Clinical Pharmacology of Integrase Inhibitors

Transcription

1 Clinical Pharmacology of Integrase Inhibitors Dr Marta Boffito MD PhD Head of Clinical Trials, St Stephen Centre (SSAT) Consultant Physician, Chelsea and Westminster Foundation Trust Reader, Imperial College London United Kingdom

2 Currently available integrase inhibitors Raltegravir (approved 10/2007) Elvitegravir* (approved 8/2012) Dolutegravir (approved 8/2013) HIV Viral Life Cycle *Currently available only as part of a co-formulated single-tablet regimen/boosted by cobicistat. Maturation Attachment fusion Uncoating Integrase inhibitors Budding Reverse transcription Transcription, translation Assembly

3 Focus on 1. Metabolism and potential for drugdrug interactions 2. Absorption and drug-drug interactions 3. Half-life and PK forgiveness

4 Tivicay SPC; Elliot et al 2015; Min et al 2010; Min et al 2011; Isentress SPC; Stribild SPC Clinical Pharmacology Profile of InSTI Dolutegravir 1 3 Raltegravir 4 Elvitegravir 5 Clinical dose t 1/2 50 mg OD (InSTI-naïve), 50 mg BID (InSTI-resistant) ~14 h Terminal ~23 h 400 mg BID 150 mg OD as Stribild ~9 h Elvitegravir ~12.9 h Cobicistat ~3.5 h PK variability Low to moderate High Moderate (with boosting) Food requirement In InSTI-naïve patients with or without food In InSTI-resistant patients with food No food restriction, but fat content affects absorption and increases PK variability Take with food Protein binding 98.9% 83% 98 99% Dose Exposure Non-linear; saturates above 50 mg Nearly dose proportional Less than dose proportional Metabolism and excretion UGT1A1 (major), CYP3A (minor), renal elimination <1% UGT1A1, renal elimination ~9% Elvitegravir- CYP3A (major), UGT1A1/3 (minor), renal elimination 6.7% Cobicistat CYP3A and/or CYP2D6-mediated oxidation

5 ARVs and Interaction Potential Highest potential Boosted PIs Perpetrators enzyme and transporter Inhibition Victim - absorption (ATV); induction Elvitegravir/cobicistat Perpetrator enzyme and transporter inhibition Victim - absorption; induction Efavirenz, nevirapine, etravirine Perpetrators enzyme and transporter induction Moderate Potential Rilpivirine Victim of enzyme inhibition and induction. Also absorption. Maraviroc Victim of enzyme inhibition and induction. Low Potential Raltegravir Victim of few induction and absorption interactions Most NRTIs Some transporter mediated Dolutegravir Victim of enzyme induction and absorption interactions Perpetrator of renal interaction

6 ARVs and Interaction Potential Highest potential Boosted PIs Perpetrators enzyme and transporter Inhibition Victim - absorption (ATV); induction Elvitegravir/cobicistat Perpetrator enzyme and transporter inhibition Victim - absorption; induction Efavirenz, nevirapine, etravirine Perpetrators enzyme and transporter induction Moderate Potential Rilpivirine Victim of enzyme inhibition and induction. Also absorption. Maraviroc Victim of enzyme inhibition and induction. Low Potential Raltegravir Victim of few induction and absorption interactions Most NRTIs Some transporter mediated Dolutegravir Victim of enzyme induction and absorption interactions Perpetrator of renal interaction

7 DTG: Perpetrator of Renal Interaction Ho & Kim 2005

8 Effect of DTG on metformin Dose adjustment of metformin may be considered Regimen C max (μg/ml) AUC 0 (µg h/ml) t 1/2 (h) Metformin + DTG (50 mg q24h) vs metformin alone Metformin + DTG (50 mg q12h) vs metformin alone 1.66 (1.53, 1.81) 1.79 (1.65, 1.93) 1.09 (0.954, 1.24) 2.11 (1.91, 2.33) 2.45 (2.25, 2.66) 1.14 (1.00, 1.29) Values shown are GLS mean ratio (90% CI) Zong et al 2014

9 Impact of moderate/strong UGT1A1 and/or CYP3A4 inducers on DTG Co-administered drug n DTG dose studied DTG C or C 24 GLS mean ratio (90% CI) Ratio of 1 = no impact Recommendation FPV/r 700/100 mg BID mg QD 0.51 ( ) DTG 50 mg BID should be given* TPV/r 500/200 mg BID mg QD 0.24 ( ) DTG 50 mg BID should be given* DRV/r 600/100 mg BID mg QD 0.62 ( ) No DTG dose adjustment required EFV 600 mg QD mg QD 0.25 ( ) DTG 50 mg BID should be given* ETR 200 mg BID mg QD 0.12 ( ) DTG 50 mg BID should be given* Rifampin 600 mg QD mg BID 0.28 ( ) DTG 50 mg BID should be given* Rifabutin 300 mg QD 9 50 mg QD 0.70 ( ) No DTG dose adjustment required CBZ 100 mg BID mg QD ( ) DTG 50 mg BID should be given The GLS ratio values in red signify that in these cases, C for DTG is reduced significantly below 75% (the lower boundary of a clinically significant alteration in DTG exposure) Tivicay SPC; Song et al 2011; Song et al 2011; Dooley et al 2013

10 ARVs and Interaction Potential Highest potential Boosted PIs Perpetrators enzyme and transporter Inhibition Victim - absorption (ATV); induction Elvitegravir/cobicistat Perpetrator enzyme and transporter inhibition Victim - absorption; induction Efavirenz, nevirapine, etravirine Perpetrators enzyme and transporter induction Moderate Potential Rilpivirine Victim of enzyme inhibition and induction. Also absorption. Maraviroc Victim of enzyme inhibition and induction. Low Potential Raltegravir Victim of few induction and absorption interactions Most NRTIs Some transporter mediated Dolutegravir Victim of enzyme induction and absorption interactions Perpetrator of renal interaction

11 2014

12 Effect of RAL on the PK of other drugs No effect on the PK of etravirine, maraviroc, tenofovir, hormonal contraceptives, methadone, midazolam or boceprevir Co-administration with DRV/r resulted in modest decrease of DRV plasma concentrations Mechanism unknown? Clinical significance? NEAT001 PK sub-study?

13 Impact of strong inducers of UGT1A1 on RAL exposure Rifampicin is a strong inducer of UGT1A1 and reduces plasma levels of RAL; the impact on the efficacy of RAL is unknown doubling of the dose can be considered in adults Arm 1: RAL RAL RIF Arm 2: RAL RAL RIF Arm 2: RAL RAL RIF

14 Mr A August 2015, Soho, London 37 y.o. MSM diagnosed with HIV infection 2 wks ago VL 5,660,523 copies/ml CD4 924 (34%) cells/mm 3 Comeds Lamotrigine 100 mg BD Carbamazepine depot 600 mg OD Valproate 1 g BD Epilepsy only partially controlled I want to start cart as TasP today What did I do? van Luin et al. 2009: no interaction between lamotrigine and RAL Not studied: low interaction potential between valproate and RAL Not studied but could decrease RAL concentrations as it is mainly glucuronidated by UGT1A1 and in vitro data suggest that carbamazepine induces UGT1A1 TDF/FTC/RAL 800 mg BD and fingers crossed

15 Mean RAL plasma concentrations following administration of multiple doses to healthy subjects for 5 days Krishna et al 2013

16 ARVs and Interaction Potential Highest potential Boosted PIs Perpetrators enzyme and transporter Inhibition Victim - absorption (ATV); induction Elvitegravir/cobicistat Perpetrator enzyme and transporter inhibition Victim - absorption; induction Efavirenz, nevirapine, etravirine Perpetrators enzyme and transporter induction Moderate Potential Rilpivirine Victim of enzyme inhibition and induction. Also absorption. Maraviroc Victim of enzyme inhibition and induction. Low Potential Raltegravir Victim of few induction and absorption interactions Most NRTIs Some transporter mediated Dolutegravir Victim of enzyme induction and absorption interactions Perpetrator of renal interaction

17 What is cobicistat? Designed as a CYP3A inhibitor (and also CYP2D6 and transmembrane transporters) No HIV activity Developed to boost elvitegravir but also available to boost Pis (ATV, DRV) Able to be co-formulated into STR Cobicistat is structurally similar to RTV Cobicistat Ritonavir

18 Mean (±95% CI) EVG concentration (ng/ml) Mechanism of PK DDIs and effect of RTV/COBI boosting Boosted Unboosted 100 IC 95 * Bioavailability 10 IC 50 * Time (h) Ramanathan et al 2011

19 Adrenocorticotropic hormone (pmol/l), morning cortisol (nmol/l), and cortisol 1 h after administration of 250mcg IM tetracosactide (nmol/l) of patient whilst taking Stribild/fluticasone and after switching fluticasone to beclomethasone

20 Classification of INI DDIs from University of Liverpool database (n=525) No clinically significant interaction expected Potential interaction may require close monitoring, alteration of drug dosage or timing of administration Drugs should not be co-administered DDI, drug-drug interaction; DTG, dolutegravir; EVG/COBI, elvitegravir/cobicistat; INI, integrase inhibitor; RAL, raltegravir Professor Back, personal communication

21 Practical matters in HIV therapy 1. Potential DDIs with recreational drugs (ChemSex) 2. Most commonly prescribed drugs in general practice and DDIs with ARVs ARV, antiretroviral; DDI, drug-drug interaction; PK, pharmacokinetic

22 ChemSex? Lancet HIV EACS Daskalopoulou M, et al. Lancet HIV 2014;1:e Stuart D, et al. EACS 2015, poster

23 Increasing use of party drugs in people living with HIV on antiretrovirals: a concern for patient safety Bracchi M, et al. AIDS 2015;29:

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25 GP survey: Methodology Online collection 42 questions focusing on: Awareness/ knowledge Stigma and discrimination Confidence, training and guidance Fieldwork dates July to September 2015 With n=3 pilot interviews prior to launch Sample GPs in England n=250 respondents Quotas on regions/ HIV prevalence areas and gender GP, general practitioner HIV Stigma and discrimination survey conducted by Ipsos MORI. 2015

26 GP survey: Confidence in their knowledge 79% But only 16% are confident in their knowledge of HIV transmission 83% in very high/high prevalence areas (81% in very high prevalence areas; 84% in high prevalence areas) 76% in low prevalence areas are confident regarding their knowledge of HIV DDIs 21% in very high/high prevalence areas (30% in very high prevalence areas; 15% in high prevalence areas) 12% in low prevalence areas % of respondents who said very or fairly confident Q14. How confident are you in your knowledge of the routes of HIV transmission? Q15. How confident are you regarding your knowledge of HIV DDIs? Base: all respondents (n=250) DDI, drug-drug interaction HIV Stigma and discrimination survey conducted by Ipsos MORI. 2015

27 GP survey: Drug-drug interactions Following a suspicion of a potential HIV DDI, 54% would contact their HIV physician directly Very high prevalence: 35% More than 15 HIV patients: 33% Q16. What would you do following suspicion of potential HIV DDI? Base: all respondents (n=250) DDI, drug-drug interaction HIV Stigma and discrimination survey conducted by Ipsos MORI. 2015

28 Top 10 drugs prescribed by GPs Items (millions) 2014 Simvastatin 37.8 Ramipril 26.0 Amlodipine 24.3 Atorvastatin 22.2 Lansoprazole 21.6 Beclometasone dipropionate 10.3 Fluticasone propionate (inhaler) 8.0 Glucose blood testing reagents 6.6 Enteral nutrition 5.8 Olanzapine 2.2 Prescriptions dispensed in the community, Prescribing and Medicines Team, Health and Social Care Information Centre, v1.0, July 2015

29 ARVs and PPI ARVs and statins Drug-drug interactions PIs NNRTIs INIs ATV DRV RTV EFV ETV NVP RPV DTG EVG/COBI RAL Simvastatin PIs NNRTIs INIs ATV DRV RTV EFV ETV NVP RPV DTG EVG/COBI RAL Atorvastatin PIs NNRTIs INIs ATV DRV RTV EFV ETV NVP RPV DTG EVG/COBI RAL Omeprazole PIs NNRTIs INIs ATV DRV RTV EFV ETV NVP RPV DTG EVG/COBI RAL Lansoprazole ARV, antiretroviral; ATV, atazanavir; COBI, cobicistat; DRV, darunavir; DTG, dolutegravir; EFV, efavirenz; ETV, etravirine; EVG, elvitegravir; INI, integrase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; NVP, nevirapine; PI, protease inhibitor; RAL, raltegravir; RPV, rilpivirine; RTV, ritonavir Adapted from: Oct 2015 Marta Boffito, personal communication

30 ARVs and calcium channel blockers ARVs and antihypertensives Drug-drug interactions Hypertension/heart failure agents Enalapril Furosemide Indapamide Lisinopril Losartan Perindopril Ramipril Calcium channel blockers Amlodipine Diltiazem Felodipine Nicardipine Nifedipine Nisoldipine PIs NNRTIs INIs ATV DRV RTV EFV ETV NVP RPV DTG EVG/COBI RAL PIs NNRTIs INIs ATV DRV RTV EFV ETV NVP RPV DTG EVG/COBI RAL Verapamil ARV, antiretroviral; ATV, atazanavir; COBI, cobicistat; DRV, darunavir; DTG, dolutegravir; EFV, efavirenz; ETV, etravirine; EVG, elvitegravir; INI, integrase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; NVP, nevirapine; PI, protease inhibitor; RAL, raltegravir; RPV, rilpivirine; RTV, ritonavir Adapted from Oct 2015 Marta Boffito, personal communication

31 ARVs and steroids Drug-drug interactions Steroids PIs NNRTIs INIs Beclometasone ATV DRV RTV EFV ETV NVP RPV DTG EVG/COBI RAL Budesonide Dexamethasone Fludrocortisone Fluticasone Hydrocortisone (oral) Megestrol acetate Mometasone Nandrolone Oxandrolone Prednisolone Testosterone Triamcinolone ARV, antiretroviral; ATV, atazanavir; COBI, cobicistat; DRV, darunavir; DTG, dolutegravir; EFV, efavirenz; ETV, etravirine; EVG, elvitegravir; INI, integrase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; NVP, nevirapine; PI, protease inhibitor; RAL, raltegravir; RPV, rilpivirine; RTV, ritonavir Adapted from Oct 2015 Marta Boffito, personal communication

32 InSTI and Cation Containing Antacids: Recommendations Integrase Inhibtor Recommendation Raltegravir Dolutegravir Elvitegravir/cobicistat Aluminium and magnesium containing antacids reduce RAL plasma levels. Co- or staggered administration of RAL with these antacids is not recommended. However with Ca ++ no dose adjustment. Magnesium/ aluminium-containing antacid should be taken well separated in time from the administration of DTG (minimum 2 hours after or 6 hours before). Applies also to Ca ++ and Fe ++ supplements. It is recommended to separate Stribild and antacid administration by at least 4 hours. No specific recommendation for Ca ++ and Fe ++. Tivicay SPC; Isentress SPC; Stribild SPC

33 Mean DTG concentration (µg/ml) Chelation of InSTI by polyvalent cations 2.0 DTG alone 1.8 DTG + antacid 1.6 DTG + antacid 2 hours later Mg 2+ Mg 2+ InSTI Time (h) Patel et al 2011

34 Mean plasma drug concentration (µg/ml) Half-life (t 1/2 ) 10.0 C max : maximum concentration t 1/2 C min /C : trough concentration 1.0 AUC: Area under the plasma concentration time curve 0.1 PA-IC 90 X µg/ml Time post-dose (hours) Time taken for the plasma concentration or the amount of drug in the body to be reduced by 50% Drug half-life considered when establishing drug dosing (long half-life makes drug suitable for a OD dosing) Terminal plasma half-life = time required to half the plasma concentration after reaching pseudo-equilibrium Terminal half-life may help to determine the PK forgiveness of a drug

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36 Pharmacokinetics (PK) of once-daily dolutegravir (DTG) and elvitegravir/cobicistat (EVG/COBI) following drug cessation Emilie Elliot 1, Alieu Amara 2, Akil Jackson 1,2, Graeme Moyle 1, Laura Else 2, Saye Khoo 2, David Back 2, Andrew Owen 2, Marta Boffito 1,3 1 St Stephen s Centre, Chelsea and Westminster Hospital, London, UK; 2 University of Liverpool, Liverpool, UK; 3 Imperial College, London 16th International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy May, Washington DC, USA

37 [Drug] (ng/ml) Drug plasma concentrations up to 216 h post dose DTG (GM) EVG (GM) COBI (GM) h: GM 711 ng/ml (range 230 to 1182, all above IC 90 ) 48 h: GM 427 ng/ml (range , all above IC 90 ) h: GM 57 ng/ml (range from 11 to 296, above IC 95 in 11/17) DTG protein binding adjusted (PA) IC 90 (64 ng/ml) EVG protein binding adjusted (PA) IC 95 (45 ng/ml) Time (h)

38 Conclusions Three drugs of the same class with very different potential for DDI Similar DDI at the levels of absorption class effect / victims of chelation Different PK forgiveness Do we know how do advise our patients when they miss a dose? Do we provide advice when our patients cross different time zone?