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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.