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C Kasserra, E Hughes, M Treitel, S Gupta, and E O'Mara

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Presentation on theme: "C Kasserra, E Hughes, M Treitel, S Gupta, and E O'Mara"— 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 Slide 1 text: Good afternoon, I would to present the clinical pharmacology of boceprevir, including its metabolism, excretion, and drug-drug interaction profiles.

2 Full time employee of Merck and Co. own stock options
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 (IC 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 Slide 2 text: Boceprevir is a potent, orally administered serine protease inhibitor employed to treat treatment-naive and experienced HCV genotype 1 patients. It is dosed 800 mg three times a day (TID) with food. Boceprevir directly inhibits the NS3 protease and, in the replicon, inhibits the GT1b replicon at 400 ng/mL. This inhibition established the initial plasma-based pharmacokinetic target. HCV, hepatitis C virus; TID, three times a day.

4 Boceprevir Absorption, Metabolism, Excretion (1)
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-administered Drug Co-administered Drug AKR inhibitors CYP3A4/P-gp inhib CYP3A4 inducer Other Ibuprofen Diflunisal Ketoconazole Ritonavir Clarithromycin* Efavirenz Tenofovir Peginterferon -2b Ribavirin CYP3A4 substrate Other Midazolam Drospirenone/ Ethinyl estradiol Efavirenz Tenofovir Peginterferon -2b Ribavirin‡

7 Diflunisal Treatment LS Meana Ratio Estimate, % (90% CI)
DIF 250 mg BID BOC 800 mg TID N = 5 healthy subjects Days: 2 4 6 8 10 12 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) Slide 8 text: In the first interaction study, diflunisal, an nonsteriodal anti-inflammatory drug with ability to inhibit AKR in vitro, was assessed with boceprevir. Five healthy subjects received boceprevir for 12 days to which diflunisal was added beginning on day 6. Pharmacokinetic assessments were performed on days 5 and 12. The mean Cmax of boceprevir, as an indicator of absorption, was somewhat lower in the presence of diflunisal and variable. The mean Cmin of boceprevir was increased about 30%, while the mean AUC for boceprevir was essentially unchanged by the presence of diflunisal. Thus modest changes indicated that AKR was not efficiently inhibited in vivo. 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 Ketoconazole Day: BOC + KET vs BOC ratio estimates (90% CI)
BOC 400-mg single dose on day 1 KET 400 mg BID days 1–6 + BOC 400-mg single dose on day 4 Day: 1 4 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) Cmax 141% (100–199) Cmin N/A Mean Concentration of Boceprevir Slide 7 text: Assessment of ketoconazole as a CYP3A4 inhibitor probe was performed in 12 healthy subjects. Boceprevir was administered as a single dose and pharmacokinetic samples were collected on day 1. After a washout, ketoconazole was administered as 400 mg twice a day (BID) for 7 days. Boceprevir was administered as a SD <<Spellout>> on day 4. The mean Cmax was increased about 41% and the mean AUC was more than doubled (231%). The profiles were similar suggesting that the changes were primarily driven by increased absorption. This may reflect ketoconazole’s effect upon P-gp or other transporters. 400 200 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 Ritonavir BOC + RTV (100 mg QD) vs BOC ratio estimates (90% CI)
BOC 400 mg TID* + RTV 100 mg QD BOC 400 mg TID *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 Slide 9 text: Boceprevir was administered as 800 mg TID for 5 days; subjects were then randomized to receive boceprevir 400 mg TID plus ritonavir 100 mg once daily or boceprevir 400 mg BID plus ritonavir 100 mg BID. Regardless of regimen and though exposures to boceprevir were lower, the trough concentration of boceprevir were similar. BOC + RTV (100 mg QD) vs BOC ratio estimates (90% CI) AUC(T) 81% (73–91) Cmax 73% (57–93) Cmin 104% (62–175) 800 Boceprevir (ng/mL) 600 400 200 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 Efavirenz Treatment LS Meana Ratio Estimate, % (90% CI)
Days 1–10: EFV 600 mg QD Days 1–5: BOC 800 mg TID Day 6: BOC 800 mg single dose Washout ≥7 days Days 11–15: BOC 800 mg TID Day 16: BOC 800 mg single dose Days 11–16: EFV 600 mg QD 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) Slide 13 text: In this 2-period study, boceprevir was administered for 5 days and evaluated on day 6. After a washout, efavirenz, an HIV NNRTI with metabolic induction properties, was administered for 10 days followed by combination with boceprevir for an additional 6 days. Coadministration of efavirenz (CYP3A4/5 inducer) with boceprevir decreased boceprevir mean exposure 19% to 44% and increased efavirenz mean exposure 11% to 20%. Notable interaction of boceprevir with efavirenz was limited to boceprevir trough concentration; however, the clinical implications are not known as there are no patient subject data to date to support a dosing recommendation for concomitant use of efavirenz with boceprevir. 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 Treatment LS Mean Ratio Estimate, % (90% CI)
MDZ 4 mg MDZ 4 mg MDZ 4 mg MDZ 4 mg BOC 800 mg TID –1 1 Days 6 8 13 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) Slide 6 text: Midazolam, a CYP3A4 probe substrate, was administered on day –1 and washed out. Boceprevir was then administered alone for 5 days. On day 6, a single dose of MDZ was added exposures measured. Midazolam was again administered on day 8 to assess boceprevir’s potential for irreversible inhibition [induction(?)] after the plasma concentration of boceprevir became undetectable. On day 13, pharmacokinetic parameters were assessed to assure midazolam’s parameters returned to baseline. The increase in the AUC of midazolam, expressed as a ratio estimate, place boceprevir as a strong CYP3A4 inhibitor, without evidence of induction. 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) Slide 14 text: In 16 healthy females who were previously on oral contraceptives received a fixed-sequence as follows: subjects received oral contraceptive (drospirenone [DRSP] 3 mg/ ethinylestradiol [EE] 0.02 mg, Yaz®) alone for 7 days (period 1) followed by 7 days of boceprevir plus oral contraceptive (period 2). Pharmacokinetic assessments were made on days 7 and 14. The pharmacokinetic parameters, particularly the AUC increased. This may be due to the inhibition of its elimination via the CYP3A4 pathway, of which progestins are a substrate, by boceprevir. Coadministration of a combination progestin/EE oral contraceptive with boceprevir increased DRSP exposure 99% and decreased EE exposure 24%. The observed changes in exposure of DRSP and EE should not affect contraceptive efficacy; however, caution should be exercised in patients with conditions that predispose them to hyperkalemia or patients taking potassium-sparing diuretics. Alternative contraceptives should be considered. 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 54.0 100 (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-administered Drug Mean AUC() Ratio† AKR inhibitors CYP3A4/P-gp inhibitors CYP3A4 inducers Other Ibuprofen Diflunisal Ketoconazole Ritonavir Clarithromycin* Efavirenz Tenofovir Peginterferon -2b Ribavirin 1.04 ↔ ↔ 2.31 ↑ ↔ ↔ 0.81 ↔ 1.08 ↔ ↔ ~0.92 ↔ † 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-administered Drug Mean AUC() Ratio† CYP3A4 substrates Other Midazolam Drospirenone/ Ethinyl estradiol Efavirenz Tenofovir Peginterferon -2b Ribavirin‡ 5.30 ↑ 1.99 ↑ 0.76 ↓ 1.20 ↔ 1.05 ↔ ↔ ~0.98 ↔ 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


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