135 /180 /, 135 /0.5 180 /0.5 Pegasys vials 135mcg/ml, 180 mcg/ml Pegasys prefilled syringes 135mcg/0.5ml, 180 mcg/0.5ml 1. (vial) (prefilled syringe) 1.0ml 135mcg Peginterferon alfa-2a 1.0ml 180mcg Peginterferon alfa-2a Peginterferon alfa-2a Peginterferon alfa-2a 2. Peginterferon alfa-2a 3. 3.1 B : HBeAg HBeAg B C : ribavirin C 3.2 3.2.1 B HBeAg HBeAg B 180mcg 48 C 1
ribavirin 180mcg ribavirin, ribavirin ( 1) 1. ribavirin 1, 4* 180 <75 = 1000 75 = 1200 2, 3 180 800 24 * 4 (N=49) 1 12 : HCV RNA HCV RNA 2 log10 ( 2) 2. 1 (N= 569) 12 ( ) ( ) 12 12 102 97 95% (97/102) 467 271 58% (271/467) 2, 3 (N=96) 3 3 100% (3/3) 93 81 98% 87% (81/93) 3.2.2 / 135mcg 90mcg 45mcg absolute neutrophil count ANC 750 /mm 3 ANC 500 /mm 3 ANC 1000 /mm 3 90mcg 50,000/mm 3 90mcg 25,000/ 2
mm 3 ALT C ALT 135mcg ALT B ALT 10 ALT ALT ribavirin ribavirin 600 / (200 400 ): <10 g/dl 8.5 g/dl 2 g/dl ribavirin : <8.5 g/dl <12 g/dl ribavirin ribavirin 600 / 800 / ribavirin (1000 1200 ) ribavirin 135mcg ribavirin ribavirin 18 (benzyl alcohol) 3
Child Pugh A Child Pugh B/C Child-Pugh 5-6, 7-9 10-15, A, B, C, " ", " " " " S-Bilirubin (mg/dl) None 1 1-2 2 3-4* 3 <2 2-3 >3 1 2 3 1 2 3 <34 SI unit = µmol/l) 34-51 >51 S-Albumin (g/dl) >3.5 3.5-2.8 <2.8 INR <1.7 1.7-2.3 >2.3 1 2 3 1 2 3 1 2 3 * Trey, Burns and Saunders (1966) 3.3 PEG polyethyleneglycol /ribavirin /ribavirin ribavirin 4
3.4 /ribavirin /ribavirin 2 4 ribavirin ribavirin /ribavirin (WBC) (ANC) 2 4 8 ANC 750 /mm 3 ANC 500 /mm 3 ANC 1000 /mm 3 /ribavirin ANC /ribavirin 50,000/mm 3 25,000/mm 3 /ribavirin1000 1200 13 % <10g/dl ; /ribavirin 800 24 3 % ribavirin ribavirin ribavirin (CBC) <1500 /mm 3 <90,000mm 3 <12 g/dl /ribavirin /ribavirin 5
( ) /ribavirin ribavirin /ribavirin /ribavirin /ribavirin /ribavirin /ribavirin /ribavirin cotton wool spots, ( ) /ribavirin ribavirin, C 6, ribavirin /ribavirin ribavirin /ribavirin ribavirin /ribavirin 6
C : /ribavirin ALT ALT B:HBV HCV ALT HBV 10 3.5 ribavirin C ribavirin lamivudine HBV lamivudine 180mcg 4 tolbutamide (CYP 2C9) mephenytoin (CYP 2C19) debrisoqiune (CYP 2D6) dapsone (CYP 3A4) P450 1A2 theophylline AUC 25% theophylline P450 /ribavirin theophylline theophylline theophylline 3.6 3.6.1 (fertility) peginterferon -2a 17 - (estradiol) (progesterone) -2a 25x10 6 IU/ 5 teratogenic -2a ribavirin ribavirin /ribavirin 7
ribavirin, 6 2 /ribavirin ribavirin 3.6.2 ribavirin ribavirin 3.6.3 (metabolic activation) peginterferon -2a (clastogenic) ribavirin 3.7 3.8 /ribavirin 3.8.1 /ribavirin /ribavirin B 48 24 B C B 3 88% lamivudine 53% 6% lamivudine 4% 5% 1% lamivudine lamivudine C 9 % /ribavirin 1000/1200 48 13 % 1 % 3% 8
/ribavirin 1000/1200 /ribavirin 24 ribavirin 800 (11% 3%) (13% 5%) ribavirin 39% 19% 3 ribavirin >10% 3 >10% 9
B C 180mg* 180mg 180mg + 180mg + 800mg 1000/1200 mg ribavirin ribavirin alfa-2b + 1000/1200 m g ribavirin (WV16240 + WV16241) (NV15801 + monotherapy program) 24 (NV15942) (NV15801 + NV15942) (NV15801) N=448 N=827 N=207 N=887 N=443 % % % % % 13 16 20 27 26 4 5 2 7 10 6 20 30 32 37 4 18 17 21 28 3 17 28 24 27 2 9 8 10 13 3 6 8 8 12 23 52 48 47 49 ( ) 6 15 13 15 14 1 5 11 13 14 2 4 8 13 7 6 24 29 28 28 6 16 15 14 10 4 15 9 10 9 17 23 25 24 33 6 13 25 21 18 <1 9 15 16 13 1 5 13 12 13 25 37 42 38 49 10 26 20 22 23 21 49 45 49 53 52 35 37 39 54 6 30 30 25 34 7 22 28 21 16 1 11 9 10 9 11 7 18 15 16 10
* 450 lamivudine /ribavirin B C >1% <10% : : : : : : : :, : : :,: : : ribavirin / ( ITP ) ribavirin Pegasys /ribavirin C ribavirin ribavirin /ribavirin 4-8 11
1% /ribavirin 1000/1200 48 10% ANC B C 4% ANC 500 /mm 3 /ribavirin C 5% ANC 500 /mm 3 5% 50,000/mm 3 75,000/mm 3 B 14% 50,000/mm3 /ribavirin C 3%(25/835) 3.9 1260mcg/ 540mcg 630mcg Copegus (ribavirin) 4. 12
4.1 Pegylated -2a PEG (bis-monomethoxypolyethylene glycol) -2a (interferon alfa-2a) -2a DNA PEG 40kDa PEG ribavirin ribavirin 4.1.1-2a C C (HCV) RNA 24-36 4-16 180mcg (effector) neopterin2-5 -oligoadenylate?? 135-180mcg 2-5 -oligoadenylate? 2-5 -oligoadenylate? 62 20-40 / 2-5 -oligoadenylate? 4.1.2 / B B HBeAg HBeAg /anti-hbe B HBV DNA ALT WV16240 HBeAg WV16241 HBeAg anti-hbe 48 24 lamivudine lamivudine HBV-HIV HBV DNA COBAS AMPLICOR HBV MONITOR 200 copies/ml 13
4. B HBeAg WV16240???????? 180 mcg 180 mcg Lamivudine 100 mg (N=271) (N=271) HBeAg Lamivudine 100 mg (N=272) HBeAg / anti-hbe WV16241???????? 180 mcg 180 mcg Lamivudine 100 mg (N=177) (N=179) Lamivudine 100 mg (N=181) 32% 1 27% 19% N/A N/A N/A HBV DNA* 32% 2 34% 22% 43% 5 44% 29% ALT 41% 3 39% 28% 59% 6 60% 44% HBsAg 3% 4 3% 0% 3% 2% 0% * HBeAg HBV DNA < 10 5 copies/ml HBeAg /anti-hbe HBV DNA < 2 x 10 4 copies/ml 1 2 3 lamivudine Odds Ratio (95% CI) = 2.00 (1.34 2.97) p ( Cochran-Mantel-Haenszel ) < 0.001 lamivudine (95% CI) = 1.64 (1.12 2.42) p ( Cochran-Mantel-Haenszel ) = 0.012 lamivudine (95% CI) = 1.77 (1.23 2.54) p ( Cochran-Mantel-Haenszel ) = 0.002 4 p ( Cochran-Mantel-Haenszel ) = 0.002 5 6 lamivudine (95% CI) = 1.84 (1.17 2.89) p ( Cochran-Mantel-Haenszel ) = 0.007 lamivudine (95% CI) = 1.86 (1.22 2.85) p ( Cochran-Mantel-Haenszel ) = 0.004 C ribavirin C HCV RNA,ALT C NV15495 ( 80%) ( 20%) HCV/HIV HCV/HIV, 4 5 2 COBAS AMPLICOR TM HCV Test HCV RNA 100 copies/ml 50 /ml 6 14
5. C NV15496 + NV15497 + NV15801 NV15495 NV15942 NV15801 alfa-2a 180 mcg 180 mcg 180 mcg 180 mcg 3 MIU alfa-2a 6 MIU/3 MIU 3 MIU Ribavirin 1000/1200 mg Ribavirin 1000/1200 mg alfa-2b 3 MIU Ribavirin 1000/1200 mg (N=701) (N=478) (N=87) (N=88) (N=436) (N=453) (N=444) 55-69% 22-28% 44% 14% 68% 69% 52% 28-39% 11-19% 30%* 8%* 63% 54%** 45%** * 95% CI : 11% ~ 33% p ( Cochran-Mantel-Haenszel ) = 0.001 ** 95% CI : 3% ~ 16% p ( Cochran-Mantel-Haenszel ) = 0.003 /ribavirin 5 NV15942 ( 1) / 1 2 3 15
6 / ribavirin C NV15942 NV15801 180 mcg 180 mcg 180 mcg 180 mcg 180 mcg alfa-2b 3 MIU Ribavirin Ribavirin Ribavirin Ribavirin Ribavirin Ribavirin 800 mg 1000/1200 mg 800 mg 1000/1200 mg 1000/1200 mg 1000/1200 mg 24 24 1 29% (29/101) 41% (21/51) 16% (8/50) 42% (49/118)* 52% (37/71) 26% (12/47) 41% (102/250)* 55% (33/60) 36% (69/190) 52% (142/271)* 65% (55/85) 47% (87/186) 45% (134/298) 53% (61/115) 40% (73/182) 36% (103/285) 44% (41/94) 33% (62/189) 2/3 84% (81/96) 81% (117/144) 79% (78/99) 80% (123/153) 71% (100/140) 61% (88/145) 85% (29/34) 83% (39/47) 88% (29/33) 77% (37/48) 76% (28/37) 65% (34/52) 84% (52/62) 80% (78/97) 74% (49/66) 82% (86/105) 70% (72/103) 58% (54/93) 4 (0/5) (8/12) (5/8) (9/11) (10/13) (5/11) * 180 mcg / ribavirin 1000/1200 mg 180 mcg / ribavirin 800 mg : (Odds Ratio) (95% CI) = 1.52 (1.07 ~ 2.17) P ( Cochran-Mantel-Haenszel ) = 0.020 * 180 mcg / ribavirin 1000/1200 mg, 180 mcg / ribavirin 1000/1200 mg, 24 : (Odds Ratio) (95% CI) = 2.12 (1.30 ~ 3.46) P ( Cochran-Mantel-Haenszel ) = 0.002. -2a 4.2 C 4 B C 4.2.1 72-96 180 3-6 24 80% 84% -2a 4.2.2 Vss 6-14 4.2.3 100 / -2a 100 10% peginterferon -2a PEG -2a PEG -2a 4.2.4 (terminal half-life) 3-4 16
60 80 50-130 C 180mcg C 180mcg 6 7 180mcg NV 15496 C 180mcg N=50 180mcg N=16 + + + [ ] [ ] [ ] C max (ng/ml) 14+5 [6-26] 15+4 [7-23] 26+9 [10-40] T max 92+27 [48-168] 80+28 [23-119] 45+36 [0-97] AUC 1-168h (ng h/ml) 1725+586 [524-3013] 1820+586 [846-2609] 3334+994 [1265-4824] /F(ml/h) 94+56 [34-337] 83+50 [33-186] 60+25 [37-142] 48 16+6 (ng/ml) [4-28] 48 1.7+0.4 (AUC /AUC [1.1-2.5] ) 2.3+1.0 [1.1-4.0] C 5~8 2-3 peginterferon -2a 48 1.5-2.0 peginterferon -2a 1 168 [ 1] 1. C 180mcg (NV15496) 180mcg / ribavirin (NV15801) 17
(ng/ml) -- NV15496 --NV15801 48 ribavirin 4.2.5 23 (creatinine clearance) 20~ > 100 ml/min 25%-45% 135 180 ribavirin 180mcg AUC 62 62 B C 4.2.6 18
-2a /ribavirin /ribavirin 5. 5.1 80 (polysorbate 80) 5.2 5.3 5.3.1 2-8 5.3.2 5.3.3, 6. 135mcg 180mcg 135mcg 000765 000766 000788 19
180mcg 000789 100 2004 7 20