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VIRTUAL MEDZONE

VIRTUAL MEDZONE. Your Resource for Hepatitis Related Innovative Medical Communication. Hepatitis Case Presentations. Alice Tseng Pharm. D., FCSHP, AAHIVP David Fletcher MD FRCPC. CASE 1. 55 yo WF, diagnosed with HIV/HCV (genotype 1) 06/2000 CD4 1350, VL 1441  LT non- progressor HCV:

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VIRTUAL MEDZONE

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  1. VIRTUAL MEDZONE Your Resource for Hepatitis Related Innovative Medical Communication

  2. Hepatitis Case Presentations Alice Tseng Pharm. D., FCSHP, AAHIVP David Fletcher MD FRCPC

  3. CASE 1 • 55 yo WF, diagnosed with HIV/HCV (genotype 1) • 06/2000 • CD4 1350, VL 1441  LT non-progressor • HCV: • 08/2001: stage 1 fibrosis (liver Bx) • 06/2009: hepatic decompensation • 03/2010: ESLD, ascites. • CD4 516, VL 47,000. Rx Atripla (for HCV) • CNS s/e to EFV, changed to Etravirineafter 1 week

  4. CASE 1 • June/10: VL<50, CD4 649, listed for liver transplant • Oct/10: replaced TDF/FTC with ABC/3TC, cont with etravirine 200 mg BID • May/11: living donor liver transplant • Rx cyclosporine, prednisone

  5. CASE 1 • June/11: episode of mild rejection; continued prednisone • Sep/11: peripheral neuropathy, elevated Scr •  CsA dose, prednisone, Rx MMF and gabapentin • also cont. with dapsone, pantoprazole, nystatin, docusate

  6. DRUG INTERACTIONS • Can have a dramatic and often clinically significant effect on drug exposure and clinical outcome • May be beneficial or detrimental

  7. DRUG INTERACTIONS • Pharmacokinetic • change in the amount of drug in body • absorption, distribution, metabolism, elimination may be affected • Pharmacodynamic • change in the pharmacological effect of a drug • additive, synergistic, or antagonistic

  8. Boceprevir and Telaprevir Pharmacology Slide adapted from Dr. J. Kiser, U of Colorado, Denver

  9. Effect of Different Types of Food on the Bioavailability of Telaprevir • Take telaprevir with food/snack (~20 g fat) • bagel/cream cheese, ½ c. nuts, 3 tbsp peanut butter, 1 c. ice cream, 2 oz cheese, 2 oz chips, ½ c. trail mix

  10. Proportion of Drugs Metabolized by the Major CYP450 Enzymes

  11. Drug Interactions with the CYP450 System • “Revolving Door” analogy Entrance Inside Bldg Exit • Terms: Substrate, Inhibitor, Inducer

  12. SUBSTRATE • Agent which is primarily cleared via CYP450 enzymes • Rate of drug breakdown affected by: • Enzyme Inhibitors • Enzyme Inducers • e.g., HIV & HCV protease inhibitors, NNRTIs

  13. ENZYME INHIBITION INTERACTIONS • Inhibitor competes with another drug for binding at enzymatic site • e.g., DAAs, protease inhibitors, azoles, macrolides •  clearance of substrate =  drug levels • effect varies according to dose (amount), potency (strength); quick onset & resolution of interaction • Can be beneficial (e.g., boosted PIs in HIV) or negative ( toxicity)

  14. MANAGING INHIBITION INTERACTIONS • Dose adjustment of one/both drugs • alter dose and/or frequency • Replace drug with another agent with less interaction potential • e.g., clarithromycin azithromycin • Therapeutic drug monitoring (if available) • Clinical monitoring (effect/toxicity) • quick onset/resolution of interaction

  15. Enzyme Induction Interactions • Inducer stimulates production of additional enzymes • e.g., rifamycins, anticonvulsants, NNRTIs, telaprevir •  clearance of substrate =  drug levels • slower onset, resolution of interaction • often undesirable clinical effect, i.e.,  efficacy, development of resistance

  16. Managing Induction Interactions • Dose adjustment of one/both drugs • alter dose and/or frequency • Replace drug with another agent with less interaction potential • e.g., rifampin  rifabutin • Therapeutic drug monitoring (if available) • Clinical monitoring (efficacy, resistance) • slower onset/resolution of interaction; usually 1-2 weeks

  17. POST-TRANSPLANT Without treatment, HCV recurs in 100% of liver transplantations1 1. Terrault NA. Clin Gastroenterol Hepatol 2005;3(10 Suppl 2):S125-S131. Slide courtesy of Dr. J. Kiser, U of Colorado, Denver

  18. Cyclosporine and Tacrolimus Concentrations are Significantly Increased by Boceprevir & Telaprevir [Hulskotte et al. HEP DART 2011, poster 123. Garg V, et al. Hepatology 2011;54:20-27.]

  19. Suggested criteria for use of TVR or BOC in liver transplant recipients: • evidence of aggressive histological HCV recurrence (stage 3 fibrosis w/o hepatic decompensation) • treating physician should be experienced in managing complex drug-drug interactions • treatment should be in context of informed consent to participate in IRB/REB-approved protocol

  20. ARV-TRANSPLANT INTERACTIONS • Significant dose  required with PI/r, possible dose  with NNRTIs, no change with RAL • Tacrolimus (usual dose 1-6 mg BID): • darunavir/r: 0.5 mg/week1, 0.03 mg/day2 • lopinavir/r: 0.5-1.5 mg q7-25 days3, 0.5 mg q8 days4 • raltegravir: standard TAC or sirolimus doses5-6 • Cyclosporine: • indinavir, lopinavir/r: CsA dose  5-20%7 • efavirenz: 54%  CsA levels8 • raltegravir: standard CsA doses5, 9 1. Mertz et al. Am J Kidney Dis 2009;54:e1-4. 2. Bickel et al. JAC 2010;65:999-1004. 3.Teicher et al. ClinPharmacokinet 2007;46:941-52. 4. Barrail-Tran et al. 8th IWCPHT 2007, #58. 5. Tricot et al. Am J Transplant 2009;9:1946-52. 6. Moreno et al. AIDS 2008;22:547-8. 7. Vogel et al. 5th IWCPHT 2004, #4.7. 8. Tseng et al. AIDS 2002;16:505-6. 9. Di Baggio et al. JAC 2009;64:874-5.

  21. TRIPLE THERAPY WITH TELAPREVIR AFTER LIVER TRANSPLANTATION • 7 HCV-1a infected, post-liver transplant patients received pegylated IFN 2a/b, ribavirin, and telaprevir. All subjects were on stable tacrolimus prior to starting HCV therapy. • TAC doses pre-emptively  to 50% of pre-treatment doses and given qweekly. Trough TAC levels checked q2d for the first 2 weeks, then weekly until telaprevir therapy was complete. Baseline TAC dosing resumed 5 days after stopping telaprevir. • No episodes of acute rejection or TAC toxicity noted • Response: eRVR (n=4), complete early virologic response (n=2), non-responder (n=1) • Main adverse effect was anemia (n=6 required transfusions); dehydration, renal insufficiency and infections also reported Mantry et al. HEP DART 2011, #90.

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