Presentation on theme: "C Kasserra, E Hughes, M Treitel, S Gupta, and E O'Mara"— Presentation transcript:
1Clinical Pharmacology of Boceprevir: Metabolism, Excretion, and Drug-Drug Interactions C Kasserra, E Hughes, M Treitel,S Gupta, and E O'MaraInternational Conference on Viral HepatitisApril 11, 2011Baltimore, MASlide 1 text:Good afternoon, I would to present the clinical pharmacology of boceprevir, including its metabolism, excretion, and drug-drug interaction profiles.
2Full time employee of Merck and Co. own stock options Disclosure StatementFull time employee of Merck and Co.own stock options
3Boceprevir: Background Boceprevir (SCH 503034, BOC)Protease inhibitor of the ketoamide classBinds 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 completehighly favourable, statistically significant increases in SVRDose: 800 mg TID with foodcurrently in regulatory reviewSlide 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.
4Boceprevir Absorption, Metabolism, Excretion (1) Rapidly absorbed: median Tmax ~2 hrsLess than dose proportional increases in steady state exposureNo accumulationFood increases exposure ~40% - 60%P-gp substrateMetabolism & ExcretionExtensively metabolized by two distinct pathwaysAldo keto reductase (AKR)CYP3A4/5single dose of 14C-radiolabeled BOC metabolized to one primary ketone-reduced metaboliteradioactivity in urine & feces accounted for ~ 9% and 79% of doseonly 3% and 8% as parent in urine and feces respectively.
5Boceprevir Absorption, Metabolism, Excretion (2) Metabolism & Excretion (cont’d)Mean plasma t½ of ~3.4 hoursPrimary route of excretion is hepatic/fecalSelectivityStrong reversible CYP3A4 inhibitorNot a CYP450 isoenzyme inducerNot a P-gp inhibitor
7Diflunisal Treatment LS Meana Ratio Estimate, % (90% CI) DIF 250 mg BIDBOC 800 mg TIDN = 5 healthy subjectsDays:24681012TreatmentLS MeanaRatio Estimate, %(90% CI)Effect of DIF (250 mg BID) on BOC (800 mg TID)Cmax (ng/mL)BOCBOC + DIF2259193686 (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)BOCBOC + DIF6868659796 (79–117)Cmin (ng/mL)BOCBOC + DIF83108131 (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.
8Ketoconazole Day: BOC + KET vs BOC ratio estimates (90% CI) BOC 400-mg single dose on day 1KET 400 mg BID days 1–6 +BOC 400-mg single dose on day 4Day:14146N = 12 healthy subjectsBoceprevir + KetoconazoleBoceprevir800600BOC + KET vs BOCratio estimates (90% CI)AUC(tf) 231% (200–267)Cmax 141% (100–199)Cmin N/AMean Concentration of BoceprevirSlide 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.400200122436486072Time (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.
9Ritonavir BOC + RTV (100 mg QD) vs BOC ratio estimates (90% CI) BOC 400 mg TID* + RTV 100 mg QDBOC 400 mg TID*BOC stopped at day 15Day 1Day 6Day 17N = 16 healthy subjects1200BOC (400 mg TID)BOC (400 mg TID) + RTV (100 mg QD)1000Slide 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 BOCratio estimates (90% CI)AUC(T) 81% (73–91)Cmax 73% (57–93)Cmin 104% (62–175)800Boceprevir (ng/mL)60040020024681012Time (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.
10Efavirenz Treatment LS Meana Ratio Estimate, % (90% CI) Days 1–10:EFV 600 mg QDDays 1–5: BOC 800 mg TIDDay 6: BOC 800 mg single doseWashout≥7 daysDays 11–15: BOC 800 mg TIDDay 16: BOC 800 mg single doseDays 11–16: EFV 600 mg QDN = 12 healthy volunteersTreatmentLS MeanaRatio Estimate, %(90% CI)Effect of EFV (600 mg QD) on BOC (800 mg TID)Cmax (ng/mL)BOCBOC + EFV2038187192 (78–108)AUC(0-8h) (ng·h/mL)BOCBOC + EFV6913563081 (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)BOCBOC + EFV94.452.556 (42–74)Effect of BOC (800 mg TID) on EFV (600 mg QD)Cmax (ng/mL)EFVEFV + BOC45735077111 (102–120)AUC(0-24h) (ng·h/mL)EFVEFV + BOC7866794655120 (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.
11Midazolam Treatment LS Mean Ratio Estimate, % (90% CI) MDZ4 mgMDZ4 mgMDZ4 mgMDZ4 mgBOC 800 mg TID–11Days6813N = 12 healthy volunteersTreatmentLS MeanRatio Estimate, %(90% CI)Effect of BOC (800 mg TID) on MDZ (4-mg single doses)Cmax ng/mLMDZ (day –1)MDZ + BOC (day 6)MDZ (day 8)MDZ (day 13)9.9627.69.828.94277 (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)52.94280.756.1043.83530 (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.
12Drospirenone/Ethinyl estradiol N = 16 healthy volunteersBOC 800 mg TIDOral contraceptive: DRSP 3 mg/EE 0.02 mg QDDay 1Day 8Day 14TreatmentLS MeanaRatio Estimate, %(90% CI)Effect of BOC (800 mg TID) on DRSPCmax (ng/mL)OCOC + BOC46.073.0157 (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)OCOC + BOC6551304199 (187–211)Effect of BOC (800 mg TID) on EECmax (ng/mL)OCOC + BOC54.0100 (91–110)AUC(0-24h) (ng·h/mL)OCOC + BOC65949976 (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.
13Drug-Drug Interactions: Boceprevir As Victim No Clinically Relevant Effect of Co-administered Drugs on BoceprevirCo-administered DrugMean AUC() Ratio†AKR inhibitorsCYP3A4/P-gp inhibitorsCYP3A4 inducersOtherIbuprofen DiflunisalKetoconazole Ritonavir Clarithromycin*EfavirenzTenofovir Peginterferon -2b Ribavirin1.04 ↔ ↔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
14Drug-Drug Interactions: Boceprevir As Perpetrator Effect of Boceprevir on Co-administeredDrugs is PredictableCo-administered DrugMean AUC() Ratio†CYP3A4 substrates OtherMidazolam Drospirenone/ Ethinyl estradiolEfavirenz 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.
15No Correlation of SVR With Plasma PK No SVR (n=29) SVR (n=87)No SVR (n=29) SVR (n=87)Tx-ExperiencedTx-NaiveMedian, QuartilesData from RESPOND-2 and SPRINT-2.AUC=area under the concentration-time curve; Cmin=minimum observed plasma concentration; PK=pharmacokinetic; SVR=sustained virologic response.
16Drug-Drug Interactions: Summary & Conclusions Unlikely VictimMetabolized by two pathwaysClinically relevant AKR inhibitors not knownEffect of CYP3A4 inhibitors & inducers modestDrugs affecting other enzymes/transporters unlikely to alter boceprevirNo dose adjustments of boceprevir requiredPredictable PerpetratorInteraction with sensitive CYP3A4 substrate drugs should be expectedMany drugs are CYP3A4 inhibitorsThese interactions are understood and managed appropriatelyCYP3A4 substrate drugs with toxicities often dose-titrated as standard practiceMany drug classes include alternatives that are not CYP3A4 substratesNo interaction with drugs metabolized by other pathways, such as standard of care (Peginterferon -2b / ribavirin)
17Thanks to:the subjects and their families who participated in these studiesinvestigatorsMerck colleagues