Pharmacology for all I have nothing to disclose. HCV Clinicians - - PDF document

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Pharmacology for all I have nothing to disclose. HCV Clinicians - - PDF document

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12/8/2017 Disclosure Pharmacology for all I have nothing to disclose. HCV Clinicians Parya Saberi, PharmD, MAS Assistant Professor, UCSF Center for AIDS Prevention Studies Medical Management of HIV/AIDS and Hepatitis December 2017

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SLIDE 1

12/8/2017 1

Pharmacology for all HCV Clinicians

Parya Saberi, PharmD, MAS

Assistant Professor, UCSF Center for AIDS Prevention Studies Medical Management of HIV/AIDS and Hepatitis December 2017

Disclosure

  • I have nothing to disclose.

Resources

  • AASLD/IDSA:

www.hcvguidelines.org

  • EASL: www.easl.eu/medias/cpg/HCV‐

recommendations/English‐report.pdf

https://www.hcvguidelines.org/

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SLIDE 2

12/8/2017 2

Resources

  • University of Liverpool:

– HEP iChart: play.google.com/store/apps – HCV drug‐drug interactions: www.hep‐ druginteractions.org – HIV drug‐drug interactions: www.hiv‐ druginteractions.org

  • Toronto General Hospital’s HCV drug‐drug

interaction tables & news: www.hcvdruginfo.ca/

  • Indiana University’s CYP drug interaction table:

Medicine.iupui.edu/clinpharm/ddis

  • Package inserts

Selecting & Refining HCV Treatment Options

Patients being considered for HCV therapy Determine all possible DAA options based on genotype, presence of cirrhosis, treatment‐naïve or ‐experienced, & drug resistance Review all prescription & OTC meds & herbal supplements Screen for interactions using resources & package inserts Refine DAA options based on interactions, prior AEs, & patient preferences

Quick DAA Recap

Brand Generic MOA Gt HD Decomp. Cirrhosis EFV/ETR PI/r /c

Epclusa sofosbuvir (SOF) + velpatasvir (VEL) NS5B inhibitor + NS5A inhibitor 1, 2, 3, 4, 5, 6 √ √ Harvoni sofosbuvir (SOF) + ledipasvir (LDV) NS5B inhibitor + NS5A inhibitor 1, 4, 5, 6 √ √ √ Mavyret glecaprevir (GLE) + pibrentasvir (PIB) NS3/4A protease inhibitor + NS5A inhibitor 1, 2, 3, 4, 5, 6 √ (√) Vosevi sofosbuvir (SOF) + velpatasvir (VEL) + voxilaprevir (VOX) NS5B inhibitor + NS5A inhibitor + NS3/4A protease inhibitor 1, 2, 3, 4, 5, 6 (√) Zepatier elbasvir (EBR) + grazoprevir (GZR) NS5A inhibitor + NS3/4A protease inhibitor 1, 4 √

Case #1

A 52 year‐old African American woman comes in for her appointment with the clinical pharmacist to start SOF/VEL (Epclusa).

  • HCV: Tx‐naïve, Gt 1a, stage 2 fibrosis, no

cirrhosis (APRI= 0.3)

  • Labs: Normal liver function, CrCl= 63
  • Meds:

– TDF/FTC/EFV: 1 tablet once‐daily – Omeprazole: 20mg once‐daily

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12/8/2017 3

Regimens Dose Duration EBR/GZR* QD fixed‐dose combo EBR(50mg)/GZR (100mg) x12 weeks GLE/PIB QD fixed‐dose combo GLE (300mg)/PIB (120mg) x8 weeks SOF/LDV QD fixed‐dose combo SOF (400mg)/LDV (90mg) x12 weeks SOF/VEL QD fixed‐dose combo SOF (400mg)/VEL (100mg) x12 weeks

Case #1 Recommended Treatment Options:

Tx‐Naïve, HCV Gt 1a, not cirrhotic

*If no baseline NS5A RAVs detected (for EBR)

Question #1: Which ARVs have a major drug‐drug interaction with SOF/VEL?

  • a. Efavirenz
  • b. Darunavir/r
  • c. Tenofovir alafenamide
  • d. Elvitegravir/c
  • e. All of the above

Mechanism of SOF/VEL Drug‐Drug Interactions

  • SOF: substrate for P‐gp & BCRP

VEL: substrate for P‐gp, BCRP, OATP, CYP3A4, CYP2C8, & CYP2B6

P‐glycoprotein: efflux enzyme that “pushes” drugs out of GI blood stream back into GI lumen; also in liver, kidneys, & blood‐brain barrier Breast Cancer Resistance Protein: expressed in small intestine, liver, kidneys, & blood‐ brain barrier & plays important role in drug disposition & tissue protection Organic anion transporting polypeptide: involved in secretion or reabsorption of drugs (organic anions); across cell membrane in kidneys, brain, & liver Cytochrome P450 Enzymes: >50 enzymes essential for metabolism of 2/3 of meds cleared by metabolism. Primary cause of drug‐drug & drug‐ food interactions

Mechanism of SOF/VEL Drug‐Drug Interactions

  • SOF: substrate for P‐gp & BCRP

VEL: substrate for P‐gp, BCRP, OATP, CYP3A4, CYP2C8, & CYP2B6

  • Inducers of P‐gp, CYP2B6, CYP2C8, or CYP3A4 (e.g.,

rifampin, St. John’s wort, EFV) ↓ plasma concentrations of SOF or VEL

– Not recommended

  • VEL is inhibitor of P‐gp, BCRP, & OATP

– Co‐administration of substrates of these transporters may increase exposure of such drugs

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12/8/2017 4

VEL‐EFV Interaction

  • VEL: substrate of CYP3A4
  • VEL + EFV: ~50% decrease in VEL exposure

Mogalian E, Luetkemeyer A, et al. AIDS 2016; Durban, South Africa.

Summary: SOF/VEL‐ARV Interactions

Drug Class Drug Name Recommendation NNRTIs RPV No dose adjustments needed EFV, ETR Not recommended PIs DRV/r, ATV/r, LPV/r No dose adjustments needed InSTI RAL No dose adjustments needed EVG/c/FTC/TDF No dose adjustments needed DTG No dose adjustments needed N(t)RTI TDF/FTC No dose adjustments needed ABC/3TC No dose adjustments needed

Case #1: OTC Interactions

You ask her about any OTCs & she reminds you that she is taking

  • meprazole 20mg once daily for

reflux.

52 y/o woman, tx‐naïve, Gt 1a, no cirrhosis, CrCl=63,

  • n TDF/FTC/EFV

Question #2: What should you tell her about omeprazole?

a. Nothing b. Try to avoid acid blockers but, if you must, take SOF/VEL with food & 4 hours before OMP c. Try to avoid acid blockers but, if you must, take OMP 40mg once daily d. Take famotidine or antacids instead of OMP, given lack of interactions

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12/8/2017 5

VEL‐OMP Interaction

  • ↑pH results in ↓VEL solubility &↓VEL

concentration

  • Try to avoid acid blockers altogether…

– PPIs: SOF/VEL with food & 4 hrs before PPI (at max dose comparable to omeprazole 20mg) – H2‐RAs: Given simultaneously with or 12 hours apart from SOF/VEL at ≤ famotidine 40mg BID – Antacid: Separate by 4 hours

Case #1: Options

  • 1. Change ART to non‐EFV‐containing

regimen (e.g., DTG)

– She tried ABC/3TC/DTG before & had severe insomnia, so she refuses any ART change OR

  • 2. Change DAA

– EBR/GZR & GLE/PIB (substrates of CYP3A &

P‐gp): incompatible with EFV

– Decide to try SOF/LDV (Harvoni)

Mechanism of SOF/LDV Drug‐Drug Interactions

  • SOF/LDV: substrates of drug transporters P‐gp

& BCRP

  • P‐gp inducers (e.g., rifampin, St. John’s wort):

may ↓SOF/LDV plasma concentraons

– not recommended

  • Clinically significant interactions mediated by

CYP450 or UGT1A1 enzymes are not expected

Question #3: Which ARV regimens have drug‐drug interactions with SOF/LDV?

  • a. DTG/ABC/3TC
  • b. Any TDF‐containing regimens
  • c. Any HIV PI/r‐based regimens
  • d. Any TAF‐containing regimens
  • e. Any NNRTI‐based regimens
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12/8/2017 6

TDF & SOF/LDV

  • Possible mechanism:

– LDV inhibits efflux transporters (P‐gp & BCRP) leading to ↑TFV exposure – In vitro, SOF/LDV increase TFV absorption

  • ↑TFV not been shown to be clinically significant. Options:

– Switch to TAF (especially if preexisting renal dysfunction) – Monitor renal function more closely if continue TDF

German P, et al. Abstract O_06. 15th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy. 2014; Washington, DC. / German P, et al. Abstract 82. 22nd CROI. 2015; Seattle, WA. / Mathias A. 16th International Workshop

  • n Clinical Pharmacology of HIV and Hepatitis Therapy. 2015; Washington, DC.

ARV TFV PK INSTI

  • TFV AUC ↑1.7‐fold in DTG+TDF/FTC

NNRTI

  • TFV AUC ↑98% in EFV/TDF/FTC
  • TFV AUC ↑40% in RPV/TDF/FTC

PI/r

  • TFV AUC ↑50% in DRV/r+TDF/FTC
  • Unchanged with 12‐hour staggering of dose

AUC: area under the concentration drug concentration‐time curve; DRV: darunavir; FTC: emtricitabine; PK: pharmacokinetics; r: ritonavir; TDF: tenofovir

TAF & SOF/LDV

SOF/LDV does not significantly impact TAF or TFV PK

Custodio JM, et al. IDSA/IDWeek 2015; San Diego, CA.

Side Note: SOF/VEL + TDF or TAF

  • SOF/VEL + TDF: increased TFV AUC by 20‐81%

– Recommend: monitor renal function or change TDF

  • SOF/VEL + TAF: no clinically significant impact on TFV

Mogalian E, Luetkemeyer A, et al. AIDS 2016; Durban, South Africa.

Summary: SOF/LDV‐ARV Interactions

Drug Class Drug Name Recommendation NNRTIs EFV, ETR, NVP, RPV No dose adjustments needed PIs ATV/r, DRV/r, LPV/r No dose adjustments needed TPV Not recommended InSTI ELV/c Monitor for TDF‐associated renal dysfunction COBI levels ↑ (possible ↑AEs) DTG, RAL No dose adjustments needed N(t)RTI TDF+EFV Monitor for TDF‐associated renal dysfunction TDF+ (ATV/r or DRV/r

  • r LPV/r)

↑TDF concentraons. Consider alternave therapy; monitor for TDF‐associated renal dysfunction TAF No dose adjustments needed 3TC, ABC, FTC, ZDV No dose adjustments needed CCR5 Inhibitor MVC No data

Only DAA compatible with EFV (& likely with ETR)

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12/8/2017 7

LDV‐OMP Interaction

  • ↑pH results in ↓LDV solubility. Drugs that ↑pH will

↓LDV concentraon.

  • PPIs:

– When omeprazole 20mg/day given 2hrs prior to LDV, ↓LDV AUC by 42% & ↓LDV Cmax by 48% – Try to avoid acid blockers. If necessary, give PPI simultaneously with SOF/LDV, under fasted conditions, & at dose comparable to omeprazole ≤20mg/day

  • H2‐RA: Give simultaneously with or 12hrs apart from

SOF/LDV; at famotidine ≤ 40mg BID

  • Antacid: Separate by 4hrs

Case #1: Options

  • 1. Change TDF to avoid TDF + SOF/LDV interaction

– TDF/FTC to ABC/3TC (if HLA‐b5701 negative) – TDF/FTC to TAF/FTC

  • 2. Continue TDF/FTC/EFV + SOF/LDV & monitor renal

function very closely

‐ e.g., every 2 weeks at least initially (Cr, electrolytes w/phosphorus, & urinary protein & glucose)

  • 3. Use other DAA regimen: issues with cost/access, pill

burden, AEs

52 y/o woman, tx‐naïve, Gt 1a, no cirrhosis, CrCl=63,

  • n TDF/FTC/EFV & Omeprazole

Case #1: Conclusion

  • Pt willing to try TAF/FTC + EFV, so you

change her ARVs.

–Recommend monitoring x1‐2 months on new ART before starting DAAs

  • She does very well on SOF/LDV & has

attained SVR12.

Case #2

A 45 year‐old male patient is being seen at the clinical pharmacy office to get started

  • n GLE/PIB (Mavyret).
  • HCV: Tx‐naïve, Gt1b, cirrhotic (Child‐Pugh

score A)

  • Meds: TAF/FTC/EVG/c, rosuvastatin,
  • meprazole

Reminder: GLE/PIB can’t be used in decompensated cirrhosis (i.e., Child‐Pugh B/C)

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12/8/2017 8

Regimens Dose Duration GLE/PIB QD fixed‐dose combo GLE (300mg)/PIB (120mg) x12 weeks EBR/GZR QD fixed‐dose combo EBR(50mg)/GZR (100mg) x12 weeks SOF/LDV QD fixed‐dose combo SOF (400mg)/LDV (90mg) x12 weeks SOF/VEL QD fixed‐dose combo SOF (400mg)/VEL (100mg) x12 weeks

Case #2 Recommended Treatment Options:

Tx‐Naïve, HCV Gt 1b, compensated cirrhosis

Question #4: Which ARV is GLE/PIB compatible with?

a. Atazanavir/r b. Elvitegravir/c c. Efavirenz or Etravirine d. Raltegravir or Dolutegravir e. All of the above

Question #4: Which ARV is GLE/PIB compatible with?

a. Atazanavir/r b. Elvitegravir/c c. Efavirenz or Etravirine d. Raltegravir or Dolutegravir e. All of the above

GLE/PIB ↑ELV/c Cmax by 29‐36%, AUC by 42‐47%. GLE Cmax & AUC 2.5‐ & 3.1‐fold higher, respectively, vs. GLE/PIB alone; PIB AUC was 57% higher. No clinical data for ELV/c + GLE/PIB, so caution when using together.

Effect of Inhibitors on GLE/PIB

  • GLE/PIB contraindicated with ATV/r
  • GLE/PIB may be okay with DRV/r, LPV/r, and ELV/c but

not recommended due to lack of clinical data

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SLIDE 9

12/8/2017 9 Summary: GLE/PIB‐ARV Interactions

Drug Class Drug Name Recommendation NNRTIs RPV No dose adjustments needed EFV, ETR Not recommended PIs ATV/r Not recommended DRV/r, LPV/r Not recommended (for now) InSTI RAL No dose adjustments needed DTG No dose adjustments needed ELV/c Not recommended (for now) N(t)RTI TDF, TAF No dose adjustments needed

GLE/PIB: CYP3A & P‐gp substrates

  • GLE/PIB inhibit BCRP, P‐gp, OATP
  • Rosuvastatin (substrate for BCRP & OATP)

– Cmax ↑462%, AUC ↑115% – Do not exceed 10mg/d

  • Pravastatin: reduced dose by 50%
  • Atorvastatin: do not co‐administer

Case #2: Drug‐Drug Interactions

SOF/LDV SOF/VEL EBR/GZR GLE/PIB SOF/VEL/VOX Atorvastatin ND 20mg Pitavastatin ND ND Lowest dose Pravastatin ↓dose by 50% 40mg Rosuvastatin 10mg 10mg 10mg

Case #2: DAA + PPI Interactions

No statistically significant difference in SVR12 between high & low PPI doses with GLE/PIB across genotypes, but caution with high dose PPIs until more data available

SOF/LDV SOF/VEL EBR/GZR GLE/PIB SOF/VEL/VOX Antacids Separate by 4 hrs Separate by 4 hrs Separate by 4 hrs H2RA Together or 12hrs apart; FAM 40mg BID Together or 12hrs apart; FAM 40mg BID Together or 12hrs apart; FAM 40mg BID PPIs Together with OMP 20mg With food, 4hrs before OMP 20mg With food, 4hrs before OMP 20mg

Flamm S, et al. World Congress of Gastroenterology at ACG 2017; 2017; Orlando, FL. P1435.

Side Note: Warfarin

  • Updated SOF, SOF/LDV, SOF/VEL, SOF/VEL/VOX:

“Fluctuations in INR values may occur in patients receiving warfarin concomitant with HCV treatment... Frequent monitoring of INR values is recommended during treatment and post‐treatment...”

  • Interaction more significant with ribavirin & PrOD
  • Interaction usually results in decreased INR, needing an

↑Warfarin dose (≥15%)

  • Mechanism unclear but eradication of HCV improves liver

function to increase clotting factor synthesis &/or warfarin metabolism

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12/8/2017 10

Case #2: Options

  • 1. Change ART

– Suggestions: DTG/ABC/3TC or RPV/TAF/FTC

  • r
  • 2. Change DAA

– SOF/LDV x12 weeks – SOF/VEL x12 weeks 45 y/o man starting GLE/PIB. Gt1b, cirrhotic, Tx‐ naïve; TAF/FTC/EVG/c, rosuvastatin, omeprazole

Contraindicated with PPIs

Case #2: Conclusion

  • Due to insurance coverage of GLE/PIB,

we decide to change ART to DTG/ABC/3TC.

– Recommend monitoring x1‐2 months on new ART before starting DAAs

  • Patient recently started HCV treatment &

is doing well.

Case #3

You’re seeing a 58 year‐old White male on hemodialysis who would like to start HCV

  • treatment. Provider is not sure what to use

given patient’s renal function.

–HCV: Tx‐naïve, Gt 3, no cirrhosis –Meds: DTG + ABC + 3TC (renally‐dosed)

Question #5: Which DAA agents are okay to use in those with eGFR <30 mL/min?

  • 1. EBR/GZR (Zepatier)
  • 2. GLE/PIB (Mavyret)
  • 3. SOF/LDV (Harvoni)
  • 4. SOF/VEL (Epclusa)
  • 5. 1 & 2
  • 6. All of the above
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CKD DAA No dose adjustment Duration 1‐3 EBR/GZR QD EBR (50mg)/GZR (100mg) x12 weeks GLE/PIB QD GLE (300mg)/PIB (120mg) X8‐16 weeks SOF/LDV QD SOF (400mg)/LDV (90mg) x12 weeks SOF/VEL QD SOF (400mg)/VEL (100mg) x12 weeks DCV + SOF QD DCV (60mg**) + SOF (400mg) x12 weeks SMV + SOF QD SMV (150mg) + SOF (400mg) x12 weeks SOF/VEL/VOX QD SOF (400mg)/VEL (100mg)/VOX (100mg) x12 weeks 4‐5 EBR/GZR QD EBR (50mg)/GZR (100mg) x12 weeks GLE/PIB QD GLE (300mg)/PIB (120mg) X8‐16 weeks

Case #3 Treatment Options:

Renal Impairment

Chronic Kidney Disease (CKD) stages: 1= normal (eGFR >90 mL/min); 2= mild CKD (eGFR 60‐89 mL/min); 3= moderate CKD (eGFR 30‐59 ml/min) 4= severe CKD (eGFR 15‐29 mL/min); 5= end‐stage CKD (eGFR <15 mL/min)

Case #3 General Options: Tx‐Naïve, Gt 3, no cirrhosis

Regimens Dose Duration SOF/VEL QD fixed‐dose combo SOF (400mg)/VEL (100mg) x12 weeks GLE/PIB QD fixed‐dose combo GLE (300mg)/PIB (120mg) x8 weeks

Case #3: Conclusion

  • He initiates GLE/PIB
  • He does very well & has SVR post‐

treatment

Important Points

  • SOF/LDV can be used with EFV or ETR.
  • SOF/LDV & SOF/VEL can be used with PI/r & EVG/c.
  • LDV & VEL ↑TFV levels (esp. with TDF + PI/r & EVG/c), either

avoid combo by changing TDF to TAF or other ARVs or monitor renal function closely.

  • EBR/GZR & GLE/PIB seem okay with PPIs (caution w/ high doses).
  • Pravastatin seems okay with most DAAs.
  • EBR/GZR & GLE/PIB can be used in ESRD.
  • SOF/VEL & SOF/LDV can be used in decompensated cirrhosis

– GLE/PIB, EBR/GZR, & SOF/VEL/VOX should not be used in those with Child‐Pugh B & C.

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12/8/2017 12

Acknowledgements

  • Annie Luetkemeyer, MD
  • Meg Newman, MD, FACP
  • Diane V. Havlir, MD