L’importanza delle interazioni farmacologiche

nella gestione dell’HIV/AIDS, delle comorbosità e della co-

infezione HCV

Stefano Bonora

Università di Torino12 Aprile 2013

Un farmaco introdotto nell’organismo (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 l’effetto desiderato.

Premessa

Premessa

Le interazioni possono avere differenti meccanismi (non solo inibizione o induzione del metabolismo).

Le interazioni possono alterare la quantità di farmaco disponibile nell’organismo con potenziale impatto su efficacia e tossicità.

L’effetto di un farmaco interagente nel tempo è diverso in funzione del meccanismo di interazione.

OUTLINE

• Epidemiology

• New antiretrovirals/drugs combination

• Sources of information

• Interpretation and management of DDIs

OUTLINE

• Epidemiology

• New antiretrovirals/drugs combination

• Sources of information

• Interpretation and management of DDIs

Considerations in Management of the Older HIV Patient

Earlier appearance of co-morbidities supports an earlier ‘older’ age designation in HIV patients, ie 55 vs 65 years!

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Drug Interactions will be greater as patients age

Marzolini C et al J Antimicrob Chemother 2011;66:2107

Failure to Recognise Drug Interactions

• HIV drugs amongst the most therapeutically risky- 20-40% 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;36:410-15 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)

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 dell’integrasi vs. NNRTI o IP).

Quindi

OUTLINE

• Epidemiology

• New antiretrovirals/drugs combination

• Sources of information

• Interpretation and management of DDIs

Drug Interaction Data for RPV (Rilpivirina)

Crauwels H, et al. ACTHIV 2011; Denver. Colorado. #TPOI-4

Rilpivirine Drug Interaction:Rationale for Contraindication & Spacing

Parameter

Mean % Change (90% CI)Cmax AUC

Famotidine40 mg single dose taken 2 hours before rilpivirine

85%( 88 to 81)

76%( 80 to 72)

Omeprazole20 mg once daily

40%( 52 to 27)

40%( 52 to 29)

• H2 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. For 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

Tuberculosis

Protease inhibitors

NNRTIs

Entry / Integrase inhibitors

Fonte: http://www.hiv-druginteractions.org/

ANRS 12 180ANRS 12 180 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 ENDPOINT n % [95% CI] n % [95% CI] n % [95% CI]

Success 32 63 [49-76] 39 76 [65-88] 40 78 [67-90]

Failure 19 37 [24-51] 12 24 [12-35] 11 22 [10-33]

Virologic failure 15 12 4

AE leading to treatment discontinuation 2 0 3

Death 2 0 2

Withdrawal / Lost to Follow-up 0 0 2

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 % [95% CI] n % [95% CI]

Success 39 76 [65-88] 41 80 [69-91] 42 82 [72-93]

Failure 12 24 [12-35] 10 20 [9-31] 9 18 [7-28]

Virologic failure 8 10 2

AE leading to treatment discontinuation 2 0 3

Death 2 0 2

Withdrawal / Lost to Follow-up 0 0 2

Immunosuppressant agents

CNI: cyclosporine, tacrolimus (CYP3A, Pgp)Antimetabolites: mycophenolate (UGT)Mamalian target-of-rapamycin (mTOR) inhibitors: sirolimus, everolimus (CYP3A, Pgp)

Glucocorticoids Calcineurin inhibitors

(CNI)

Antimetabolites mTOR inhibitors

NRTIs - 0 0 -

NNRTIs [GCs] [CNI] 0 [mTOR]

Protease inhibitors [GCs] [CNI] 0 [mTOR]

Integrase inhibitors - 0 - 0

CCR5-antagonists - - - -

Fusion inhibitors - - - -

Van Maarseveen EM, et al. AIDS Pat Care & STD 2012

Antineoplastic agents

Edmunds-Ogbuokiri et al. HIV Clinician 2009

Drug Metabolism Potential significance

Cyclophosphamide 2B6 active3A4toxic

IDV CPA CL by 1.5 in 40 patients

Ifosfamide 3A4 active2B6, 3A4toxic

Docetaxel 3A4 RTV DOC AUC x50-fold in mice

Paclitaxel 2C8>>3A4 Mild interactions with NVPSevere mucositis/neutropenia with SQV/DLV

Vinca alkaloids 3A4 Neurotoxicity, myelosuppressionSevere neutropenia with vinblastine + LPV/r

DoxorubicinDaunorubicin

AKR No interactions in 40 patients with IDVNo interactions in 19 patients with IDV/NFV/SQV

Etoposide 3A4>>2E1,1A2 Mucositis, myelosuppression, transaminitisHigher incidence of severe mucositis with SQV

Irinotecan CarboxylesterasesUGT, CYP3A4

LPV/r IRI CL by 47% in 7 patients50% dose-reductionPersistent neutropenia in one patient

Recreational drugs

Drug Metabolism Actual/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/rtvBradycardia, 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

HepatotoxicityHypotension with erectile disfunction agents

Antoniou et al. Ann Pharmacother 2002

Summary of Telaprevir – ARV interactions

HIV drug Effect 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

HIV drug Effect 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% -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

?

?

?

?

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 dell’epatite.

Affiancare queste nuove terapie a combinazioni farmacologiche anti-HIV con scarse interazioni aumenta la probabilità dell’esito positivo di questo percorso, come ci dicono gli studi clinici sui farmaci anti-HIV di nuove classi (es.: INI).

OUTLINE

• Epidemiology

• New antiretrovirals/drugs combination

• Sources of information

• Manegement of DDIs

Nachega JB et al AIDS 2012

Statins and HAART: management of drug-drug interactions

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).

Corticosteroids

• Case report of Cushing’s syndrome and adrenal suppression in a patient on ATV/r and dexamethasone 0.1% eye drops1

• Cushing’s syndrome reported with the use of intra articular triamcinolone injections in patients on boosted PIs2–4

• Several cases of Cushing’s syndrome with inhaled fluticasone and ritonavir7

1.Molloy A, et al. AIDS. 2011;25:1337–9. 2. Dort K, et al. AIDS Res Ther. 2009;6:10. 3. Danaher PJ, et al. Orthopedics 2009;32:450. 4.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 MEDICATIONCheck every route of administration

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.

http://www.hiv-druginteractions.org è importante per il clinico ma non è RISOLUTIVO.

OUTLINE

• Epidemiology

• New antiretrovirals/drugs combination

• Sources of information

• Interpretation and management of DDIs• HIV+ vs Healthy volunteers

• Interindividual variability

• Clinical significance

• New mechanisms?

PK differences (versus healthy volunteers)

Drug HIV-infected HIV/HCVco-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. 11th EACS 2011)↔ cirrhosis vs. historical controls (Curran et al. 13th 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. 19th CROI 2012)

↔ Ұ (Iwamoto et al. AAC 2009)

*Compared to HIV mono-infected; †Healthy individuals with & without mild/moderate hepatic impairmentҰHealthy individuals with and without moderate hepatic impairment

Physiological changes (versus healthy volunteers)

Parameter HIV-infected HCV-infectedHIV/HCV

co-infected

Albumin ↓1,2 ↓*3 ↓†4

α1-acid glycoprotein ↑5 ↑6 ↑

Gastric pH ↑7 ↑8 ↑

Cytochrome P450 ↓ ↓ ↓

Cytokines ↑ ↑ ↑

Parameter HIV-infected HCV-infectedHIV/HCV

co-infected

Albumin ↓1,2 ↓*3 ↓†4

α1-acid glycoprotein ↑5 ↑6 ↑

Gastric pH ↑7 ↑8 ↑

Cytochrome P450 ↓ ↓ ↓

Cytokines ↑ ↑ ↑

* Decreased albumin associated more with cirrhosis and significant liver damage† Significantly lower than HIV or HCV mono-infected patients

1Mehta SH, et al. AIDS Res Human Retrovir 2006;22:14–21; 2Graham SM, et al. AIDS Res Human Retrovir 2007;23:1197–12003Nagao Y & Sata M. Virology Journal 2010;7:375; 4Monga HK, et al. Clin Infect Dis 2001;33:240–7

; 5Boffito M, et al. Drug Metab Dispos 2002;30:859–60; 6Ozeki T, et al. Br J Exp Path 1988;69:589–95 7Welage LS, et al. Clin Infect Dis 1995;21:1431–38; 8Nam YJ, et al. Korean J Hepatol 2004;10:216–22

DHHS Guidelines (2002 -2008):

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

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.

One concentration does not fit all patients!!

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IC50 IC50 IC50IC50

Pravastatin and DRV/RTVPatient Pravastatin AUC Ratio (+DRV:-DRV)

1 5.53

2 6.78

3 4.69

4 3.80

5 1.0

6 0.85

7 0.57

8 1.16

9 2.16

10 1.31

11 2.43

12 0.92

13 1.16

14 1.49

Mean, CI Mean, 1.81; 90% CI, 1.23, 2.66

Range 0.57, 6.78Sekar VJ, et al. Pharmacology Workshop. 2007. Abstract 55.

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

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Wide therapeutic window

Adverse eventsAdverse events

Therapeutic failureTherapeutic failure

Adapted from D Back

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?

Proportion (%) of Patients Achieving HIV RNA <50 copies/mL (95% CI) Over Time

Non-Completer = Failure Approach

86

82

81

79

75

69

76

67

281 278 279 280 281 281 277 280 281 281 277 279

282 282 282 281 282 282 281 281 282 282 282 279

Raltegravir 400 mg bid.

Efavirenz 600 mg qHS.

0 12 24 48 72 96 120 144 168 192 216 240

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61%

Yearly Efficacy Analyses

Study Week

% (n/N) of Patients with vRNA <50 copies/mLChange (cells/mm3) from

BL CD4 Count

RAL (N=281)

EFV (N=282)

RAL – EFV (95% CI)

RAL (N=281)

EFV (N=282)

RAL – EFV (95% CI)

48 86.1 (241/280) 81.9 (230/281) 4.2 (-1.9, 10.3)* 189 163 26 (4, 47)

96 81.1 (228/281) 78.7 (222/282) 2.4 (-4.3, 9.0)* 240 225 15 (-12, 43)

156 75.4 (212/281) 68.8 (194/282) 6.6 (-0.8, 14.0)* 331 295 36 (3, 68)

192 76.2 (214/281) 67.0 (189/282) 9.0 (1.6, 16.4)*° 361 301 60 (24, 95)

240 71.0 (198/279) 61.3 (171/279) 9.5 (1.7, 17.3)*° 374 312 62 (22, 102)

* P-value for non-inferiority <0.001.

° Met criteria for superiority.

Sensitivity Analyses of Virologic Efficacy at Week 240

  

Different Approaches to Handling Missing Data

Response by Treatment Group

Treatment Effect

Responder/Evaluable† Difference Estimates‡

RALGroup

EFVGroup

Difference(95% CI)

p-Value for Non-inferiority*

Superiority Concluded*

Prespecified as Primary Analysis

Non-Completer=Failure198/279

(71.0)171/279

(61.3)9.5

(1.7, 17.3)<0.001 Yes

Prespecified as Secondary Analyses 

Treatment-Related D/C=Failure

198/236 (83.9)

171/239 (71.5)

12.4(4.9, 19.8)

<0.001 Yes

Observed Failure198/222

(89.2)171/212

(80.7)8.6

(1.9, 15.5)<0.001 Yes

† 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).

Subgroup Analyses

Total

Baseline Plasma HIV RNA

50,000 copies/mL

> 50,000 copies/mL

Baseline Plasma HIV RNA

100,000 copies/mL

> 100,000 copies/mL

Screening Plasma HIV RNA

50,000 copies/mL

> 50,000 copies/mL

Baseline CD4 Cell Counts

50 cells/mm3

> 50 and 200 cells/mm3

> 200 cells/mm3

(cells/mm3)

(copies/mL)

(copies/mL)

(copies/mL)

-50 -25 0 25 50

Difference (95% CI)

HIV RNA < 50 Copies/mL (%)

favors EFV favors RAL

-50 -25 0 25

Difference (95% CI)

mk518p21CSRSubgroupsw k240 June 7, 2012

HIV RNA < 400 Copies/mL (%)

favors EFV favors RAL

-100 -50 0 50 100 150

Difference (95% CI)

CD4 Cell Counts

(cells/mm3)

favors EFV favors RAL

Specific Drug-Related Clinical Adverse Experiences Occurring in ≥ 5% of Either Group

RAL Group(N = 281)

EFV Group(N = 282)

n (%) n (%)

Gastrointestinal Disorders

57 (20.3) 81 (28.7)

Diarrhoea

14 ( 5.0) 27 ( 9.6)

Flatulence

10 ( 3.6) 14 ( 5.0)

Nausea

25 ( 8.9) 29 (10.3)

General Disorders 28 (10.0) 47 (16.7) Fatigue

12 ( 4.3) 25 ( 8.9)

Nervous System Disorders

51 (18.1) 140 (49.6)

Dizziness

22 ( 7.8) 99 (35.1)

Headache

26 ( 9.3) 40 (14.2)

Somnolence

3 ( 1.1) 21 ( 7.4)

Psychiatric Disorders

52 (18.5) 87 (30.9)

Abnormal Dreams

19 ( 6.8) 37 (13.1)

Insomnia

21 ( 7.5) 23 ( 8.2)

Nightmare

8 ( 2.8) 15 ( 5.3)

Skin And Subcutaneous Tissue Disorders

16 ( 5.7) 63 (22.3)

Rash

3 ( 1.1) 23 ( 8.2)

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.

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