In this study, the PK/PD profiles of gemigliptin after multiple oral doses of gemigliptin/metformin FDC extended-release tablets (25/500 mg u2) were predicted by modeling and simulation. The predicted PK/PD results of gemigliptin in the FDC were compared with those of gemigliptin capsules (50 mg). Comparison of inhibition of DPP-4 activity after single or multiple oral administration of 50 mg gemigliptin given as two gemigliptin/metformin 25/500 mg extended-release tablets under fed conditions versus a 50 mg gemigliptin capsule under fasting conditions.
Individual percent inhibition by baseline DPP-4 activity–gemigliptin plasma concentration profiles (left: linear scale; right: semilog scale). Observed versus predicted plasma concentration-time profiles (top, . inset: linear scale) and percent inhibition of DPP-4 activity-time profiles (bottom) of gemigliptin after a single oral administration of 50 mg, given as two fixed-dose tablets of the gemigliptin/metformin sustained-release combination 25/500 mg versus one gemigliptin 50 mg capsule.
LIST OF ABBREVIATIONS
1752'8&7,21
SURSHUWLHV SUHVHQWHG RYHU WKH GRVH UDQJH RI ± PJ DQG D VWHDG\ VWDWH ZDVDSSDUHQWO\DFKLHYHGDIWHUWKHVHFRQGGRVHRI±PJ7KHPXHFDWDL HYHGDIWHUWKHVHFRQGGRVHRI±PJ7KHPHDQDFFXPXODWLRQUDWLRV ZHUH±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
7DNLQJ WKHVH ILQGLQJV WRJHWKHU WKH UHODWLRQVKLS EHWZHHQ 3. DQG 3' WKH SHUFHQW LQKLELWLRQ RI '33 DFWLYLW\ RI JHPLJOLHVKLSWLSWL. IRUPXODWLRQ DIWHU UHSHDWHG GRVHV DV LI LQ FOLQLFDO XVH E\ WKH PRGHOLQJ DQG VLPXODWLRQ FDUULHG RXW LQ WKLV VWXG\ $GGLWLRQDOO. DUWPHQWDODQDO\VLVFDQEHFRPSDUHGZLWKWKRVHIURPDQRQFRPSDUWPHQWDODQDO\VLV 1&$ZKLFKPD\SURYLGHXVHIXOLQIRUPDWLRQZKHQDSSOODWLRQZKHQDSSOODQRQFRPSDUWPHQWDODQDO\VLV .3'SDUDPHWHUVLQFOLQLFDOWULDOVDVKDVEHHQWKHFDVHLQSUHYLRXV VWXGLHV.
2EMHFWLYHV
6LQJOHDQG0XOWLSOH$VFHQGLQJ'RVH6WXGLHVZLWK*HPLJOLSWLQ
SUHGRVHKDQGDW DQGK SRVWGRVHH[FHSWIRUWKHDQGPJ JURXSVLQZKLFKEORRGVDPSOLQJIRU WKH3.DQDO\VLVZDVSHUIRUPHGXSWR KSRVWGRVHQWGDQVGD' GRVHRQ'D\V±DQGSUH GRVHKDQG DQGKSRVW GRVH'D\. SUHGRVHKDQGDW DQG KSRVWGRVH %LRDQDO\WLFDOLQVWLWXWHV 3ODVPDFRQFHQWUDWLRQRI JHPLJOLSWLQ//24,ȝJ/,ȝJ/,ȝJ/,ȝJ/,ȝJ/,ȝJ/,ȝJ/ 3\D2P'PL,ȝ3/2PWLPD ,P2'PLQ 'HPRJUDSKLFFKDUDFWHULVWLFVD $JH\ HDUV>±@>±@>±@ +HLJKWFP>±@>±@>±@ :HLJKWNJ>±@>±@>±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
FKDQJHGDIWHUIRRGLQWDNH%DVHGRQWKLVWKHUDWLRRI.D0.DXQGHUIHGFRPSDUHGWR IDVWHG FRQGLWLRQV ZDV HVWLPDWHG ZLWK ELRDYDLODELOLW\ IL[HG DW XVLQJ WKH HTXDWLRQ UHSRUWHGSUHYLRXVO\$S SHQGL[. WRYDOLGDWHWKHUHOLDELOLW\DQGVWDELOLW\RIWKHPRGHODQRQSDUDPHWULFERRWVWUDSDQDO\VLV ZDVSHUIRUPHG7KHILQDO3.DQG3'SDUDPHWHUVZHUHFRPSDUHGZLWKFRQILGHQFH LQWHUYDOV &,V FDOFXODWHG XVLQJ WKH DQG SHUFHQWLOHV REWDLQHG IURP ERRWVWUDSHVWLPDWLRQV.
L[HG'RVH&RPELQDWLRQRI*HPLJOLSWLQDQG0HWIRUPLQ6WXG\
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
XVLQJ ORJWUDQVIRUPHG GDWD D JHQHUDO OLQHDU PL[HG HIIHFWV PRGHO ZDV GHYHORSHG WR FRPSDUHWKH3.SDUDPHWHUV$8&KDQG&PD[EHWZHHQWPHQHWHDGHD WPHQWZHUHIL[HGHIIHFWVZKHUHDVVXEMHFWVQHVWHGLQVHTXHQFHZDVWKH UDQGRPHIIHFW8VLQJWKHPRGHOWKHJHRPHWULFPHDVVXEMHFWVQHVWHGLQVHTXHQFHZDVWKH UDQGRPHIIHFW8VLQJWKHPRGHOWKHJHRPHWULFPHDQUDWLR*05DQXGWLVGHV )'&WDEOHWVRUDVVHSDUDWHWDEOHWVZHUHHVWLPDWHGIRUWKH3.
RU WKH 3.3' FRPSDULVRQ RI JHPLJOLSWLQ EHWZHHQ FDSVXOHV DQG LQ )'& .. IRUPXODWLRQ3.SDUDPHWHUVLQFOXGLQJ$8&KDIWHUVLQJOHGRVLQJ&PD[DQGDUHDXQGHU WKHSODVPDFRQFHQWUDWLRQWLPHFXUYHZ LWKLQDGRVLQJLQWHUYDO$8&IJDWVWHDG\VWDWHZHUH HVWLPDWHG)RUWKHFRPSDULVRQRI3'SDUDPHWHUV$8(&KDIWHUDVLQJOHGRVH(PD[DQG DUHDXQGHUWKHSHUFHQWLQKLELWLRQRI'33DFWLYLW\WLPHFXUY HZLWKLQDGRVLQJLQWHUYDO.WRWDORIVXEMHFWVFRPSOHWHGWKHVWXG\DIWHUKDYLQJEHHQUDQGRPO\ DVVLJQHGWRRQH RIWKHGRVHJURXSVLQWKHVLQJOHRUPXOWLSOHGRVHVWXGLHV7KHPHDQDJHDQGZHLJKWRI WKHVXEMHFWVZHUH\HDUVUDQJH±\HDUVDQGNJUDQJH±NJ UHVSHFWLYHO\ WKH GHPRJUDSKLF FKDUDFWHULVWLFV RI WKH VXEMHFWV IRU HDFK VWXG\ DUH VXPPDUL]HGLQ7DEOH$PRQJWKHVXEMHFWVDGPLQLVWHUHGZLWKWKHWHVWGUXJZHUH LQFOXGHGIRU3.3'DQDO\VHV .. 3RSXODWLRQ3KDUPDFRNLQHWLF3KDUPDFRG\QDPLF$QDO \VLV.WZRFRPSDUWPHQW PRGHO ZLWK D ILUVWRUGHU DEVRUSWLRQ FRPELQHGZLWK ODJWLPH ZDV VHOHFWHGDVWKHILQDO3.PRGHOEDVHGRQDFRPSDULVRQRIWKHLQGLYLGXDOSORWVGLDJQRVWLF SORWUHVXOWVDQGWKH2)9IURPWKHPRGHOLQJUHVXOWVRIWKHFDQGLGDWH PRGHOV7KHVHOHFWHG ILQDOPRGHOLQFOXGHGH[SRQHQWLDOUDQGRPHIIHFWVIRU,9RQ&/9.DDQG/DJWKH 3.SDUDPHWHUHVWLPDWHVIURPWKHILQDOPRGHODUHVKRZQLQ7DEOH7KHW\SLFDOYDOXHV RI &/ ZHUH JHQHUDOO\ FRQVLV WHQW ZLWK WKH &/).
ODFN OLQH OLQH RI LGHQWLW\ EOXH FLUFOHV REVHUYDWLRQV UHG OLQH /2:(66 ILW 3(5 SHUFHQW LQKLELWLRQ RI '33 DFWLYLW\ IRP WOLKHLXLGHL5: VLGXDOV. Q WKH 93& SHUIRUPHG IRU HYDOXDWLRQ RI WKH VHOHFWHG ILQDO 3 . . HORIWKHDQG PJGRVHJURXSV) LJXUH. GZLWKLQWKH&,VRI WKHFRUUHVSRQGLQJSDUDPHWHUVLQGLFDWLQJWKHUREXVWQHVVVRIWKHILQDOPRGHOVHH7DEOHV DQG.
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amp;PD[RIȝJ/DWDPHGLDQRIKUDQJH±KDIWHUDGPLQLVWUDWLRQ7KH$8&.
K RI JHPLJOLSWLQ DIWHU )'& DGPLQLVWUDWLRQ ZDV a KLJKHU WKDQ WKDW DIWHU PJ JHPLJOLSWLQFDSVXOHDGPLQLVWUDWLRQ,QFRQWUDVWWKHPHDQ&PDQ[DIWGLRQ&PDQLVDGLRQ&PDQLVDGLRQ&PDQLVDGLRQ&PDQGLDQH V VOLJKWO\ ORZHU WKDQ WKDW DIWHU JHPLJOLSWLQ FDSVXOH PJ DGPLQLVWUDWLRQXQGHUIDVWHGFRQGLWLRQVZLWKWKHPHGLDQ7PD[GHOD\HGWRK2QWKH & LVWHULQJVHSDUDWHWDEOHWVRIPJ JHPLJOLSWLQDQGPJPHWIRUPLQZHUHVLPLODUWRWKRVHDIWHUDGPLQVWHULQJDPJ JHPLJOLSWLQ FDSVXOH DOWKRXJK WKH 3. FKDUDFWHULVWLFV RI JHPLJOLSWLQ ZHUH FRPSDUDEOH ZKHQJLYHQDV)'&IRUPXODWLRQRUDVVHSDUDWHWDEOHWVRIPJJHPLJOLSWLQDQG PJ PHWIRUPLQ VLPOHXHVKWHQ 7DEOHXODX7KWHQ 8&K DQG. D*HRPHWULFPHDQUDWLRRIIL[HGGRVHFRPELQDWLRQWRVHSDUDWHWDEOHWVFRQILGHQFHLQWHUYDO 7PD[ WLPH WR UHDFK PD[LPXP EORRG FRQFHQWUDWLRQ DIWHU DGPLQLVJXWUDKHLRQ DIWHU DGPLQLVJXWUDKHLRQ. PD[LPXPSODVPDFRQFHQWUDWLRQRIGUXJ$8&K DUHDXQGHUWKHSODVPDFRQFHQWUDWLRQWLPH FXUYH IURP WR K SRVWGRVH 7PD[VV WLPH WR UHDFK PD[LPXP EORRG FRQFWLRQ DPLXP EORRG FRQFWLRQ JDWVWHDG\VWDWH&PD[VV PD[LPXPSODVPDFRQFHQWUDWLRQRIWKHGUXJDW VWHDG\ VWDWH $8&IJVV DUHD XQGHU WKH SODVPD FRQFHQWUDWLRQWLPH FX8YH WKLWLHQD $QUYH WKLWL DGRVLQJLQWHUYDODWVWHDG\VWDWH .
7DEOH &RPSDULVRQ RI '33 DFWLYLW\ LQKLELWLRQ DIWHU VLQJOH RU PXOWLSOH RUDO DGPLQLVWUDWLRQ RI PJ JHPLJOLSWLQ JLYHQ DV WZR WDEOHWOLSWLWLHPHVX XQGHUIHGFRQGLWLRQVYHUVXVDJHPLJOLSWLQFDSVXOHPJ XQGHUIDVWHGFRQGLWLRQV. 'DWD DUH SUHVHQWHG DV DULWKPHWLF PHDQ VWDQGDUG GHYLDWLRQ )RU REVHUYHG YDOXH PHDQ DQG VWDQGDUGGHYLDWLRQVRILQGLYLGXDOVRQVRILQGLYLGXDOVHWHWHFDGDGD GHYLDWLRQVRI LQGLYLGXDOVWXGLHV.
6&866,21
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
PRGHO7KHLQGLYLGXDOSODVPDFRQFHQWUDWLRQSHUFHQWLQKLELWLRQRI'33DFWLYLW\SURILOHV VXJJHVWWKDWDVLJPRLG(PD[PRGHOLVDSSURSULDWHIRUWKHVLQJOHDQGPXOWLSOHGRVHVWXGLHV ZLWKJHPLJOLSWLQ)LJXU H$GGLWLRQDOO\LQWKHSUHYLRXVVWXGLHVZLWK'33LQKLELWRUV FKDQJHVLQ'33LQKLELWLRQZDVZHOOFRUUHODWHGZLWKSODVPDFRQFHQWUDWLRQE\DVLJPRLG PD[LPDO HIIHFW (PD[ PRGHO 7KH HIIHFW FRPSDU WPHQW DGGHG WR WKH 3. PRGHO LPSURYHGWKHPRGHOILWVHH)LJXUH8VLQJWKLV3.3'PRGHOWKH(&ZDVHVWLPDWHG WREHȝJ/ Q0LQGLFDWLQJWKHKLJKSRWHQF\RIJHPLJOLSWLQFRPSDUHGZLWK RWKHU'33LQKLELWRUV7KLVKLJKSRWHQF\RIJHPLJOLSWLQVXSSRUWVWKHDVVXPSWLRQWKDW WKHPD[LPXPHIIHFWRQ'33LQKLELWLRQ ZDVDFKLHYHGDWDFRQFHQWUDWLRQSULRUWR&PD[. OWKRXJK WKH SUHGLFWHG &PD[ DW VWHDG\ VWDWH IRU JHPLJOLSWLQ ZDV a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
Q WKH SUHVHQW VWXG\ SHUFHQW LQKLELWLRQ RI '33 DFWLYLW\ ZDV XVHG DV D 3' PDUNHUWRUHSUHVHQWKHHIIHFWRIJHPLJOLSWLQ$OWKRXJKWKLVSUR[LPDOELRPDUNHUUHIOHFWV WKH GUXJ¶V PRGH RI DFWLRQ RWKHU G LVWDO RU GLVHDVHUHODWHG ELRPDUNHUV VXFK DV VHUXP JOXFRVHLQVXOLQUHIOHFWLQJȕFHOOUHVSRQVHRUJOXFDJRQUHIOHFWLQJĮ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
5()(5(1&(6
LP.6&KR-<.LP%+HWDO3KDUPDFRNLQHWLFVDQGSKDUPDFRG\QDPLFVRI /&ဨDQRYHOGLSHSWLG\OSHSWLGDVH,9LQKLELWRUDIWHUPXOWLSOHGRVLQJLQ KHDOWK\YROXQWHHUV British Journal of Clinical Pharmacology. 5KHH:
OPHWK\OGLK\GURSXULQHGLRQH%,DQRYHO[DQWKLQHEDVHG GLSHSWLG\OSHSWLGDVHLQKLELWRUKDVDVXSHULRUSRWHQF\DQGORQJHUGXUDWLRQRI DFWLRQFRPSDUHGZLWKRWKHUGLSHSWLG\OSHSWLGDVHLQKLELWRUVThe Journal of pharmacology in experimental therapy.
33(1',&(6
SKDUPDFRNLQHWLFSKDUPDFRG\QDPLFPRGHO
3KDUPDFRNLQHWLFSKDUPDFRG\QDPLF PRGHO IRU VLPXODWLRQV XVLQJ 7ULDO6LPXODWRU #
