1. Your Resource for Hepatitis Related Innovative Medical Communication
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 HCV:
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

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 Pharmacodynamic
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
Drug interactions may be classified as being either pharmacokinetic or pharmacodynamic in nature. With pharmacokinetic interactions, absorption, distribution, metabolism, or elimination may be affected, resulting in an alteration of the amount and/or concentration of one or both agents in the body. Sometimes this is desirable if the pharmacokinetic profile of a drug is improved. On the other hand, certain interactions may be undesirable when the disposition of an agent with a narrow therapeutic index is affected.
With pharmacodynamic interactions, additive, synergistic, or antagonistic drug combinations may affect parameters of pharmacological response, including efficacy and toxicity.
Pharmacodynamic drug–drug interactions may be beneficial, when agents with complementary mechanisms of action (eg, reverse transcriptase inhibitors plus PIs or NNRTIs) are administered to enhance clinical efficacy.
In contrast, certain combinations may be undesirable if antagonism or additive toxicity occurs. For example, lamivudine and zalcitabine have been shown to negatively interact in vitro, likely via competition for intracellular phosphorylation, and thus should not be coadministered. Similar concern exists regarding the combination of zidovudine and stavudine.

8. PHARMACODYNAMIC DRUG INTERACTIONS - EXAMPLES
Beneficial:
 Efficacy
combination HCV therapy
DAA + RBV/IFN
 Toxicity
INH + Pyridoxine
Undesirable:
 Efficacy
(in vitro antagonism)
 Toxicity
Boceprevir/Telaprevir + ribavirin (anemia)

9. Pharmacokinetic Drug Interactions
Change in the concentrations of one/both drugs in the body
Mechanisms:
altered drug absorption*
altered drug distribution
inhibition/induction of metabolism*
inhibition of renal excretion
*most common with DAAs

10. Boceprevir and Telaprevir Pharmacology
Boceprevir (Victrelis®)
800 mg q7-9h
Telaprevir (Incivek®)
750 mg q7-9h
Route of Metabolism
AKR1C2 + 1C3, CYP3A
CYP3A
Transporter effects
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
not 1A2, 2C9, 2C19, or 2D6
% recovery urine/feces
9/79
1/82
Protein Binding
68-75%
59-76%
Food Effect
60%  AUC
Meal or light snack
%  AUC
Not 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

11. 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
Breakfast Type (kcal/g fat) Example
Standard
(533 kcal, 21 g fat) 4 slices bread, 1 slice ham, 1 slice cheese, butter, jelly, 2 cups tea/coffee w/ milk & sugar
High Fat
(928 kcal, 56 g fat) 2 fried eggs, 2 strips bacon, 2 slices toast with butter, 1 croissant with 1 slice cheese, 1 cup whole milk
High Protein
(260 kcal, 9 g fat) 115 g turkey (no skin), 1 slice bread, 1 tsp mayo/butter
Low Fat
(249 cal, 3.6 g fat) 2 slices bread, 20 g jam, 100g low calorie/low fat yogurt
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

12. Proportion of Drugs Metabolized by the Major CYP450 Enzymes

13. Drug Interactions with the CYP450 System
“Revolving Door” analogy
Entrance Inside Bldg Exit
Terms: Substrate, Inhibitor, Inducer
Metabolic interactions may be more easily explained by using the “Revolving Door” analogy.
For instance, imagine that CYP enzymes function as revolving doors which rotate at a fixed speed. Drugs which are administered must pass through a specific type of “door” (I.e., CYP isoenzyme) in order to be eliminated from the body.
The rate that substrates may pass through these doors may be influenced by the presense of enzyme inhibitors or inducers.

14. 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
A substrate is any drug that is metabolized by one or more of the P450 enzymes
Most drugs are primarily metabolized by a single P450 enzyme
Over 50% of metabolized drugs are substrates for the CYP3A4 enzyme
All protease inhibitors and NNRTIs are substrates of the cytochrome P system.
More specifically, these agents are substrates of CYP3A4; therefore, their disposition may be affected by the presence of enzyme inducers, particularly those that affect CYP3A4.
In addition, all protease inhibitors and NNRTIs possess enzyme inhibiting and/or inducing properties, and may thus affect the metabolism of other CYP450 substrates.

15. 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)
Inhibition interactions occur when two agents compete for the same enzymatic binding site (I.e., revolving door)
Competitive inhibition depends upon:
the affinity of the substrate for the enzyme being inhibited
the concentration of substrate required for inhibition
the half-life of the inhibitor drug
These types of interactions usually occur rapidly, i.e., within a few doses, once sufficient concentrations of the inhibiting agent are present in the liver.
These interactions also tend to resolve quickly once the offending agent (inhibitor) is removed
Another, less common mechanism of inhibition is noncompetitive; this can occur as a result of inactivation of the enzyme. The duration of this type of inhibition may be longer if new enzymes need to be synthesized after removal of the inhibitor drug.
Revolving door analogy:
A group of people (substrate) are depart at a constant rate via the continuous revolving door.
The presence of other people (e.g., inhibitor) will impede their ability to exit through this door, especially if there are very many people ahead (I.e., large dose), or if the people are very large/slow (I.e., potency)
NB: occasionally, if one CYP isoenzyme is inhibited, a substrate may be able to utilize another pathway for elimination; in such cases, the overall effect on substrate concentrations may not be as pronounced as anticipated.

16. 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

17. 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
Enzyme induction interactions do not usually become apparent for a week or more, since the enzyme inducer must first reach steady state, and new drug metabolizing enzymes need to be synthesized
Similarly, once the inducing agent is removed, the interaction may take a few weeks to resolve (time for the inhibitor to be cleared, and for enzymes to degrade)
Revolving Door Analogy:
new revolving doors (I.e.,inducing enzymes) need to be built, once this is done, there is a net increase in revolving doors
thus, people (substrates) are able to leave more quickly, since there are more exit doors available

18. 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

19. POST-TRANSPLANT
Without treatment, HCV recurs in 100% of liver transplantations1
Medications
Adverse Effects
Route of
Metabolism
Transporters
Cyclosporine
(Neoral, Sandimmune)
nephrotoxicity, neurotoxicity, hypertension 3A
P-gp
Tacrolimus
(Prograf)
nephrotoxicity, neurotoxicity, diabetes mellitus
Sirolimus
(Rapamune)
thrombocytopenia, leukopenia, anemia, hyperlipidemia
Mycophenolate
Mofentil (CellCept)
gastrointestinal toxicity, anemia, neutropenia
UGT
Azathioprine
(Imuran)
lymphoma, pancreatitis XO
Desirable to prevent recurrence post-transplant with the use of antivirals
List of medications used post-operatively to prevent allograft rejection, narrow therapeutic index and wide interpatient variability
Telaprevir has been studied with single doses of tacrolimus and cyclosporine in healthy volunteers
1. Terrault NA. Clin Gastroenterol Hepatol 2005;3(10 Suppl 2):S125-S131.
Slide courtesy of Dr. J. Kiser, U of Colorado, Denver 19

20. Cyclosporine and Tacrolimus Concentrations are Significantly Increased by Boceprevir & Telaprevir
GMR
Telaprevir
Cyclosporine
AUC
Cmax
2.70
2.01
4.64
62.2
Tacrolimus
17.1
9.9
70.3
9.35
[Hulskotte et al. HEP DART 2011, poster Garg V, et al. Hepatology 2011;54:20-27.]

21. Cyclosporine Exposures are Increased by Telaprevir
CSA 100mg
(n=10)
CSA 10mg +
TVR Day 1 (n=9)
TVR Day 8 (n=9)
Mean (SD) CL/F (L/hr)
56.3 (14)
14.3 (5.86)
12.5 (3.33)
Mean (SD) t1/2 (hr)
12 (1.67)
52.5 (20.5)
42.1 (11.3)
Mean (SD) V/F (L)
955 (195)
1010 (444)
735 (198)
Mean (SD) AUC0-∞ (ng*hr/mL)
1880 (489)
805 (306)
853 (218)
DN AUC0-∞GLS Mean Ratio (90% CI)
4.11 (3.49, 4.85)
4.64 (3.9, 5.51)
Cmax (ng/mL)
489 (142)
65.7 (24.9)
62.2 (18.9)
DN Cmax GLS Mean Ratio (90% CI)
1.36 (1.12, 1.65)
1.32 (1.08, 1.6)
CSA similar on day 1 and day 8 suggesting an absence of time-dependent inhibition of CSA metabolism by TPV
TPV PK appears similar to historic data – 21 vs 22 mcg*hr/mL
10 patients got single CSA dose, 9 got CSA + TVR, 1 dc due to moderate neutropenia
Open-label, PK study in healthy subjects
Cyclosporine (CSA) 100 mg as a single oral dose, followed by a minimum 8-day washout period, and subsequent co-administration of a single 10-mg oral dose of CSA with either single dose (750 mg) or steady state (750 mg q8h) telaprevir
CSA exposures  4.6-fold in the presence of steady-state telaprevir
[Garg V, et al. Hepatology 2011;54:20-27.]
Slide courtesy of Dr. J. Kiser, U of Colorado, Denver 21

22. Cyclosporine Exposures are Increased by Boceprevir
[Hulskotte et al. HEP DART 2011, poster 123.]

23. Tacrolimus Exposures are Significantly Increased by Telaprevir
TAC 2mg (n=10)
TAC 0.5mg + TVR Day 8 (n=9)
Mean (SD) CL/F (L/hr)
32 (10.2)
0.48 (0.19)
Mean (SD) t1/2 (hr)
40.7 (5.85)
196 (159)
Mean (SD) V/F (L)
1910 (859)
106 (34.2)
Mean (SD) AUC0-∞
67.3 (17.3)
1310 (866)
DN AUC0-∞GLS Mean Ratio (90% CI)
70.3 (52.9, 93.4)
Mean (SD) Cmax
3.97 (1.82)
8.7 (3.23)
DN Cmax GLS Mean Ratio (90% CI)
9.35 (6.73, 13)
10 got single TAC dose, 9 got TAC + TVR, 1 withdrawn due to noncompliance
Open-label, PK study in healthy subjects
Tacrolimus (TAC) 2 mg as a single oral dose, followed by a minimum 14-day washout period, and subsequent co-administration of TAC 0.5 mg single dose
TAC exposures  70-fold in the presence of steady-state telaprevir
[Garg V, et al. Hepatology 2011;54:20-27.]
Slide courtesy of Dr. J. Kiser, U of Colorado, Denver 23

24. Tacrolimus Exposures are Significantly Increased by Boceprevir
[Hulskotte et al. HEP DART 2011, poster 123.]

25. 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

26. 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: 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
tacrolimus usual dose 1-6 mg BID
1. Mertz et al. Am J Kidney Dis 2009;54:e Bickel et al. JAC 2010;65: Teicher et al. Clin Pharmacokinet 2007;46: Barrail-Tran et al. 8th IWCPHT 2007, # Tricot et al. Am J Transplant 2009;9: Moreno et al. AIDS 2008;22: Vogel et al. 5th IWCPHT 2004, # Tseng et al. AIDS 2002;16: Di Baggio et al. JAC 2009;64:874-5.

27. 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.