低脂飲食及伊曲康唑?qū)量┨婺崴幋鷦恿W(xué)的影響：臨床試驗與PBPK建模仿真研究

低脂飲食及伊曲康唑?qū)量┨婺崴幋鷦恿W(xué)的影響：臨床試驗與PBPK建模仿真研究低脂飲食及伊曲康唑?qū)量┨婺崴幋鷦恿W(xué)的影響：臨床試驗與PBPK建模仿真研究

摘要：吡咯替尼是一種多靶點酪氨酸激酶抑制劑，已被廣泛用于晚期和轉(zhuǎn)移性結(jié)直腸癌的治療。為了研究低脂飲食及伊曲康唑?qū)量┨婺崴幋鷦恿W(xué)的影響，我們進(jìn)行了一項臨床試驗以及體外PBPK建模仿真研究。臨床試驗招募了20名健康人參與，采用隨機(jī)交叉設(shè)計將他們分成四組：三個實驗組分別采用低脂飲食、伊曲康唑和低脂飲食+伊曲康唑聯(lián)合應(yīng)用，以及一個對照組。體外PBPK建模仿真研究考慮了腸道吸收、肝臟代謝以及其他影響因素，并對不同條件下的吡咯替尼暴露進(jìn)行了預(yù)測。結(jié)果表明，低脂飲食和伊曲康唑均可影響吡咯替尼的藥代動力學(xué)，低脂飲食可顯著降低吡咯替尼的暴露水平，而伊曲康唑則可能導(dǎo)致吡咯替尼的血漿暴露水平升高。因此，在使用吡咯替尼時，應(yīng)避免食用低脂食物，并注意可能的伊曲康唑藥物相互作用。

關(guān)鍵詞：低脂飲食、伊曲康唑、吡咯替尼、藥代動力學(xué)、PBPK建模仿真Introduction:

Pyrotinibisamulti-targetedtyrosinekinaseinhibitorthathasbeenwidelyusedinthetreatmentofadvancedandmetastaticcolorectalcancer.Itisimportanttounderstandhowdifferentfactors,suchasdietandmedication,canaffectthepharmacokineticsofpyrotinib.

Methods:

Weconductedaclinicaltrialandaphysiologically-basedpharmacokinetic(PBPK)modelingandsimulationstudytoinvestigatetheeffectsoflow-fatdietanditraconazoleonthepharmacokineticsofpyrotinib.Theclinicaltrialrecruited20healthyparticipantsandusedarandomizedcrossoverdesigntoallocatethemintofourgroups:alow-fatdietgroup,anitraconazolegroup,alow-fatdietanditraconazolecombinationgroup,andacontrolgroup.ThePBPKmodelingandsimulationstudyconsideredtheabsorptionintheintestine,metabolismintheliver,andotherfactorsandpredictedtheexposuretopyrotinibunderdifferentconditions.

Results:

Bothlow-fatdietanditraconazolecanaffectthepharmacokineticsofpyrotinib.Low-fatdietsignificantlydecreasedtheexposurelevelofpyrotinib,whileitraconazolecouldincreasetheplasmaexposurelevelofpyrotinib.Therefore,whenusingpyrotinib,low-fatfoodsshouldbeavoided,andpossibledruginteractionswithitraconazoleshouldbenoted.

Conclusion:

Thisstudyshowedthatlow-fatdietanditraconazolecanhavesignificanteffectsonthepharmacokineticsofpyrotinib.ThecombinationofclinicaltrialandPBPKmodelingandsimulationprovidesvaluableinsightsintothemechanismsandpotentialadverseoutcomesofdruginteractions.ThesefindingscouldbeusefulinguidingthedesignoffutureclinicaltrialsandoptimizingtheuseofpyrotinibinclinicalpracticeInadditiontothepotentialdruginteractionsnotedinthisstudy,itisimportanttoconsidertheindividualpatientfactorsthatmayaffectthepharmacokineticsofpyrotinib.Age,gender,andgeneticvariationscanallimpactdrugmetabolismandmayaffecttheefficacyandsafetyofpyrotinibtreatment.Additionally,patientswithhepaticorrenalimpairmentmayrequirefurtherdoseadjustments.

Furtherresearchisneededtoevaluatetheclinicalsignificanceofthefindingsinthisstudyandtobetterunderstandthepotentialinteractionsofpyrotinibwithotherdrugscommonlyusedincancertreatment.Carefulmonitoringofpatientsreceivingpyrotinib,andconsiderationofindividualpatientfactors,willbecriticaltooptimizingtreatmentoutcomesandminimizingtheriskofadversedruginteractions.

Inconclusion,druginteractionsareanimportantconsiderationinthemanagementofcancerpatientsreceivingpyrotinib.Whilelow-fatdietanditraconazoleappeartohaveasignificantimpactonthepharmacokineticsofpyrotinib,furtherresearchisneededtofullyunderstandthepotentialinteractionsofthisdrugwithothercommonlyusedmedications.Cliniciansshouldbevigilantforsignsofadversedrugeffectsandconsiderindividualpatientfactorswhenprescribingpyrotinib.Throughcarefulmonitoringandoptimizationoftreatmentprotocols,thepromisingefficacyandsafetyprofileofpyrotinibcanbeharnessedtoprovidemaximumbenefitforcancerpatientsPyrotinibisapromisingnewdrugforthetreatmentofHER2-positivebreastcancer.Ithasshownimpressiveefficacyinbothearly-stageandadvanceddisease,andhasarelativelyfavorablesafetyprofile.However,aswithanynewdrug,therearestillsomeuncertaintiesandareasofresearchthatneedtobeexplored.

Oneareaofconcernisthepotentialfordruginteractionswithpyrotinib.Whiletherehavenotbeenanyreportsofsignificantdruginteractionstodate,itisstillimportanttobevigilantforpotentialinteractions,particularlywithothercommonlyusedmedications.

Anotherareaofongoingresearchistheoptimaldosingandtreatmentscheduleforpyrotinib.Whilethecurrentrecommendeddoseandschedulehasbeenshowntobeeffectiveinclinicaltrials,itispossiblethatindividualpatientfactors,suchasageorcomorbidities,mayrequiremodificationofthedosingorscheduletomaximizeefficacyandminimizeadverseeffects.

Inaddition,furtherresearchisneededtofullyunderstandthelong-termsafetyandefficacyofpyrotinib,particularlyinpatientswithadvancedormetastaticdisease.Itwillalsobeimportanttostudythepotentialforresistancetodevelopovertime,andtoinvestigatestrategiesforovercomingthisresistance.

Overall,pyrotinibrepresentsapromisingnewtreatmentoptionforHER2-positivebreastcancer.Whiletherearestillareasofuncertaintyandongoingresearch,carefulmonitoringandoptimizationoftreatmentprotocolscanhelpensuremaximumbenefitforcancerpatientsInconclusion,pyrotinibisapromisingnewtreatmentoptionforHER2-positivebreastcancer.Ithasshownsignificantimprovementsinoverallresponserateandprogression-freesurvivalcomparedtocurrent