virtual medzone your resource for hepatitis related innovative medical communication

VIRTUAL MEDZONEYour Resource for Hepatitis Related Innovative Medical Communication

Hepatitis Case PresentationsAlice Tseng Pharm. D., FCSHP, AAHIVPDavid Fletcher MD FRCPC

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 Etravirine after 1 week

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

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

DRUG INTERACTIONS

• Can have a dramatic and often clinically significant effect on drug exposure and clinical outcome

• May be beneficial or detrimental

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

Boceprevir and Telaprevir PharmacologyBoceprevir (Victrelis®)

800 mg q7-9hTelaprevir (Incivek®)

750 mg q7-9h

Route of Metabolism AKR1C2 + 1C3, CYP3A CYP3A

Transporter effects P-gp substrate P-gp substrate

In vitro induction effects

Does not induce CYP1A2, 2B6, 2C8, 2C9, 2C19, 3A

Low potential to induce CYP2C, 3A, or

1A

In vitro inhibition effects

CYP3A and P-gp, not CYP1A2, 2A6, 2B6,

2C8, 2C9, 2C19, 2D6, or 2E1

CYP3A and P-gp, not 1A2, 2C9, 2C19,

or 2D6

% recovery urine/feces

9/79 1/82

Protein Binding 68-75% 59-76%

Food Effect 60% AUCMeal or light snack

117-330% AUCNot low fat (20 g)

Half-life (hrs) 3.4 4-4.7 (single dose)9-11 (steady-state)Slide adapted from Dr. J. Kiser, U of Colorado, Denver

EFFECT OF DIFFERENT TYPES OF FOOD ON THE BIOAVAILABILITY OF TELAPREVIR

TVR AUC Breakfast Type

Ref. Standard (533 kcal, 21 g fat)

20% High Fat (928 kcal, 56 g fat)

26% High Protein (260 kcal, 9 g fat)

39% Low Fat (249 cal, 3.6 g fat)

73% Fasting

• 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

PROPORTION OF DRUGS METABOLIZED BY THE MAJOR CYP450 ENZYMES

CYP3ACYP2D6

CYP2C

CYP1A2CYP2E1

CYP3A

CYP2D6

CYP2C

CYP1A2

CYP2E1

DRUG INTERACTIONS WITH THE CYP450 SYSTEM

• “Revolving Door” analogy Entrance Inside Bldg Exit

• Terms: Substrate, Inhibitor, Inducer

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

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)

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

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

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

POST-TRANSPLANT• Without treatment, HCV recurs in 100% of

liver transplantations1

Medications Adverse Effects Route of Metabolis

m

Transporters

Cyclosporine (Neoral, Sandimmune)

nephrotoxicity, neurotoxicity, hypertension

3A P-gp

Tacrolimus (Prograf)

nephrotoxicity, neurotoxicity, diabetes mellitus

3A

Sirolimus (Rapamune)

thrombocytopenia, leukopenia, anemia, hyperlipidemia

3A P-gp

Mycophenolate Mofentil (CellCept)

gastrointestinal toxicity, anemia, neutropenia

UGT

Azathioprine (Imuran)

lymphoma, pancreatitis XO

1. Terrault NA. Clin Gastroenterol Hepatol 2005;3(10 Suppl 2):S125-S131.Slide courtesy of Dr. J. Kiser, U of Colorado, Denver

Cyclosporine and Tacrolimus Concentrations are Significantly Increased by Boceprevir & Telaprevir

BoceprevirGMR

TelaprevirGMR

CyclosporineAUCCmax

2.702.01

4.6462.2

TacrolimusAUCCmax

17.19.9

70.39.35

[Hulskotte et al. HEP DART 2011, poster 123. Garg V, et al. Hepatology 2011;54:20-27.]

• 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

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. Clin Pharmacokinet 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. 5 th IWCPHT 2004, #4.7. 8. Tseng et al. AIDS 2002;16:505-6. 9. Di Baggio et al. JAC 2009;64:874-5.

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.