan CA, Vyas KP, Kari PH, Arison B, Prakash SR, Ramjit HG, Pitzenberger SM, Stokker G, Duggan DE (1990) In vitro and in vivo biotransformation of simvastatin, an inhibitor of HMG CoA reductase. Drug Metab Dispos 18: 476–483
Walker JF (1989) Simvastatin: the clinical profile. Am J Med 87: 44S–46S
Yokochi K, Yokochi A, Chiba K, Ishizaki T (1982) Phenytoin – allopurinol interaction: Michaelis–Menten kinetic parameters of phenytoin with and without allopurinol in a child with Lesch–Nyhan syndrome. Ther Drug Monit 4: 353–357
This study was sponsored by Novartis Pharma AG. The study was presented in part at the 43rd Annual Meeting of the American Society of Hematology, 6–10 December 2001, Orlando, FL. Five authors (BP, CD, GM, SM and RC) are employees of Novartis Pharma AG
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O'Brien, S., Meinhardt, P., Bond, E. et al. Effects of imatinib mesylate (STI571, Glivec) on the pharmacokinetics of simvastatin, a cytochrome P450 3A4 substrate, in patients with chronic myeloid leukaemia. Br J Cancer 89, 1855–1859 (2003). https://doi.org/10.1038/sj.bjc.6601152
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