KR20150022894A - 유전자형- 또는 표현형-기초의 약제학적 제제 - Google Patents
유전자형- 또는 표현형-기초의 약제학적 제제 Download PDFInfo
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- KR20150022894A KR20150022894A KR1020147036212A KR20147036212A KR20150022894A KR 20150022894 A KR20150022894 A KR 20150022894A KR 1020147036212 A KR1020147036212 A KR 1020147036212A KR 20147036212 A KR20147036212 A KR 20147036212A KR 20150022894 A KR20150022894 A KR 20150022894A
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- tamoxifen
- cyp2d6
- genotype
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Abstract
본 발명은 2가지 이상의 약제학적 활성 물질의 복합제로서, 이중 적어도 하나는 다른 하나("모물질(parent substance)")의 대사 산물("대사물")이며, 여기에서 특히 특정 개인에 있어서 모물질의 대사물로의 변환에서 유전자형적으로 또는 표현형적으로 관련된 가변성이 보완되도록 그의 투여량이 선택된 복합제에 관한 것이다.
Description
본 발명은 2가지 이상의 약제학적 활성 물질의 복합제로서, 이중 적어도 하나는 다른 하나("모물질(parent substance)")의 대사 산물("대사물")이며, 특히 특정 개인에 있어서 모물질의 대사물(들)로의 변환에서 유전자형적으로 또는 표현형적으로(유전자형의 정의: http://de.wikipedia.org/wiki/Genotyp, 표현형의 정의: http://de.wikipedia.org/wiki/Ph%C3%A4notyp) 관련된 가변성이 보완되도록 그의 투여량이 선택된 복합제에 관한 것이다.
본 발명은 추가로 2가지 이상의 약제학적 활성 물질의 복합제로서, 이중 적어도 하나는 다른 하나의 대사 산물이며, 특정 개인에 있어서 모물질 및 대사물(들)의 약동학적(pharmacokinetic) 또는 약력학적(pharmacodynamic) 과정에 관여된 운반자(transporter), 수용체 또는 기타 단백질에서 유전자형적으로 또는 표현형적으로 관련된 가변성이 보완되도록 그의 투여량이 선택된 복합제에 관한 것이다.
본 발명에 따른 원리는 유방암 약제 타목시펜 및 그의 활성 대사물 엔독시펜의 복합제의 예를 사용하여 설명될 것이다.
약물 요법에는, 그의 약리학적 작용이 투여된 모물질과 환자의 체내에서 발생하는 대사물과의 상호 작용으로부터 발생하는 수많은 제약 예가 있다. 일반적으로 이러한 소위 활성 대사물은 효소적으로 촉매화된 과정을 통해 형성되며, 이는 예를 들어 신체의 간, 신장, 소장 또는 임의의 기타 기관에서 일어날 수 있다. 이러한 효소적 과정의 활성은 상이한 개체에서 폭넓게 상이할 수 있다. 자연에서 효소 활성이 개체별로 상이한 이유는 다양하다. 첫째로, 예를 들어, 효소 저해제 또는 유도제 또는 그밖의 유전적 원인에 의해 유발될 수 있는, 발현된 효소 변이체의 양에 있어서 개체간 가변성이 존재한다. 둘째로, 예를 들어, 효소 저해제 또는 유도제 또는 그밖의 유전적 원인으로 인하여 일어날 수 있는, 발현된 효소 변이체의 활성에 있어서 개체간 가변성이 존재한다. 다음과 같은 많은 활성 약제학적 성분들이 사이토크롬 P450 효소 저해제로 공지되어 있다:
2-(4-클로로페녹시)에탄올, 아카르보스, 아세부톨롤, 아세노쿠마롤, 아세타졸아미드, 아데포비르, 아데메티오닌, 아즈말린, 알벤다졸, 알리트레티노인, 알로퓨리놀, 알로세트론, 암브록솔, 암페타민, 아밀로리드, 아미노글루테티미드, 아미노페나존, 아미오다론, 아미트립틸린, 암로디핀, 아모디아퀸, 암프레나비르, 아나스트로졸, 안드로스탄돌론, 아프레피탄트, 아리피프라졸, 아르제닉 트리옥사이드, 아르테미시닌, 아르테수네이트, 아스테미졸, 아타자나비르, 아토목세틴, 아토르바스타틴, 아토바쿠온, 아트로핀, 아자프로파존, 아젤라스틴, 아지트로마이신, 바르니디핀, 베나제프릴, 베니디핀, 벤즈브로마론, 벤제토니움, 벤조카인, 베르갑텐, 베타메타손, 베탁솔롤, 베자피브레이트, 비칼루타미드, 비포나졸, 비페리덴, 보르테조밉, 브로마제팜, 브로모크립틴, 브롬페니라민, 부디핀, 부프레노르핀, 부프로프리온, 칼시트리올, 칸데사르탄, 카페시타빈, 카르바마제핀, 카르비녹사민, 카르테올롤, 카스포푼긴, 셀레콕십, 세리바스타틴, 퀴니딘, 퀴닌, 클로람페니콜, 클로르마디논, 클로로퀸, 클로르페나민, 클로르프로마진, 클로르족사존, 시클로스포린, 시메티딘, 시프로피브레이트, 시프로플록사신, 시사프라이드, 시스플라틴, 시탈로프람, 클라리트로마이신, 클레마스틴, 클레비디핀, 클린다마이신, 클로베타솔, 클로파지민, 클로페노탄, 클로피브레이트, 클로메티아졸, 클로미펜, 클로미프라민, 클로나제팜, 클로피도그렐, 클로티아제팜, 클로트리마졸, 클로자핀, 코카인, 코데인, 카페인, 콜키신, 콜레칼시페롤, 사이클리진, 실코포스파미드, 시프로테론, 다카르바진, 닥티노마이신, 달포프리스틴, 다나졸, 단트롤렌, 다우노루비신, 데페록사민, 델라르비르딘, 데시프라민, 데슬로라타딘, 데스벤라팍신, 덱사메타손, 덱삼페타민, 덱스펜플루라민, 덱시부프로펜, 덱스트로메토르판, 덱스트로프로폭시펜, 디아제팜, 디클로페낙, 디쿠마롤, 디하이드랄라진, 디하이드로에르고타민, 디요오도하이드록시프로판, 딜티아젬, 디메틸 설폭사이드, 디메토티아진, 디오스멕타이트, 디오스민, 디펜하이드라민, 디설피람, 도세탁셀, 돌라세트론, 도파민, 독세핀, 독소루비신, 독시사이클린, 에바스틴, 에코나졸, 에파비렌쯔, 에메틴, 에녹사신, 에녹솔론, 엔프로스틸, 엔타카폰, 에피나스틴, 에피네프린, 에플레레논, 에프로사르탄, 에르고메트린, 에르고타민, 에리트로마이신, 에시탈로프람, 에스트리올, 에타나우틴, 에탄올, 에티닐에스트라디올, 에토토인, 에토돌락, 에토미데이트, 에토포시드, 에토리콕십, 에트레티네이트, 엑세메스탄, 에제티미브, 펠바메이트, 펠로디핀, 펜플루라민, 페노피브레이트, 펜타닐, 펙소페나딘, 플레카이니드, 플루메퀸, 플루오로우라실, 플루옥세틴, 플루페나진, 플루라제팜, 플루르비프로펜, 플루리트로마이신, 플루타미드, 플루바스타틴, 플루복사민, 포메피졸, 포르메스탄, 포삼프레나비르, 포스페니토인, 게피티닙, 겜피브로질, 글리벤클라미드, 글리클라지드, 글루코스, 글루테티미드, 그라니세트론, g-스트로판틴, 할로판트린, 할로페리돌, 히스타민, 하이드랄라진, 하이드로코르티손, 하이드록시카르바미드, 하이드록시클로로퀸, 하이드록시진, 이부프로펜, 이다루비신, 이포스파미드, 이마티닙, 이미프라민, 인디나비르, 인도메타신, 인슐린, 이프리플라본, 이르베사르탄, 이리노테칸, 이소코나졸, 이소플루란, 이소니아지드, 이소프레날린, 이소프로판올, 이소소르비드 디니트레이트, 이스라디핀, 이트라코나졸, 조사마이신, 케토코나졸, 케토프로펜, 라베탈롤, 라푸티딘, 란소프라졸, 레플루노미드, 렌티난, 레르카르니디핀, 레트로졸, 레보플록사신, 레보메프로마진, 레보노르게스트렐, 리도카인, 로메플록사신, 로무스틴, 로페라미드, 로피나비르, 로라타딘, 로르녹시캄, 로사르탄, 로바스타틴, 마니디핀, 마소프로콜, 메클로진, 메다제팜, 메드록시프로게스테론, 메드리손, 메페남산, 메플로퀸, 메글루톨, 멜라토닌, 멜록시캄, 멜페론, 메만틴, 메나디온, 메페니토인, 메퀴타진, 메숙시미드, 메탐페타민, 메트포르민, 메타돈, 메타졸라미드, 메톡살렌, 메틸페니데이트, 메틸페노바르비탈, 메틸프레드니솔론, 메토클로프라미드, 메토프롤롤, 메트로니다졸, 메티라폰, 멕실레틴, 미안세린, 미베프라딜, 미코나졸, 미다졸람, 미데카마이신, 미도드린, 미페프리스톤, 미녹시딜, 미오카마이신, 미르타자핀, 미톡산트론, 미졸라스틴, 모클로베미드, 모다피닐, 모메타손, 몬텔루카스트, 모라시진, 네파조돈, 넬피나비르, 네오스티그민, 네비라핀, 니카르디핀, 니클로사미드, 니코티나미드, 니페디핀, 니코틴, 니코트산, 닐루타미드, 닐바디핀, 니메술리드, 니솔디핀, 니트렌디핀, 니트로프루시드, 노르에피네프린, 노르플록사신, 노르트립틸린, 노스카핀, 옥토파민, 오플록사신, 올란자핀, 올레안도마이신, 오메프라졸, 온단세트론, 오르페나드린, 옥삼니퀸, 옥사토미드, 옥스카르바제핀, 옥스프레놀롤, 옥시부티닌, 옥시코돈, 파클리탁셀, 판크레오지민(콜레시스토키닌), 판토프라졸, 파라세타몰, 파레콕십, 파르길린, 파록세틴, 파조파닙, 페플록사신, 펜톡시베린, 페라진, 페르골리드, 페르헥실린, 페르페나진, 페나존, 페넬진, 페노바르비탈, 펜숙시미드, 펜테르민, 페닐부타존, 페닐프로파놀아민, 페니토인, 피소스티그민, 필로카르핀, 피모지드, 핀돌롤, 피오글리타존, 피록시캄, 프란루카스트, 프라스테론, 프라바스타틴, 프라지콴텔, 프레드니솔론, 프레드니손, 프리마퀸, 프리스티나마이신, 프로베네시드, 프로게스테론, 프로구아닐, 프로메타진, 프로파페논, 프로파놀, 프로피베린, 프로포폴, 프로프라놀롤, 피리메타민, 쿠아시아, 머큐리, 쿠에티아핀, 퀴니딘, 퀴닌, 퀴누프리스틴, 라베프라졸, 랄록시펜, 라니티딘, 레복세틴, 레티놀, 리팜피신, 리스페리돈, 리토나비르, 리바스티그민, 로페콕십, 로키타마이신, 로피니롤, 로시글리타존, 로수바스타틴, 록시트로마이신, 루토시드, 살부타몰, 살리실아미드, 살메테롤, 사퀴나비르, 셀레길린, 세라트로다스트, 세르타코나졸, 세르트랄린, 실데나필, 실리마린, 심바스타틴, 시롤리무스, 소마토스타틴, 소르비톨, 스파르테인, 스피로놀락톤, 이산화질소, 설코나졸, 설파디아진, 설파디메톡신, 설파디미딘, 설파푸라졸, 설파메티졸, 설파메톡사졸, 설파목솔, 설파닐아미드, 설파페나졸, 설파피리딘, 설핀피라존, 설린닥, 설피리드, 수프로펜, 타크롤리무스, 타목시펜, 테가세로드, 텔리트로마이신, 텔미사르탄, 테마플록사신, 테니포시드, 테노포비르, 테르비나핀, 테르코나졸, 테르페나딘, 테리파라티드, 테스토스테론, 테트라사이클린, 테오필린, 티아마졸, 티오펜탈, 티오리다진, 티오설페이트, 티오테파, 티아벤다졸, 티볼론, 티클로피딘, 티몰롤, 티니다졸, 티오코나졸, 티오프로닌, 티오틱센, 토카이니드, 토코페롤, 토피소팜, 톨부타미드, 톨카폰, 토피라메이트, 토포테칸, 토라세미드, 트라마돌, 트라닐시프로민, 트라투주맙, 트레오설판, 트레티노인, 트리암테렌, 트리아졸람, 트리클로로에틸렌, 트리클로산, 트리메토프림, 트리펠렌아민, 트리프롤리딘, 트로글리타존, 트롤레안도마이신, 트로피세트론, 트로스피움, 우르소데옥시콜산, 발데콕십, 발프로산, 발사르탄, 벤라팍신, 베라파밀, 빈블라스틴, 빈크리스틴, 비노렐빈, 비르기니아마이신, 보리코나졸, 보로졸, 와르파린, 요힘빈, 자피르루카스트, 지프라시돈, 졸피뎀, 조니사미드.
하기의 것이 특별히 강조된다: 플루복사민, 시프로플록사신, 겜피브로질, 부프로피온, 시나칼셋, 플루옥세틴, 파록세틴, 퀴니딘, 인디나비르, 넬피나비르, 리토나비르, 클라리트로마이신, 이트라코나졸, 케토코나졸, 네파조돈, 사퀴나비르, 텔리트로마이신, 트리메토프림, 아미오다론, 둘록세틴, 세르트랄린, 테르비나핀, 아프레피탄트, 에리트로마이신, 베라파밀, 딜티아젬, 시메티딘, 아미오다론[http://medicine.iupui.edu/clinpharm/ddis/table.aspx as of 09.05.2012].
2 상(phase 2) 효소의 공지 저해제는 특히 다음과 같다:
아카르보스, 아세틸콜린, 아세틸살리실산, 아미트립틸린, 아포몰핀, 아르테미시닌, 아스코르브산, 벤드로플루메티아지드, 베르캅텐, 브로모크립틴, 카르바콜, 카르바마제핀, 카르무스틴, 셀레콕십, 케노데옥시콜산, 퀴닌, 클로르헥시딘, 클로로퀸, 시메티딘, 클로미프라민, 클로니딘, 코카인, 코르티손, 닥티노마이신, 데시프라민, 디아제팜, 디쿠마롤, 디사이클로베린, 디오스민, 디설피람, 독세핀, 에녹솔론, 엔타카폰, 에스트라디올, 에타크린산, 플루코나졸, 플루페나진, 엽산, 할로페리돌, 헤마틴, 하이드로코르티손, 히메크로몬, 이부프로펜, 이미프라민, 인도메타신, 이프로니아지드, 케토프로펜, 리도카인, 로피나비르, 메드록시프로게스테론, 멜라토닌, 메파크린, 메르캅타민, 메르살릴, 메살라진, 메틸도파, 모클로베미드, 나프록센, 시트르산나트륨, 살리실산나트륨, 니플룸산, 니코틴, 올살라진, 옥세드린, 파클리탁셀, 파르길린, 페닐부타존, 피소스티그민, 피팜페론, 폴리헥사니드, 프리마퀸, 프로베네시드, 프로게스테론, 프로필티오우라실, 피리독살, 피리독신, 피리메타민, 라니티딘, 리토나비르, 살리실아미드, 살리실산, 사퀴나비르, 실리마린, 설포브로모프탈레인, 설린닥, 타크린, 타목시펜, 테트라사이클린, 티오메르살, 톨카폰, 트리클로산, 투보쿠라린, 베큐로니움, 와르파린, 과산화수소.
공지의 사이토크롬 P450 효소 유도제는 다음과 같다:
2-(4-클로로페녹시)에탄올, 아카르보스, 아세틸살리실산, 아크리플라비니움 클로라이드, 알벤다졸, 알도스테론, 알룸, 아미노글루테티미드, 아미노살리실산, 아모바르비탈, 안지오텐시나미드, 아프레피탄트, 아프로바르비탈, 아리피프라졸, 아르테미시닌, 아스코르브산, 아자티딘, 베클로메타손, 베녹사프로펜, 베타-카로텐, 베타메타손, 벡사로텐, 베자피브레이트, 비오틴, 보센탄, 부클라데신, 부세렐린, 캅토프릴, 카르바마제핀, 카르바미드, 카르보플라틴, 퀴니딘, 퀴닌, 클로르디아제폭시드, 클로로티아지드, 클로르프로마진, 시클로스포린, 시프로피브레이트, 시프로플록사신, 시스플라틴, 칼시트리올, 클라리트로마이신, 클로페노탄, 클로피브레이트, 클로미펜, 클로나제팜, 클로니딘, 클로트리마졸, 클로자핀, 콜키신, 콜레스티라민, 코르티코트로핀, 사이클로바르비탈, 사이클로포스파미드, 답손, 다우노루비신, 덱사메타손, 덱스트로프로폭시펜, 디아제팜, 디부틸 프탈레이트, 디클로페나미드, 디클록사실린, 디사이클로베린, 디에틸 에테르, 디에틸스틸베스트롤, 디요오도하이드록시프로판, 디노프로스톤, 디오스멕타이트, 디오스민, 도세탁셀, 독소루비신, 독실라민, 에파비렌쯔, 엘레트립탄, 에녹사신, 에르고칼시페롤, 에리트로마이신, 에스트리올, 에탄올, 에티닐에스트라디올, 에토포시드, 펜벤다졸, 펠바메이트, 플루코나졸, 플루클록사실린, 플루페남산, 플루오레세인, 플루바스타틴, 겜피브로질, 글루코스, 글루타티온, 글리세롤, 글리시리즈산, 그라니세트론, 그리세오플빈, 구아네티딘, 할로페리돌, 히스타민, 하이드로코르티손, 하이드록시카르바미드, 이포스파미드, 인슐린, 이프리플라본, 이소플루란, 이소니아지드, 이소프레날린, 이소프로판올, 이트라코나졸, 케토코나졸, 코카인, 란소프라졸, 린단, 로라타딘, 로바스타틴, 리네스트레놀, 메벤다졸, 메카밀라민, 메드록시프로게스테론, 메타미졸, 메타돈, 메타르비탈, 메토헥시탈, 메틸프레드니솔론, 메틸테스토스테론, 메토클로프라미드, 메티라폰, 미페프리스톤, 미르타자핀, 미토브로니톨, 미토마이신, 미토탄, 모클로베미드, 모다피닐, 염화나트륨, 살리실산나트륨, 넬피나비르, 네비라핀, 니카르디핀, 니코틴아미드, 니페디핀, 니코틴, 니트라제팜, 노르에티스테론, 오메프라졸, 온단세트론, 옥스카르바제핀, 옥시코나졸, 옥솔라민, 옥소메마진, 파클리탁셀, 판토프라졸, 파라세타몰, 페르메트린, 페티딘, 페노바르비탈, 페녹시메틸페니실린, 펜테르민, 페닐부타존, 페닐에프린, 페니토인, 핀돌롤, 피오글리타존, 피팜페론, 플레코나릴, 프레드니솔론, 프레드니손, 프리마퀸, 프리미돈, 프리스티나마이신, 프로베네시드, 프로게스테론, 프로필티오우라실, 피리도스티그민, 피리독신, 머큐리, 퀴닌, 라베프라졸, 레복세틴, 레세르핀, 레티놀, 리파부틴, 리팜피신, 리파펜틴, 리팍시민, 리토나비르, 로페콕십, 살리실산, 세코바르비탈, 세라트로다스트, 실리마린, 스피로놀락톤, 스트렙토조신, 설파디미딘, 설핀피라존, 타목시펜, 테모졸로미드, 테르비나핀, 테르페나딘, 테스토스테론, 테트라베나진, 테트라메트린, 탈리도미드, 티아민, 티람, 티아벤다졸, 티에닐산, 토코페롤, 토피라메이트, 토포테칸, 트레티노인, 트리암시놀론 아세토니드, 트리암시놀론, 트로글리타존, 트립토판, 우르소데옥시콜산, 발프로산, 베라파밀, 빈블라스틴, 비르기니아마이신, 보글리보스.
하기의 것이 특히 강조된다: 모다피닐, 나프실린, 오메프라졸, 페노바르비탈, 페니토인, 리팜핀, 세코바르비탈, 카르바마제핀, 노르에틴드론, 프레드니손, 리팜피신, 덱사메타손, 이소니아지드, 에파비렌쯔, 네비라핀, 바르비투레이트, 글루코코르티코이드, 옥스카르바제핀, 피오글리타존, 리파부틴, 트로글리타존 [http://medicine.iupui.edu/clinpharm/ddis/table.aspx as of 09.05.2012].
2 상 효소의 공지 유도제는 특히 다음과 같다:
아세틸콜린, 아세틸살리실산, 아데노신, 암페타민, 아미노필린, 안드로스타놀론, 안지오텐시나미드, 아르가트로반, 아스코르브산, 벤플루오렉스, 베타-카로텐, 베타메타손, 부클라데신, 칼시트리올, 카르바마제핀, 클로람부실, 클로르페나민, 시사프리드, 시스플라틴, 클로피브레이트, 클로자핀, 코카인, 코르티코트로핀, 데시프라민, 덱사메타손, 덱삼페타민, 디아제팜, 디클로페낙, 디에틸카르바마진, 디에틸 에테르, 디노프로스톤, 디설피람, 독소루비신, 엔타카폰, 에피네프린, 에스케타민, 에스트라디올, 에스트리올, 에탄올, 플루나리진, 플루옥세틴, 가바펜틴, 글리세릴 트리니트레이트, 글리신, g-스트로판틴, 하이드랄라진, 하이드로코르티손, 히메크로몬, 이부프로펜, 이미프라민, 인도메타신, 인슐린, 이소프레날린, 케타민, 라모트리긴, 레베티라세탐, 레보도파, 린단, 멜라토닌, 멜팔란, 메퀴놀, 메타미졸, 메티오닌, 메토트렉세이트, 메토클로프라미드, 나부메톤, 난드롤론, 노르에피네프린, 올란자핀, 파라세타몰, 파르길린, 페노바르비탈, 페니토인, 피팜페론, 프로게스테론, 프로메게스톤, 프로필티오우라실, 레티놀, 로페콕십, 스피로놀락톤, 일산화질소, 설린닥, 설티암, 타목시펜, 테스토스테론, 테오필린, 티아데놀, 티볼론, 티오구아닌, 트리암시놀론, 트리메토프림, 트로글리타존, 발프로산, 베라파밀, 와르파린, 과산화수소[http://bioinformatics.charite.de/supercyp as of 24.04.2012]. 활성 약제학적 성분 이외에 식이 성분도 효소, 운반자, 수용체 또는 기타 단백질에 대해 저해 및/또는 유도 효과를 나타낼 수 있다.
그의 공지된 예는 특히 다음과 같다: 브로콜리, 구운 고기, 고추나물(St John's wort), 담배 연기, 치즈, 적포도주, 자몽 쥬스, 엽산, 비타민 K, 비타민 E, 비타민 B6 및 고추나물[Groeber, U. (2009) "Interaktionen Arzneimittel und Mikronaehrstoffe fuer die Kitteltasche [Interactions: Pharmaceuticals and Micronutrients(Pocket Guide)]" Wissenschaftliche Verlagsgesellschaft mbH Stuttgart; Wentworth, J. M., M. Agostini, et al. (2000). "St John's wort, a herbal antidepressant, activates the steroid X receptor." J Endocrinol 166(3): R11-16., http://medicine.iupui.edu/clinpharm/ddis/table.aspx as of 09.05.2012]. 사이토크롬 P450 1A1(CYP1A1)에 대한 구운 고기의 유도 효과와 유사하게, 효소는 또한 담배 연기에 존재하는 폴리사이클릭 방향족에 의해 유도될 수 있다. 예를 들어, 흡연자의 폐, 간 및 소장내 CYP1A1의 활성이 이들의 담배 소비에 비례하여 증가한다는 것이 문헌에 기재되어 있다[Czekaj, P., A. Wiaderkiewicz, et al. (2005). "Tobacco smoke-dependent changes in cytochrome P450 1A1, 1A2, and 2E1 protein expressions in fetuses, newborns, pregnant rats, and human placenta." Arch Toxicol 79(1): 13-24.; Fontana, R. J., K. S. Lown, et al. (1999). "Effects of a chargrilled meat diet on expression of CYP3A, CYP1A, and P-glycoprotein levels in healthy volunteers." Gastroenterology 117(1): 89-98.; Kim, J. H., M. E. Sherman, et al. (2004). "Expression of cytochromes P450 1A1 and 1B1 in human lung from smokers, non-smokers, and ex-smokers." Toxicol Appl Pharmacol 199(3): 210-219. Pelkonen, O., M. Pasanen, et al. (1986). "The effect of cigarette smoking on 7-ethoxyresorufin O-deethylase and other monooxygenase activities in human liver: analyses with monoclonal antibodies." Br J Clin Pharmacol 22(2): 125-134.; Zevin, S. and N. L. Benowitz (1999). "Drug interactions with tobacco smoking. An update." Clin Pharmacokinet 36(6): 425-438.].
또한, 모물질 및 그의 대사물(들)의 약리학적 작용도 발현된 단백질 변이체, 수용체 변이체 또는 운반자 변이체의 양 또는 활성에 좌우될 수 있는데, 이는 마찬가지로 저해 또는 유도 또는 유전적 원인으로 인하여 개체간에 또는 개체 내부에서 크게 상이할 수 있다.
운반자 유도제의 예는 다음과 같다: 덱사메타손, 독소루비신, 플라보노이드, 고추나물, 페노바르비탈, 페니토인, 리팜피신, 빈블라스틴.
운반자 저해제의 예는 다음과 같다:
리팜피신, 사이클로스포린 A, 겜피브로질, 로피나비르, 리토나비르, 클라리트로마이신, 푸로세미드, 인도메타신, 프로베네시드, 나프록센, 이부프로펜, 피록시캄, 아세틸살리실산, 파라세타몰, 페나세틴, 케토프로펜, 에날라프릴, 부메타니드, 세포페라존, 아자티오프린, 메토트렉세이트, 발프로에이트, 플루페나메이트, 페닐부타존, 레보플록사신, 덱사메타손, 사이타라빈, 암피실린, 아목시실린, 시클라실린, 세팔렉신, 세파드록실, 세프라딘, 세프디니르, 세프티부텐, 세픽심, 캅토프릴, 아미오다론, 퀴니딘, 리도카인, 이트라코나졸, 케토코나졸, 딜티아젬, 펠로디핀, 니카르디핀, 니페디핀, 니트렌디핀, 베라파밀, 인디나비르, 넬피나비르, 사퀴나비르, 에티닐에스트라디올, 노르게스트렐, 프로게스테론, 테스토스테론, 타크롤리무스, 에리트로마이신, 미페프리스톤, 파록세틴, 탈리놀롤, 타목시펜, 테르페나딘, 트리플루오페라진, 빈크리스틴[Shitara, Y. (2011). "Clinical importance of OATP1B1 and OATP1B3 in drug-drug interactions." Drug Metab Pharmacokinet 26(3): 220-227.; Van Aubel, R. A., R. Masereeuw, et al. (2000). "Molecular pharmacology of renal organic anion transporters." Am J Physiol Renal Physiol 279(2): F216-232.; http://www.pharmazeutische-zeitung.de/index.php?id=2381].
약물 요법에 특히 중요한 것은 유전적 원인을 갖는 단백질 활성에 있어서의 차이이다. 대립 유전자에서의 서열 변화의 결과(http://de.wikipedia.org/wiki/ Polymorphismus) 및/또는 존재하는 대립 유전자의 개수 변화의 결과, 상이한 변이체 및/또는 양의 단백질이 발현될 수 있다. 발현된 변이체 및 발현된 양의 단백질 양자 모두 단백질 변이체의 활성에 강력한 영향을 미칠 수 있다.
문헌에서, 다형성 단백질의 잘 연구된 예는 사이토크롬 P450 2D6(CYP2D6)이며, 이는 4가지 상이한 표현형으로 분류될 수 있는 다중의 상이한 유전자 변이체가 있는 것으로 공지된 효소이다. 이러한 목적으로 사용되는 통상의 명칭은 다음과 같다: PM = "느린 대사자(poor metabolizer)", IM = "중간 대사자(intermediate metabolizer)", EM = "광범위 대사자(extensive metabolizer)" 및 UM = "초고속 대사자(ultrarapid metabolizer)"[Zanger, U. M., J. Fischer, et al. (2001). "Comprehensive analysis of the genetic factors determining expression and function of hepatic CYP2D6." Pharmacogenetics 11(7): 573-585].
CYP2D6 이외에도, 사이토크롬 P450(CYP) 동종효소 계열의 수많은 기타 다형성 효소가 존재한다:
CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C11, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2F1, CYP2J2, CYP2S1, CYP2W1, CYP3A4, CYP3A5, CYP3A7, CYP3A43, CYP4A11, CYP4B1, CYP4F2, CYP4F22, CYP7A1, CYP4B1, CYP7B1, CYP8A1, CYP8B1, CYP11A, CYP11B1, CYP11B2, CYP17A, CYP19A, CYP21A, CYP24A, CYP26A1, CYP26B, CYP27A, CYP27B, CYP46A, CYP51A.
다음의 것이 특별히 강조된다: CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A5, CYP3A7 [http://bioinformatics.charite.de/ supercyp as of 24.04.2012; Tamaki, Y., T. Arai, et al. (2011). "Association between cancer risk and drug-metabolizing enzyme gene (CYP2A6, CYP2A13, CYP4B1, SULT1A1, GSTM1, and GSTT1) polymorphisms in cases of lung cancer in Japan." Drug Metab Pharmacokinet 26(5): 516-522.].
예를 들어, 유사하게, 대사 중의 수많은 다형성 2 상 효소 또는 기타 효소가 존재한다:
N-아세틸트랜스퍼라제 2(NAT2), 티오퓨린 S-메틸트랜스퍼라제(TPMT), 우리딘 5'-디포스포-글루쿠로노실트랜스퍼라제(UGT) 1A1, UGT1A3, UGT1A4, UGT1A5, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2A1, UGT2A2, UGT2A3, UGT2B4, UGT2B7, UGT2B10, UGT2B15, UGT2B17, 설포트랜스퍼라제(SULT) 1A1, SULT1A2, SULT1A3, SULT1E1, SULT2A1, SULT2B1, SULT4A1, 글루타치온 S-트랜스퍼라제(GST) A1, GSTA2, GSTA3, GSTA4, GSTA5, GSTM1, GSTM2, GSTM3, GSTM4, GSTM5, GSTP1, GSTT1, GSTT2, GSTO1, GSTO2, 카테콜-o-메틸트랜스퍼라제(COMT), 플라빈-의존성 모노옥시게나제 3(FMO), 디하이드로피리미딘 데하이드로게나제(DPD), 메틸렌테트라하이드로폴레이트 리덕타제(MTHFR).
다음의 것이 특별히 강조된다: NAT2, TPMT, UGT1A1, UGT1A4, UGT2B7, UGT2B15, SULT1A1, SULT1A2, SULT2A1, GSTM1, GSTP1, GSTT1, COMT, DPD, MTHFR [Hickman, D. and E. Sim (1991). "N-acetyltransferase polymorphism. Comparison of phenotype and genotype in humans." Biochem Pharmacol 42(5): 1007-1014.; Yates, C. R., E. Y. Krynetski, et al. (1997). "Molecular diagnosis of thiopurine S-methyltransferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance." Ann Intern Med 126(8): 608-614.; Bernard, O., J. Tojcic, et al. (2006). "Influence of nonsynonymous polymorphisms of UGT1A8 and UGT2B7 metabolizing enzymes on the formation of phenolic and acyl glucuronides of mycophenolic acid." Drug Metab Dispos 34(9): 1539-1545.; Bushey, R. T., G. Chen, et al. (2011). "Characterization of UDP-glucuronosyltransferase 2A1 (UGT2A1) variants and their potential role in tobacco carcinogenesis." Pharmacogenet Genomics 21(2): 55-65.; Carlini, L. E., N. J. Meropol, et al. (2005). "UGT1A7 and UGT1A9 polymorphisms predict response and toxicity in colorectal cancer patients treated with capecitabine/irinotecan." Clin Cancer Res 11(3): 1226-1236.; Chen, G., A. S. Blevins-Primeau, et al. (2007). "Glucuronidation of nicotine and cotinine by UGT2B10: loss of function by the UGT2B10 Codon 67 (Asp>Tyr) polymorphism." Cancer Res 67(19): 9024-9029.; Chen, G., R. W. Dellinger, et al. (2008). "Identification of a prevalent functional missense polymorphism in the UGT2B10 gene and its association with UGT2B10 inactivation against tobacco-specific nitrosamines." Pharmacogenet Genomics 18(3): 181-191.; Chen, Y., S. Chen, et al. (2006). "Genetic variants of human UGT1A3: functional characterization and frequency distribution in a Chinese Han population." Drug Metab Dispos 34(9): 1462-1467.; Dellinger, R. W., J. L. Fang, et al. (2006). "Importance of UDP-glucuronosyltransferase 1A10 (UGT1A10) in the detoxification of polycyclic aromatic hydrocarbons: decreased glucuronidative activity of the UGT1A10139Lys isoform." Drug Metab Dispos 34(6): 943-949.; Guo, Y., C. Hu, et al. (2012). "Effects of UGT1A6, UGT2B7, and CYP2C9 genotypes on plasma concentrations of valproic acid in Chinese children with epilepsy." Drug Metab Pharmacokinet.; He, X., L. M. Hesse, et al. (2009). "Evidence for oxazepam as an in vivo probe of UGT2B15: oxazepam clearance is reduced by UGT2B15 D85Y polymorphism but unaffected by UGT2B17 deletion." Br J Clin Pharmacol 68(5): 721-730.; Park, W. B., P. G. Choe, et al. (2010). "Genetic factors influencing severe atazanavir-associated hyperbilirubinemia in a population with low UDP-glucuronosyltransferase 1A1*28 allele frequency." Clin Infect Dis 51(1): 101-106.; Parmar, S., J. C. Stingl, et al. (2011). "Impact of UGT2B7 His268Tyr polymorphism on the outcome of adjuvant epirubicin treatment in breast cancer." Breast Cancer Res 13(3): R57.; Saeki, M., Y. Saito, et al. (2004). "Single nucleotide polymorphisms and haplotype frequencies of UGT2B4 and UGT2B7 in a Japanese population." Drug Metab Dispos 32(9): 1048-1054.; Sneitz, N., M. H. Court, et al. (2009). "Human UDP-glucuronosyltransferase UGT2A2: cDNA construction, expression, and functional characterization in comparison with UGT2A1 and UGT2A3." Pharmacogenet Genomics.; Sun, D., G. Chen, et al. (2006). "Characterization of tamoxifen and 4-hydroxytamoxifen glucuronidation by human UGT1A4 variants." Breast Cancer Res 8(4): R50.; Swanson, C., D. Mellstrom, et al. (2007). "The uridine diphosphate glucuronosyltransferase 2B15 D85Y and 2B17 deletion polymorphisms predict the glucuronidation pattern of androgens and fat mass in men." J Clin Endocrinol Metab 92(12): 4878-4882.; Yang, J., L. Cai, et al. (2012). "Genetic Variations and Haplotype Diversity of the UGT1 Gene Cluster in the Chinese Population." PLoS One 7(4): e33988.; Arslan, S. (2010). "Genetic polymorphisms of sulfotransferases (SULT1A1 and SULT1A2) in a Turkish population." Biochem Genet 48(11-12): 987-994.; Hirata, H., Y. Hinoda, et al. (2008). "CYP1A1, SULT1A1, and SULT1E1 polymorphisms are risk factors for endometrial cancer susceptibility." Cancer 112(9): 1964-1973.; Ji, Y., I. Moon, et al. (2007). "Human hydroxysteroid sulfotransferase SULT2B1 pharmacogenomics: gene sequence variation and functional genomics." J Pharmacol Exp Ther 322(2): 529-540.; Ramsey, T. L., H. Y. Meltzer, et al. (2011). "Evidence for a SULT4A1 haplotype correlating with baseline psychopathology and atypical antipsychotic response." Pharmacogenomics 12(4): 471-480.; Tamaki, Y., T. Arai, et al. (2011). "Association between cancer risk and drug-metabolizing enzyme gene (CYP2A6, CYP2A13, CYP4B1, SULT1A1, GSTM1, and GSTT1) polymorphisms in cases of lung cancer in Japan." Drug Metab Pharmacokinet 26(5): 516-522.; Thomae, B. A., B. W. Eckloff, et al. (2002). "Human sulfotransferase SULT2A1 pharmacogenetics: genotype-to-phenotype studies." Pharmacogenomics J 2(1): 48-56.; Thomae, B. A., O. F. Rifki, et al. (2003). "Human catecholamine sulfotransferase (SULT1A3) pharmacogenetics: functional genetic polymorphism." J Neurochem 87(4): 809-819.; Breton, C. V., H. Vora, et al. (2009). "Variation in the GST mu locus and tobacco smoke exposure as determinants of childhood lung function." Am J Respir Crit Care Med 179(7): 601-607.; Chen, Y. L., H. S. Tseng, et al. (2010). "Glutathione S-Transferase P1 (GSTP1) gene polymorphism increases age-related susceptibility to hepatocellular carcinoma." BMC Med Genet 11: 46.; Coles, B. F., F. Morel, et al. (2001). "Effect of polymorphism in the human glutathione S-transferase A1 promoter on hepatic GSTA1 and GSTA2 expression." Pharmacogenetics 11(8): 663-669.; Moyer, A. M., Z. Sun, et al. (2010). "Glutathione pathway genetic polymorphisms and lung cancer survival after platinum-based chemotherapy." Cancer Epidemiol Biomarkers Prev 19(3): 811-821.; Tetlow, N., M. Coggan, et al. (2004). "Functional polymorphism of human glutathione transferase A3: effects on xenobiotic metabolism and steroid biosynthesis." Pharmacogenetics 14(10): 657-663.; Tran, A., F. Bournerias, et al. (2008). "Serious haematological toxicity of cyclophosphamide in relation to CYP2B6, GSTA1 and GSTP1 polymorphisms." Br J Clin Pharmacol 65(2): 279-280.; White, D. L., D. Li, et al. (2008). "Genetic variants of glutathione S-transferase as possible risk factors for hepatocellular carcinoma: a HuGE systematic review and meta-analysis." Am J Epidemiol 167(4): 377-389.; Zhao, Y., M. Marotta, et al. (2009). "Linkage disequilibrium between two high-frequency deletion polymorphisms: implications for association studies involving the glutathione-S transferase (GST) genes." PLoS Genet 5(5): e1000472.; Motika, M. S., J. Zhang, et al. (2009). "Novel variants of the human flavin-containing monooxygenase 3 (FMO3) gene associated with trimethylaminuria." Mol Genet Metab 97(2): 128-135.; Voisey, J., C. D. Swagell, et al. (2011). "A novel SNP in COMT is associated with alcohol dependence but not opiate or nicotine dependence: a case control study." Behav Brain Funct 7: 51.; Fisher, M. C. and B. N. Cronstein (2009). "Metaanalysis of methylenetetrahydrofolate reductase (MTHFR) polymorphisms affecting methotrexate toxicity." J Rheumatol 36(3): 539-545.; Zhang, X. P., Z. B. Bai, et al. (2012). "Polymorphisms of dihydropyrimidine dehydrogenase gene and clinical outcomes of gastric cancer patients treated with fluorouracil-based adjuvant chemotherapy in Chinese population." Chin Med J (Engl) 125(5): 741-746.].
또한, 수많은 예의 다형성 운반자 및/또는 수용체 및/또는 기타 단백질이 존재한다.
다형성 운반자의 예는 다음과 같다:
ABCA1, ABCA2, ABCA3, ABCA4, ABCA7, ABCA8, ABCA12, ABCA13, ABCB1, ABCB2, ABCB4, ABCB5, ABCB7, ABCB8, ABCB9, ABCB10, ABCB11, ABCC1, ABCC2, ABCC3, ABCC4, ABCC5, ABCC6, ABCC8, ABCC9, ABCC10, ABCC11, ABCD1, ABCD2, ABCD3, ABCD4, ABCe1, ABCF1, ABCG1, ABCG2, ABCG4, ABCG5, ABCG8, OAT1, OAT2, OAT3, OAT4, URAT5, OATP1A2, OATP1B1, OATP1B3, OATP1C1, OATP1B1, OCT1, OCT2, OCT3, OCTN1, OCTN2, SLC22A16[Akiyama, Y., K. I. Fujita, et al. (2011). "Association of ABCC2 genotype with efficacy of first-line FOLFIRI in Japanese patients with advanced colorectal cancer." Drug Metab Pharmacokinet.; Fukao, M., K. Ishida, et al. (2011). "Effect of genetic polymorphisms of SLC28A1, ABCG2, and ABCC4 on bioavailability of mizoribine in healthy Japanese males." Drug Metab Pharmacokinet 26(5): 538-543.; Garcia-Donas, J., E. Esteban, et al. (2011). "Single nucleotide polymorphism associations with response and toxic effects in patients with advanced renal-cell carcinoma treated with first-line sunitinib: a multicentre, observational, prospective study." Lancet Oncol 12(12): 1143-1150.; Hollingworth, P., D. Harold, et al. (2011). "Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease." Nat Genet 43(5): 429-435.; Iida, A., S. Saito, et al. (2002). "Catalog of 605 single-nucleotide polymorphisms (SNPs) among 13 genes encoding human ATP-binding cassette transporters: ABCA4, ABCA7, ABCA8, ABCD1, ABCD3, ABCD4, ABCE1, ABCF1, ABCG1, ABCG2, ABCG4, ABCG5, and ABCG8." J Hum Genet 47(6): 285-310.; Karadeniz, M., M. Erdogan, et al. (2011). "Effect Of G2706A and G1051A polymorphisms of the ABCA1 gene on the lipid, oxidative stress and homocystein levels in Turkish patients with polycystic ovary syndrome." Lipids Health Dis 10: 193.; Kelsell, D. P., E. E. Norgett, et al. (2005). "Mutations in ABCA12 underlie the severe congenital skin disease harlequin ichthyosis." Am J Hum Genet 76(5): 794-803.; Knight, H. M., B. S. Pickard, et al. (2009). "A cytogenetic abnormality and rare coding variants identify ABCA13 as a candidate gene in schizophrenia, bipolar disorder, and depression." Am J Hum Genet 85(6): 833-846.; Kwan, P., V. Wong, et al. (2011). "Gene-wide tagging study of the association between ABCC2, ABCC5 and ABCG2 genetic polymorphisms and multidrug resistance in epilepsy." Pharmacogenomics 12(3): 319-325.; Liptrott, N. J., S. Pushpakom, et al. (2012). "Association of ABCC10 polymorphisms with nevirapine plasma concentrations in the German Competence Network for HIV/AIDS." Pharmacogenet Genomics 22(1): 10-19.; Maia-Lopes, S., J. Aguirre-Lamban, et al. (2009). "ABCA4 mutations in Portuguese Stargardt patients: identification of new mutations and their phenotypic analysis." Mol Vis 15: 584-591.; Matsukawa, T., M. Asheuer, et al. (2011). "Identification of novel SNPs of ABCD1, ABCD2, ABCD3, and ABCD4 genes in patients with X-linked adrenoleukodystrophy (ALD) based on comprehensive resequencing and association studies with ALD phenotypes." Neurogenetics 12(1): 41-50.; Minster, R. L., S. T. DeKosky, et al. (2009). "No association of DAPK1 and ABCA2 SNPs on chromosome 9 with Alzheimer's disease." Neurobiol Aging 30(11): 1890-1891.; Moitra, K., M. Scally, et al. (2011). "Molecular evolutionary analysis of ABCB5: the ancestral gene is a full transporter with potentially deleterious single nucleotide polymorphisms." PLoS One 6(1): e16318.; Pietrzak-Nowacka, M., K. Safranow, et al. (2012). "Association of C49620T ABCC8 polymorphism with anthropometric and metabolic parameters in patients with autosomal dominant polycystic kidney disease: a preliminary study." Nefrologia 32(2): 153-159.; Saito, S., A. Iida, et al. (2002). "Identification of 779 genetic variations in eight genes encoding members of the ATP-binding cassette, subfamily C (ABCC/MRP/CFTR." J Hum Genet 47(4): 147-171.; Saito, S., A. Iida, et al. (2002). "Three hundred twenty-six genetic variations in genes encoding nine members of ATP-binding cassette, subfamily B (ABCB/MDR/TAP), in the Japanese population." J Hum Genet 47(1): 38-50.; Sasaki, T., T. Hirota, et al. (2011). "Systematic screening of human ABCC3 polymorphisms and their effects on MRP3 expression and function." Drug Metab Pharmacokinet 26(4): 374-386.; Schulz, V., D. Hendig, et al. (2005). "Analysis of sequence variations in the ABCC6 gene among patients with abdominal aortic aneurysm and pseudoxanthoma elasticum." J Vasc Res 42(5): 424-432.; Shulenin, S., L. M. Nogee, et al. (2004). "ABCA3 gene mutations in newborns with fatal surfactant deficiency." N Engl J Med 350(13): 1296-1303.; Toyoda, Y. and T. Ishikawa (2010). "Pharmacogenomics of human ABC transporter ABCC11 (MRP8): potential risk of breast cancer and chemotherapy failure." Anticancer Agents Med Chem 10(8): 617-624.; Wasmuth, H. E., A. Glantz, et al. (2007). "Intrahepatic cholestasis of pregnancy: the severe form is associated with common variants of the hepatobiliary phospholipid transporter ABCB4 gene." Gut 56(2): 265-270.; Yin, J. Y., Q. Huang, et al. (2009). "Characterization and analyses of multidrug resistance-associated protein 1 (MRP1/ABCC1) polymorphisms in Chinese population." Pharmacogenet Genomics 19(3): 206-216.; Yu, X., H. Xie, et al. (2011). "Association of MDR1 gene SNPs and haplotypes with the tacrolimus dose requirements in Han Chinese liver transplant recipients." PLoS One 6(11): e25933.; Lee, W., H. Glaeser, et al. (2005). "Polymorphisms in human organic anion-transporting polypeptide 1A2 (OATP1A2): implications for altered drug disposition and central nervous system drug entry." J Biol Chem 280(10): 9610-9617.; Mougey, E. B., H. Feng, et al. (2009). "Absorption of montelukast is transporter mediated: a common variant of OATP2B1 is associated with reduced plasma concentrations and poor response." Pharmacogenet Genomics 19(2): 129-138.; Trdan Lu 353 In, T., B. Stieger, et al. (2012). "Organic anion transporting polypeptides OATP1B1 and OATP1B3 and their genetic variants influence the pharmacokinetics and pharmacodynamics of raloxifene." J Transl Med 10(1): 76.; van der Deure, W. M., P. S. Hansen, et al. (2008). "Thyroid hormone transport and metabolism by organic anion transporter 1C1 and consequences of genetic variation." Endocrinology 149(10): 5307-5314.; Vormfelde, S. V., M. Schirmer, et al. (2006). "Torsemide renal clearance and genetic variation in luminal and basolateral organic anion transporters." Br J Clin Pharmacol 62(3): 323-335.; Xu, G., V. Bhatnagar, et al. (2005). "Analyses of coding region polymorphisms in apical and basolateral human organic anion transporter (OAT) genes [OAT1 (NKT), OAT2, OAT3, OAT4, URAT (RST)]." Kidney Int 68(4): 1491-1499.; Becker, M. L., L. E. Visser, et al. (2011). "OCT1 polymorphism is associated with response and survival time in anti-Parkinsonian drug users." Neurogenetics 12(1): 79-82.Lal, S., Z. W. Wong, et al. (2007). "Novel SLC22A16 polymorphisms and influence on doxorubicin pharmacokinetics in Asian breast cancer patients." Pharmacogenomics 8(6): 567-575. Park, T. J., J. H. Kim, et al. (2011). "Possible association of SLC22A2 polymorphisms with aspirin-intolerant asthma." Int Arch Allergy Immunol 155(4): 395-402. Sakata, T., N. Anzai, et al. (2010). "Functional analysis of human organic cation transporter OCT3 (SLC22A3) polymorphisms." J Pharmacol Sci 113(3): 263-266. Tahara, H., S. W. Yee, et al. (2009). "Functional genetic variation in the basal promoter of the organic cation/carnitine transporters OCTN1 (SLC22A4) and OCTN2 (SLC22A5)." J Pharmacol Exp Ther 329(1): 262-271.]
다음의 것이 특별히 강조된다: ABCB1(p-당단백질), ABCC1(MRP1), ABCG2(BCRP), OATP1B1, OAT3, OCT1, OCT2, OCT3, SLC22A16.
약물 요법에서, 효소 활성 또는 효소량에 있어서의 이러한 차이는 치료 성공에 대해 극적인 영향을 미칠 수 있는데, 왜냐하면 이들은 하나 이상의 다형성 효소에 대한 기질인 물질 및 다형성 효소에 의해 형성된 대사물(들)의 약동학-그리고 여기에서는 특히 노출-에 직접적으로 영향을 미치기 때문이다. 동일한 사실이 단백질 활성 또는 단백질 양에 있어서의 이러한 차이에 적용되는데, 왜냐하면 수용체, 운반자 또는 기타 단백질이 하나 이상의 다형성 단백질에 대한 기질인 물질의 약동학-그리고 여기에서는 특히 노출-에도 직접적으로 영향을 미칠 수 있기 때문이다. 또한, 이들 단백질이 작용 메카니즘에 관여하는 경우에는 약력학에 대한 직접적인 효과도 발생할 수 있다.
따라서, 작용이 발현되고/되거나 저해된/유도된 단백질 변이체, 효소 변이체, 수용체 변이체 또는 운반자 변이체의 양 또는 활성에 의존성인 활성 성분의 사용에 있어서 개선된 약물 요법에 대한 필요가 존재하며, 상기 약물 요법은 상기 언급된 변화를 보완한다.
본 발명은 새로운 제제 개념, 더욱 특히 고정-용량 복합제(fixed-dose combination; FDC)의 형태를 기본으로 하며, 여기에서 관련 단백질의 활성에 있어서 이미-공지된 개체간 차이는 치료의 최적 성공을 보장하기 위하여 2가지 이상의 약리학적 활성 물질(이중의 하나 이상은 다른 물질의 대사물이다)의 투여량에 고려된다. 새로운 제제 개념은 유전자형 또는 표현형에 맞추어 개별적으로 조정된 모물질 및 하나/이상의 대사물 복합제의 특정 투여량에 의해 모물질 및 하나 이상의 활성 대사물에 대해 변화하는 노출의 보완을 기본으로 한다. 약동학적 목표는 특정 맥락(context)으로부터 정의되어야 하는 기준 개체군(reference population)에 대하여, "생물학적 동등성"-유사 항정-상태 상황(즉, 반복된 섭취 후에), 즉, 미리 정해진 한도 내에서 대상 물질의 혈장 농도 변화의 순응도를 확립하는 것이다(이 목적을 위해, 예를 들어, 다른 맥락에서 공통적인 기준을 사용할 수 있다; 이와 관련하여 "선행기술" 참조).
본 발명에 따른 제제 개념을 연구하기 위하여, 예로서 타목시펜을 사용한 약물 요법이 선택되었지만, 상기 예로 개념이 제한되는 것은 아니다.
CYP2D6 다형성의 경우에, 광범위 대사자(EM)로 구성된 개체군이 의미있는 기준 개체군의 예일 수 있는데, 왜냐하면 이 표현형이 야생형을 나타내며 많은 지리적 영역에 가장 널리 퍼져있기 때문이다[Sistonen, J., A. Sajantila, et al. (2007). "CYP2D6 worldwide genetic variation shows high frequency of altered activity variants and no continental structure." Pharmacogenet Genomics 17(2): 93-101.]. 공지의 암 약제의 일례인 타목시펜을 사용하여, 활성 대사물의 유전자형- 또는 표현형-의존성 노출의 문제가 설명될 것이지만, 이로 제한되지는 않는다.
타목시펜은 에스트로겐 수용체-양성(ER+) 유방암을 치료하는데 사용되는 주지의 약제학적 성분이다. 모물질은 복잡한 대사과정 체계의 대상이 되며, 이를 도 1에 나타내었다. (다른 것 중에서) 인간 신체에서, 타목시펜은 3가지 활성 대사물(N-데스메틸타목시펜, 4-하이드록시타목시펜, 엔독시펜)로 변환된다. 활성 대사물 중에서, 특히 타목시펜의 2차 대사물인 엔독시펜이 중요한데, 왜냐하면 엔독시펜 형성의 대부분이 다형성 CYP2D6를 통해 촉매되기 때문이다. 그 결과, 유방암 환자의 혈중 엔독시펜 농도는 그의 CYP2D6 유전자형 또는 표현형에 좌우된다. CYP2D6 PM의 경우, 실제적으로 CYP2D6 활성이 존재하지 않으며, 이에 따라 활성 대사물 엔독시펜의 농도가 매우 낮다[Murdter, T. E., W. Schroth, et al. (2011). "Activity levels of tamoxifen metabolites at the estrogen receptor and the impact of genetic polymorphisms of phase I and II enzymes on their concentration levels in plasma." Clin Pharmacol Ther 89(5): 708-717.; Jin, Y., Z. Desta, et al. (2005). "CYP2D6 Genotype, Antidepressant Use, and Tamoxifen Metabolism During Adjuvant Breast Cancer Treatment." Journal of the National Cancer Institute 97(1): 30-39.; Gjerde, J., M. Hauglid, et al. (2008). "Effects of CYP2D6 and SULT1A1 genotypes including SULT1A1 gene copy number on tamoxifen metabolism." Ann Oncol 19(1): 56-61.; Borges, S., Z. Desta, et al. (2006). "Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism: implication for optimization of breast cancer treatment." Clin Pharmacol Ther 80(1): 61-74.; Madlensky, L., L. Natarajan, et al. (2011). "Tamoxifen metabolite concentrations, CYP2D6 genotype, and breast cancer outcomes." Clin Pharmacol Ther 89(5): 718-725.; Lim, J. S., X. A. Chen, et al. (2011). "Impact of CYP2D6, CYP3A5, CYP2C9 and CYP2C19 polymorphisms on tamoxifen pharmacokinetics in Asian breast cancer patients." Br J Clin Pharmacol 71(5): 737-750.; Lim, H. S., H. Ju Lee, et al. (2007). "Clinical implications of CYP2D6 genotypes predictive of tamoxifen pharmacokinetics in metastatic breast cancer." J Clin Oncol 25(25): 3837-3845.; Kiyotani, K., T. Mushiroda, et al. (2010). "Significant effect of polymorphisms in CYP2D6 and ABCC2 on clinical outcomes of adjuvant tamoxifen therapy for breast cancer patients." J Clin Oncol 28(8): 1287-1293.; Irvin, W. J., Jr., C. M. Walko, et al. (2011). "Genotype-Guided Tamoxifen Dosing Increases Active Metabolite Exposure in Women With Reduced CYP2D6 Metabolism: A Multicenter Study." J Clin Oncol 29(24): 3232-3239.]. CYP2D6 IM의 경우, 엔독시펜 농도는 마찬가지로 여전히 뚜렷하게 EM 또는 (유럽인들에게는 상대적으로 드문) UM 표현형의 경우 관찰될 수 있는 기준 이하이다. 이와 관련하여, 한 연구는 또한 CYP2D6 EM, IM 및 PM 유전자형 또는 표현형 및 이들 각각의 항정-상태 엔독시펜 농도 사이의 구별되는 유전자 투여량 효과를 보여주었다[Jin, Y., Z. Desta, et al. (2005). "CYP2D6 Genotype, Antidepressant Use, and Tamoxifen Metabolism During Adjuvant Breast Cancer Treatment." Journal of the National Cancer Institute 97(1): 30-39]. 엔독시펜의 유전자형- 또는 표현형-의존성 노출을 도 2에서 예시적으로 나타내었다. 유방암 환자 개체군 내에서, 따라서, 엔독시펜의 노출은 다양한 CYP2D6 유전자형 또는 표현형의 빈도 분포에 의존한다. 이 빈도 분포는 지역 또는 인종 집단 사이에 매우 상이하다[Bernard, S., K. A. Neville, et al. (2006). "Interethnic differences in genetic polymorphisms of CYP2D6 in the U.S. population: clinical implications." Oncologist 11(2): 126-135.; Bradford, L. D. (2002). "CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants." Pharmacogenomics 3(2): 229-243.; Sachse, C., J. Brockmoller, et al. (1997). "Cytochrome P450 2D6 variants in a Caucasian population: allele frequencies and phenotypic consequences." Am J Hum Genet 60(2): 284-295.; Sistonen, J., A. Sajantila, et al. (2007). "CYP2D6 worldwide genetic variation shows high frequency of altered activity variants and no continental structure." Pharmacogenet Genomics 17(2): 93-101.]. 유럽인의 경우, EM이 우세한 유전자형이다[Sistonen, J., A. Sajantila, et al. (2007). "CYP2D6 worldwide genetic variation shows high frequency of altered activity variants and no continental structure." Pharmacogenet Genomics 17(2): 93-101.].
현재 CYP2D6 유전자형 또는 표현형에 대한 타목시펜 치료 성공의 의존성에 관한 증거를 제공하는 다양한 연구들이 있다[Bijl, M., R. van Schaik, et al. (2009). "The CYP2D6*4 polymorphism affects breast cancer survival in tamoxifen users." Breast Cancer Res Treat 118(1): 125-130.; Bonanni, B., D. Macis, et al. (2006). "Polymorphism in the CYP2D6 Tamoxifen-Metabolizing Gene Influences Clinical Effect but Not Hot Flashes: Data From the Italian Tamoxifen Trial." Journal of Clinical Oncology 24(22): 3708-3709.; Brauch, H., W. Schroth, et al. (2008). "Clinical Relevance of CYP2D6 Genetics for Tamoxifen Response in Breast Cancer." Breast Care (Basel) 3(1): 43-50.; Brauch, H. B., W. Schroth, et al. (2011). "CYP2D6 and Tamoxifen: Awaiting the Denouement." Journal of Clinical Oncology 29(34): 4589-4590.; Goetz, M. P., A. Kamal, et al. (2008). "Tamoxifen pharmacogenomics: the role of CYP2D6 as a predictor of drug response." Clin Pharmacol Ther 83(1): 160-166.; Goetz, M. P., S. K. Knox, et al. (2007). "The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen." Breast Cancer Res Treat 101(1): 113-121.; Goetz, M. P., J. M. Rae, et al. (2005). "Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes." J Clin Oncol 23(36): 9312-9318.; Ingelman-Sundberg, M., S. C. Sim, et al. (2007). "Influence of cytochrome P450 polymorphisms on drug therapies: pharmacogenetic, pharmacoepigenetic and clinical aspects." Pharmacol Ther 116(3): 496-526.; Newman, W. G., K. D. Hadfield, et al. (2008). "Impaired tamoxifen metabolism reduces survival in familial breast cancer patients." Clin Cancer Res 14(18): 5913-5918.; Schroth, W., L. Antoniadou, et al. (2007). "Breast cancer treatment outcome with adjuvant tamoxifen relative to patient CYP2D6 and CYP2C19 genotypes." J Clin Oncol 25(33): 5187-5193.; Schroth, W., M. P. Goetz, et al. (2009). "Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with tamoxifen." JAMA 302(13): 1429-1436; Goetz, M.P., et al., CYP2D6 metabolism and patient outcome in the Austrian Breast and Colorectal Cancer Study Group trial (ABCSG) 8. Clin Cancer Res, 2013. 19(2): p. 500-7.; Brauch, H., et al., Tamoxifen Use in Postmenopausal Breast Cancer: CYP2D6 Matters. J Clin Oncol, 2012.]. 이들 연구에 따르면, PM은 결과적으로 IM 보다 타목시펜 요법으로부터 뚜렷하게 더 적은 이익을 얻으며, 이들은 차례로 EM 또는 UM 보다 더 적은 이익을 얻는데, 이는 예를 들어 공개된 무재발 생존 곡선(relapse-free survival curve)(소위 카플란-마이어 플롯)에 반영되어 있다. 이와 같이 공개된 플롯의 예를 도 3에 나타내었다. 과거에는, 이들 연구 결과가 타목시펜을 사용한 유방암 요법의 주된 작용이 그의 대사물인 엔독시펜으로부터 유래함을 의미하는 것으로 해석되었다(타목시펜은 문헌에서 가끔 "전구약물"로도 지칭된다)[Goetz, M. P., A. Kamal, et al. (2008). "Tamoxifen pharmacogenomics: the role of CYP2D6 as a predictor of drug response." Clin Pharmacol Ther 83(1): 160-166.]). 당업자들은 또한 현재 타목시펜 대신에 엔독시펜이 직접 투여될 수 없는지 여부의 제안을 논의중에 있으며, 유방암 치료제로서 순수 엔독시펜의 허가를 목표로 하는 초기 연구가 공개되어 있다[Ahmad, A., S. M. Ali, et al. (2010). "Orally administered endoxifen is a new therapeutic agent for breast cancer." Breast Cancer Res Treat 122(2): 579-584.; Ahmad, A., S. Shahabuddin, et al. (2010). "Endoxifen, a new cornerstone of breast cancer therapy: demonstration of safety, tolerability, and systemic bioavailability in healthy human subjects." Clin Pharmacol Ther 88(6): 814-817.].
유사하게, 더 많은 이익을 얻는 EM 및 UM에의 투여로 제한하기 위하여 타목시펜 치료 전에 환자의 유전자형 또는 표현형을 분석해서는 안되는지 여부(그래서 CYP2D6 PM 및 IM 유전자형 또는 표현형을 나타내는 환자는 이와 같이 내재적으로 중요한 치료 옵션없이 병을 극복해야만 할 것인지)에 대한 논의가 한동안 당업자 사이에 있어왔다[de Graan, A. J., S. F. Teunissen, et al. (2011). "Dextromethorphan as a phenotyping test to predict endoxifen exposure in patients on tamoxifen treatment." J Clin Oncol 29(24): 3240-3246.; Irvin, W. J., Jr., C. M. Walko, et al. (2011). "Genotype-Guided Tamoxifen Dosing Increases Active Metabolite Exposure in Women With Reduced CYP2D6 Metabolism: A Multicenter Study." J Clin Oncol 29(24): 3232-3239.; Brauch, H., W. Schroth, et al. (2008). "Clinical Relevance of CYP2D6 Genetics for Tamoxifen Response in Breast Cancer." Breast Care (Basel) 3(1): 43-50.; Lim, J. S., X. A. Chen, et al. (2011). "Impact of CYP2D6, CYP3A5, CYP2C9 and CYP2C19 polymorphisms on tamoxifen pharmacokinetics in Asian breast cancer patients." Br J Clin Pharmacol 71(5): 737-750.]. 현재 논의 중에 있는 추가의 요법 전략은 정상적인 타목시펜 요법 하의 CYP2D6 EM 환자에서 달성되는 것과 유사한 엔독시펜 농도를 CYP2D6 IM 및 PM 표현형 환자에서 달성하기 위하여 유전자형 또는 표현형을 기초로 하여 타목시펜 용량을 증가시키는 것이다. 이와 관련하여, 한 연구는 이러한 접근법이 CYP2D6 IM 환자에 대한 해결책이 될 수는 있지만, 유사한 농도의 엔독시펜이 절대로 달성되지 않는 CYP2D6 PM 표현형 환자의 경우에는 그렇지 않음을 보여준다. 결과적으로, 이 옵션은 CYP2D6 PM 표현형 환자의 경우 고려될 수 없다[Irvin, W. J., Jr., C. M. Walko, et al. (2011). "Genotype-Guided Tamoxifen Dosing Increases Active Metabolite Exposure in Women With Reduced CYP2D6 Metabolism: A Multicenter Study." J Clin Oncol 29(24): 3232-3239.].
최근의 과학적 지식에 따르면, ER+ 유방암에서 타목시펜의 긍정적 작용은 활성 성분의 배합에 기인할 수 있는 것으로 추정되어야 한다. 의심할 여지 없이, 타목시펜 자체는 2가지의 일차적인 대사물 4-하이드록시타목시펜 및 N-데스메틸타목시펜(이는 엔독시펜이 투여되는 경우 환자의 혈장 내에서 순환하지 않을 것이다)이 그러한 것처럼 항-에스트로겐(이에 따른 암-억제) 작용을 나타내며, 타목시펜 요법의 전반적인 작용은 모물질 및 그의 활성 대사물의 상호작용을 통해서만 달성된다고 추정되어야 한다[V.C. Craig, Long-Term Tamoxifen Treatment for Breast Cancer, S. 32, Allen, K. E., E. R. Clark, et al. (1980). "Evidence for the metabolic activation of non-steroidal antioestrogens: a study of structure-activity relationships." Br J Pharmacol 71(1): 83-91.; Kemp, J. V., H. K. Adam, et al. (1983). "Identification and biological activity of tamoxifen metabolites in human serum." Biochem Pharmacol 32(13): 2045-2052.]. 결론적으로, 배타적인 엔독시펜 요법이 타목시펜 요법에 대한 의미있는 대안이 될 수 있는지에 대한 의문이 있으며; 반면에, 엔독시펜 단독 투여는 에스트로겐 수용체-양성 유방암에서 타목시펜 요법의 CYP2D6-의존성에 대한 적절한 조치가 아닌 것으로 추정되어야 한다.
유방암에서 타목시펜 요법에 관한 종래의 과학적 기술은 매우 잘 문서화되어 있다. 비록 이는 비교적 오래된 물질에 관한 것이지만, 타목시펜 요법의 CYP2D6 유전자형- 또는 표현형-의존성은 전문 분야에서 현재의 리서치 및 활발한 논의의 주제이다.
따라서, CYP2D6 유전자형 또는 표현형을 고려하며, CYP2D6 IM 및 PM 표현형 환자가 정상적인 타목시펜 요법 하에 CYP2D6 EM 환자에서 달성되는 것과 유사한 엔독시펜 농도를 달성하도록 함으로써, 유방암 위험을 최소화하는 형태로 PM 및 IM에서의 유망한 요법에 이를 수 있는 타목시펜 치료에 대한 특정의 요구가 존재하였다.
상기 목적을 달성하기 위하여, 본 발명은 약제학적 제제, 더욱 특히 고정-용량 복합제(FDC)로, 타목시펜과 엔독시펜의 복합 투여를 제안한다. 바람직한 구체예에서, 본 발명에 따른 제제, 더욱 특히 FDC는 유전자형- 또는 표현형-특이적 방식으로 투여된다.
모물질 및 대사물과 같은 상호간의 관련이 없는 2가지 이상의 물질로 구성된 FDC는 선행기술에 따라 공지되어 있으며, 예를 들어, HIV 요법, 2형 당뇨병 요법, 고혈압 요법, 고지혈증 요법 또는 말라리아 및 결핵 요법에서 성공적으로 사용된다[Anvikar, A. R., B. Sharma, et al. (2012). "Artesunate-amodiaquine fixed dose combination for the treatment of Plasmodium falciparum malaria in India." Malar J 11(1): 97. Ayede, I. A., A. G. Falade, et al. (2010). "An open randomized clinical trial in comparing two artesunate-based combination treatments on Plasmodium falciparum malaria in Nigerian children: artesunate/sulphamethoxypyrazine/pyrimethamine (fixed dose over 24 hours) versus artesunate/amodiaquine (fixed dose over 48 hours)." Malar J 9: 378. Bramlage, P., W. P. Wolf, et al. (2010). "Effectiveness and tolerability of a fixed-dose combination of olmesartan and amlodipine in clinical practice." Vasc Health Risk Manag 6: 803-811. Gadzhanova, S., M. Gillies, et al. (2011). "Fixed dose combination diabetes medicines - usage in the Australian veteran population." Aust Fam Physician 40(10): 811-815. Honda, M., M. Ishisaka, et al. (2011). "Open-label randomized multicenter selection study of once daily antiretroviral treatment regimen comparing ritonavir-boosted atazanavir to efavirenz with fixed-dose abacavir and lamivudine." Intern Med 50(7): 699-705. Kauf, T. L., K. L. Davis, et al. (2012). "Spillover adherence effects of fixed-dose combination HIV therapy." Patient Prefer Adherence 6: 155-164. Kim, S. H., K. H. Ryu, et al. (2011). "Efficacy of fixed-dose amlodipine and losartan combination compared with amlodipine monotherapy in stage 2 hypertension: a randomized, double blind, multicenter study." BMC Res Notes 4: 461. Mathew, J. L. (2009). "Fixed dose drug combination for treatment of tuberculosis." Indian Pediatr 46(10): 877-880. Mengden, T., R. Hubner, et al. (2011). "Office and ambulatory blood pressure control with a fixed-dose combination of candesartan and hydrochlorothiazide in previously uncontrolled hypertensive patients: results of CHILI CU Soon." Vasc Health Risk Manag 7: 761-769. Mengden, T., S. Uen, et al. (2009). "Management of hypertension with fixed dose combinations of candesartan cilexetil and hydrochlorothiazide: patient perspectives and clinical utility." Vasc Health Risk Manag 5: 1043-1058. Okpechi, I. G., H. S. Schoeman, et al. (2011). "Achieving blood preSsure goals sTudy in uncontrolled hypeRtensive pAtients treated with a fixed-dose combination of ramipriL/hydrochlorothiazide: the ASTRAL study." Cardiovasc J Afr 22(2): 79-84. Reynolds, J. K. (2009). "Fixed-dose combination of sitagliptin and metformin for the treatment of type 2 diabetes." Diabetes Metab Syndr Obes 2: 127-134. Shiga, Y., S. Miura, et al. (2011). "Comparison of the efficacy and safety of single-pill fixed-dose combinations of losartan/hydrochlorothiazide and valsartan/ hydrochlorothiazide in patients with hypertension (SALT-VAT study)." Intern Med 50(21): 2477-2483.].
2가지 이상의 활성 성분을 분리하여 투여하는 것과 비교할 때의 이점은 더욱 단순한 실행 계획, 제조 및 유통 비용 감소, 및 (타목시펜/엔독시펜의 경우 결정적인) 환자의 순응도 개선이다.
모물질 및 하나 이상의 잠재적인 대사물을 함유하며, 대사물 농도의 유전자형- 또는 표현형-관련 가변성을 보완하기 위하여 제공되는 고정-용량 복합제, 더욱 특히 유전자형- 또는 표현형-특이적 FDC는 선행기술에 따라 공지되어 있지 않다. 유사하게, 모물질 및 하나 이상의 잠재적인 대사물을 함유하며, 대사물 농도의 "표현형-카핑(phenotype-copying)" 관련 가변성을 보완하기 위하여 제공되는 고정-용량 복합제는 선행기술에 따라 공지되어 있지 않다. 여기에서, "표현형-카핑"은 효소를 통해 하나/이상의 활성 대사물로 변환되는 한가지 약제와 상기 변환을 저해하거나 유도하는 한가지 강력한 효소 저해제 또는 효소 유도제를 동시 투여한 결과 효소 및 효소 저해제 또는 효소 유도제 사이의 상호작용에 기초하여 환자의 원래 표현형이 다른 것으로 변환되는 것을 의미한다. 여기에서 그럴듯한 예는 동시에 타목시펜을 수령하는 CYP2D6 EM 표현형 환자에게 강력한 CYP2D6 저해제(예를 들어, 파록세틴)을 투여하는 것이다. 활성 성분-매개된(예를 들어, 파록세틴) CYP2D6 저해의 결과, 원래의 CYP2D6 EM 환자는 사실상 IM 또는 PM으로 되며, 이에 따라 타목시펜의 활성 2차 대사물인 엔독시펜 농도가 낮아진다[Borges, S., Z. Desta, et al. (2006). "Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism: implication for optimization of breast cancer treatment." Clin Pharmacol Ther 80(1): 61-74.; Jin, Y., Z. Desta, et al. (2005). "CYP2D6 Genotype, Antidepressant Use, and Tamoxifen Metabolism During Adjuvant Breast Cancer Treatment." Journal of the National Cancer Institute 97(1): 30-39. Stearns, V., M. D. Johnson, et al. (2003). "Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine." J Natl Cancer Inst 95(23): 1758-1764.].
순수하게 엔독시펜을 사용하는 유방암 요법 대신에, 본 발명에 따라 타목시펜과 엔독시펜을 복합 투여하는 접근법은 타목시펜, N-데스메틸타목시펜 및 4-하이드록시타목시펜의 입증된 효능으로 인하여 충분히 엔독시펜을 형성할 수 없는 환자(즉, CYP2D6 PM 및 IM)에게 유리하다. 이러한 복합 투여의 목표는 적절한 엔독시펜 용량의 투여에 의해 유전자형- 또는 표현형-관련 엔독시펜 형성 감소를 보완하는 동시에 PM 및 IM이 타목시펜 단독 투여 하의 EM 또는 UM과 유사한 타목시펜, N-데스메틸타목시펜, 4-하이드록시타목시펜 및 엔독시펜의 항정-상태 혈장 농도를 달성하도록 필요한 경우 타목시펜 용량을 조정하는 것이어야 한다.
CYP2D6 IM 및 PM에 대한 타목시펜-엔독시펜 FDC의 상기 언급된 이점 이외에, 제안된 고정 복합제, 더욱 특히 20 mg의 타목시펜과 3 mg의 엔독시펜의 적용은 또한 CYP2D6 EM 및 IM에서 특정 환경 하에 유리할 수 있다. 예를 들어, 타목시펜 요법의 초기 단계에서, 목적하는 평형 농도(항정-상태 농도로도 지칭됨)가 달성되기까지의 기간이 상당히 단축될 수 있다. 20 mg 타목시펜의 표준 치료 투여량의 경우, CYP2D6 EM 유전자형 또는 표현형의 유럽 환자로 구성된 예시적인 개체군에서 엔독시펜의 항정-상태 농도는 약 80일 후에 달성된다[Fabian C, Sternson L, El-Serafi M, Cain L, Hearne E.; Clinical pharmacology of tamoxifen in patients with breast cancer: correlation with clinical data. Cancer. 1981 Aug 15;48(4):876-82.; Jin Y, Desta Z, Stearns V, Ward B, Ho H, Lee KH, Skaar T, Storniolo AM, Li L, Araba A, Blanchard R, Nguyen A, Ullmer L, Hayden J, Lemler S, Weinshilboum RM, Rae JM, Hayes DF, Flockhart DA.; CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst. 2005 Jan 5;97(1):30-9.; Fuchs WS, Leary WP, van der Meer MJ, Gay S, Witschital K, von Nieciecki A.; Pharmacokinetics and bioavailability of tamoxifen in postmenopausal healthy women. Arzneimittelforschung. 1996 Apr;46(4):418-22.]. 반면에, 타목시펜 요법이 제안된 고정 복합제를 사용하여 처음에 수행되는 경우, 도 11 및 12에 나타낸 바와 같이, PBPK 모델을 기준으로 할 때 엔독시펜의 효과적인 항정-상태 농도가 뚜렷하게 더 빨리, 즉, 단지 9일 후에 나타났다.
부가적으로, 타목시펜을 사용하는 유방암 요법의 개시에 대해 보여지는 고정 타목시펜-엔독시펜 복합제의 이점은 지속적인 약제 섭취가 중단되는 빈번하게 발생하는 실제 상황(불이행(non-compliance)으로도 지칭됨)에 연결될 수도 있다. 이러한 불이행이 타목시펜 환자에 있어서 공지되어 있으며 잘 문서화되어 있다. 부족한 이행은 타목시펜 요법에 대한 더 열등한 반응과 연계될 수 있다[Barron, T.I., et al., Early discontinuation of tamoxifen: a lesson for oncologists. Cancer, 2007. 109(5): p. 832-9.; Dezentje, V.O., et al., Effect of concomitant CYP2D6 inhibitor use and tamoxifen adherence on breast cancer recurrence in early-stage breast cancer. J Clin Oncol, 2010. 28(14): p. 2423-9.; Friese, C.R., et al., Adjuvant endocrine therapy initiation and persistence in a diverse sample of patients with breast cancer. Breast Cancer Res Treat, 2013.; Hershman, D.L., et al., Early discontinuation and nonadherence to adjuvant hormonal therapy in a cohort of 8,769 early-stage breast cancer patients. J Clin Oncol, 2010. 28(27): p. 4120-8.; McCowan, C., et al., Cohort study examining tamoxifen adherence and its relationship to mortality in women with breast cancer. Br J Cancer, 2008. 99(11): p. 1763-8.; Partridge, A.H., Non-adherence to endocrine therapy for breast cancer. Ann Oncol, 2006. 17(2): p. 183-4.; Rae, J.M., et al., Cytochrome P450 2D6 activity predicts discontinuation of tamoxifen therapy in breast cancer patients. Pharmacogenomics J, 2009. 9(4): p. 258-64.; Ruddy, K.J. and A.H. Partridge, Adherence with adjuvant hormonal therapy for breast cancer. Ann Oncol, 2009. 20(3): p. 401-2.; Ziller, V., et al., Adherence to adjuvant endocrine therapy in postmenopausal women with breast cancer. Ann Oncol, 2009. 20(3): p. 431-6.].
타목시펜 약물 섭취를 거르는 경우, 타목시펜 및 그의 활성 대사물(따라서, 특히 엔독시펜도)의 혈장 수준은 치료적으로 유효한 임계치 아래로 떨어진다. 초기 타목시펜 요법과 유사하게, 고정 복합제도 마찬가지로, 도 15 내지 18에서의 시뮬레이션 결과에 의해 보여지는 바와 같이 효과적인 농도의 재개된 달성을 가속화하기 위하여 CYP2D6 EM 및 IM에서 유리하게 사용될 수 있다.
따라서, 본 발명은 먼저 작용이 발현되고/되거나 저해된/유도된 단백질 변이체, 효소 변이체, 수용체 변이체 또는 운반자 변이체의 양 또는 활성에 의존하는 모물질, 및 모물질의 하나 이상의 잠재적 대사물을 함유하는 약제학적 제제를 제공한다. 특히, 본 발명에 따른 제제의 투여량은 유전자형- 또는 표현형-특이적 방식으로 정의된다.
그러나, 이와 같이 다중의 약제학적 활성 물질의 복합제에는 어려움이 있다. 주된 어려움은 CYP2D6 PM 및 IM 에서 치료적으로 효과적인 항정-상태 혈장 수준을 보장하는 최적의 엔독시펜 및 타목시펜 용량을 결정하는 것이다.
본 발명에서, 이 추가의 목적은, 예시적으로 타목시펜, 4-하이드록시타목시펜, N-데스메틸타목시펜 및 엔독시펜에 대한 커플링된 생리학적 약동학(physiologically based pharmacokinetic; PBPK) 모델의 사용을 기본으로 하는 방법에 의해 달성되었다. 상기 방법 및 상응하는 상업적으로 구입가능한 모델 PK-Sim®/MoBi®이 출원 WO2007/147539, WO05/116854 및 WO 05/033982호에 기재되어 있으며, 이와 관련하여 그의 교시가 본 명세서에 통합되고, 커플링된 PBPK 모델을 기본으로 하는 방법을 개발하기 위해 본 발명에서 사용된다. CYP2D6 EM 및 PM에서 타목시펜, N-데스메틸타목시펜, 4-하이드록시타목시펜 및 엔독시펜에 대해 커플링된 PBPK 모델의 개발이 이미 기재되어 있다[Dickschen, K., et al., Physiologically-based pharmacokinetic modeling of tamoxifen and its metabolites in women of different CYP2D6 phenotypes provides new insight into the tamoxifen mass balance. Frontiers in Pharmacology, 2012. 3.]. 이 방법이, 예시적으로, CYP2D6 PM 및 IM에서 타목시펜 및 엔독시펜 용량을 최적화하기 위하여 나중에 사용되었다. 공개된 CYP2D6 PM 모델 매개변수화 및 부가적으로 본 명세서에 제시된 CYP2D6 IM 매개변수화 사이의 유일한 차이는 CYP2D6 효소 활성에 대해 사용된 인자이다(IM: 0.62; PM 0.015 [Coller, J. K., N. Krebsfaenger, et al. (2002). "The influence of CYP2B6, CYP2C9 and CYP2D6 genotypes on the formation of the potent antioestrogen Z-4-hydroxy-tamoxifen in human liver." Br J Clin Pharmacol 54(2): 157-167.]). 도 4는 타목시펜과 그의 3가지 활성 대사물(N-데스메틸타목시펜, 4-하이드록시타목시펜, 엔독시펜)에 대한 커플링된 PBPK 모델의 도표를 보여준다.
따라서, 본 발명은 하기 단계를 포함하는, 작용이 발현되고/되거나 저해된/유도된 단백질 변이체, 효소 변이체, 수용체 변이체 또는 운반자 변이체의 양 또는 활성에 의존하는 모물질, 및 모물질의 적어도 하나의 대사물을 포함하는 고정-용량 복합 약제학적 제제의 제조 방법을 추가로 제공한다:
a) 유기체, 그의 유전자형 또는 표현형, 모물질 및 적어도 모물질의 대사물, 모물질을 단독으로 전달하는 경우 기준 유전자형 또는 기준 표현형에 대한 모물질의 최적의 기준 항정-상태 혈장 수준을 입력 모듈(input module) 내로 입력하는 단계,
b) a)로부터의 데이터를 물질 데이터 모듈, 유기체 데이터 모듈, 유전자형 데이터 모듈 또는 표현형 데이터 모듈, 및 생리학적 약동학 모델을 포함하는 계산 모듈 내로 전송하며, 여기에서 물질 데이터 모듈은 물질(들)의 물리화학적 및/또는 생화학적 특성에 관한 데이터를 포함하고, 유기체 모듈은 유기체의 구획(compartment)에 관한 데이터를 포함하며, 유전자형 데이터 모듈 또는 표현형 데이터 모듈은 유전자형- 또는 표현형-특이적 데이터를 포함하는 단계,
c) 물질 데이터 모듈로부터 모물질 및 대사물-특이적 데이터를 자동적으로 선택하는 단계,
d) 입력 a)를 기초로 하여 유기체 데이터 모듈로부터 유기체-특이적 데이터를 자동적으로 선택하는 단계,
e) 유전자형 데이터 모듈 또는 표현형 데이터 모듈로부터 유전자형- 또는 표현형-특이적 데이터를 자동적으로 선택하는 단계,
f) a) 내지 e)로부터 선택된 데이터를 생리학적 약동학 모델 내로 전송하는 단계,
g) 생리학적 약동학 모델을 사용하여, a)로부터의 모물질에 대해 입력된 최적의 기준 혈장 수준에 이르기 위하여 기준 유전자형 또는 기준 표현형에 대한 모물질의 최적화된 투여량을 계산하는 단계,
h) g)에서 계산된 모물질 용량을 투여하는 경우에 기준 유전자형 또는 기준 표현형에 대한 대사물들(N-데스메틸타목시펜, 4-하이드록시타목시펜, 엔독시펜)의 기준 항정-상태 혈장 수준을 계산하는 단계,
i) g)에서 계산된 모물질 용량을 투여하는 경우에 상응하는 기준 혈장 수준에 관하여 a)에서 입력된 유전자형 또는 표현형으로 인하여 감소된 대사물(들)의 혈장 수준을 계산하는 단계,
j) h)로부터의 대사물(들)의 기준 혈장 수준 및 a)로부터의 모물질의 기준 혈장 수준의 조합 획득을 위한 대사물 용량 및 모물질 용량을 계산하는 단계,
k) 출력 모듈을 통해 고정-용량 복합 약제학적 제제에 대한 대사물 용량 및 모물질 용량을 출력하는 단계, 및/또는
l) 약제의 투여를 위해 j)에서 계산된 용량을 자동화 장치 내로 전송하는 단계.
본 발명에서, 약제를 투여하기 위한 자동화 장치는 정제, 캡슐제, 액체 투여형 또는 그의 구성요소와 같은 투여형을 제조하기 위한 장치, 및 또한 저울, 선행기술에 공지된 단위-용량 시스템과 같이 투여량을 측정하기 위한 기구, 또는 액체를 부피로 또는 중량으로 측정하기 위한 장치를 의미한다.
임의로, 계산 모듈은 부가적으로 정제, 캡슐제, 액체 투여형, 또는 그의 구성요소와 같은 투여형에 관한 데이터를 포함하는 투여 모듈을 가진다. 상기 데이터는 보통 복합제에 대한 투여형의 방출 특성, 예컨대 즉시 방출, 지연 방출 및 또한 차별화 방출(예: 층을 이룬 활성-성분 분포를 사용하여) 또는 동시 방출(예: 공동 과립화를 사용하여)을 포함한다. 입력 모듈에서, 투여형은 선택적으로 정의될 수 있으며, 상응하는 투여형에 관한 데이터는 투여 모듈로부터 자동적으로 선택되어 생리학적 약동학 모델로 전송된다.
계산 모듈은 모물질 및 대사물(들)에 대한 최적의 약제 용량, 및 경우에 따라 최적 투약 방식(dosing regimen)을 계산한다. 이는 컴퓨터-실행 소프트웨어 및 프로그램을 실행하기에 필요한 하드웨어로 구성된다. 하드웨어는 일반적으로 상업적으로 구입가능한 PC이다. 내장 키보드 또는 칩 카드 판독기가 달린 랩톱 컴퓨터의 경우에서와 같이 이는 직접 입력 장치와 연결되거나, 근처에 설치되어 입력 장치(서버)에 연결된다. 원칙적으로, 유선 및 무선 방법 양자 모두의 모든 일반적인 전송 기술이 적합하며 고려될 수 있다. 휴대용 입력 모듈 또는 칩 카드 판독기를 통해 입력된 환자 정보의 무선 전송이 특히 바람직하다.
소프트웨어는 하나 이상의 데이터베이스에서 최적의 약제 투여량 계산과 관련된 모든 정보를 취급할 수 있도록 한다. 본 방법의 바람직한 구체예에서, 환자-특이적 용량을 계산하는 것도 가능하다. 약제 용량의 계산과 관련된 이 정보는 보통 유기체-특이적, 물질-특이적, 유전자형- 또는 표현형-특이적 및 바람직하게 투여-특이적 데이터로 나뉘며, 바람직하게 상응하는 데이터 모듈 내에 자동적으로 복구가능하게 저장된다.
특히 맞춤형 치료제(personalized medication)와 관련한 바람직한 구체예에서, 생리학적(또는 신체계측) 정보, 병리학적 정보, 가능하게는 부가적으로 투여된 약제, 소위 공동-약제와 관련한 정보도 마찬가지로 환자-특이적 데이터와 같은 데이터 모듈 내에 자동적으로 복구가능하게 저장된다.
물질 데이터는, 예를 들어, 친유성, 유리 혈장 분획(free plasma fraction), 혈액-혈장 비율, 분배 계수, 투과성, 분포 부피, 청소율, 청소율 성질, 청소율비, 배설 성질, 투약 방식, 운반자 기질, 약동학 및/또는 약력학적 종말점 및 불리한 효과를 포함한다.
관련 약제 정보는, 더욱 특히, 권장 치료 투여량(제조자로부터의 정보에 따라), 약동학적 및/또는 약력학적 종말점, 청소율(기준 개체군 또는 기준 개체에서의 혈액 또는 혈장 청소율로서의 총 청소율) 및 청소율 성질(간-대사성, 담즙성, 신장성 등) 및 총 청소율에 관한 개체 프로세스 비율, 약제 및/또는 그의 대사물(들)이 하나 이상의 활성 운반자/수용체/효소에 대한 기질인 경우 활성 운반자/수용체/효소의 운동 파라미터 및 물리화학적 및 약동학적 정보, 예컨대, 친유성, 혈장에서의 비결합 분획, 약제 및/또는 그의 대사물(들)이 결합하는 혈장 단백질, 혈액-혈장 분포 계수 또는 분포 부피이다.
예를 들어, 사례 연구의 리서치를 통해 얻을 수 있는 실험적 지식도 또한 부가적으로 물질 정보 또는 공동-치료제과 관련한 정보를 동반하는 데이터베이스의 일부일 수 있다.
환자-특이적 정보와 유사하게, 관련 생리학적 또는 신체계측 및 병태생리학적 정보는, 예를 들어, 각 경우에 연령, 성별, 인종, 체중, 키, 신체 용적 지수, 무지방 체중(lean body mass), 제지방 체중(fat-free body manss), 유전자 발현 데이터, 질환, 알러지, 약물치료, 신장기능 및 간기능이다. 관련 병태생리학적 정보는 더욱 특히 질환, 알러지, 신장기능 및 간기능이다.
공동-치료제의 경우, 모든 부가적인 투여 약제와 관련하여 상응하는 전기 정보는 공동-치료제와 관련한 데이터베이스의 일부이다.
최적 투여량, 및 경우에 따라 최적 투약 방식은 데이터베이스 내에 존재하는 정보를 기초로 하여 투여하고자 하는 물질(모물질 및 대사물(들))의 약동학적 및 약력학적 거동을 계산하기 위한 합리적인 수학적 모델을 사용하여, 가능하게는 투여-특이적 데이터와 조합된 물질-특이적 데이터, 유기체-특이적 데이터 및 유전자형- 또는 표현형-특이적 데이터를 기초로 하여 계산된다. 이와 관련하여, 합리적인 수학적 모델은, 예를 들어, 상대성장 척도 기능(allometric scaling function) 또는 생리학적 약동학 모델일 수 있다.
본 발명의 바람직한 구체예에서, 생리학적 약동학/약력학 시뮬레이션 모델은 개체 투여량을 계산하는데 사용된다. WO2005/633982호에 구체적으로 기재된 역학적으로 생성된 생리학적 시뮬레이션 모델이 특히 바람직하다.
WO2005/633982호의 생리학적 시뮬레이션 모델을 사용하는 경우의 특별한 이점은 다중 약제의 동시 투여 및 이들의 상호작용을 역학적으로 시뮬레이션할 수 있다는 점이다. 이와 관련하여, 역학적으로는 상호작용에서 2가지(가능하게는, 또한, 2가지 초과) 상호작용하는 물질들의 동력학이 고려될 수 있다는 것을 의미한다. 이는, 예를 들어, 효소 또는 운반자가 시간-독립적인 방식으로 완전히 또는 부분적으로 저해되는 정적 고려에 비해 유리한데, 왜냐하면 역학적 시뮬레이션은 투약 방식의 최적화를 허용하기 때문이다. 이러한 투약 방식의 최적화의 결과, 예를 들어, 상호 영향을 최소화하기 위하여 2가지 상호작용하는 물질을 투여하는 경우, 예를 들어, 12시간의 최대 간격(1일 1회 투여를 위해)의 유지가 가능해진다.
본 발명에 따른 방법을 수행하기에 특히 적합한 것은 바이엘 테크놀로지 서비시즈 게엠베하(Bayer Technology Services GmbH)로부터의 PK-Sim® 및 MoBi®로 구성된 시스템즈 바이올로지 소프트웨어 세트이다.
단백질 저해 또는 유도와 같은 과정은 시간-의존성인 것으로 알려져 있으므로, 상기 과정을 기본으로 하는 상호작용 효과도 마찬가지로 시간-의존성이다. 특정의 경우, 수일 또는 수주의 시간 척도로 발생하는 이들 역학적 효과는 요법 과정 중에 약제 용량의 조정을 필요로 할 수 있다. 선행기술에 따라 공지되어 있는 바와 같이, 상호 영향을 주는 약제를 즉시 투여하는 경우에 단순한 정적 고려 또는 취급자에게 단순히 경고하는 정도로는 이와 같이 복잡한 역학적 효과를 제대로 처리하지 못한다.
예시적으로, 본 발명에 따른 방법은 타목시펜 용량에 따라 CYP2D6 유전자형 또는 표현형이 상이한 유방암 환자에서 4가지 물질 타목시펜, 4-하이드록시타목시펜, N-데스메틸타목시펜 및 엔독시펜의 항정-상태 혈장 수준을 시뮬레이션할 수 있다. 필요할 수 있는 타목시펜 용량의 조정 및 엔독시펜 투여량을 증가시키는 투여의 동시 시뮬레이션을 통해, 이 모델은 CYP2D6 IM 및 PM에서 2가지 활성 성분의 최적 투여량의 문제를 해결할 수 있도록 한다. 이러한 특정 경우에서, 항정-상태 혈장 수준은 약리학적 임계 파라미터이며; 여기서 혈장 농도의 정확한 시간 경로는 이차적인 것이다. 본 발명에 따라, 적합한 물질 조합이 보통 유전자형 또는 표현형 별로 결정되며, 이 조합은 기준과 비교하여 상기 유전자형 또는 표현형의 차이를 보완한다.
투여형으로서, 상업적으로 구입가능한 20 mg 타목시펜 정제 제제를 1일 1회 투여하는 것을 기준으로 삼았으며, 어떤 제제도 제제 때문에 지연되거나 지체되지 않는다. 이러한 투여형은, 예를 들어, 양쪽 경우에 섹션 6.1에서 아스트라 제네카의 Nolvadex® 20 mg 필름-코팅된 정제 또는 라티오팜의 Tamoxifen-ratiopharm® 10 mg/20 mg/30 mg 정제에 대한 제품 정보에 기재되어 있다.
본 실시예는 CYP2D6 PM에서 20 mg의 타목시펜 및 3 mg의 엔독시펜으로 구성된 복합제가 CYP2D6 EM에서 20 mg의 타목시펜을 단독 투여하는 경우와 유사한 타목시펜, N-데스메틸타목시펜, 4-하이드록시타목시펜 및 엔독시펜의 혈장 수준을 초래하는 것을 보여줄 수 있다. CYP2D6 IM에서는, 20 mg의 타목시펜 및 1 mg의 엔독시펜 복합제가 최적인 것으로 밝혀졌다(도 5-7).
따라서, 본 발명은 추가로 다음을 제공한다:
- 15-25 mg의 타목시펜 및 0.25-5.0 mg의 엔독시펜을 포함하는 고정-용량 복합제.
더욱 특히 다음을 제공한다:
- 15-25 mg의 타목시펜 및 0.25-2.00 mg의 엔독시펜, 더욱 특히 18-22 mg의 타목시펜 및 0.5-1.5 mg의 엔독시펜, 특히 바람직하게 20 mg의 타목시펜 및 1.0 mg의 엔독시펜을 포함하는 CYP2D6 IM 환자용 고정-용량 복합제(도 8Ab) 및
- 15-25 mg의 타목시펜 및 1.0-5.0 mg의 엔독시펜, 더욱 특히 18-22 mg의 타목시펜 및 2.0-4.0 mg의 엔독시펜, 더욱 특히 20 mg의 타목시펜 및 3.0 mg의 엔독시펜을 포함하는 CYP2D6 PM 환자용 고정-용량 복합제(도 8Ac).
본 발명에 따른 제제의 추가 구성요소는 상기 언급된 선행기술에 공지되어 있다. 본 발명에 따른 제제를 제조하기 위하여, 그중에서도 특히, 아스트라 제네카의 Nolvadex® 20 mg 필름-코팅된 정제 또는 라티오팜의 Tamoxifen-rationpharm® 10 mg/20 mg/30 mg 정제에 대한 제품 정보 및 Ahmad, A. 등의 엔독시펜, 유방암 요법의 새로운 초석: 건강한 인간 대상에서의 안전성, 용인성 및 전신 생물학적 이용성에 대한 입증(Clin Pharmacol Ther, 2010. 88(6): p. 814-7 bzw. US 2009-0291134 A1)으로부터의 제제를 사용한다.
유방암 환자에서 더 높은 엔독시펜 노출을 달성하기 위하여, 과거에는 타목시펜 용량도 실험을 기초로 하여 증가시켰다. CYP2D6 EM에서 효과적인 1일 20 mg의 타목시펜 대신에 CYP2D6 IM 및 PM에서 2명분의 용량인 1일 40 mg 이하의 타목시펜을 투여하였다. 그러나, 이와 같이 모물질의 용량을 심하게 증가시켰음에도 20 mg 타목시펜의 치료 용량 후 CYP2D6 EM에서 관찰되는 엔독시펜 농도에 이르지 못하였다[Irvin, W.J., Jr., et al., Genotype-Guided Tamoxifen Dosing Increases Active Metabolite Exposure in Women With Reduced CYP2D6 Metabolism: A Multicenter Study. J Clin Oncol, 2011. 29(24): p. 3232-9.]. 따라서, 기재된 타목시펜 및 엔독시펜의 유전자형- 또는 표현형-특이적 복합 투여의 특별한 이점은 CP2D6 EM과 비교하여 CYP2D6 IM 및 PM에서의 타목시펜 노출이 크게 상승하지 않는다는 점이다(과학계에서 현재 전파되고 있는 타목시펜 용량의 증가와 대조적으로).
그러나, 타목시펜(및 유사하게, CYP2D6 PM 및 IM에서 타목시펜 및 엔독시펜의 전파된 비-고정-용량 복합 요법)은 장기간(전형적으로 5년)에 걸쳐 1일 1회 섭취되어야 하므로, 잠재적인 복합 요법의 두 번째 어려움은 최상의 가능한 순응도를 확보하는 것이다. 약물 요법의 경우 순응도(및 이에 따른 치료 성공)는 섭취되어야 하는 정제 개수에 따라 떨어지는 것으로 알려져 있다. 이러한 이유로, 타목시펜과 엔독시펜을 조합하여 FDC를 형성하는 것이 유리하다. 그러면, FDC는 단일 투여형(예: 정제 또는 캡슐제)의 형태로 CYP2D6 유전자형 또는 표현형(PM 또는 IM)에 따라 각 경우에 정의된 용량의 2가지 활성 성분을 함유한다.
따라서, 본 발명의 추가로 바람직한 구체예는 각 경우에 상기 언급된 비율의 타목시펜 및 엔독시펜의 유전자형- 또는 표현형-특이적 고정-용량 복합제이다.
타목시펜/엔독시펜의 예를 사용하여 보여진 접근법은 또한 모물질과 그의 형성이 유전자형 또는 표현형 특이성에 의해 그리고 앞에서 이미 언급된 "표현형 카핑"의 현상에 의해 영향을 받는 하나(또는 그 이상)의 대사물의 기타 복합제에도 쉽게 적용될 수 있다. 더욱 특히, 코데인 작용의 최적화를 위하여, FDC, 더욱 정확히 코데인과 몰핀(코데인으로부터 그의 변환도 마찬가지로 CYP2D6에 의해 촉매된다)의 유전자형- 또는 표현형-특이적 FDC가 응용될 수 있다.
추가의 잠재적인 후보물질의 예는, 그중에서도 특히, 다음과 같다: 에즐로피탄트, 도네페질, 클로피도그렐, 사이클로포스파미드, 아자티오프린, 이리노테칸, 레플루노미드, 카페시타빈, 프라수그렐, 벤라팍신, 로사르탄, 톨테로딘, 트라마돌, 옥시코돈, 하이드로코돈, 독소루비신, 미코페놀레이트 모페틸, 에스트라무스틴, 이포스파미드, 겜시타빈, 에토포시드, 테르페나딘, 메토트렉세이트.
모물질 및 하나 이상의 대사물을 함유하는, 기재된 약제학적 제제 발명, 바람직하게 FDC는 기타 활성-성분 후보물질에 쉽게 적용될 수 있다. 상술된 타목시펜-엔독시펜 예에서, 문제는 CYP2D6 IM 또는 PM 표현형을 나타내는 환자에서 타목시펜이 엔독시펜으로 불충분하게 변환되는 것이다. 예시적으로 나타낸 바와 같이, 고정된 복합 약제학적 제제에서 CYP2D6 IM 또는 CYP2D6 PM에 대한 유전자형- 또는 표현형-특이적 엔독시펜 용량과 모물질의 표준 용량의 배합은 이러한 불충분함을 만회할 수 있으며, 요법 반응에서의 차이가 제거된다.
본질적으로, 모물질 및 하나 이상의 대사물로 구성된 유전자형- 또는 표현형-특이적 약제학적 제제, 바람직하게 FDC의 원리는 먼저 다형성 효소, 단백질, 수용체 또는 운반자로 인하여 하나 이상의 활성 대사물로 변환되고/되거나 결합되고/되거나 운반되고/되거나 이들의 약력학적 작용이 발생하는 모든 모물질에 적용될 수 있다.
다형성 효소를 통해 모물질이 활성 대사물로 변환되는 추가 예는 클로피도그렐이다. 클로피도그렐은 그의 활성 대사물로 변환된 후, 당단백질 IIb/IIIa 수용체 복합체를 통해 ADP-의존성 혈소판 활성화를 차단함으로써 혈액 응고를 저해한다. 클로피도그렐은 그중에서도 특히 다형성 효소 CYP2C19를 통해 그의 활성 대사물로 변환된다. CYP2C19는 현저한 유전자 다형성을 나타낸다. 따라서, CYP2D6와 유사하게, CYP2C19 PM이 개체군에서 발견될 수 있다. 여기에서도 CYP2C19 PM 유전자형 또는 표현형을 나타내는 환자가 클로피도그렐을 사용하는 요법으로부터 충분히 이익을 얻지 못하리라고 의심하는 것이 합리적이다[Simon T, Bhatt DL, Bergougnan L, Farenc C, Pearson K, Perrin L, Vicaut E, Lacreta F, Hurbin F, Dubar M.; Genetic polymorphisms and the impact of a higher clopidogrel dose regimen on active metabolite exposure and antiplatelet response in healthy subjects., Clin Pharmacol Ther. 2011 Aug;90(2):287-95.; Lee JB, Lee KA, Lee KY.; Cytochrome P450 2C19 polymorphism is associated with reduced clopidogrel response in cerebrovascular disease. Yonsei Med J. 2011 Sep;52(5):734-8.; Kazui M, Nishiya Y, Ishizuka T, Hagihara K, Farid NA, Okazaki O, Ikeda T, Kurihara A.; Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite. Drug Metab Dispos. 2010 Jan;38(1):92-9.; Savi P, Pereillo JM, Uzabiaga MF, Combalbert J, Picard C, Maffrand JP, Pascal M, Herbert JM.; Identification and biological activity of the active metabolite of clopidogrel. Thromb Haemost. 2000 Nov, 84(5):891-6.; Cervinski MA, Schwab MC, Lefferts JA, Lewis LD, Lebel KA, Tyropolis AM, Pflueger SM, Tsongalis GJ.; Establishment of a CYP2C19 genotyping assay for clinical use. Am J Clin Pathol. 2013 Feb, 139(2):202-7; Frelinger AL 3rd, Lee RD, Mulford DJ, Wu J, Nudurupati S, Nigam A, Brooks JK, Bhatt DL, Michelson AD.; A randomized, 2-period, crossover design study to assess the effects of dexlansoprazole, lansoprazole, esomeprazole, and omeprazole on the steady-state pharmacokinetics and pharmacodynamics of clopidogrel in healthy volunteers. J Am Coll Cardiol. 2012 Apr 3, 59(14):1304-11.; Gong IY, Crown N, Suen CM, Schwarz UI, Dresser GK, Knauer MJ, Sugiyama D, Degorter MK, Woolsey S, Tirona RG, Kim RB.; Clarifying the importance of CYP2C19 and PON1 in the mechanism of clopidogrel bioactivation and in vivo antiplatelet response. Eur Heart J. 2012 Nov, 33(22):2856-2464a.; Mega JL, Hochholzer W, Frelinger AL 3rd, Kluk MJ, Angiolillo DJ, Kereiakes DJ, Isserman S, Rogers WJ, Ruff CT, Contant C, Pencina MJ, Scirica BM, Longtine JA, Michelson AD, Sabatine MS.; Dosing clopidogrel based on CYP2C19 genotype and the effect on platelet reactivity in patients with stable cardiovascular disease. JAMA. 2011 Nov 23, 306(20):2221-8.; Zabalza M, Subirana I, Sala J, Lluis-Ganella C, Lucas G, Tomas M, Masia R, Marrugat J, Brugada R, Elosua R.; Meta-analyses of the association between cytochrome CYP2C19 loss- and gain-of-function polymorphisms and cardiovascular outcomes in patients with coronary artery disease treated with clopidogrel. Heart. 2012 Jan;98(2):100-8., Yamamoto K, Hokimoto S, Chitose T, Morita K, Ono T, Kaikita K, Tsujita K, Abe T, Deguchi M, Miyagawa H, Saruwatari J, Sumida H, Sugiyama S, Nakagawa K, Ogawa H., Impact of CYP2C19 polymorphism on residual platelet reactivity in patients with coronary heart disease during antiplatelet therapy. J Cardiol. 2011 Mar;57(2):194-201.; Jin B, Ni HC, Shen W, Li J, Shi HM, Li Y.; Cytochrome P450 2C19 polymorphism is associated with poor clinical outcomes in coronary artery disease patients treated with clopidogrel. Mol Biol Rep. 2011 Mar;38(3):1697-702., Shuldiner AR, O'Connell JR, Bliden KP, Gandhi A, Ryan K, Horenstein RB, Damcott CM, Pakyz R, Tantry US, Gibson Q, Pollin TI, Post W, Parsa A, Mitchell BD, Faraday N, Herzog W, Gurbel PA.; Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA. 2009 Aug 26, 302(8):849-57.; Sibbing D, Stegherr J, Latz W, Koch W, Mehilli J, Doerrler K, Morath T, Schoemig A, Kastrati A, von Beckerath N.; Cytochrome P450 2C19 loss-of-function polymorphism and stent thrombosis following percutaneous coronary intervention. Eur Heart J. 2009 Apr, 30(8):916-22.; Hulot JS, Bura A, Villard E, Azizi M, Remones V, Goyenvalle C, Aiach M, Lechat P, Gaussem P.; Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood. 2006 Oct 1, 108(7):2244-7.]. 본 발명에 따른 개념을 사용하여, 이 경우에도 CYP2C19 PM에서 활성 대사물의 불충분한 형성을 만회하기 위하여 클로피도그렐 및 그의 활성 대사물로 구성된 유전자형- 또는 표현형-특이적 약제학적 제제, 바람직하게 FDC를 계산할 수 있다.
최적의 기준 항정-상태 혈장 수준을 결정하기 위하여, 결정된 데이터, 또는 기준 용량의 입력 후 혈장 수준을 계산할 수 있는 약동학적 모델, 예컨대 PK-Sim® 및 MoBi®를 사용할 수 있다.
또한, 모물질 및 하나 이상의 대사물로 구성된 유전자형- 또는 표현형-특이적 약제학적 제제, 바람직하게 FDC의 원리는 저해되고/유도될 수 있는 효소, 단백질, 수용체 또는 운반자를 사용하여 하나 이상의 활성 대사물로 변환되고/되거나 결합되고/되거나 운반되고/되거나 이들의 약력학적 작용이 발생하는 모든 모물질에 적용될 수 있다.
타목시펜 및 CYP2D6 저해제 파록세틴의 예를 사용하여 앞에서 이미 자세히 설명한 바와 같이, 약제학적 성분 A 및 약제학적 성분 B(여기에서 A의 전반적인 작용을 발생시키기 위해 이는 효소를 통해 활성 대사물로 변환되어야 하고 B는 상기 효소를 저해한다)의 요구되는 동시 투여는 사실상 환자를 EM 유전자형 또는 표현형으로부터 PM 유전자형 또는 표현형으로 변환시킬 수 있다. 의학적으로 표시된 파록세틴의 동시 투여의 결과, 환자는 사실상 CYP2D6 PM으로 변환되며, 이에 따라 타목시펜은 엔독시펜으로 덜 변환될 수 있다. 상술한 개념을 사용하여, 여기에서도 파록세틴에 의해 유발된 CYP2D6의 저해로 인하여 타목시펜으로부터 엔독시펜이 불충분하게 형성되는 것을 만회할 수 있는, 타목시펜 및 엔독시펜으로 구성된 유전자형- 또는 표현형-특이적 약제학적 제제, 바람직하게 FDC를 계산하는 것이 가능하다.
유사하게, 본 발명에 따른 개념은 필요하며 의학적으로 표시된 클로피도그렐 및 경쟁적인 CYP2C19 저해제 오메프라졸의 동시 투여의 경우에 적용가능하다. 상술된 개념 및 방법을 사용하여 클로피도그렐 및 그의 활성 대사물로 구성된 유전자형- 또는 표현형-특이적 약제학적 제제, 바람직하게 FDC를 계산함으로써 클로피도그렐의 그의 활성 대사물로의 결과적인 변환 감소가 마찬가지로 만회될 수 있다.
상술된 개념은 또한 동일하거나 상이한 효소 또는 단백질 또는 수용체 또는 운반자를 이들의 활성 측면에서 부가적으로 감소/증가시키는 효소 저해 및/또는 효소 유도와 유전자 다형성의 조합을 보완할 수 있다. 이는 타목시펜 요법을 받는 중이며 부가적으로 파록세틴의 투여를 필요로 하는, CYP2D6 PM 유전자형 또는 표현형을 나타내는 환자의 예를 사용하여 예시적으로 설명된다. CYP2D6를 통해 타목시펜으로부터 엔독시펜이 형성되는 것에 대한 효과는 상술한 원리에 의해 고려될 수 있으며, 타목시펜 및 엔독시펜으로 구성된 최적의 유전자형- 또는 표현형-특이적 약제학적 제제, 바람직하게 FDC가 계산될 수 있다. 유사하게, 이는 클로피도그렐 요법 하에 CYP2C19 PM 유전자형 또는 표현형을 나타내며 현재 오메프라졸의 투여를 필요로 하는 환자의 예를 사용하여 이해될 수도 있다.
도면들은 타목시펜 요법에 대한 본 발명의 개념을 설명하며, 실시예로서 본 발명에 따른 방법에 따라 PK-Sim®을 사용하여 얻어지는 타목시펜/엔독시펜 FDC 용량 결과를 보여주지만, 상기 실시예로 개념이 한정되지는 않는다.
도 1은 인체내 타목시펜에 대한 복잡한 생체내 변화 도식으로부터의 초록을 보여준다. 타목시펜의 약 90%가 N-데스메틸타목시펜으로 대사되고 약 7%가 4-하이드록시타목시펜으로 대사된다. N-데스메틸타목시펜으로부터 전적으로 다형성 사이토크롬 P450 (CYP) 2D6를 통해 엔독시펜이 형성된다. 타목시펜으로부터 4-하이드록시타목시펜의 형성은 약 50% 정도까지 다형성 CYP2D6를 통해 일어난다. 따라서, CYP2D6는 필수적인 엔독시펜 형성 단계에 주로 관여한다[Coller, J. K., N. Krebsfaenger, et al. (2002). "The influence of CYP2B6, CYP2C9 and CYP2D6 genotypes on the formation of the potent antioestrogen Z-4-hydroxy-tamoxifen in human liver." Br J Clin Pharmacol 54(2): 157-167.; Desta, Z., B. A. Ward, et al. (2004). "Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6." J Pharmacol Exp Ther 310(3): 1062-1075.; Kaku, T., K. Ogura, et al. (2004). "Quaternary ammonium-linked glucuronidation of tamoxifen by human liver microsomes and UDP-glucuronosyltransferase 1A4." Biochem Pharmacol 67(11): 2093-2102.; Murdter, T. E., W. Schroth, et al. (2011). "Activity levels of tamoxifen metabolites at the estrogen receptor and the impact of genetic polymorphisms of phase I and II enzymes on their concentration levels in plasma." Clin Pharmacol Ther 89(5): 708-717.; Nishiyama, T., K. Ogura, et al. (2002). "Reverse geometrical selectivity in glucuronidation and sulfation of cis- and trans-4-hydroxytamoxifens by human liver UDP-glucuronosyltransferases and sulfotransferases." Biochem Pharmacol 63(10): 1817-1830.; Sun, D., G. Chen, et al. (2006). "Characterization of tamoxifen and 4-hydroxytamoxifen glucuronidation by human UGT1A4 variants." Breast Cancer Res 8(4): R50.; Sun, D., A. K. Sharma, et al. (2007). "Glucuronidation of active tamoxifen metabolites by the human UDP glucuronosyltransferases." Drug Metab Dispos 35(11): 2006-2014.]
도 2는 CYP2D6 광범위 대사자(EM), 중간 대사자(IM) 또는 느린 대사자(PM) 표현형의 환자에서 타목시펜 요법과 관련하여 엔독시펜의 사이토크롬 P450 (CYP) 2D6 유전자형- 또는 표현형-의존성 항정-상태 농도를 보여준다. 엔독시펜 농도의 유전자 투여량 효과는 명백하다: 2가지 작용성 CYP2D6 대립 유전자를 갖는 환자(EM)는 단지 한가지 CYP2D6 작용성 대립 유전자를 갖는 환자(IM) 또는 작용성 CYP2D6 대립 유전자를 갖지 않는 환자(PM)보다 뚜렷하게 더 높은 엔독시펜 노출을 보여준다[(좌측 상단에서부터 우측 하단으로의) 도면: [Kiyotani, K., T. Mushiroda, et al. (2010). "Significant effect of polymorphisms in CYP2D6 and ABCC2 on clinical outcomes of adjuvant tamoxifen therapy for breast cancer patients." J Clin Oncol 28(8): 1287-1293.; Murdter, T. E., W. Schroth, et al. (2011). "Activity levels of tamoxifen metabolites at the estrogen receptor and the impact of genetic polymorphisms of phase I and II enzymes on their concentration levels in plasma." Clin Pharmacol Ther 89(5): 708-717.; Lim, J. S., X. A. Chen, et al. (2011). "Impact of CYP2D6, CYP3A5, CYP2C9 and CYP2C19 polymorphisms on tamoxifen pharmacokinetics in Asian breast cancer patients." Br J Clin Pharmacol 71(5): 737-750.; Lim, H. S., H. Ju Lee, et al. (2007). "Clinical implications of CYP2D6 genotypes predictive of tamoxifen pharmacokinetics in metastatic breast cancer." J Clin Oncol 25(25): 3837-3845.; Borges, S., Z. Desta, et al. (2006). "Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism: implication for optimization of breast cancer treatment." Clin Pharmacol Ther 80(1): 61-74.; Jin, Y., Z. Desta, et al. (2005). "CYP2D6 Genotype, Antidepressant Use, and Tamoxifen Metabolism During Adjuvant Breast Cancer Treatment." Journal of the National Cancer Institute 97(1): 30-39.]
도 3은 사이토크롬 P450 (CYP) 2D6 광범위 대사자(EM), 중간 대사자(IM), 또는 느린 대사자(PM) 유전자형 또는 표현형에 따른 타목시펜 요법 하의 유방암 환자에 대한 무재발 생존 곡선(카플란-마이어)를 보여준다[(그룹 1 내지 3)으로부터의 도면: Schroth, W., M. P. Goetz, et al. (2009). "Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with tamoxifen." JAMA 302(13): 1429-1436.; Goetz, M. P., S. K. Knox, et al. (2007). "The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen." Breast Cancer Res Treat 101(1): 113-121.; Goetz, M. P., J. M. Rae, et al. (2005). "Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes." J Clin Oncol 23(36): 9312-9318.]
도 4는 모물질 타목시펜의 투여 후 N-데스메틸타목시펜, 4-하이드록시타목시펜 및 엔독시펜의 사이토크롬 P450 (CYP) 2D6 유전자형- 또는 표현형-특이적 형성의 시뮬레이션을 위해, 또는 CYP2D6 유전자형 또는 표현형에 따른 타목시펜 및 엔독시펜의 동시 투여 시뮬레이션을 위해, PK-Sim®에서 사용된 커플링된 생리학적 약동학(PBPK) 모델의 구획 도표 및 얻어진 혈청 농도를 보여준다. 간의 세포내 구획에서, 타목시펜은 N-데스메틸타목시펜 및 4-하이드록시타목시펜을 생성하므로, 타목시펜 PBPK 모델은 2가지 일차적인 대사물에 대한 발생 기능으로 작용한다. 유사하게, 이차적인 대사물 엔독시펜은 N-데스메틸타목시펜 및 4-하이드록시타목시펜의 PBPK 모델의 세포내 구획에서 생성된다.
도 5a는 CYP2D6 광범위 대사자, 중간 대사자 및 느린 대사자(EM/IM/PM) 유전자형 또는 표현형 개체군에서 타목시펜(TAM), N-데스메틸타목시펜(NDM), 4-하이드록시타목시펜(4OH), 엔독시펜(END)에 대한 커플링된 PBPK 모델을 보여준다. 사이토크롬 P450 (CYP) 2D6 광범위 대사자(EM), 중간 대사자(IM) 및 느린 대사자(PM) 유전자형 또는 표현형의 유럽 여성의 예시적인 개체군에서 1년 동안 20 mg의 타목시펜을 1일 1회 투여한 후의 타목시펜, N-데스메틸타목시펜, 4-하이드록시타목시펜 및 엔독시펜의 항정-상태 혈장 농도. 박스-앤-위스커 플롯(Box-and-whisker plot)은 각 개체군의 5, 25, 50, 75 및 95 백분위수를 보여준다. 기호들은 모델 유효화를 위한 실험 데이터를 나타낸다[좌측에서 우측으로: Gjerde, J. Geisler, et al. (2010). "Associations between tamoxifen, estrogens, and FSH serum levels during steady state tamoxifen treatment of postmenopausal women with breast cancer." BMC Cancer 10: 313.; Gjerde, J., M. Hauglid, et al. (2008). "Effects of CYP2D6 and SULT1A1 genotypes including SULT1A1 gene copy number on tamoxifen metabolism." Ann Oncol 19(1): 56-61.; Madlensky, L., L. Natarajan, et al. (2011). "Tamoxifen metabolite concentrations, CYP2D6 genotype, and breast cancer outcomes." Clin Pharmacol Ther 89(5): 718-725.; Murdter, T. E., W. Schroth, et al. (2011). "Activity levels of tamoxifen metabolites at the estrogen receptor and the impact of genetic polymorphisms of phase I and II enzymes on their concentration levels in plasma." Clin Pharmacol Ther 89(5): 708-717.; Irvin, W. J., Jr., C. M. Walko, et al. (2011). "Genotype-Guided Tamoxifen Dosing Increases Active Metabolite Exposure in Women With Reduced CYP2D6 Metabolism: A Multicenter Study." J Clin Oncol 29(24): 3232-3239.]. 도 5b는 대안적인 묘사를 보여준다.
도 6a는 CYP2D6 IM 환자에서 타목시펜과의 동시 투여를 위해 본 발명에 따른 방법에 따라 PK-Sim®을 사용하여 발견한 엔독시펜 용량 결과를 보여준다. 도 6a는 CYP2D6 EM 유전자형 또는 표현형 환자로부터의 실험 데이터와 비교하여 사이토크롬 P450 (CYP) 2D6 광범위 대사자(EM) 또는 중간 대사자(IM) 유전자형 또는 표현형을 지닌 유럽 환자의 예시적인 개체군에서 1년 동안 매일 20 mg의 타목시펜을 1일 1회 투여한 후의 타목시펜(TAM), N-데스메틸타목시펜(NDM), 4-하이드록시타목시펜(4OH) 및 엔독시펜(END)의 항정-상태 혈장 농도를 보여준다. 1년 동안, 부가적으로, 20 mg의 타목시펜 플러스 0.5 mg 또는 1 mg 또는 1.5 mg의 엔독시펜을 1일 1회 동시 투여한 후 CYP2D6 IM 유전자형 또는 표현형의 유럽 환자의 예시적인 개체군에서 타목시펜, N-데스메틸타목시펜, 4-하이드록시타목시펜 및 엔독시펜의 항정-상태 혈장 농도. 20 mg의 타목시펜 플러스 1 mg의 엔독시펜을 수령한 CYP2D6 IM 환자는 1년 동안 1일 1회 20 mg의 타목시펜을 수령한 CYP2D6 EM 환자에 대해 균등한 엔독시펜 농도를 보였다[좌측으로부터 우측으로: Gjerde, J. Geisler, et al. (2010). "Associations between tamoxifen, estrogens, and FSH serum levels during steady state tamoxifen treatment of postmenopausal women with breast cancer." BMC Cancer 10: 313.; Gjerde, J., M. Hauglid, et al. (2008). "Effects of CYP2D6 and SULT1A1 genotypes including SULT1A1 gene copy number on tamoxifen metabolism." Ann Oncol 19(1): 56-61.; Madlensky, L., L. Natarajan, et al. (2011). "Tamoxifen metabolite concentrations, CYP2D6 genotype, and breast cancer outcomes." Clin Pharmacol Ther 89(5): 718-725.; Murdter, T. E., W. Schroth, et al. (2011). "Activity levels of tamoxifen metabolites at the estrogen receptor and the impact of genetic polymorphisms of phase I and II enzymes on their concentration levels in plasma." Clin Pharmacol Ther 89(5): 708-717.; Irvin, W. J., Jr., C. M. Walko, et al. (2011). "Genotype-Guided Tamoxifen Dosing Increases Active Metabolite Exposure in Women With Reduced CYP2D6 Metabolism: A Multicenter Study." J Clin Oncol 29(24): 3232-3239]. 도 6b는 대안적인 묘사를 보여준다. 중간값(암회색 라인)을 동반하는 회색 밴드(5-95 백분위수)로 나타낸, 1년 동안 20 mg의 타목시펜을 1일 1회 투여한 후 CYP2D6 EM 유전자형 또는 표현형의 유럽 환자에서 타목시펜(TAM), N-데스메틸타목시펜(NDM), 4-하이드록시타목시펜(4OH) 및 엔독시펜(END)의 결정된 항정-상태 최저(trough) 혈장 농도를 비교를 위해 제공하였다. 20 mg의 타목시펜 플러스 1 mg의 엔독시펜을 수령한 CYP2D6 IM 환자는 1년 동안 1일 1회 20 mg의 타목시펜을 수령한 CYP2D6 EM 환자에 대해 균등한 엔독시펜 농도를 보였다.
도 7a는 CYP2D6 PM 환자에서 1일 1회 타목시펜과의 동시 투여를 위해 본 발명에 따른 방법에 따라 PK-Sim®을 사용하여 발견한 엔독시펜 용량의 결과를 보여준다. 도 7a는 CYP2D6 EM 유전자형 또는 표현형 환자로부터의 실험 데이터와 비교하여 사이토크롬 P450 (CYP) 2D6 광범위 대사자(EM) 또는 느린 대사자(PM) 유전자형 또는 표현형을 지닌 유럽 환자의 예시적인 개체군에서 1년 동안 20 mg의 타목시펜을 1일 1회 투여한 후의 타목시펜(TAM), N-데스메틸타목시펜(NDM), 4-하이드록시타목시펜(4OH) 및 엔독시펜(END)의 항정-상태 혈장 농도를 보여준다. 1년 동안, 부가적으로, 20 mg의 타목시펜 플러스 1 mg 또는 2 mg 또는 3 mg 또는 4 mg의 엔독시펜을 동시 투여한 후 CYP2D6 PM 유전자형 또는 표현형의 유럽 환자의 예시적인 개체군에서 타목시펜, N-데스메틸타목시펜, 4-하이드록시타목시펜 및 엔독시펜의 항정-상태 혈장 농도. 20 mg의 타목시펜 플러스 3 mg의 엔독시펜을 수령한 CYP2D6 PM 환자는 1년 동안 1일 1회 20 mg의 타목시펜을 수령한 CYP2D6 EM 환자에 대해 균등한 엔독시펜 농도를 보였다[좌측으로부터 우측으로: Gjerde, J. Geisler, et al. (2010). "Associations between tamoxifen, estrogens, and FSH serum levels during steady state tamoxifen treatment of postmenopausal women with breast cancer." BMC Cancer 10: 313.; Gjerde, J., M. Hauglid, et al. (2008). "Effects of CYP2D6 and SULT1A1 genotypes including SULT1A1 gene copy number on tamoxifen metabolism." Ann Oncol 19(1): 56-61.; Madlensky, L., L. Natarajan, et al. (2011). "Tamoxifen metabolite concentrations, CYP2D6 genotype, and breast cancer outcomes." Clin Pharmacol Ther 89(5): 718-725.; Murdter, T. E., W. Schroth, et al. (2011). "Activity levels of tamoxifen metabolites at the estrogen receptor and the impact of genetic polymorphisms of phase I and II enzymes on their concentration levels in plasma." Clin Pharmacol Ther 89(5): 708-717.; Irvin, W. J., Jr., C. M. Walko, et al. (2011). "Genotype-Guided Tamoxifen Dosing Increases Active Metabolite Exposure in Women With Reduced CYP2D6 Metabolism: A Multicenter Study." J Clin Oncol 29(24): 3232-3239.]. 도 7b는 대안적인 묘사를 보여준다. 중간값(암회색 라인)을 동반하는 회색 밴드(5-95 백분위수)로 나타낸, 1년 동안 20 mg의 타목시펜을 1일 1회 투여한 후 CYP2D6 EM 유전자형 또는 표현형의 유럽 환자에서 타목시펜(TAM), N-데스메틸타목시펜(NDM), 4-하이드록시타목시펜(4OH) 및 엔독시펜(END)의 예비-결정된 항정-상태 최저 혈장 농도를 비교를 위해 제공하였다. 20 mg의 타목시펜 플러스 3 mg의 엔독시펜을 수령한 CYP2D6 PM 환자는 1년 동안 1일 1회 20 mg의 타목시펜을 수령한 CYP2D6 EM 환자에 대해 균등한 엔독시펜 농도를 보였다.
도 8은 개별복용 복합제(loose combination)(A) 또는 FDC(B)로서 타목시펜 및 엔독시펜의 유전자형- 또는 표현형-기준 투약을 보여준다.
도 9 및 10은 PK-Sim®의 모듈 디자인의 도표를 보여준다.
도 11 내지 14는 CYP2D6 EM 및 IM에 대한 PBPK 모델을 사용하여 조직적으로 조사된 것으로서, 엔독시펜 항정-상태 농도를 얻는데 대한 20 mg 타목시펜 및 3 mg 엔독시펜의 고정 복합제를 사용한 초기 유방암 요법의 영향을 보여준다.
도 11은 CYP2D6 EM 환자에서 타목시펜과 엔독시펜의 동시 투여를 위해 본 발명에 따른 방법에 따라 PK-Sim®을 사용한 로딩 용량 연구 결과를 보여준다. 도 11은 사이토크롬 P450 (CYP) 2D6 광범위 대사자(EM) 유전자형 또는 표현형을 나타내는 유럽 환자에서 20 mg의 타목시펜과 3 mg의 엔독시펜을 1일 1회 동시 투여한 후 타목시펜(TAM), N-데스메틸타목시펜(NDM), 4-하이드록시타목시펜(4OH) 및 엔독시펜(END)의 최저 혈장 농도를 보여준다. 중간값(암회색 라인)을 동반하는 회색 밴드(5-95 백분위수)로 나타낸, 1년 동안 20 mg의 타목시펜을 1일 1회 투여한 후 CYP2D6 EM 유전자형 또는 표현형의 유럽 환자에서 타목시펜(TAM), N-데스메틸타목시펜(NDM), 4-하이드록시타목시펜(4OH) 및 엔독시펜(END)의 예비-결정된 항정-상태 최저 혈장 농도를 비교를 위해 제공하였다. 표준 요법 하의 CYP2D6 EM 유전자형 또는 표현형의 유럽 환자로 구성된 예시적인 개체군에서 엔독시펜 농도의 중간 최저 수준이 처음으로 중간 최저-수준 엔독시펜 농도를 초과한 날의 하루전을 시점으로 취하였으며, 이 경우에 제9일이었다.
도 12는 CYP2D6 EM 환자에서 타목시펜과 엔독시펜의 동시 투여를 위해 본 발명에 따른 방법에 따라 PK-Sim®을 사용한 로딩-용량 제어 연구 결과를 보여준다. 도 12는 사이토크롬 P450 (CYP) 2D6 광범위 대사자(EM) 유전자형 또는 표현형을 나타내는 유럽 환자에서 20 mg의 타목시펜을 1일 1회 동시 투여한 후 타목시펜(TAM), N-데스메틸타목시펜(NDM), 4-하이드록시타목시펜(4OH) 및 엔독시펜(END)의 최저 혈장 농도를 보여준다. 중간값(암회색 라인)을 동반하는 회색 밴드(5-95 백분위수)로 나타낸, 1년 동안 20 mg의 타목시펜을 1일 1회 투여한 후 CYP2D6 EM 유전자형 또는 표현형의 유럽 환자에서 타목시펜(TAM), N-데스메틸타목시펜(NDM), 4-하이드록시타목시펜(4OH) 및 엔독시펜(END)의 예비-결정된 항정-상태 최저 혈장 농도를 비교를 위해 제공하였다. 표준 요법 하의 CYP2D6 EM 유전자형 또는 표현형의 유럽 환자로 구성된 예시적인 개체군에서 엔독시펜 농도의 중간 최저 수준이 처음으로 중간 최저-수준 엔독시펜 농도에 도달한 날을 시점으로 취하였으며, 이 경우에 제120일이었다.
도 13은 CYP2D6 IM 환자에서 타목시펜과 엔독시펜의 동시 투여를 위해 본 발명에 따른 방법에 따라 PK-Sim®을 사용한 로딩 용량 연구 결과를 보여준다. 도 13은 사이토크롬 P450 (CYP) 2D6 중간 대사자(IM) 유전자형 또는 표현형을 나타내는 유럽 환자에서 20 mg의 타목시펜과 3 mg의 엔독시펜을 1일 1회 동시 투여한 후 타목시펜(TAM), N-데스메틸타목시펜(NDM), 4-하이드록시타목시펜(4OH) 및 엔독시펜(END)의 최저 혈장 농도를 보여준다. 중간값(암회색 라인)을 동반하는 회색 밴드(5-95 백분위수)로 나타낸, 1년 동안 20 mg의 타목시펜을 1일 1회 투여한 후 CYP2D6 EM 유전자형 또는 표현형의 유럽 환자에서 타목시펜(TAM), N-데스메틸타목시펜(NDM), 4-하이드록시타목시펜(4OH) 및 엔독시펜(END)의 예비-결정된 항정-상태 최저 혈장 농도를 비교를 위해 제공하였다. 표준 요법 하의 CYP2D6 EM 유전자형 또는 표현형의 유럽 환자로 구성된 예시적인 개체군에서 엔독시펜 농도의 중간 최저 수준이 처음으로 중간 최저-수준 엔독시펜 농도를 초과한 날의 하루전을 시점으로 취하였으며, 이 경우에 제13일이었다.
도 14는 CYP2D6 IM 환자에서 타목시펜과 엔독시펜의 동시 투여를 위해 본 발명에 따른 방법에 따라 PK-Sim®을 사용한 로딩 용량 제어 연구 결과를 보여준다. 도 14는 사이토크롬 P450 (CYP) 2D6 중간 대사자(IM) 유전자형 또는 표현형을 나타내는 유럽 환자에서 20 mg의 타목시펜과 1 mg의 엔독시펜을 1일 1회 동시 투여한 후 타목시펜(TAM), N-데스메틸타목시펜(NDM), 4-하이드록시타목시펜(4OH) 및 엔독시펜(END)의 최저 혈장 농도를 보여준다. 중간값(암회색 라인)을 동반하는 회색 밴드(5-95 백분위수)로 나타낸, 1년 동안 20 mg의 타목시펜을 1일 1회 투여한 후 CYP2D6 EM 유전자형 또는 표현형의 유럽 환자에서 타목시펜(TAM), N-데스메틸타목시펜(NDM), 4-하이드록시타목시펜(4OH) 및 엔독시펜(END)의 예비-결정된 항정-상태 최저 혈장 농도를 비교를 위해 제공하였다. 표준 요법 하의 CYP2D6 EM 유전자형 또는 표현형의 유럽 환자로 구성된 예시적인 개체군에서 엔독시펜 농도의 중간 최저 수준이 처음으로 중간 최저-수준 엔독시펜 농도에 도달한 날을 시점으로 취하였으며, 이 경우에 제67일이었다.
요약하면, CYP2D6 EM에서의 20 mg 타목시펜 투여 또는 IM에서 본 발명에 따라 20 mg 타목시펜과 1 mg 엔독시펜의 투여 및 CYP2D6 EM 또는 IM에서 20 mg 타목시펜과 3 mg 엔독시펜의 본 발명에 따른 투여 사이의 직접적인 비교를 통해 표준 용량(EM의 경우 20 mg 타목시펜, 및 본 발명에 따라 20 mg 타목시펜과 1 mg 엔독시펜으로 구성)에 비해 FDC(20 mg 타목시펜과 3 mg 엔독시펜으로 구성)를 투여한 경우 실질적으로 평균 약 111일 또는 54일 더 빨리 엔독시펜 항정-상태 농도에 도달함을 명백히 알 수 있다.
도 15 내지 18은 불이행 조사에서의 시뮬레이션을 보여준다. 하기 시나리오들이 시뮬레이션되었다.
도 15는 CYP2D6 EM 환자에서 타목시펜과 엔독시펜의 동시 투여를 위해 본 발명에 따른 방법에 따라 PK-Sim®을 사용한 순응도-용량 연구(compliance-dose study) 결과를 보여준다. 도 15는 사이토크롬 P450 (CYP) 2D6 광범위 대사자(EM) 유전자형 또는 표현형을 나타내는 유럽 환자에서 6개월간 1일 1회의 20 mg 타목시펜 투여 및 기간 중 2, 4, 8 및 12주의 휴약 기간 후 타목시펜(TAM), N-데스메틸타목시펜(NDM), 4-하이드록시타목시펜(4OH) 및 엔독시펜(END)의 최저 혈장 농도를 보여준다. 그 다음에 20 mg 타목시펜과 3 mg 엔독시펜을 1일 1회 동시 투여하였다. 중간값(암회색 라인)을 동반하는 회색 밴드(5-95 백분위수)로 나타낸, 1년 동안 20 mg의 타목시펜을 1일 1회 투여한 후 CYP2D6 EM 유전자형 또는 표현형의 유럽 환자에서 타목시펜(TAM), N-데스메틸타목시펜(NDM), 4-하이드록시타목시펜(4OH) 및 엔독시펜(END)의 예비-결정된 항정-상태 최저 혈장 농도를 비교를 위해 제공하였다. 표준 요법 하의 CYP2D6 EM 유전자형 또는 표현형의 유럽 환자로 구성된 예시적인 개체군에서 엔독시펜 농도의 중간 최저 수준이 처음으로 중간 최저-수준 엔독시펜 농도를 초과한 날의 하루전을 시점으로 취하였으며, 이 경우에, 2-주 휴약 기간의 경우 FDC 섭취 개시 후 제2일, 4-주 휴약 기간의 경우 FDC 섭취 개시 후 제3일, 8-주 휴약 기간의 경우 FDC 섭취 개시 후 제7일, 12-주 휴약 기간의 경우 FDC 섭취 개시 후 제9일이었다.
도 16은 CYP2D6 EM 환자에서 타목시펜과 엔독시펜의 동시 투여를 위해 본 발명에 따른 방법에 따라 PK-Sim®을 사용한 순응도-용량 제어 연구(compliance-dose control study) 결과를 보여준다. 도 16은 사이토크롬 P450 (CYP) 2D6 광범위 대사자(EM) 유전자형 또는 표현형을 나타내는 유럽 환자에서 6개월간 1일 1회의 20 mg 타목시펜 투여 및 기간 중 2, 4, 8 및 12주의 휴약 기간 후 타목시펜(TAM), N-데스메틸타목시펜(NDM), 4-하이드록시타목시펜(4OH) 및 엔독시펜(END)의 최저 혈장 농도를 보여준다. 그 다음에 20 mg 타목시펜을 1일 1회 투여하였다. 중간값(암회색 라인)을 동반하는 회색 밴드(5-95 백분위수)로 나타낸, 1년 동안 20 mg의 타목시펜을 1일 1회 투여한 후 CYP2D6 EM 유전자형 또는 표현형의 유럽 환자에서 타목시펜(TAM), N-데스메틸타목시펜(NDM), 4-하이드록시타목시펜(4OH) 및 엔독시펜(END)의 예비-결정된 항정-상태 최저 혈장 농도를 비교를 위해 제공하였다. 표준 요법 하의 CYP2D6 EM 유전자형 또는 표현형의 유럽 환자로 구성된 예시적인 개체군에서 엔독시펜 농도의 중간 최저 수준이 처음으로 중간 최저-수준 엔독시펜 농도에 도달한 날을 시점으로 취하였으며, 이 경우에, 2-주 휴약 기간의 경우 FDC 섭취 개시 후 제269일, 4-주 휴약 기간의 경우 FDC 섭취 개시 후 제334일, 8-주 휴약 기간의 경우 FDC 섭취 개시 후 제>336일, 12-주 휴약 기간의 경우 FDC 섭취 개시 후 제>336일이었다.
도 17은 CYP2D6 IM 환자에서 타목시펜과 엔독시펜의 동시 투여를 위해 본 발명에 따른 방법에 따라 PK-Sim®을 사용한 순응도-용량 연구 결과를 보여준다. 도 17은 사이토크롬 P450 (CYP) 2D6 중간 대사자(IM) 유전자형 또는 표현형을 나타내는 유럽 환자에서 6개월간 1일 1회의 20 mg 타목시펜 및 1 mg 엔독시펜의 동시 투여 및 기간 중 2, 4, 8 및 12주의 휴약 기간 후 타목시펜(TAM), N-데스메틸타목시펜(NDM), 4-하이드록시타목시펜(4OH) 및 엔독시펜(END)의 최저 혈장 농도를 보여준다. 그 다음에 20 mg 타목시펜과 3 mg 엔독시펜을 1일 1회 동시 투여하였다. 중간값(암회색 라인)을 동반하는 회색 밴드(5-95 백분위수)로 나타낸, 1년 동안 20 mg의 타목시펜을 1일 1회 투여한 후 CYP2D6 EM 유전자형 또는 표현형의 유럽 환자에서 타목시펜(TAM), N-데스메틸타목시펜(NDM), 4-하이드록시타목시펜(4OH) 및 엔독시펜(END)의 예비-결정된 항정-상태 최저 혈장 농도를 비교를 위해 제공하였다. 표준 요법 하의 CYP2D6 EM 유전자형 또는 표현형의 유럽 환자로 구성된 예시적인 개체군에서 엔독시펜 농도의 중간 최저 수준이 처음으로 중간 최저-수준 엔독시펜 농도를 초과한 날의 하루전을 시점으로 취하였으며, 이 경우에, 2-주 휴약 기간의 경우 FDC 섭취 개시 후 제4일, 4-주 휴약 기간의 경우 FDC 섭취 개시 후 제7일, 8-주 휴약 기간의 경우 FDC 섭취 개시 후 제10일, 12-주 휴약 기간의 경우 FDC 섭취 개시 후 제11일이었다.
도 18은 CYP2D6 IM 환자에서 타목시펜과 엔독시펜의 동시 투여를 위해 본 발명에 따른 방법에 따라 PK-Sim®을 사용한 순응도-용량 제어 연구 결과를 보여준다. 도 18은 사이토크롬 P450 (CYP) 2D6 중간 대사자(IM) 유전자형 또는 표현형을 나타내는 유럽 환자에서 6개월간 1일 1회의 20 mg 타목시펜 및 1 mg 엔독시펜의 동시 투여 및 기간 중 2, 4, 8 및 12주의 휴약 기간 후 타목시펜(TAM), N-데스메틸타목시펜(NDM), 4-하이드록시타목시펜(4OH) 및 엔독시펜(END)의 최저 혈장 농도를 보여준다. 그 다음에 20 mg 타목시펜과 1 mg 엔독시펜을 1일 1회 동시 투여하였다. 중간값(암회색 라인)을 동반하는 회색 밴드(5-95 백분위수)로 나타낸, 1년 동안 20 mg의 타목시펜을 1일 1회 투여한 후 CYP2D6 EM 유전자형 또는 표현형의 유럽 환자에서 타목시펜(TAM), N-데스메틸타목시펜(NDM), 4-하이드록시타목시펜(4OH) 및 엔독시펜(END)의 예비-결정된 항정-상태 최저 혈장 농도를 비교를 위해 제공하였다. 표준 요법 하의 CYP2D6 EM 유전자형 또는 표현형의 유럽 환자로 구성된 예시적인 개체군에서 엔독시펜 농도의 중간 최저 수준이 처음으로 중간 최저-수준 엔독시펜 농도에 도달한 날을 시점으로 취하였으며, 이 경우에, 2-주 휴약 기간의 경우 FDC 섭취 개시 후 제217일, 4-주 휴약 기간의 경우 FDC 섭취 개시 후 제250일, 8-주 휴약 기간의 경우 FDC 섭취 개시 후 제283일, 12-주 휴약 기간의 경우 FDC 섭취 개시 후 제315일이었다.
요약하면, 도 15 내지 18의 시뮬레이션 결과는 20 mg 타목시펜과 3 mg 엔독시펜의 고정 복합 투여가 불이행의 경우에도 엔독시펜의 효과적인 항정-상태 농도에 이르는 속도를 높이는데 유리함을 보여준다.
Claims (7)
- 작용이 발현된 단백질 변이체, 효소 변이체, 수용체 변이체 또는 운반자 변이체의 양 또는 활성에 의존하는 모물질, 및 적어도 하나의 그의 대사물을 함유하는 고정-용량 복합 약제학적 제제.
- 제1항에 있어서, 투여량이 유전자형- 또는 표현형-특이적 방식으로 정의되는 제제.
- 제1항 또는 제2항에 있어서, 타목시펜 및 엔독시펜을 포함하는 제제.
- 제3항에 있어서, 15-25 mg의 타목시펜 및 0.25-5.0 mg의 엔독시펜을 포함하는 제제.
- 제4항에 있어서, 15-25 mg의 타목시펜 및 0.25-2.00 mg의 엔독시펜을 포함하는 CYP2D6 IM 환자용 제제.
- 제4항에 있어서, 15-25 mg의 타목시펜 및 1.0-5.0 mg의 엔독시펜을 포함하는 CYP2D6 PM 환자용 제제.
- 하기 단계를 포함하는, 제1항 내지 제4항 중 어느 한 항에 따른 고정-용량 복합 약제학적 제제의 제조 방법:
a) 유기체, 그의 유전자형 또는 표현형, 모물질 및 모물질의 적어도 하나의 대사물, 모물질을 단독으로 전달하는 경우 기준 유전자형 또는 기준 표현형에 대한 모물질의 최적의 기준 항정-상태 혈장 수준을 입력 모듈(input module) 내로 입력하는 단계,
b) a) 및 b)로부터의 데이터를 물질 데이터 모듈, 유기체 데이터 모듈, 유전자형 데이터 모듈 또는 표현형 데이터 모듈, 및 생리학적 약동학 모델(physiologically based pharmacokinetic model)을 포함하는 계산 모듈 내로 전송하며, 여기에서 물질 데이터 모듈은 물질의 물리화학적 및/또는 생화학적 특성에 관한 데이터를 포함하고, 유기체 모듈은 유기체의 구획(compartment)에 관한 데이터를 포함하며, 유전자형 데이터 모듈 또는 표현형 데이터 모듈은 유전자형- 또는 표현형-특이적 데이터를 포함하는 단계,
c) 물질 데이터 모듈로부터 모물질 및 대사물-특이적 데이터를 자동적으로 선택하는 단계,
d) 입력 a)를 기초로 하여 유기체 데이터 모듈로부터 유기체-특이적 데이터를 자동적으로 선택하는 단계,
e) 유전자형 데이터 모듈 또는 표현형 데이터 모듈로부터 유전자형-특이적 또는 표현형-특이적 데이터를 자동적으로 선택하는 단계,
f) a) 내지 e)로부터 선택된 데이터를 생리학적 약동학 모델 내로 전송하는 단계,
g) 생리학적 약동학 모델을 사용하여, a)로부터의 모물질에 대해 입력된 최적의 기준 혈장 수준에 이르기 위하여 기준 유전자형 또는 기준 표현형에 대한 모물질의 최적화된 투여량을 계산하는 단계,
h) g)에서 계산된 모물질 용량을 투여하는 경우에 기준 유전자형 또는 기준 표현형에 대한 대사물들의 기준 항정-상태 혈장 수준을 계산하는 단계,
i) g)에서 계산된 모물질 용량을 투여하는 경우에 상응하는 기준 혈장 수준에 관하여 유전자형 또는 표현형으로 인하여 감소된 대사물들의 혈장 수준을 계산하는 단계,
j) h)로부터의 대사물들의 기준 혈장 수준 및 a)로부터의 모물질의 기준 혈장 수준의 조합 획득을 위한 대사물 용량 및 모물질 용량을 계산하는 단계,
k) 출력 모듈을 통해 고정-용량 복합 약제학적 제제에 대한 대사물 용량 및 모물질 용량을 출력하고/하거나 약제의 투여를 위해 j)에서 계산된 용량을 자동화 장치 내로 전송하는 단계.
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