1 / 17

Clinical Pharmacology of Boceprevir: Metabolism, Excretion, and Drug-Drug Interactions

Clinical Pharmacology of Boceprevir: Metabolism, Excretion, and Drug-Drug Interactions. C Kasserra, E Hughes, M Treitel, S Gupta, and E O'Mara International Conference on Viral Hepatitis April 11, 2011 Baltimore, MA. Disclosure Statement. Full time employee of Merck and Co.

tfrederick
Download Presentation

Clinical Pharmacology of Boceprevir: Metabolism, Excretion, and Drug-Drug Interactions

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Clinical Pharmacology of Boceprevir: Metabolism, Excretion, and Drug-Drug Interactions C Kasserra, E Hughes, M Treitel, S Gupta, and E O'Mara International Conference on Viral Hepatitis April 11, 2011 Baltimore, MA

  2. Disclosure Statement Full time employee of Merck and Co. own stock options

  3. Boceprevir: Background Boceprevir (SCH 503034, BOC) Protease inhibitor of the ketoamide class Binds reversibly to active site of HCV NS3 protease to inhibit HCV replication (IC90 400 nM) Phase 3 trials in treatment-naive and treatment-experienced genotype 1 HCV patients complete highly favourable, statistically significant increases in SVR Dose: 800 mg TID with food currently in regulatory review HCV, hepatitis C virus; TID, three times a day.

  4. Boceprevir Absorption, Metabolism, Excretion (1) Absorption Rapidly absorbed: median Tmax ~2 hrs Less than dose proportional increases in steady state exposure No accumulation Food increases exposure ~40% - 60% P-gp substrate Metabolism & Excretion Extensively metabolized by two distinct pathways Aldo keto reductase (AKR) CYP3A4/5 single dose of 14C-radiolabeled BOC metabolized to one primary ketone-reduced metabolite radioactivity in urine & feces accounted for ~ 9% and 79% of dose only 3% and 8% as parent in urine and feces respectively.

  5. Boceprevir Absorption, Metabolism, Excretion (2) Metabolism & Excretion (cont’d) Mean plasma t½ of ~3.4 hours Primary route of excretion is hepatic/fecal Selectivity Strong reversible CYP3A4 inhibitor Not a CYP450 isoenzyme inducer Not a P-gp inhibitor

  6. Drug-Drug Interaction Studies Boceprevir As Victim Boceprevir As Perpetrator Co-administeredDrug Co-administeredDrug Midazolam Drospirenone/Ethinyl estradiol Efavirenz TenofovirPeginterferon -2b Ribavirin‡ CYP3A4 substrate Other AKR inhibitors CYP3A4/P-gp inhib CYP3A4 inducer Other IbuprofenDiflunisal KetoconazoleRitonavirClarithromycin* Efavirenz TenofovirPeginterferon -2bRibavirin

  7. Diflunisal DIF 250 mg BID BOC 800 mg TID Days: 0 2 4 8 10 12 6 N = 5 healthy subjects Treatment LS Meana Ratio Estimate, % (90% CI) Effect of DIF (250 mg BID) on BOC (800 mg TID) Cmax (ng/mL) BOC BOC + DIF 2259 1936 86 (56–132) AUC(T) (ng·h/mL) BOC BOC + DIF 6868 6597 96 (79–117) Cmin (ng/mL) BOC BOC + DIF 83 108 131 (104–165) aModel-based (least squares) geometric mean; ANOVA extracting the effects due to treatment and subject. AUC(T), area under the plasma concentration versus time curve from time 0 dosing interval; BID, two times a day; BOC, boceprevir; CI, confidence interval; Cmax, maximum observed plasma concentration; Cmin, minimum observed plasma concentration; DIF, diflunisal; LS, least squares; TID, three times a day.

  8. BOC 400-mg single dose on day 1 KET 400 mg BID days 1–6 + BOC 400-mg single dose on day 4 Ketoconazole Day: 4 1 1 4 6 N = 12 healthy subjects Boceprevir + Ketoconazole Boceprevir 800 600 BOC + KET vs BOC ratio estimates (90% CI) AUC(tf) 231% (200–267) Cmax141% (100–199) Cmin N/A Mean Concentration of Boceprevir 400 200 0 0 12 24 36 48 60 72 Time (h) AUC(tf), area under the plasma concentration versus time curve to the final measurable sampling time; BID, two times a day; BOC, boceprevir; CI, confidence interval; KET, ketoconazole; TID, three times a day.

  9. BOC 400 mg TID* + RTV 100 mg QD BOC 400 mg TID Ritonavir *BOC stopped at day 15 Day 1 Day 6 Day 17 N = 16 healthy subjects 1200 BOC (400 mg TID) BOC (400 mg TID) + RTV (100 mg QD) 1000 BOC + RTV (100 mg QD) vs BOC ratio estimates (90% CI) AUC(T) 81% (73–91) Cmax 73% (57–93) Cmin104% (62–175) 800 Boceprevir (ng/mL) 600 400 200 0 0 2 4 6 8 10 12 Time (h) AUC(T), area under the plasma concentration versus time curve from time 0 dosing interval; BID, two time a day; BOC, boceprevir; CI, confidence interval; RTV, ritonavir; TID, three times a day.

  10. Days 1–10: • EFV 600 mg QD Days 11–15: BOC 800 mg TID Day 16: BOC 800 mg single dose Days 11–16: EFV 600 mg QD Days 1–5: BOC 800 mg TID Day 6: BOC 800 mg single dose Washout ≥7 days Efavirenz N = 12 healthy volunteers Treatment LS Meana Ratio Estimate, % (90% CI) Effect of EFV (600 mg QD) on BOC (800 mg TID) Cmax (ng/mL) BOC BOC + EFV 2038 1871 92 (78–108) AUC(0-8h) (ng·h/mL) BOC BOC + EFV 6913 5630 81 (75–89) Cmin (ng/mL) BOC BOC + EFV 94.4 52.5 56 (42–74) Effect of BOC (800 mg TID) on EFV (600 mg QD) Cmax (ng/mL) EFV EFV + BOC 4573 5077 111 (102–120) AUC(0-24h) (ng·h/mL) EFV EFV + BOC 78667 94655 120 (115–126) aModel-based (least squares) geometric mean; ANOVA extracting the effects due to treatment and subject. AUC, area under the plasma concentration-time curve; BOC, boceprevir; CI, confidence interval; Cmax, maximum observed plasma concentration; Cmin, minimum observed plasma concentration; EFV, efavirenz; LS, least squares; QD, once daily; TID, three times a day.

  11. Midazolam MDZ 4 mg MDZ 4 mg MDZ 4 mg MDZ 4 mg BOC 800 mg TID 1 –1 6 13 Days 8 N = 12 healthy volunteers Treatment LS Mean Ratio Estimate, % (90% CI) Effect of BOC (800 mg TID) on MDZ (4-mg single doses) Cmax ng/mL MDZ (day –1) MDZ + BOC (day 6) MDZ (day 8) MDZ (day 13) 9.96 27.6 9.82 8.94 277 (236–325) AUC(0-12hr) (ng·h/mL) MDZ (day –1) MDZ + BOC (day 6) MDZ (day 8) MDZ (day 13) 52.94 280.7 56.10 43.83 530 (466–603) AUC, area under the plasma concentration-time curve; BOC, boceprevir; CI, confidence interval; Cmax, maximum observed plasma concentration; MDZ, midazolam; TID, three times a day.

  12. Drospirenone/Ethinyl estradiol N = 16 healthy volunteers BOC 800 mg TID Oral contraceptive: DRSP 3 mg/EE 0.02 mg QD Day 1 Day 8 Day 14 Treatment LS Meana Ratio Estimate, % (90% CI) Effect of BOC (800 mg TID) on DRSP Cmax (ng/mL) OC OC + BOC 46.0 73.0 157 (146–170) AUC(0-8h) (ng·h/mL) OC OC + BOC 655 1304 199 (187–211) Effect of BOC (800 mg TID) on EE Cmax (ng/mL) OC OC + BOC 54.0 54.0 100 (91–110) AUC(0-24h) (ng·h/mL) OC OC + BOC 659 499 76 (73–79) aModel-based (least squares) geometric mean; ANOVA extracting the effects due to treatment and subject. AUC, area under the plasma concentration-time curve; BOC, boceprevir; CI, confidence interval; Cmax, maximum observed plasma concentration; DRSP, drospirenone; EE, ethinylestradiol; LS, least squares; OC, oral contraceptive; QD, once daily; TID, three times a day.

  13. Drug-Drug Interactions:Boceprevir As Victim No Clinically Relevant Effect of Co-administered Drugs on Boceprevir Co-administeredDrug Mean AUC() Ratio† 1.04 ↔ 0.96 ↔ 2.31 ↑ 0.81 ↔ 1.21 ↔ 0.81 ↔ 1.08 ↔ 1.00 ↔ ~0.92 ↔ IbuprofenDiflunisal KetoconazoleRitonavirClarithromycin* Efavirenz TenofovirPeginterferon -2bRibavirin AKR inhibitors CYP3A4/P-gp inhibitors CYP3A4 inducers Other † Ratio estimate of boceprevir PK parameters (in combination vs. alone);  = ratio estimate <0.8;  = ratio estimate ≥0.8 and ≤1.25;  = ratio estimate >1.25. * in presence of diflunisal, compared with boceprevir + diflunisal

  14. Drug-Drug Interactions:Boceprevir As Perpetrator Effect of Boceprevir on Co-administered Drugs is Predictable Co-administeredDrug Mean AUC() Ratio† MidazolamDrospirenone/Ethinyl estradiol EfavirenzTenofovirPeginterferon -2bRibavirin‡ 5.30 ↑ 1.99 ↑0.76 ↓ 1.20 ↔1.05 ↔ 0.99 ↔~0.98 ↔ CYP3A4 substratesOther Phase 3 sub-analyses: similar safety profile when CYP3A4 substrates (eg. benzodiazepines) or inhibitors (eg. azoles) administered with boceprevir † Ratio estimate of concomitant drug PK parameters (in combination with Boceprevir vs. alone);  = ratio estimate <0.8;  = ratio estimate ≥0.8 and ≤1.25;  = ratio estimate >1.25.

  15. No Correlation of SVR With Plasma PK No SVR (n=29) SVR (n=87) No SVR (n=29) SVR (n=87) Tx-Experienced Tx-Naive Median, Quartiles Data from RESPOND-2 and SPRINT-2. AUC=area under the concentration-time curve; Cmin=minimum observed plasma concentration; PK=pharmacokinetic; SVR=sustained virologic response.

  16. Drug-Drug Interactions: Summary & Conclusions • Unlikely Victim • Metabolized by two pathways • Clinically relevant AKR inhibitors not known • Effect of CYP3A4 inhibitors & inducers modest • Drugs affecting other enzymes/transporters unlikely to alter boceprevir • No dose adjustments of boceprevir required • Predictable Perpetrator • Interaction with sensitive CYP3A4 substrate drugs should be expected • Many drugs are CYP3A4 inhibitors • These interactions are understood and managed appropriately • CYP3A4 substrate drugs with toxicities often dose-titrated as standard practice • Many drug classes include alternatives that are not CYP3A4 substrates • No interaction with drugs metabolized by other pathways, such as standard of care (Peginterferon -2b / ribavirin)

  17. Thanks to: the subjects and their families who participated in these studies investigators Merck colleagues

More Related