審議結果報告書 平成 28 - pmda.go.jp

1 28 11 16 .. 25 mg .. 28 3 31 .. 28 11 11 .. 10 .. 28 10 18 .. 25 mg .. 28 3 31 . 1 28 mg . 25 mg . 1 .. NH2. O CH3. N O H. N N. P O CH3 CO2H. N N O O CH. H HO2C. 3. H. CH3. 2. (C21H29N6O5P)2 C4H4O4.. N-[(S)-{[(1R)-2-(6- -9H- -9- )-1- ] } ]-L- . 1- .. 1-Methylethyl N-[(S)-{[(1R)-2-(6-amino-9H-purin-9-yl)- 1-methylethoxy]methyl}phenoxyphosphinoyl ]-L- alaninate hemifumarate 28 4 12 0412 2 .. B .. B B B .. 1 25mg 1 1 .. 2.. 1 . 28 9 6 .. 25 mg .. 28 3 31 . 1 28 mg . 25 mg . B B . B . 1 25mg . 28mg 1 1 .. 1. 1.. 4. 2.. 5. 3.. 6. 4.. 8. 5.. 9. 6. 10. 7.. 16. 8.. 33. 9. 1 .. 33.. ADV Adefovir pivoxil . ALT Alanine aminotransferase . ATV Atazanavir . AUC Area under the plasma concentration versus . time curve AUCinf AUC extrapolated to infinite time 0 AUC.

2 AUClast AUC from time of administration up to the 0 . last time point with a measurable AUC. concentration after dosing AUCtau AUC over the dosing interval AUC. BCRP Breast Cancer Resistance Protein . BID bis in die 1 2 . CC50 Drug concentration that results in a 50% 50% . reduction in cell viability CLcr Creatinine clearance . CL/F Apparent clearance . CLr Renal clearance . Cmax Maximum plasma concentration . COBI Cobicistat . Ctau Observed drug concentration at the end of . the dosing interval CYP Cytochrome P450 P450. CV Coefficient of valiation . DRV Darunavir . DTG Dolutegravir . EC50 50% effective concentration 50% . efflux Basal-to-apical versus apical-to-basal ratio .. eGFRCG Estimated glomerular filtration rate Cockcroft-Gault.

3 Calculated using the Cockcroft-Gault equation ETV Entecavir . EVG Elvitegravir . FAS Full analysis set . HBV Hepatitis B virus B . HCV Hepatitis C virus C . HIV Human immunodeficiency virus . LAM Lamivudine . LPV Lopinavir . MedDRA/J Medical Dictionary for Regulatory ICH . Activities Japanese version OATP Organic anion transporting polypeptide . OCT Organic cation transporter . P-gp P-glycoprotein P . PK Pharmacokinetics . PPK Population pharmacokinetics . QD quaque die 1 1 . RPV Rilpivirine . RT Reverse transcriptase . 2.. RTV Ritonavir . tmax Time to maximum plasma concentration . t1/2 Estimate of the terminal elimination half- . life TAF Tenofovir alafenamide . TDF Tenofovir disoproxil fumarate . TFV Tenofovir . Vc/F Apparent volume of distribution central.

4 Compartment . Vd/F Apparent volume of distribution . Vp/F Apparent volume of distribution peripheral . compartment . B B , .. , 2016 5 .. 0108 GS-US-320-0108 . 0110 GS-US-320-0110 . HBe Hepatitis B e antigen HBs Hepatitis B surface antigen . 25 mg 3. 1.. TAF Gilead Sciences . TFV HBV DNA HIV-1 . TAF TFV . TDF 300 mg B TDF HIV-1.. TAF TFV 1 . TAF 1 CES1 A CatA . TFV TDF TFV . 1 . 1 TAF TFV . HBV HBV 150 . 1 B Lancet 2015; 386: 1546-55 Hepatol Res 2011;41: 1-21 . HBV 15 40% . Guidelines for the Prevention, Care and Treatment of Persons with Chronic Hepatitis B Infection, WHO, 2015 Am J Gastroenterol, 2006, 101: S1-S6 . B .. B 2016 1 . TAF HIV-1 . 2016 6 . 300 mg .. 1 . TAF 25 mg 300 mg TDF 300 mg TFV . 92% . 4. 2.. TAF MF MF 227MF10232.

5 1 TAF mg TAF 25 mg .. 85F120028 .. 1 . 1 .. 3 . 36 . 30 . 1 . 30 75%RH 18 . 30 . 3 . 12 . 14 . 6 . 6 . 30 . 40 75%RH. 3 . 6 . 14 . 30 . 36 14 12 . 14 30 . 14 30 . 36 .. 5.. 3.. 300 mg .. in vitro CTD . HBV pHY92 HepG2 . TAF 2 HepG2 . TAF CC50 44,400 nmol/L . 2 A H TAF . HBV a EC50 nmol/L . pHY92 A A B C. D. E F pol/RT pol/RT G. pol/RT H pol/RT . a A H HBV . pol/RT . HepG2 . ADV LAM ETV Gastroenterology 2006; 131: 1743-51 Gastroenterology 2003; 125: 1714-22 HBV HepG2 . TAF 3 . 6. 3 ADV LAM ETV HBV TAF . EC50 nmol/L a . RT . TAF TFV LAM ETV TAF TFV LAM ETV. rtA181T/sW172*b . rtA181T/sW172L . ADV rtA181V . rtN236T . rtA181V + rtN236T . rtM204I >200 > . LAM rtL180M + rtM204V >200 > . rtV173L + rtL180M + rtM204V >200 > . rtL180M + rtM204V + rtT184G >500 > ETV rtL180M + rtM204V + rtS202G >500 > rtL180M + rtM204V + rtM250V >500 >.

6 A EC50 EC50 b rtA181T HBs W172 .. TAF HBV CTD . HBV HepAD38 TAF HBV . 4 . 4 HepAD38 TAF HBV . a TAF b . HIV DRV mol/L mol/L HCV Boceprevirc mol/L mol/L CYP3A COBI mol/L mol/L Xa . mol/L mol/L . mol/L -4 mol/L a Cmax 25% . Cmax . b TAF EC50 TAF EC50. c Boceprevir . HepAD38 TAF HBV A 1. 5 TAF HBV A . mol/L 1 Bis- p-nitrophenyl phosphate 50 mol/L Bis- p-nitrophenyl phosphate TAF HBV . 5 HepAD38 TAF HBV A 1 . a . A 1 Bis-p-nitrophenyl phosphate A 1 Bis-p-nitrophenyl phosphate a EC50 EC50. TAF HCV CTD . HCV 1a Huh-7 HCV . TAF TAF . NS3/4A boceprevir NS5B . NS5A GS-5816 HCV EC50 TAF. 7. TAF CC50 .. TAF HBV . TAF HBV . TAF . TAF . TAF TDF TFV TFV .. 0108 0110. TAF TDF B . 6 TDF TDF . Hepatology 2014;59:434-42 TAF. TFV TDF TDF. TAF TAF.

7 TAF . TAF TDF TAF TDF . TAF .. 4.. 300 mg . TAF TFV . TFV TFV . / TFV nmol/L TFV pmol/106 cells . TAF .. CTD . TAF mol/L OATP1B1 OATP1B3 . TFV OATP . 20 mol/L 13% OATP . 38% TAF OATP . TAF .. P-gp MDCK TFV mol/L . P-gp MDCK efflux P-gp . A 10 mol/L P-gp MDCK efflux . TFV P-gp . 8. BCRP MDCK TFV mol/L . efflux BCRP Ko134 10 mol/L . BCRP MDCK efflux TFV BCRP .. OCT2 CHO TFV 1 10 mol/L . 2 20 OCT2 CHO CHO . TFV 1 mol/L TFV 10 mol/L . TFV OCT2 . CTD . BCRP MDCK OATP1B1 OATP1B3 CHO BCRP OATP1B1 . OATP1B3 TFV IC50 100 mol/L . OCT1 CHO BSEP OCT1 BSEP . TFV IC50 100 mol/L .. TAF TFV .. 5.. B .. TAF 25 mg/ TAF TFV . AUClast 267 392 ng h/mL Cmax 284 ng/mL . TAF 10 mg/ TAF TFV .. AUCtau 206 293 ng h/mL Cmax 162 ng/mL. ng/mL 28 5 19.

8 TAF TDF . TAF . TDF .. 14 12. 16 1216001 . TAF . 9. TAF .. TAF 2 . TDF 3 TFV . TAF 25 mg QD TFV . AUCtau . 392 ng h/mL TDF 300 mg QD AUC 3224 ng h/mL .. 6.. 3 1 3 4 3 . 1 TAF 8 25 40 mg TAF . 2 TAF 10 25 mg TAF . 3 TAF 25 mg TAF . 3 .. TAF TFV / .. TAF 1 ng/mL TFV 5 ng/mL PK . TAF . CTD GS-US-320-1382 20 20 . PK 40 800 kcal . 50% 5 3 TAF 25 mg 2 2 . 6 TAF . Cmax AUCinf 90% , , tmax . 6 3 PK . Cmax tmaxa AUCinf t1/2 CL/F Vd/F.. ng/mL h ng h/mL h L/h L . 39 - . 40 - . CV% a . 2 . 4 4 CTD . 26 CTD . 39 CTD 28. 5 19 . 3 . 300 mg 16 2 6 . 4 . 1 GS-US-320-0101 2 GS-US-120-0117 3 GS-US-120-1538. GS-US-120-1554 GS-US-320-1228 GS-US-320-0108 GS-US-320-0110 . 10.. B .. PPK .. PK .. CTD GS-US-320-1228 20 20 . PK 10 TAF 25mg . TAF TFV PK 7 TAF TFV.

9 Cmax AUCinf . 7 TAF TAF TFV PK . Cmax tmaxa AUCinf t1/2.. ng/mL h ng h/mL h . TAF PK . 10 - . 10 - b b . TFV PK . 10 - . 10 - . CV% a b 9 .. CTD GS-US-320-0101 2011 12 2013 4 . B PK 51 TAF 8 120 mg TDF 300 mg QD 28 . 1 TAF TFV PK 2 28 . 1 PK 8 TAF Cmax AUCinf 8. 120 mg TAF TFV . 10 10 29 TFV TDF. 300 mg 29 120 mg .. 8 TAF TDF TAF TFV PK . mg Cmax ng/mL tmaxa h AUCinf ng h/mL t1/2 h . TAF PK . 8 10 - . 25 10 - . TAF. 40 11 - . 120 10 1,129 - . TFV PK . 8 10 - . 25 10 - . TAF. 40 11 - . 120 10 - 1,518 . TDF 300 10 - 2,268 . CV% a . CTD GS-US-320-0110 2013 8 . B 7 TDF 6 TAF 25 mg TDF 300 mg QD TAF TFV . 11. TFV PK TAF 25 mg TAF TFV Cmax tmax . AUClast TAF 284 ng/mL 267 ng h/mL TFV ng/mL 392 ng h/mL TFV pg/106. cells TDF 300 mg TFV Cmax tmax AUClast 389 ng/mL 3224 ng h/mL TFV pg/106.

10 Cells . PPK CTD . HIV-1 5 B . GS-US-320-0101 0108 0110 TAF TFV PK TAF . 1,268 5,333 TFV 1,462 10,938 PPK NONMEM version . TAF TFV 0 1 2 . 6 . TAF . ATV/RTV . ATV/RTV LPV/RTV Vc/F HIV . TFV . ATV/RTV DRV/RTV . ATV/RTV LPV/RTV DRV/RTV Vc/F CLcr . Vp/F CLcr CL/F CLcr . HIV HBV HBV . HIV HBV 7 . B TAF 25 mg QD TAF . TFV Cmax AUC TAF ng/mL ng h/mL TFV . ng/mL ng h/mL . CTD . PPK 0108 0110 B . TAF Cmax AUCtau TAF Cmax AUCtau . 8 0108. 0110 . TAF Cmax AUCtau . B TAF TFV Cmax AUCtau . 0108 0110 .. TAF TFV Cmax AUCtau . TAF Cmax AUCtau TFV Cmax AUCtau . 5 . GS-US-120-0107 GS-US-120-0108 GS-US-120-0109 GS-US-120-0117 GS-US-120-0118 . GS-US-292-0101 GS-US-320-1228 HIV-1 GS-US-120-0104 GS-US-311-1089 . 6 . 0 D1 1 ka . 7 . TAF TFV ATV/RTV LPV/RTV DRV/RTV.