Current Drugs: Drug-Drug Interactions

Transcription

1 Slide 1 Current Drugs: Drug-Drug Interactions David Back University of Liverpool UK David Back University of Liverpool May 2013

2 Toxicity HCV med Comed Reduced Efficacy The major effect of DAAs is to increase concentrations of co-meds but they may also decrease AND co-meds can interact with DAA

3 Clinical Pharmacology of DAAs DRUG CYP450 Non- CYP450 Telaprevir CYP3A4 Substrate Inhibitor Boceprevir CYP3A4 Substrate Inhibitor AKR substrate Transport Proteins Transported by P-gp Inhibits P-gp Inhibits OATP1B1 Transported by P-gp Inhibits P-gp Inhibits OATP1B1; OCT1/2 Kessara C et al 18 th CROI, Abs 118; Garg V et al 18 th CROI, Abs 629; Telaprevir SmPC, 2013; Boceprevir SmPC, 2013; Kiser JJ et al Hepatology 2012; 55: ; Kunze A et al Biochem Pharmacol 2012; 84:

4 Clinical case: patient characteristics at time of treatment Description 54-year-old male Smoker and no alcohol abuse Treatment naïve HCV disease characteristics Genotype: HCV G1a Fibrosis stage: F3 Other medical information BMI: 28 Type 2 diabetes (taking metformin) High cholesterol and cardiovascular risk >20% (taking atorvastatin) Total Chol: 1.70 g/l; HDL: 0.42 g/l Hypertension (taking propranolol) Suffering from mild depression (receiving behavioural therapy) Hb level: 14 g/dl BMI: body mass index; Hb: haemoglobin; HCV: hepatitis C virus; HDL: high-density lipoprotein

5 DDIs: patient s medications Telaprevir PR Propranolol Atorvastatin Metformin

6 Which medications are a concern with telaprevir? Metformin Renal excretion no interaction expected but we are constantly learning about renal transporters Not anticipated to cause a problem when combined with DAAs Propranolol Metabolised by CYP2D6 (major) no interaction expected ED: erectile dysfunction

7 Telaprevir increases exposure to statins Telaprevir Recommendation Atorvastatin AUC 788% Contra-indicated Other recommendations: 1,2 Simvastatin Pravastatin Rosuvastatin Contra-indicated (CYP 3A4 substrate) Potential interaction may require close monitoring or change of dosing AUC: area under curve 1. Telaprevir EU SmPC 2.

8 Treatment decision Because of interactions Atorvastatin was temporarily stopped for 12 weeks after consultation with the cardiologist No changes were made to the metformin and propranolol prescriptions

9 Week 2 8 visits: results HCV RNA (log 10 IU/mL) HCV RNA levels Telaprevir + PR Patient health Patient develops an upper respiratory tract infection (deemed unrelated to treatment) He develops mild rash His depression worsens (becomes moderate) Weeks

10 Management of the patient s upper respiratory tract infection Clarithromycin CYP 3A inhibitor & substrate Concern about increase in telaprevir exposure Also concern of increase in CLA this may warrant ECG monitoring due to the possible risk of QT prolongation Azithromycin Not a CYP 3A inhibitor or substrate Drug interactions unlikely A 5-day course of azithromycin was chosen due its reduced likelihood of interactions Choose carefully ECG: electrocardiogram

11 Management of mild rash: which corticosteroid? Systemic corticosteroids Not recommended with telaprevir and boceprevir Prednisone and methylprednisolone are CYP3A substrates; levels may significantly increase and lead to side effects Topically applied steroids OK to use concomitantly with HCV PIs Although not expected to cause significant systemic absorption be watchful (lessons form HIV) In this patient, a topically applied corticosteroid (betamethasone) was initiated Cacoub P, et al. J Hepatol 2012;56:

12 Antidepressants and telaprevir Some Antidepressants are metabolized by CYP 3A4 Some Antidepressants metabolized primarily by non CYP 3A4 Trazodone Mirtazapine Paroxetine Fluoxetine Sertraline Venlafaxine Interaction is likely, caution is advised Interaction is unlikely* * Caution note escitalopram

13 Week 8: patient has a car accident The patient has a car accident at week 8 (breaking his leg) The emergency unit requests advice since the patient informed them about his Hep C medication? The internist wants to administer Morphine and iv Midazolam

14 Interaction with morphine and midazolam Morphine Based on metabolism and clearance, a clinically significant interaction is unlikely. Midazolam IV Midazolam IV exposure is likely to be increased (respiratory depression and/or prolonged sedation risk) Co-administration should be done in a setting ensuring clinical monitoring and appropriate medical management Back home, the patient is prescribed paracetamol Telaprevir EU SmPC

15 Treatment outcome: summary HCV RNA (log 10 IU/mL) Telaprevir + PR Betamethasone Fluoxetine Morphine and midazolam IV PR Restart statin Rash disappeared; topical steroid stopped Depression symptoms improved Weeks SVR12

16 Telaprevir Boceprevir Ribavirin Drugs in pipeline HCV med Toxicity Comed Reduced Efficacy HIV med ATV/r DRV/r LPV/r Efavirenz Rilpivirine Etravirine Raltegravir Elvitegravir/cobi Maraviroc NRTIs In a co-infected patient we now need to manage the interactions between the HCV and HIV medication as well as other co-meds

17 HCV HIV DDIs: The predictable and the unpredictable!

18 Telaprevir & Boceprevir increase exposure to CYP3A substrates: Perpetrator Drug TVR effect on AUC (exposure) BOC effect on AUC (exposure) Cyclosporine A 4.6-fold increase 2.7-fold increase Midazolam 9-fold increase (oral) 6.3-fold increase (oral) Atorvastatin 7.9-fold increase 2.3-fold increase Garg V, et al. Heptatology 2011:54:20 27; Garg V, et al. J Clin Pharmacol 2012 ; Lee JE, et al. Antimicrob Agents Chemother 2011;55: ; Telaprevir SmPC; Hulskotte EGJ et al HEPDart 2011; Abs 122 and Abs 123; Kessara C et al, CROI 2011, Abs 118; Boceprevir SmPC

19 Effect of Boceprevir and Telaprevir on the PK of Maraviroc CYP3A4 drug Vourvahis M et al. IWCPHT 2013 Abs O-17

20 Conclusions Slide 20 Maraviroc should be dosed at 150 mg BID when co-administered with either TVR or BOC consistent with recommendations for potent CYP3A inhibitors. No dose modification for TVR or BOC (relative to historical data).

21 Effect of Telaprevir and Boceprevir on the PK of Rilpivirine (CYP3A4) Parameter TVR on Rilpivirine BOC on Rilpivirine Cmin, ng/ml 93% 51% Cmax, ng/ml 49% 15% AUC, ng.hr/ml 78% 39% The effect of the DAA on Rilpivirine PK was < 12% Finding consistent with CYP3A inhibition Increase in RPV exposure probably not clinically significant and no dose adjustment recommended. Rhee EG, et al. CROI 2013; Atlanta, GA. #537; Kakuda T et al; IWCPHT, 2012, Barcelona, #O-18

22 Effect of Boceprevir on Dolutegravir PK DOL metabolised: UGT1A1 (major) & CYP3A4 (minor)

23 Slide 23 Effect of Telaprevir on Dolutegravir PK Similar to Raltegravir AUC is increased by 30%

24 Interactions of Telaprevir with Boosted HIV PIs (Healthy volunteer data) LSM ratio (90% CI), based on AUC Co-administered drug Lopinavir/r (LPV/r) Atazanavir/r (ATV/r) Darunavir/r (DRV/r) Fosamprenavir/r (fapv/r) n HIV PI Telaprevir * LPV/r, DRV/r and fapv/r not recommended in combination with telaprevir * Cmin increased by ~ 70% Mechanistic understanding of observed DDI is inconsistent with CYP3A4 interactions q8h: every 8 hours Telaprevir EU SmPC

25 Interaction of Boceprevir and Boosted HIV PIs (Healthy volunteer data) % Change in AUC of Boosted PI % Change in AUC of Boceprevir Atazanavir/r 35% Lopinavir/r 34% 45% Darunavir/r 44% 32% Not recommended to coadminister boceprevir and ritonavir boosted PIs (FDA; Merck) ATV/r can be considered on a case by case basis if patient has no prior HIV drug resistance (EMEA) Hulskotte E et al; CROI 2012 Abs 771LB

26 But remember that ritonavir has inhibited ~95% of CYP3A activity so TVR and BOC are exerting other effects.

27 Effect of Ritonavir and Cobicistat (GS-9350) on midazolam (CYP3A4 drug) clearance RTV and Cobi are potent inhibitors of CYP3A4

28 What if the interaction between Telaprevir & Boceprevir and Boosted HIV PIs was similar to the Methadone interaction?

29 But what if the HCV PI and HIV PI interaction was similar to TVR-Methadone?: During telaprevir co-administration vs methadone alone: Total C min of R-methadone reduced by 31% Free fraction of R-methadone increased by 26% No change in the unbound (effective) concentration of R-methadone 15 Total C min of R- methadone (ng/ml) Methadone Methadone + TVR Median free fraction of R-methadone (%) Methadone Methadone + TVR Median unbound R- methadone C min (ng/ml) Protein Binding Displacement Methadone Methadone + TVR van Heeswijk R, et al. J Hepatol 2011;54(Suppl. 1):S491

30 Effect of Protein Binding on Darunavir PK with and without Telaprevir Bertelsen K. IWCPHT 2013.

31 Effect of Protein Binding on Telaprevir PK with and without Darunavir/r Bertelsen K IWCPHT 2013

32 Bertelsen K. IWCPHT 2013

33 What if DDI s were significantly different in HCV patients compared to healthy volunteers?

34 Most DDI studies are in Healthy Subjects: Physiological Changes in Patients Slide 34 Parameter HCV-infected Albumin * 1 α1-acid glycoprotein 3 Gastric ph 4 Cytokines 6 CYP450 s expression or function 5 Transporter expression or function? * Magnitude of effect dependent on stage of liver involvement Also hemodynamic changes (portal systemic shunting) and renal changes with hepatic impairment 1 Nagao Y & Sata M. Virology Journal 2010; 7: 375; 2 Monga HK et al. Clin Infect Dis 2001; 33: 240-7; 3 Ozeki T et al. Br J Exp Path 1988; 69: ; 4 Nam YJ et al. Korean J Hepatol 2004; 10: ; 5 Frye RF et al. Clinical Pharmacol Ther 2006; 80: ; 6 Huang et al Clin Pharmacol Ther 2010; 87: 32-36

35 CYP enzyme expression with progressive hepatic impairment Slide CYP3A4 CYP3A4 % of control CP-A (6) CP-B (21) CP-C (21)* Maybe this would lead you to think that a CYP3A drug would automatically be increased in hepatic impairment! Frye RF et al. Clinical Pharmacol Ther 2006; 80: Johnson TN et al. Clinical Pharmacokin 2010; 49:

36 Impact of Hepatic Impairment on Telaprevir PK Slide 36 Reduced Absorption Increased clearance due to reduced protein binding

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38 Impact of Hepatic Impairment on Boceprevir PK Treitel M et al., Clin Pharmacokin 2012; 51:

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40 Suggests Slide 40 Complex interplay between an individual drug and hepatic function. Involves CYP3A4 and probably transporters Involves protein binding (TVR 59-76%; BOC 75%; Daclatasvir 99%; Asunaprevir 99%) Clear differences in hepatic impairment on PK of the DAAs Need DDI data in target population healthy volunteers can only be a guide

41 HIV-HCV Interaction Studies The HIV-HCV interaction studies to date have mostly been performed in Healthy volunteers: some are unexpected and difficult to explain. Need information on PK in HCV patients the magnitude of interactions maybe different due to difference in enzyme or transporter expression. Mechanisms such as protein binding displacement may be involved. Need data. Interferon may be exerting enough anti HIV activity to protect against low HIV drug concentration.

42 What about DDI s and the next generation of DAA s?

43 Management of Hep Drug-Drug Interactions

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