Your Resource for Hepatitis Related Innovative Medical Communication 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 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

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 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.

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)

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

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 117-330%  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

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

Proportion of Drugs Metabolized by the Major CYP450 Enzymes

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.

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 P450 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.

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.

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 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

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 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

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 123. Garg V, et al. Hepatology 2011;54:20-27.]

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

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

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

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

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 tacrolimus usual dose 1-6 mg BID 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. 5th 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.