关于体内生物利用度研究,FDA要说的和你要做的都在碗里啦!

1、关于体内生物利用度研究，FDA要说的和你要做的都在碗里啦!(a)Guidingprinciples.(a)指导原则(1) Thebasicprincipleinaninvivobioavailabilitystudyisthatnounnecessaryhumanresearchshouldbedone.(1)体内生物利用度研究的基本原理是无需进行不必要的人体研究。(2)Aninvivobioavailabilitystudyisgenerallydoneinanormaladultpopulationunderstandardizedconditions.Insomesituations,a

2、ninvivobioavailabilitystudyinhumansmaypreferablyandmoreproperlybedoneinsuitablepatients.Criticallyillpatientsshallnotbeincludedinaninvivobioavailabilitystudyunlesstheattendingphysiciandeterminesthatthereisapotentialbenefittothepatient.(2)通常在标准情况下于健康成年人群中进行体内生物利用度研究。在莫些情况下，可以选择在合适的患者中进行体内生物利用度研究。不得将危

3、重病人纳入体内生物利用度研究，除非主治医师确认参与的体内生物利用度试验对患者有潜在好处。(b)Basicdesign.Thebasicdesignofaninvivobioavailabilitystudyisdeterminedbythefollowing:(b)体内生物利用度研究的基本设计如下：(1)Thescientificquestionstobeanswered.(1)要回答的科学问题(2)Thenatureofthereferencematerialandthedosageformtobetested.(2)参比制剂和受试制剂的性质(3)Theavailabilityofanaly

4、ticalmethods.(3)分析方法的有效性(4)Benefit-riskconsiderationsinregardtotestinginhumans.(4)在人体中进行的试验要考虑利益-风险(c)Comparisontoareferencematerial.Invivobioavailabilitytestingofadrugproductshallbeincomparisontoanappropriatereferencematerialunlesssomeotherapproachismoreappropriateforvalidscientificreasons.(c)与参比制剂

5、的比较。进行体内生物利用度的受试制剂应与适当的参比制剂比较，除非有其他更适合的有效的科学方法。(d)Previouslyunmarketedactivedrugingredientsortherapeuticmoieties.(d)先前未上市的药物活性成分或治疗结构(1)Aninvivobioavailabilitystudyinvolvingadrugproductcontaininganactivedrugingredientortherapeuticmoietythathasnotbeenapprovedformarketingcanbeusedtomeasurethefollowing

6、pharmacokineticdata:(1)涉及含有未获批上市的药物活性成分或治疗结构的药物的体内生物利用度研究可通过检测如下药代动力学数据：(i) Thebioavailabilityoftheformulationproposedformarketing;and(i)计划上市的制剂的生物利用度；(ii) Theessentialpharmacokineticcharacteristicsoftheactivedrugingredientortherapeuticmoiety,suchastherateofabsorption,theextentofabsorption,thehalf-l

7、ifeofthetherapeuticmoietyinvivo,andtherateofexcretionand/ormetabolism.Doseproportionalityoftheactivedrugingredientorthetherapeuticmoietyneedstobeestablishedaftersingle-doseadministrationandincertaininstancesaftermultiple-doseadministration.Thischaracterizationisanecessarypartoftheinvestigationofthed

8、rugtosupportdruglabeling.(ii)药物活性成分或治疗结构的基本药代动力学特征，例如吸收速率、吸收程度、体内治疗部位的半衰期以及排泄和/或代谢速率。需建立药物活性成分或治疗结构经单剂量给药多剂量给药后莫些情况下的剂量比例。这是支持药品标签的药物研究的必要部分。(2)Thereferencematerialinsuchabioavailabilitystudyshouldbeasolutionorsuspensioncontainingthesamequantityoftheactivedrugingredientortherapeuticmoietyastheformul

9、ationproposedformarketing.(2)在止匕生物禾U用度研究中的参比制剂应该是溶液剂或者混悬液，而且要求含有与计划上市受试制剂等量的药物活性成分或治疗结构。(3)Thereferencematerialshouldbeadministeredbythesamerouteastheformulationproposedformarketingunlessanalternativeoradditionalrouteisnecessarytoanswerthescientificquestionunderstudy.Forexample,inthecaseofanactivedr

10、ugingredientortherapeuticmoietythatispoorlyabsorbedafteroraladministration,itmaybenecessarytocomparetheoraldosageformproposedformarketingwiththeactivedrugingredientortherapeuticmoietyadministeredinsolutionbothorallyandintravenously.(3)参比制剂应与受试制剂具有相同的给药途径，除非需其它给药途径可证明该项研究的科学性问题。例如，经口服给药后不宜吸收的药物活性成分或结

11、构，则有必要将被计划上市的受试制剂的口服剂型与该药的口服和静脉滴注的溶液进行比较。(e)Newformulationsofactivedrugingredientsortherapeuticmoietiesapprovedformarketing.(e)药物活性成分或治疗结构的新制剂的获批上市：(1)Aninvivobioavailabilitystudyinvolvingadrugproductthatisanewdosageform,oranewsaltoresterofanactivedrugingredientortherapeuticmoietythathasbeenapproved

12、formarketingcanbeusedto:(1)体内生物禾U用度的研究包括已获准上市药物的新剂型，或药物活性成分或治疗结构的盐或酯：(i) Measurethebioavailabilityofthenewformulation,newdosageform,ornewsaltoresterrelativetoanappropriatereferencematerial;and(i)相对适当的参比制剂，测定新处方、新剂型或新盐或酯的生物利用度；(ii) Definethepharmacokineticparametersofthenewformulation,newdosageform,o

13、rnewsaltorestertoestablishdosagerecommendation.(ii)明确新制齐心新齐U型或新盐或酯的药代动力学参数和推荐剂量。(2)Theselectionofthereferencematerial(s)insuchabioavailabilitystudydependsuponthescientificquestionstobeanswered,thedataneededtoestablishcomparabilitytoacurrentlymarketeddrugproduct,andthedataneededtoestablishdosagerecom

14、mendations.(2)在该生物利J用度研究中要依据所要回答的科学问题来选择参比制剂，研究数据需要与市售药品建立可比性并且确定建议剂量。(3)Thereferencematerialshouldbetakenfromacurrentbatchofadrugproductthatisthesubjectofanapprovednewdrugapplicationandthatcontainsthesameactivedrugingredientortherapeuticmoiety,ifthenewformulation,newdosageform,ornewsaltoresterisint

15、endedtobecomparabletoortomeetanycomparativelabelingclaimsmadeinrelationtothedrugproductthatisthesubjectofanapprovednewdrugapplication.(3)如果新处方、新剂型或新盐或酯想要与目前批准许可新药的标签要求具有可比性或者能与其媲美。那么参比制剂应选用目标批准许可新药的当前批次且含有相同的活性成分和治疗结构的产品。Extendedreleaseformulations.(f)缓释制剂(1)Thepurposeofaninvivobioavailabilitystudyi

16、nvolvingadrugproductforwhichanextendedreleaseclaimismadeistodetermineifallofthefollowingconditionsaremet:(1)进行体内生物利用度研究的目的是为了确定缓释行为是否满足以下所有条件：(i) Thedrugproductmeetstheextendedreleaseclaimsmadeforit.(i)药品符合延缓释放的要求(ii) Thebioavailabilityprofileestablishedforthedrugproductrulesouttheoccurrenceofanydos

17、edumping.(ii)为药品设定的生物利用度特性排除任何剂量倾泻行为的发生(iii) Thedrugproduct'ssteady-stateperformanceisequivalenttoacurrentlymarketednonextendedreleaseorextendedreleasedrugproductthatcontainsthesameactivedrugingredientortherapeuticmoietyandthatissubjecttoanapprovedfullnewdrugapplication.(iii)药物的稳态性能与含有相同药物活性成分或治

18、疗结构的已获准上市的非缓释制剂或缓释制剂等效，且需经新药申请获得批准。(iv) Thedrugproduct'sformulationprovidesconsistentpharmacokineticperformancebetweenindividualdosageunits.(iv)各单位剂量之间的药物制剂需具有相同的药代动力学行为(2)Thereferencematerial(s)forsuchabioavailabilitystudyshallbechosentopermitanappropriatescientificevaluationoftheextendedreleas

19、eclaimsmadeforthedrugproduct.Thereferencematerialshallbeoneofthefollowingoranycombinationthereof:(2)应选择参比制剂进行生物利用度研究，以便对药品的缓释行为进行科学评估。参比制剂应为以下之一或任何组合：(i)Asolutionorsuspensionoftheactivedrugingredientortherapeuticmoiety.(i)活性成分的溶液或混悬剂(ii)Acurrentlymarketednoncontrolledreleasedrugproductcontainingthes

20、ameactivedrugingredientortherapeuticmoietyandadministeredaccordingtothedosagerecommendationsinthelabelingofthenoncontrolledreleasedrugproduct.(ii)目前市售含有相同的活性成分或活性结构的非控缓释药品，并根据非控缓释药品的说明书中的建议剂量进行研究(iii) Acurrentlymarketedextendedreleasedrugproductsubjecttoanapprovedfullnewdrugapplicationcontainingthes

21、ameactivedrugingredientortherapeuticmoietyandadministeredaccordingtothedosagerecommendationsinthelabelingproposedfortheextendedreleasedrugproduct.(iii)目前市售含有相同活性成分的的缓释药品，并根据缓药品的说明书中的建议剂量进行研究(iv) Areferencematerialotherthanonesetforthinparagraph(f)(2)(i),(ii)or(iii)ofthissectionthatisappropriateforva

22、lidscientificreasons.(iv)在本节第(f)(2)(i),(ii)or(iii)段落陈述中之外的可提供有效科学证据的参比物质。(g)Combinationdrugproducts.(g)复方制齐U(1)Generally,thepurposeofaninvivobioavailabilitystudyinvolvingacombinationdrugproductistodetermineiftherateandextentofabsorptionofeachactivedrugingredientortherapeuticmoietyinthecombinationdru

23、gproductisequivalenttotherateandextentofabsorptionofeachactivedrugingredientortherapeuticmoietyadministeredconcurrentlyinseparatesingle-ingredientpreparations.(1)通常复方制剂体内生物利用度研究是为了确定复方制剂中的每种活性成分的吸收速率和程度是否等同于服用单一成分的制剂中活性成分的吸收速率和程度。(2)Thereferencematerialinsuchabioavailabilitystudyshouldbetwoormorecur

24、rentlymarketed,single-ingredientdrugproductseachofwhichcontainsoneoftheactivedrugingredientsortherapeuticmoietiesinthecombinationdrugproduct.TheFoodandDrugAdministrationmay,forvalidscientificreasons,specifythatthereferencematerialshallbeacombinationdrugproductthatisthesubjectofanapprovednewdrugappli

25、cation.(2)复方制剂的生物利用度研究应选用两种或多种市售单一成分的制剂，每种制剂含有复方制剂中的一种活性成分。由于有效的科学证据，FDA可能规定参比制剂为目前批准许可的新复方制剂。(3)TheFoodandDrugAdministrationmaypermitabioavailabilitystudyinvolvingacombinationdrugproducttodeterminetherateandextentofabsorptionofselected,butnotall,activedrugingredientsortherapeuticmoietiesinthecombin

26、ationdrugproduct.TheFoodandDrugAdministrationmaypermitthisdeterminationifthepharmacokineticsandtheinteractionsoftheactivedrugingredientsortherapeuticmoietiesinthecombinationdrugproductarewellknownandthetherapeuticactivityofthecombinationdrugproductisgenerallyrecognizedtoresideinonlyoneoftheactivedru

27、gingredientsortherapeuticmoieties,e.g.,ampicillininanampicillin-probenecidcombinationdrugproduct.(3)FDA允许使用复方制剂进行生物利用度研究，以确定所选择复方制剂的吸收速率和程度，但不是复方制剂中所有的活性成分的吸收速率和程度。如果复方制剂中活性成分的药代动力学和相互作用是众所周知的，并且复方制剂的仅是一种成分发挥治疗作用，则FDA允许这样测定。比如氨节青霉素-丙磺舒复方制剂中的氨节青霉素。(h)Useofaplaceboasthereferencematerial.Whereappropriateorwherenecessarytodemonstratethesensitivityofthetest,therefer