Increase in INR after switching from atazanavir/ritonavir to - - PowerPoint PPT Presentation

Increase in INR after switching from atazanavir/ritonavir to darunavir/cobicistat in a patient on warfarin: boosters are not always equal

Tseng A, Luetkehoelter J, Walmsley S. HIV Endgame Conference, OHTN October 25, 2016

Disclosures

• Unrestricted educational grants:

– Abbvie, Bristol Myers Squibb, Gilead, Merck, ViiV

• Speaker honoraria/consulting:

– Abbvie, Gilead, Merck

• Advisory board:

– ViiV

Background

• The oral anticoagulant warfarin is a racemic

mixture comprised of:

– R‐isomer, substrate of CYP1A2, 3A4 – S‐isomer, substrate of CYP2C9

• Potential for interactions with antiretrovirals

including ritonavir, which induces 2C9

– case reports where 45‐100%  warfarin dose required to maintain therapeutic INR after boosted PI therapy was initiated

Background/Purpose

• In contrast to ritonavir, cobicistat does not

induce CYP450 or transporter activity

• We describe an HIV‐infected individual on

stable warfarin who experienced increased international normalized ratio (INR) after switching from atazanavir/ritonavir to darunavir/cobicistat

Case

• 72 year old Causasian male, HIV+ 1987, on

atazanavr/ritonavir plus 2 NRTIs since 2005 with suppressed VL, current CD4 437 cells/mm3

– MI (1999, CABG 2012), DLBC lymphoma (2007 – CHOP), atrial flutter (2013), COPD/emphysema, neuropathy

• Switched to darunavir/cobicistat/emtricitabine/TAF

STR in September 2015 (study)

– Concomitant meds: acyclovir, pravastatin, EC ASA, metoprolol, warfarin, Advair, salbutamol, pregabalin

• Had been on stable warfarin dose of 10 mg daily for
• ver the past year with a recent INR of 2.5 prior to

antiretroviral switch

Case: INR & Warfarin Dosing

2 4 6 8 10 12 0.5 1 1.5 2 2.5 3 3.5 4 Jun‐15 Jul‐15 Aug‐15 Sep‐15 Oct‐15 Nov‐15 Dec‐15 Jan‐16 Feb‐16 Mar‐16 Apr‐16

Daily Warfarin Dose (mg) INR INR Warfarin Dose ATV/r‐TDF‐FTC DRV/cobi/FTC‐TAF

• One month after switch, INR was 3.4 and warfarin  to 8.75 mg/day
• In January (4 months later), INR was 3.6, warfarin  to 7.5 mg/day.

Patient also reported recurrent nosebleeds

• Warfarin further  to 4 mg/day and INR returned to baseline

Baseline:

• Warfarin 10 mg/d
• INR 2.5

Using Warfarin with Antiretrovirals

• Racemic mixture (R: CYP1A2, 3A, 2C19; S: 2C9)
• Close monitoring recommended, especially when

starting/changing antiretrovirals

Fulco et al. Pharmacother 2008;28:945‐9. Hughes et al. CMAJ 2007;177:357‐9. Dionisio et al. AIDS 2001;15:277‐8. Bonora et al. CID 2008;46:146‐7. Good et al. AIDS 2015;29:985‐6.

Impact on Warfarin Concentrations Protease Inhibitors NNRTIs InSTIs  Warfarin due to 2C9 induction Ritonavir:

• 45‐100%  warfarin

dose to maintain INR

Nevirapine

• Doubling/exceeding

max recommended warfarin dose

Elvitegravir

• 60%  warfarin

dose to maintain INR (case report)

 Warfarin due to 2C9 inhibition Efavirenz

• 4‐fold  reduction

in warfarin dose

No impact Rilpivirine Dolutegravir Raltegravir

Note: Cobicistat Not Always Equal to Ritonavir

PK Booster Substrate CYP450 and UGT Transporters (Inhibitor) Inhibitor Inducer Ritonavir CYP3A4, P‐gp, MRP1 CYP3A4 (potent)>>2D6 >2C9>2C19>2A 6>1A2>2E1 UGT, CYP1A2, CYP2C9, 2C19, 2B6 P‐gp, OATP1B1/3, BCRP, OATP2B1, OCT2 Cobicistat CYP3A4, 2D6 (minor) CYP3A4>> 2D6 none P‐gp, BCRP, OATP1B1/3, MATE1

• Generally, cobicistat 150 mg provides equivalent

boosting to ritonavir 100 mg (but some exceptions)

• One key difference is that cobicistat lacks significant

enzyme inducing effects

Interaction Between Acenocoumarol and Antiretroviral Drugs

• 56 yo male required 38%

increase in acenocoumarol dose to maintain therapeutic INR while on atazanavir 300/100 mg daily.

• When atazanavir/ritonavir

was replaced with raltegravir, the acenocoumarol dose was reduced and therapeutic INR was maintained.

• Mechanism: induction of

CYP2C9 and 1A2 by ritonavir

• Acenocoumarol: oral vit. K antagonist

– R enantiomer: 2C9>1A2, 2C9, 3A4 – S enantiomer: 2C9 (no pharmacologic activity in vivo)

Welzen MEB et al. Antiviral Ther 2011;16:249‐52.

Hypothesis: Warfarin Interaction with Darunavir/Cobicistat

• Previously stable on warfarin 10mg daily while
• n atazanavir/ritonavir

– Ritonavir induces 2C9, likely required higher warfarin dose

• Switch to darunavir/cobicistat: no 2C9

enzyme induction effect

– Led to increased warfarin concentrations and elevated INR with symptoms

• A 60%  in warfarin dose was required

Drug Interaction Probability Scale (DIPS)

Total Score: 4 (possible)

Horn et al. Ann Pharmacother 2007;41:674‐80.

Discussion

• While cobicistat and ritonavir have generally similar

CYP3A4 inhibiting properties, cobicistat does not induce CYP isoenzymes or transporters

– ritonavir induces CYP1A2, 2B6, 2C8, 2C9, 2C19 and UGT  leads to  drug concentrations and dose 

• When switching from ritonavir to cobicistat, may

need to  doses of drugs metabolized via these pathways

– enzyme inducing effects may take 2‐3 weeks to dissipate – monitor and adjust (decrease) dose of target medication as needed

• Generally similar CYP3A4 inhibiting properties
• Ritonavir induces CYP1A2, 2B6, 2C8, 2C9, 2C19 and

UGT  leads to  concentrations and dose 

• Cobicistat does not induce enzymes
• When switching from ritonavir  cobicistat, may

need to  doses of drugs metabolized via these pathways

Examples of Medications Affected Differently by Ritonavir vs. Cobicistat

Class Example Metabolic Pathway Ritonavir Effect Cobicistat Effect Anticoagulant warfarin 2C9>1A2, 3A4, 2C19   Antidepressant bupropion 2B6  ‐ duloxetine 2D6, 1A2 /  sertraline 2B6>2C9/19, 2D6, 3A4   Antidiabetic sulfonyureas 2C9  ‐ Antipsychotic

• lanzapine

1A2, UGT1A4  ‐ Bronchodilator theophylline 1A2  ‐ Contraceptives EE, NE 3A4>2C9, UGT   Immunosuppresant MMF UGT  ‐ Lipid‐lowering Gemfibrozil, fenofibrate, pitavastatin UGT  ‐

Adapted from: Marzolini et al. JAC 2016 [epub ahead of print]

Don’t forget what cobicistat is paired with

Inhibiting effects Inducing effects Atazanavir Evotaz CYP3A, 2C8, UGT1A1 Darunavir Prezcobix, DRV/co/F/TAF CYP3A CYP3A4 (?) Elvitegravir Stribild CYP2C9

• Stribild

monograph:

• Case report:

– 42 yo HIV+ male on efavirenz/TDF/FTC and stable warfarin 50 mg/wk for recurrent lower DVT; changed to Stribild due to CNS effects – On day 20, INR was subtherapeutic – Warfarin  to 80 mg/wk to achieve therapeutic INR (= 60% dose ) – Suggests 2C9 induction by EVG outweighs CYP3A4 inhibition by cobicistat

Good et al. AIDS 2015;29:985‐6.

Conclusions

• When switching from a ritonavir‐ to a

cobicistat‐boosted protease inhibitor regimen, clinicians should be aware of the potential for increased warfarin exposures

• INR monitoring is recommended and warfarin

dose adjustments may be required

• Causality assessments (e.g., DIPS) may be

helpful

• Publish new observations!