Pharmacology for all HCV Clinicians

Transcription

1 Pharmacology for all HCV Clinicians Disclosure I have nothing to disclose. Parya Saberi, PharmD, MAS Assistant Professor, UCSF Center for AIDS Prevention Studies Medical Management of HIV/AIDS and Hepatitis December 2017 Resources AASLD/IDSA: EASL: report.pdf 1

2 Resources University of Liverpool: HEP ichart: play.google.com/store/apps HCV drug drug interactions: HIV drug drug interactions: Toronto General Hospital s HCV drug drug interaction tables & news: 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) + NS5B inhibitor + 1, 2, 3, velpatasvir (VEL) NS5A inhibitor 4, 5, 6 Harvoni sofosbuvir (SOF) + NS5B inhibitor + 1, 4, 5, ledipasvir (LDV) NS5A inhibitor 6 Mavyret glecaprevir (GLE) + NS3/4A protease inhibitor + 1, 2, 3, pibrentasvir (PIB) NS5A inhibitor 4, 5, 6 ( ) Vosevi sofosbuvir (SOF) + NS5B inhibitor + velpatasvir (VEL) + NS5A inhibitor + voxilaprevir (VOX) NS3/4A protease inhibitor Zepatier elbasvir (EBR) + grazoprevir (GZR) NS5A inhibitor + NS3/4A protease inhibitor 1, 2, 3, 4, 5, 6 ( ) 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 2

3 Case #1 Recommended Treatment Options: Tx Naïve, HCV Gt 1a, not cirrhotic 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 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 *If no baseline NS5A RAVs detected (for EBR) 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, & bloodbrain 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 & drugfood 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 3

4 VEL EFV Interaction VEL: substrate of CYP3A4 VEL + EFV: ~50% decrease in VEL exposure 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 Mogalian E, Luetkemeyer A, et al. AIDS 2016; Durban, South Africa. Case #1: OTC Interactions 52 y/o woman, tx naïve, Gt 1a, no cirrhosis, CrCl=63, on TDF/FTC/EFV You ask her about any OTCs & she reminds you that she is taking omeprazole 20mg once daily for reflux. 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 4

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 concentra ons 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 5

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 TAF & SOF/LDV SOF/LDV does not significantly impact TAF or TFV PK 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 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 nd CROI. 2015; Seattle, WA. / Mathias A. 16th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy. 2015; Washington, DC. 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 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 TDF concentra ons. Consider alterna ve therapy; or LPV/r) 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) Mogalian E, Luetkemeyer A, et al. AIDS 2016; Durban, South Africa. 6

7 LDV OMP Interaction ph results in LDV solubility. Drugs that ph will LDV concentra on. 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 52 y/o woman, tx naïve, Gt 1a, no cirrhosis, CrCl=63, on TDF/FTC/EFV & Omeprazole 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 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 on GLE/PIB (Mavyret). HCV: Tx naïve, Gt1b, cirrhotic (Child Pugh score A) Meds: TAF/FTC/EVG/c, rosuvastatin, omeprazole Reminder: GLE/PIB can t be used in decompensated cirrhosis (i.e., Child Pugh B/C) 7

8 Case #2 Recommended Treatment Options: Tx Naïve, HCV Gt 1b, compensated cirrhosis 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 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? Effect of Inhibitors on GLE/PIB 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. 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 8

9 Summary: GLE/PIB ARV Interactions GLE/PIB: CYP3A & P gpsubstrates 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 Case #2: Drug Drug Interactions 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 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 Flamm S, et al. World Congress of Gastroenterology at ACG 2017; 2017; Orlando, FL. P1435. 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 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 9

10 Case #2: Options 45 y/o man starting GLE/PIB. Gt1b, cirrhotic, Txnaïve; TAF/FTC/EVG/c, rosuvastatin, omeprazole 1. Change ART Suggestions: DTG/ABC/3TC or RPV/TAF/FTC or 2. Change DAA SOF/LDV x12 weeks SOF/VEL x12 weeks 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 10

11 Case #3 Treatment Options: Renal Impairment 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 Chronic Kidney Disease (CKD) stages: 1= normal (egfr >90 ml/min); 2= mild CKD (egfr ml/min); 3= moderate CKD (egfr ml/min) 4= severe CKD (egfr 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 x12 weeks (400mg)/VEL (100mg) 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 posttreatment 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. 11

12 Acknowledgements Annie Luetkemeyer, MD Meg Newman, MD, FACP Diane V. Havlir, MD 12