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Limportanza delle interazioni farmacologiche nella gestione dellHIV/AIDS, delle comorbosità e della co-infezione HCV Stefano Bonora Università di Torino.

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Presentazione sul tema: "Limportanza delle interazioni farmacologiche nella gestione dellHIV/AIDS, delle comorbosità e della co-infezione HCV Stefano Bonora Università di Torino."— Transcript della presentazione:

1 Limportanza delle interazioni farmacologiche nella gestione dellHIV/AIDS, delle comorbosità e della co-infezione HCV Stefano Bonora Università di Torino 12 Aprile 2013

2 Un farmaco introdotto nellorganismo (per via orale, parenterale, ecc.) può subire varie trasformazioni, in funzione delle sue caratteristiche fisico-chimiche, ed essere eliminato per vie diverse, in varie forme molecolari. Può accadere che un farmaco non venga quasi per nulla modificato e sia eliminato come tale, oppure che subisca numerose trasformazioni verso forme che possono essere ancora farmacologicamente attive (o anche più attive rispetto alla molecola originale) oppure del tutto inerti (non attive) per quanto concerne leffetto desiderato. Premessa

3 Le interazioni possono avere differenti meccanismi (non solo inibizione o induzione del metabolismo). Le interazioni possono alterare la quantità di farmaco disponibile nellorganismo con potenziale impatto su efficacia e tossicità. Leffetto di un farmaco interagente nel tempo è diverso in funzione del meccanismo di interazione.

4 OUTLINE Epidemiology New antiretrovirals/drugs combination Sources of information Interpretation and management of DDIs

5 OUTLINE Epidemiology New antiretrovirals/drugs combination Sources of information Interpretation and management of DDIs

6 Considerations in Management of the Older HIV Patient Earlier appearance of co- morbidities supports an earlierolder age designation in HIV patients, ie 55 vs 65 years!

7 >8 number of co-medications patients (%) < 50 years ? 50 years A >8 Number of co-medications Patients (%) < 50 years >50 years A Drug Interactions will be greater as patients age Marzolini C et al J Antimicrob Chemother 2011;66:2107

8 Failure to Recognise Drug Interactions HIV drugs amongst the most therapeutically risky % patients on ARVs at risk of clinically significant interactions PIs > NNRTIs >> MVC/RAL > NRTIs - PIs associated with 5-fold prevalence risk of significant DDIs compared to raltegravir, and 10-fold risk compared to NRTIs Physicians recognise only around a third correctly - Pharmacist pre-screening of 200 HIV clinic patients told physicians something they did not know about medication history (20%), adherence (31%) or drug interactions (38%), and changed patient management in 13.6% Patel et al. Ann Pharmacother 2011, Miller et al Pharmacother 2007;27:1379, Evans-Jones et al. CID 2010;50:1419, de Maat et al. Ann Pharmacother 2002;36: Mok et al. Am J Health Sys Pharm 2008;65:55, Seden et al. Int J STD AIDS 2012 (in press) Seden et al (unpublished)

9 Il rischio di interazione è funzione del numero di farmaci assunti dal paziente. Tale rischio è probabilmente sottostimato nella pratica clinica. Alcune classi di farmaci hanno un rischio di interazione significativamente ridotto rispetto ad altre (per es. INI, inibitori dellintegrasi vs. NNRTI o IP). Quindi

10 OUTLINE Epidemiology New antiretrovirals/drugs combination Sources of information Interpretation and management of DDIs

11 Drug Interaction Data for RPV (Rilpivirina) Crauwels H, et al. ACTHIV 2011; Denver. Colorado. #TPOI-4

12 Rilpivirine Drug Interaction: Rationale for Contraindication & Spacing Parameter Mean % Change (90% CI) C max AUC Famotidine 40 mg single dose taken 2 hours before rilpivirine 85% ( 88 to 81) 76% ( 80 to 72) Omeprazole 20 mg once daily 40% ( 52 to 27) 40% ( 52 to 29) H 2 antagonists must be taken 12 hours before or 4 hours after RPV since when taken 2 hours before RPV resulted in 85% reduction in RPV exposures PPIs are contraindicated with RPV due to significant 40% reduction in RPV exposure Antacids should be given 2h before or 4h after RPV RPV/TVD US Prescribing Information, Gilead Sciences, Inc. July 22, 2011 Do not copy or distribute Atripla does NOT have an indication for the treatment of naïve patients and there is NO Atripla promotion concerning treatment NAÏVE patients. F or internal Gilead use only Eviplera does NOT have an indication for the treatment of experienced patients and there is NO Eviplera promotion concerning treatment experienced patients and until Italian AIC is granted

13 Tuberculosis Protease inhibitors NNRTIs Entry / Integrase inhibitors Fonte:

14 ANRS Efficacy Outcomes, W24 Primary endpoint : HIV RNA<50 cp/mL at W20 and W24, mITT (M=F, D/C=F) EFV N = 51 RAL 400 N = 51 RAL 800 N = 51 PRIMARY ENDPOINTn% [95% CI]n %[95% CI]n% Success 3263[49-76]3976[65-88]4078[67-90] Failure 1937[24-51]1224[12-35]1122[10-33] Virologic failure AE leading to treatment discontinuation 203 Death202 Withdrawal / Lost to Follow-up002 Secondary endpoint : HIV RNA<400 cp/mL at W20 and W24, mITT (M=F, D/C=F) EFV N = 51 RAL 400 N = 51 RAL 800 N = 51 SECONDARY ENDPOINT n%[95% CI]n% n% Success 3976[65-88]4180[69-91]4282[72-93] Failure 1224[12-35]1020[9-31]918[7-28] Virologic failure 8102 AE leading to treatment discontinuation 203 Death202 Withdrawal / Lost to Follow-up002

15 Immunosuppressant agents CNI: cyclosporine, tacrolimus (CYP3A, Pgp) Antimetabolites: mycophenolate (UGT) Mamalian target-of-rapamycin (mTOR) inhibitors: sirolimus, everolimus (CYP3A, Pgp) Van Maarseveen EM, et al. AIDS Pat Care & STD 2012

16 Antineoplastic agents Edmunds-Ogbuokiri et al. HIV Clinician 2009 Drug MetabolismPotential significance Cyclophosphamide 2B6 active 3A4 toxic IDV CPA CL by 1.5 in 40 patients Ifosfamide 3A4 active 2B6, 3A4 toxic Docetaxel 3A4RTV DOC AUC x50-fold in mice Paclitaxel 2C8>>3A4Mild interactions with NVP Severe mucositis/neutropenia with SQV/DLV Vinca alkaloids 3A4Neurotoxicity, myelosuppression Severe neutropenia with vinblastine + LPV/r Doxorubicin Daunorubicin AKRNo interactions in 40 patients with IDV No interactions in 19 patients with IDV/NFV/SQV Etoposide 3A4>>2E1,1A2Mucositis, myelosuppression, transaminitis Higher incidence of severe mucositis with SQV Irinotecan Carboxylesterases UGT, CYP3A4 LPV/r IRI CL by 47% in 7 patients 50% dose-reduction Persistent neutropenia in one patient

17 Recreational drugs Drug MetabolismActual/theoretical interaction Potential significance Ecstasy (X, MDMA) 2D6>>1A2, 2B6, 3A4 2-3 fold with RTV or EFV Fatal interactions reported. Hyponatremia, hypertermia, arrhytmias, seizures, rhabdomyolysis Amphetamines (speed, cristal) 2D6 Possible with RTV Hypertension, hypertermia, arrhytmias, seizures GHB (liquid ecstasy) Expired breath as CO2; first-pass metabolism Possible with RTV Life-threatening case with SQV/rtv Bradycardia, respiratory depression, seizures LSD (acid, blotters) Unknown Possible with RTV Hallucinations, psychosis Ketamine (special K, Kit-Kat) 2B6>2C9, 3A4 Possible with RTV or EFV Respiratory depression, loss of consciousness, hallucinations Cocaine hydrolysis, hepatic cholinesterase >>CYP3A4 Possible norcocaine with NVP or EFV Hepatotoxicity PCP (angel dust) CYP3A4 Possible with RTV Hypertermia, seizures, rhabdomyolysis Erectile disfunction (Sildenafil….) CYP3A4 Possible with RTV Hypotension, arrhytmias Amyl nitrite (poppers) glutathione-organic nitrates reductase Hepatotoxicity Hypotension with erectile disfunction agents Antoniou et al. Ann Pharmacother 2002

18

19 Summary of Telaprevir – ARV interactions HIV drugEffect on ARV AUC Effect on TVR AUC Can be used?Reference EFV*-7% -18% Yes Van Heeswijk et al. CROI 2011 ETR-6% -16% Yes Kakuda et al. HIV PK 2012 RPV+79% -8% Yes Kakuda et al. HIV PK 2012 ATV/r+17% -20% Yes Van Heeswijk et al. CROI 2011 DRV/r-40% -35% No Van Heeswijk et al. CROI 2011 FPV/r-47% -32% No Van Heeswijk et al. CROI 2011 LPV/r+6% -54% No Van Heeswijk et al. CROI 2011 RAL+31% +7% Yes Van Heeswijk et al. ICAAC 2011 TDF+30% 0% Yes Van Heeswijk et al. ICAAC 2008 *TVR dose 1125mg q8h

20 HIV drugEffect on ARV AUC Effect on BOC AUC Can be used?Reference TDF+5%+8%Yes Kassera et al. CROI 2011 EFV+20%-19%No Kassera et al. CROI 2011 ETR-23%+10%Yes Hammond et al. JAIDS 2013 ATV/r-35%-5%No Hulskotte et al. CID 2012 LPV/r-34% No Hulskotte et al. CID 2012 DRV/r-44%-32%No Hulskotte et al. CID 2012 RAL+1%+7%*Yes De Kanter et al. CID 2012 * vs. historical controls Summary of Boceprevir – ARV interactions ? ? ? ?

21 Epatite C e HIV: cenni Per una persona sieropositiva, che deve assumere una terapia per tutta la vita, prendersi cura del proprio fegato è una priorità. Il fegato è il principale organo deputato al metabolismo e alla detossificazione dai farmaci e, quindi, soggetto a danno da parte delle sostanze chimiche e farmacologiche da cui ci depura. Oggi esistono terapie che aumentano in modo sostanziale la possibilità di un successo terapeutico per la cura dellepatite. Affiancare queste nuove terapie a combinazioni farmacologiche anti-HIV con scarse interazioni aumenta la probabilità dellesito positivo di questo percorso, come ci dicono gli studi clinici sui farmaci anti-HIV di nuove classi (es.: INI).

22 OUTLINE Epidemiology New antiretrovirals/drugs combination Sources of information Manegement of DDIs

23

24 Nachega JB et al AIDS 2012 Statins and HAART: management of drug-drug interactions

25 Cardiovascular drugs and HAART: scarce data Digoxin serum concentrations were increased by 86% with RTV coadministration due to inhibition of P- glycoprotein (NO DATA IN HIV+) Many antiarrhythmic medications are CYP450 3A4 substrates. The use of amiodarone, bepridil, flecainide, propafenone and quinidine are contraindicated with PI/r due to the potential risk of exacerbating cardiac arrhythmias (NO CLINICAL DATA).

26 Corticosteroids Case report of Cushings syndrome and adrenal suppression in a patient on ATV/r and dexamethasone 0.1% eye drops 1 Cushings syndrome reported with the use of intra articular triamcinolone injections in patients on boosted PIs 2–4 Several cases of Cushings syndrome with inhaled fluticasone and ritonavir 7 1.Molloy A, et al. AIDS. 2011;25:1337–9. 2. Dort K, et al. AIDS Res Ther. 2009;6: Danaher PJ, et al. Orthopedics 2009;32: Ramanathan R, et al. Clin Infect Dis. 2008;47:e97–9. 5. Gray D, et al. S Afr Med J. 2010;100:296–7. 6. Frankel JK, & Packer CD. Ann Pharmacother. 2011;45:823–4. 7. Foisy MM, et al. HIV Medicine 2008;9:389–96. CHECK EVERY KIND OF MEDICATION Check every route of administration

27 Le interazioni farmacologiche esistono e bisogna conviverci. Il numero di possibili interazioni è altissimo, pertanto non è prevedibile avere dati certi di farmacocinetica per tutte le possibili interazioni. è importante per il clinico ma non è RISOLUTIVO.

28 OUTLINE Epidemiology New antiretrovirals/drugs combination Sources of information Interpretation and management of DDIs HIV+ vs Healthy volunteers Interindividual variability Clinical significance New mechanisms?

29 PK differences (versus healthy volunteers) DrugHIV-infectedHIV/HCV co-infected* ATV (Reyataz SPC) (Regazzi et al. Ther Drug Monit 2011) ATV/r (Reyataz SPC) (Di Biagio et al. J Infect Chemother 2012) (Regazzi et al. Ther Drug Monit 2011) DRV/r (Prezista SPC) (Sekar et al. Clin Pharmacokinet 2010) RTV (Sekar et al. Clin Pharmacokinet 2010) (Sekar et al. 11 th EACS 2011) cirrhosis vs. historical controls (Curran et al. 13 th WCPHT 2012) LPV/r (Kaletra SPC) (Barreiro et al. J Infect Dis 2007) (Peng et al. J Clin Pharmacol 2006) RTV (Peng et al. J Clin Pharmacol 2006) (Canta et al. JAC 2005) but V/F (Molto et al. Clin Pharmacokinet 2007) RTV, CL/F V/F (Molto et al. Clin Pharmacokinet 2007) (Seminari et al. JAC 2005) (Dominguez et al. JAC 2010) EFV (Mukonzo et al. Clin Pharmcokinet 2011) (Ugandan study) (Dupont review report 1998) ( Caucasian; Black) (Katsounas et al. Eur J Med Res 2007) (Pereira et al. BJCP 2008) cirrhosis versus no cirrhosis (Barreiro et al. J Infect Dis 2007) (Dominguez et al. JAC 2010) RAL (Arab-Alameddine et al. AAC 2012 ) (composite analysis, Merck) cirrhosis versus no cirrhosis (Hemandez-Novoa et al. 19 th CROI 2012) Ұ (Iwamoto et al. AAC 2009) * Compared to HIV mono-infected; Healthy individuals with & without mild/moderate hepatic impairment Ұ Healthy individuals with and without moderate hepatic impairment

30 Physiological changes (versus healthy volunteers) * Decreased albumin associated more with cirrhosis and significant liver damage Significantly lower than HIV or HCV mono-infected patients 1 Mehta SH, et al. AIDS Res Human Retrovir 2006;22:14–21; 2 Graham SM, et al. AIDS Res Human Retrovir 2007;23:1197– Nagao Y & Sata M. Virology Journal 2010;7:375; 4 Monga HK, et al. Clin Infect Dis 2001;33:240–7 ; 5 Boffito M, et al. Drug Metab Dispos 2002;30:859–60; 6 Ozeki T, et al. Br J Exp Path 1988;69:589–95 7 Welage LS, et al. Clin Infect Dis 1995;21:1431–38; 8 Nam YJ, et al. Korean J Hepatol 2004;10:216–22

31 DHHS Guidelines ( ): Rifabutin 150 mg (half dose) every other day or three times a week is recommended

32 10 patients with HIV infection and active tuberculosis Lopinavir-ritonavir at, twice daily + rifabutin at 150 mg thrice weekly: 9 of 10 had low rifabutin Cmax values values for the area under the plasma concentration–time curve of rifabutinwere as low or lower than those associated with treatment failure or relapse and with acquired rifamycin resistance One of the 10 patients experienced relapse with acquired rifamycin resistance.

33 One concentration does not fit all patients!! Concentration Time % Inhibiition IC 50

34 Pravastatin and DRV/RTV PatientPravastatin AUC Ratio (+DRV:-DRV) Mean, CIMean, 1.81; 90% CI, 1.23, 2.66 Range0.57, 6.78 Sekar VJ, et al. Pharmacology Workshop Abstract 55.

35 Statistical vs. Clinical Significance A statistically significant effect may not be clinically relevant A clinically relevant PK interaction would require a dose modification/warning/contra-indication A consistent 10% decrease in AUC in 10 subjects is statistically significant (p<0.01), but not clinically relevant. Adapted from D Back

36 Therapeutic window Drug concentration Narrow therapeutic windowWide therapeutic window Adverse events Therapeutic failure Adapted from D Back

37 Ci sono scenari clinici dove il valore aggiunto di QD e STR rispetto a schemi più complessi (BID o QD multipill) può essere controbilanciato da altri fattori? Farmaci concomitanti (QD o BID)? Tollerabilità a lungo termine?

38 Proportion (%) of Patients Achieving HIV RNA <50 copies/mL (95% CI) Over Time Non-Completer = Failure Approach

39 Yearly Efficacy Analyses Study Week % (n/N) of Patients with vRNA <50 copies/mL Change (cells/mm 3 ) from BL CD4 Count RAL (N=281) EFV (N=282) RAL – EFV (95% CI) RAL (N=281) EFV (N=282) RAL – EFV (95% CI) (241/280)81.9 (230/281)4.2 (-1.9, 10.3)* (4, 47) (228/281)78.7 (222/282)2.4 (-4.3, 9.0)* (-12, 43) (212/281)68.8 (194/282)6.6 (-0.8, 14.0)* (3, 68) (214/281)67.0 (189/282)9.0 (1.6, 16.4)*° (24, 95) (198/279) 61.3 (171/279)9.5 (1.7, 17.3)*° (22, 102) * P-value for non-inferiority < ° Met criteria for superiority.

40 Sensitivity Analyses of Virologic Efficacy at Week 240 Different Approaches to Handling Missing Data Response by Treatment Group Treatment Effect Responder/Evaluable Difference Estimates RAL Group EFV Group Difference (95% CI) p-Value for Non-inferiority* Superiority Concluded* Prespecified as Primary Analysis Non-Completer=Failure 198/279 (71.0) 171/279 (61.3) 9.5 (1.7, 17.3) <0.001Yes Prespecified as Secondary Analyses Treatment-Related D/C=Failure 198/236 (83.9) 171/239 (71.5) 12.4 (4.9, 19.8) <0.001Yes Observed Failure 198/222 (89.2) 171/212 (80.7) 8.6 (1.9, 15.5) <0.001Yes Number of evaluable patients in each treatment group according to the specified approach to handling missing data. The 95% CIs and p-values for treatment differences were calculated using weights proportional to the size of each stratum (screening vRNA level >50,000 copies/mL or 50,000 copies/mL). * RAL would be considered non-inferior to EFV if the lower bound of the 95% CI for the difference in response rates was above -12%, and superior to EFV if the entire 95% CI was >0. Two post-hoc snapshot analyses with windows of +/- 6 weeks or +/- 12 weeks around the Week-240 visit were performed to test the robustness of the prespecified analyses: 1.The 6-week window resulted in the additional exclusion of 8 patients falling outside of the window (6 came in too early and 2 came in too late) compared to the protocol-specified NC=F analysis which used the nominal visit data and yielded response rates of 66.2% (186/281) in the RAL group and 59.6% (168/282) in the EFV group with a (95% CI) = 6.6% (-1.4, 14.5). All 8 excluded patients were in the RAL group, with 7 having vRNA levels <50 copies/mL at their nominal Week-240 visit. 2.Since more patients fell outside the 6-week window for the Week-240 visit compared to previous time points, an analysis using a +/- 12 weeks window (extending the window to the prior visit at Week 228) was untaken at Week 240 which yielded response rates of 70.8% (199/281) in the RAL group and 62.8% (177/282) in the EFV group with a (95% CI) = 8.1% (0.3, 15.8).

41 Subgroup Analyses

42 Specific Drug-Related Clinical Adverse Experiences Occurring in 5% of Either Group RAL Group (N = 281) EFV Group (N = 282) n(%)n Gastrointestinal Disorders57(20.3)81(28.7) Diarrhoea14( 5.0)27( 9.6) Flatulence10( 3.6)14( 5.0) Nausea25( 8.9)29(10.3) General Disorders28(10.0)47(16.7) Fatigue12( 4.3)25( 8.9) Nervous System Disorders51(18.1)140(49.6) Dizziness22( 7.8)99(35.1) Headache26( 9.3)40(14.2) Somnolence3( 1.1)21( 7.4) Psychiatric Disorders52(18.5)87(30.9) Abnormal Dreams19( 6.8)37(13.1) Insomnia21( 7.5)23( 8.2) Nightmare8( 2.8)15( 5.3) Skin And Subcutaneous Tissue Disorders16( 5.7)63(22.3) Rash3( 1.1)23( 8.2)

43 Patients who tolerated EFV, with less than 50 copies/ml HIV-RNA, were randomized into two groups: the RAL-first group started with RAL (400 mg twice daily) and EFV placebo, and the EFV- first group with EFV (600 mg once daily) and RAL placebo. After 2 weeks, both groups switched to the alternate regimen. Half of patients previously on a stable EFV preferred to switch to RAL, after double-blind exposure to RAL for 2 weeks. Substitution of EFV by RAL significantly impacted on lipid levels, stress, and anxiety scores.

44 Studio STaR (Glasgow, Cohen O425) Spring 2 e Single (Glasgow, Eron P204) Sailing (Atlanta, Croi 2013, Pozniak 179 LB) Altri esempi

45 Grazie al contributo di MSD Italia


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