临床药代动力学文献

Effect of St John’s wort on imatinib mesylate pharmacokineticsObjective:Imatinib is a potent inhibitor of the Bcr-Abl and c-kit tyrosine kinases and is approved for thetreatment of Philadelphia chromosome–positive chronic myelogenous leukemia and gastrointestinal stromal tumors.Because imatinib is predominantly metabolized by cytochrome P450(CYP)3A4,its pharmacoki-netics may be altered when it is coadministered with drugs or herbs(eg,St John’s wort)that modulate CYP3A4activity.Thus we examined the effects of St John’s wort on imatinib pharmacokinetics.Methods:This2-period,open-label,fixed-sequence study was completed by12healthy subjects(6men and6 women)aged between20and51years.Each subject received400mg imatinib orally on study day1,St John’s wort(300mg3times daily)on days4to17,and400mg imatinib again on day15.Serial blood samples were obtained over a72-hour period after each imatinib dose.Imatinib and N-desmethyl-imatinib(CGP74588) were quantified in plasma by liquid chromatography–mass spectrometry.Results:St John’s wort administration increased imatinib clearance by43%(P<.001),from12.5؎3.6L/h to17.9؎5.6L/h;imatinib area under the concentration versus time curve(AUC)extrapolated to infinity was decreased by30%,from34.5؎9.5␮g·h/mL to24.2؎7.0␮g·h/mL(P<.001).Imatinib half-life(12.8hours versus9.0hours)and maximum concentration(Cmax)(2.2␮g/mL versus1.8␮g/mL)were alsosignificantly decreased(P<.005).N-desmethyl-imatinib Cmaxwas increased from285؎95ng/mL to318؎95ng/mL during St John’s wort dosing,but the AUC from0to72hours was not altered.Conclusions:These data indicate that St John’s wort increases imatinib clearance.Thus patients taking imatinib should avoid taking St John’s wort.Concomitant use of enzyme inducers,including St John’s wort, may necessitate an increase in the imatinib dose to maintain clinical effectiveness.(Clin Pharmacol Ther 2004;76:323-9.)Reginald F.Frye,PharmD,PhD,Sara M.Fitzgerald,MS,Theodore gattuta,BS, Matthew W.Hruska,PharmD,and Merrill J.Egorin,MD Pittsburgh,Pa,and Gainesville,FlaThe phenylaminopyrimidine derivative imatinib (Gleevec or Glivec;Novartis Pharmaceuticals Corp)is an inhibitor of several protein-tyrosine kinases that are believed to play a role in the proliferation of tumor cells.These include the tyrosine kinases associated with Bcr-Abl,the platelet-derived growth factor recep-tor,and c-kit of the receptor for stem cell factor.1 Imatinib has been identified as a potent inhibitor of the Bcr-Abl tyrosine kinase at the in vitro,cellular,and in vivo levels,2which provided the rationale for testing imatinib in human cancers,where dysregulation of these pathways may contribute to malignant growth. Indeed,imatinib has been shown to be very effective for the treatment of Philadelphia chromosome–positive chronic myelogenous leukemia(CML)and gastrointes-tinal stromal tumors.3-5Imatinib is extensively metabolized by the cyto-chrome P450(CYP)enzyme system;CYP3A4is the major enzyme responsible for metabolism of imatinib, whereas the enzymes CYP1A2,CYP2D6,CYP2C9, and CYP2C19contribute to a minor extent.6The major circulating metabolite,which is formed by CYP3A4,is an N-desmethylated piperazine derivative that pos-sesses in vitro activity comparable to that of imatinib.From the Department of Pharmaceutical Sciences,School of Phar-macy,University of Pittsburgh,Pittsburgh;Molecular Therapeu-tics/Drug Discovery Program,University of Pittsburgh CancerInstitute,Pittsburgh;Department of Pharmacy Practice,College ofPharmacy,University of Florida,Gainesville;and Departments ofMedicine and Pharmacology,University of Pittsburgh School ofMedicine,Pittsburgh.Supported in part by a grant from Novartis Pharmaceuticals Corp andgrants funded by the National Institute of Mental Health and theOffice of Dietary Supplements(R01MH63458),the NationalCancer Institute(P30CA47904),and a General Clinical ResearchCenter Award(M01RR00056).Received for publication May20,2004;accepted June29,2004.Reprint requests:Reginald F.Frye,PharmD,PhD,University of Florida,College of Pharmacy,PO Box100486,Gainesville,FL32610.E-mail:frye@cop.ufl.edu0009-9236/$30.00Copyright©2004by the American Society for Clinical Pharmacologyand Therapeutics.doi:10.1016/j.clpt.2004.06.007323The importance of CYP3A4in the disposition of ima-tinib has been shown in 2drug-drug interaction studies.In healthy volunteers,coadministration of the potent CYP3A4inhibitor ketoconazole increased the imatinib maximum concentration (C max )and area under the con-centration versus time curve (AUC)by 26%and 40%,respectively.7Conversely,coadministration of rifampin (INN,rifampicin),which is a potent inducer of multiple CYP enzymes including CYP3A4,decreased the C max and AUC of imatinib by 54%and 74%,respectively.8Thus concurrent administration of other drugs or herbal products that modulate CYP3A4activity may alter imatinib exposure.Several important and clinically relevant interactions between St John ’swort and conventional drugs have been reported over the last few years.9-12The primary mechanism by which St John ’s wort induces CYP3A activity is known to be mediated through the pregnane X receptor,because the constituent hyperforin is a potent ligand for this receptor.13Given the widespread availability of St John ’s wort,it is important to under-stand what effects its concomitant use may have on the disposition of other medications (eg,calcium channel blockers,antidepressants,benzodiazepines,and immu-nosuppressants).Speci fically,induction of CYP metab-olism could result in lower circulating drug concentra-tions,which could in turn lead to a reduction in ef ficacy.The use of complementary and alternative medicine is reportedly high 14and depression is relatively com-mon in patients with cancer.15In that there is the potential for cancer patients to self-medicate with St John ’s wort in an attempt to alleviate symptoms of depression,there is a need to assess how St John ’s wort may affect the disposition of cancer agents such as imatinib.Thus the purpose of this study was to deter-mine the effect of St John ’s wort administration on the pharmacokinetics of imatinib and N -desmethyl-imatinib in healthy volunteers.METHODS SubjectsThe study was approved by the Institutional Review Board at the University of Pittsburgh (Pittsburgh,Pa)and was conducted at the University of Pittsburgh Gen-eral Clinical Research Center.After providing written informed consent,12healthy,nonsmoking subjects (6men and 6women)participated in this study.The subjects ’mean age (ϮSD)was 28.3Ϯ11.9years (range,21-57years),they weighed 72.2Ϯ16.6kg (range,50.9-101kg),and they had a body mass index of 23.6Ϯ3.0kg/m 2(range,19.5-28.0kg/m 2).Elevensubjects were white and 1was black.Subjects were determined to be healthy on the basis of medical his-tory,a physical examination,and routine clinical labo-ratory tests.Subjects were excluded if they were taking any medications other than multivitamins and oral con-traceptives.The volunteers were asked to abstain from alcohol and caffeine-containing foods and beverages for 24hours before and during each study visit and from grapefruit or grapefruit juice for 48hours before and during each study visit.Study designThe study used an open-label,fixed-sequence design.The pharmacokinetics of 400mg imatinib (Gleevec;Novartis Pharmaceuticals Corp,East Hanover,NJ)was assessed before (day 1)and during (day 15)the oral administration of 300mg St John ’s wort extract (Kira [LI 160];Lichtwer Pharma AG,Berlin,Germany)3times a day.St John ’s wort administration was started on study day 4after imatinib sample collection was completed and continued through study day 17.Imatinib pharmacokineticsA single oral dose of imatinib (400mg)was admin-istered with 8oz of water on the morning of study days 1and 15.Venous blood samples (N ϭ13,6mL each)were drawn from an indwelling catheter into heparin-containing tubes at 0hours (before the dose)and at 0.5,1,2,4,6,8,12,16,24,36,48,and 72hours after imatinib administration.The blood samples were cen-trifuged at 3000g for 10minutes,and the resulting plasma was stored at Ϫ20°C or colder until analyzed.Cortisol ratioUrine was collected from 0to 24hours after imatinib administration,and aliquots were stored at Ϫ20°C or colder until analyzed.Analytic proceduresPlasma concentrations of imatinib and N -desmethyl-imatinib were determined by use of a previously de-scribed liquid chromatography –mass spectrometry method that was developed and validated in our labo-ratory.16In brief,plasma samples (0.2mL)were mixed in a microcentrifuge tube with internal standard (imatinib-D 8;Novartis Pharmaceuticals Corp)before plasma proteins were precipitated with acetonitrile (1mL).Samples were centrifuged,and an aliquot of the resulting supernatant was evaporated to dryness under a stream of nitrogen.The dried residue was dissolved in 100␮L methanol/distilled water (20:80[vol/vol])and transferred to autosampler vials,and 3␮L was injectedCLINICAL PHARMACOLOGY &THERAPEUTICS324Frye et alOCTOBER 2004into the HPLC system.The HPLC system consisted of an Agilent model1100Autosampler(Agilent Technol-ogies,Palo Alto,Calif),an Agilent1100Quaternary pump,and a Phenomenex Luna C18(2)(5␮m,50ϫ4.6mm)reverse-phase analytic column(Phenomenex, Torrance,Calif).Determination of concentrations of imatinib,N-desmethyl-imatinib,and the deuterated in-ternal standard was achieved with a ThermoFinnigan aQa Mass Spectrometer(Thermo Electron Corporation, San Jose,Calif)operating in positive-electrospray, single-ion mode(493.7mass-to-charge ratio[m/z]for imatinib,479.7m/z for N-desmethyl-imatinib,and 501.7m/z for imatinib-D8).Standard curves were linear over the range of30to10,000ng/mL,and the intraday and interday coefficients of variation were less than 10%.Concentrations of6␤-hydroxycortisol and cortisol in urine were determined by liquid chromatography–tan-dem mass spectrometry.17,18After addition of the in-ternal standardfluorocortisone acetate(500ng),the urine samples(1mL)were extracted with ethyl acetate (5mL).The organic layer was transferred to a clean tube and evaporated to dryness at45°C under a stream of nitrogen.The samples were reconstituted in200␮L of methanol/water(70:30[vol/vol])and placed into an autosampler vial for injection.Separation was achieved with a Symmetry C18column(5␮m,3.0ϫ150mm; Waters Corporation,Milford,Mass).The mobile phases consisted of(A)water/methanol(80:20[vol/ vol])and(B)methanol and were delivered in a gradient at a totalflow rate of500␮L/min.The gradient was maintained at100:0(A/B)for0.2minutes,increased to 12.5:87.5over a period of2.3minutes,maintained at 12.5:87.5for1minute,decreased to100:0over a period of0.5minutes,and held at100:0for1.5min-utes,for a total run time of5.5minutes.Analytes were detected by tandem mass spectrometry with atmo-spheric pressure chemical ionization in positive-ion mode(TSQ Quantum Triple Quadrupole Mass Spec-trometer;Thermo Electron Corporation).Precursor [MϩH]ϩand product ions detected were m/z363.2/ 327.1,379.2/325.1,and423.2/239.1for cortisol,6␤-hydroxycortisol,andfluorocortisone,respectively.The lower limit of quantification for both6␤-hydroxycortisol and cortisol was5ng/mL,and the intraday and interday coefficients of variation were less than7%.Data analysisCortisol ratio.The ratio of endogenous6␤-hydroxycortisol to cortisol in urine is a noninvasive biomarker of CYP3A induction.19In this study the urinary6␤-hydroxycortisol–to–cortisol ratio served as a positive control for CYP3A induction by St John’s wort.Imatinib pharmacokinetics.The pharmacokinetic parameter estimates of imatinib disposition were deter-mined by standard noncompartmental methods.The imatinib elimination rate constant(k e)was obtained by use of nonlinear least-squares regression of the terminal concentration-time data.The imatinib AUC was calcu-lated by the combination linear and logarithmic trape-zoidal method with extrapolation to infinity(AUC0-ϱ). The AUC from0to72hours(AUC0-72)of N-desmethyl-imatinib was determined by the linear-log trapezoidal method.The C max and time to reach C max (t max)were determined by visual inspection of the plasma concentration versus time curves.Imatinib ap-parent oral clearance(CL/F)was determined as Dose/AUC0-ϱ.Statistical analysisThe data are expressed as meanϮSD,except for t max, which is presented as median and range.Calculations were performed by use of the SAS System for Windows v9.0(SAS Institute,Cary,NC),and PՅ.05was consid-ered significant.The urinary6␤-hydroxycortisol–to–cor-tisol ratio and the pharmacokinetic parameter estimates of imatinib determined in the presence and absence of St John’s wort were compared by use of a2-tailed paired t test after logarithmic transformation.The t max data were compared by use of the Wilcoxon signed rank test.The equivalence of imatinib and N-desmethyl-imatinib phar-macokinetics in the presence and absence of St John’s wort was assessed by90%confidence intervals(CIs)for the geometric mean ratio of imatinib plus St John’s wort over imatinib alone.A lack of interaction was concluded if these90%CI values fell within the range of0.8to1.25. RESULTSSubjectsImatinib was well tolerated by all of our healthy and there were no serious adverse events. All12subjects successfully completed the study.Pill count,completed diary sheets,and subject questioning indicated that no doses of St John’s wort were missed. Effect of St John’s wort on the6␤-hydroxycortisol–to–cortisol ratioAfter treatment with St John’s wort extract at a dose of300mg3times daily,the urinary ratio of6␤-hydroxycortisol to cortisol increased1.6-fold from7.3Ϯ3.0(meanϮSD)to11.5Ϯ5.5(Pϭ.0058), indicating an induction of CYP3A in our subjects.CLINICAL PHARMACOLOGY&THERAPEUTICS2004;76(4):323-9St John’s wort and imatinib interaction325Effect of St John ’s wort on imatinib pharmacokineticsThe pharmacokinetic parameter estimates for ima-tinib and N -desmethyl-imatinib determined in 12healthy subjects are shown in Table I .The concentra-tion versus time curve of imatinib and N -desmethyl-imatinib in the presence and absence of St John ’s wort is shown in Fig 1,and the imatinib AUC and C max in the presence and absence of St John ’s wort are shown in Fig 2.Imatinib concentrations were signi ficantly decreased during St John ’s wort administration (Fig 1).The imatinib AUC 0-ϱwas decreased by 30%,from 34.5Ϯ9.5␮g ·h/mL to 24.2Ϯ7.0␮g ·h/mL (P Ͻ.0001),and the apparent oral clearance was increased by 43%,from 12.5Ϯ3.6L/h to 17.9Ϯ5.6L/h (P Ͻ.0001)(Table I and Fig 2).The imatinib half-life was signif-icantly shorter (9.0Ϯ2.3hours)during St John ’s wort administration,as compared with 12.8Ϯ3.2hours alone (P ϭ.0018).The N -desmethyl-imatinib AUC 0-72was not affected by St John ’s wort administration,but the C max was increased by 13%,from 285Ϯ95ng/mL to 318Ϯ95ng/mL,during St John ’s wort administra-tion (P Ͻ.0272).DISCUSSIONThe results of this study show that St John ’s wort decreases imatinib plasma concentrations.St John ’s wort administration caused a 44%increase in imatinib apparent oral clearance and a corresponding 30%de-crease in the plasma AUC.A decrease in imatinib exposure was observed in all of the subjects.Although the magnitude of effect is modest,it is clinically im-portant because it could result in concentrations with the standard 400-mg dose falling below the putativeminimum effective concentration for several hours within a given dosing interval.Thus patients taking imatinib should avoid taking St John ’s wort.In previous drug interaction studies conducted in healthy volunteers,imatinib oral clearance was decreased by 29%with administration of ketoconazole (single dose of 400mg)7and was increased by 385%by rifampin,8findings that are consistent with in vitro data indicating that imatinib is primarily metabolized by CYP3A4.8,20Results from the current study show that St John ’s wort administration has a much smaller impact on imatinib pharmacokinetics (15%decrease in C max and 30%de-crease in AUC)than was seen with the more potent inducer rifampin (54%decrease in C max and 74%de-crease in AUC).8In this study the 6␤-hydroxycortisol –to –cortisol ratio increased 1.6-fold with St John ’s wort administration,which is consistent with previous reports involving St John ’s wort,in which 1.4-to 1.8-fold in-creases in this ratio were observed.21-23However,after St John ’s wort administration,the magnitude of increase in the 6␤-hydroxycortisol –to –cortisol ratio,a biomarker of CYP3A induction,is much smaller than the typical 5-fold increase seen after rifampin administration.8,24-26Imatinib is well absorbed after oral administration and undergoes limited first-pass metabolism,as evidenced by a mean absolute bioavailability for the capsule of 98%.27Thus factors contributing to the smaller effect seen with St John ’s wort include more potent CYP3A induction by rifampin and the limited presystemic metabolism of ima-tinib,which is important because the predominant effect of St John ’s wort appears to be on CYP3A-mediatedintestinal rather than hepatic metabolism.11,28A change in imatinib exposure is important because complete hematologic response in patients with CML isTable I.Mean pharmacokinetic parameter estimates for imatinib and N -desmethyl-imatinib before and during 300mg St John ’s wort 3times per day (N ϭ12)Parameter Imatinib alone Imatinib plus St John ’s wort Geometric mean ratioand 90%CI P value ImatinibAUC (␮g ·h/mL)34.5Ϯ9.524.2Ϯ7.00.698(0.651-0.750)Ͻ.0001CL/F (L/h)12.5Ϯ3.617.9Ϯ5.6 1.430(1.333-1.535)Ͻ.0001t 1/2(h)12.8Ϯ3.29.0Ϯ2.30.702(0.603-0.817).0018C max (ng/mL)2153Ϯ4911840Ϯ4890.847(0.787-0.911).0009t max (h)*3.0(2.0-6.0) 2.0(2.0-4.0).1563N-desmethyl-imatinib AUC (␮g ·h/mL) 6.3Ϯ2.6 6.3Ϯ2.7 1.041(0.916-1.183).9558C max (ng/mL)285Ϯ95318Ϯ95 1.134(1.032-1.246).0272t max (h)*4.0(2.0-6.0)2.0(1.0-6.0).2754CI,Con fidence interval;AUC,area under concentration versus time curve;CL/F,apparent oral clearance;t 1/2,half-life;C max ,maximum concentration;t max ,time to maximum concentration.*Values are median and range.CLINICAL PHARMACOLOGY &THERAPEUTICS326Frye et alOCTOBER 2004highly dependent on the administered dose of imatinib.29Indeed,a clear dose-response relationship was evident in the first phase 1trial of imatinib in patients with CML,because those patients treated with 350mg imatinib per day or greater had the greatest likelihood of complete hematologic response,de fined as a reduction in the white blood cell count to less than 10,000/mm 3that was main-tained for at least 4weeks.4Normalization of the white blood cell count typically occurred in 4weeks and was associated with a trough concentration greater than 1␮mol/L (493ng/mL),the in vitro concentration at which imatinib inhibits the proliferation of Bcr-Abl –positive leukemia cells.4,29Simulations based on the pharmacokinetic-pharmacodynamic response relationship predict that 400mg/d would lead to complete hematologic response in approximately 76%of patients after 28days of treatment.29It has recently been suggested that treat-ment with larger doses of imatinib (eg,800mg daily)may produce higher rates of complete cytogenetic response,de fined as 0%Philadelphia chromosome –positive cells,than are associated with the standard 400-mg treatment.30Collectively,these data support imatinib exposure being related to hematologic response in patients with CML.Thus a decrease in imatinib exposure such as that pro-duced by St John ’s wort is likely to be clinically relevant and may lead to treatment failure (ie,lack of hematologic response).Such an effect was observed in a patient in the phase 1clinical trial who was being treated with the enzyme inducer phenytoin.Although that patient initially did not respond to 350mg imatinib daily,a complete hematologic response was observed after the phenytoin was discontinued and the imatinib dose was increasedtoFig 1.Mean log concentration (SD)versus time pro file ofimatinib (A )and N -desmethyl-imatinib (B )after oral admin-istration of 400mg before (day 1)and during (day 15)administration of 300mg St John ’s wort 3times per day (N ϭ12).Fig 2.Imatinib area under the concentration versus timecurve (AUC)(A )and maximum concentration (C max )(B )before (day 1)and during (day 15)administration of 300mg St John ’s wort 3times per day (N ϭ12).In the box-and-whisker plots ,the central box represents values from the lower to upper quartiles (25th to 75th percentiles),the middle line represents the median,and the whiskers extend to the lowest and highest data points.CLINICAL PHARMACOLOGY &THERAPEUTICS 2004;76(4):323-9St John ’s wort and imatinib interaction 327500mg daily.29Notably,the patient’s steady-state ima-tinib AUC from0to24hours was20%of the mean value for the AUC associated with the350-mg dose level.29 In conclusion,administration of St John’s wort re-sults in a significant decrease in imatinib exposure, which has the potential to affect treatment outcome adversely.Thus patients taking imatinib should avoid taking St John’s wort.Concomitant use of any drugs that are CYP3A inducers may necessitate an increase in the imatinib dose to achieve therapeutic concentrations and to maintain clinical effectiveness.Dr Egorin has served as a consultant for and has received grant funding from Novartis Pharmaceuticals Corp.None of the other authors has a conflict of interest to disclose.References1.Traxler 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