Interactions médicamenteuses mettant en jeu

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1 Interactions médicamenteuses mettant en jeu
les antirétroviraux Rodolphe Garraffo CHU de Nice

2 Objectifs médicamenteuses dans la pathologie VIH
Prendre conscience de l’importance clinique des interactions médicamenteuses dans la pathologie VIH En comprendre les mécanismes pharmacologiques Intérêt du «boost » Prise en compte dans la prescription

3 Pourquoi les patients VIH+ sont-ils à risque?
Utilisation systématique de plusieurs ARV Nombreuses médications préventives: - infections opportunistes - effets secondaires connus des ARV Patients vivent plus longtemps et sont traités pour des pathologie chroniques (diabetes, maladies cardiovasculaires, vieillissement…) Beaucoup d’ARV ont des effets marqués sur les enzymes du système des CYP 450.

4 Drug-drug interaction mechanisms
Absorption First pass metabolism CYP450 P-gp Metabolism PXR Glucuronidation Distribution Protein binding (?) Elimination

5 Piscitelli, et al. N Engl J Med, Vol 344 (13): March 29, 2001

6 Pharmacocinétique des ARVs et anti- VHC
Absorption intestinale CYPs P-gp Métabolisme Administration Orale (Comprimés/capsules) FOIE Dissolution Alcool Déshy-drogénase Muqueuse entérocytaire Effet de 1er passage hépatique INTIs/INNTIs/IPs CYP3A4/5 CYP2B6 CYP2C19 P-gp CIRCULATION SYSTEMIQUE Dissolution Dépôt IPs INNTIs Administration Sous Cutanée Fraction libre Fraction liée aux Protéines P-gp PegIFN,ENF Distribution Excretion & Sécrétion tubulaire TISSUS hOAT MRP CELLULE CIBLE INTIs (Phosphorylation Intracellulaire) IPs INNTIs Fraction libre Fraction liée aux Protéines URINES INTIs/INNTIs/ENF Glucuroconjugués

7 Proportion de médicaments métabolisés par les principaux CYP
*CYP2C metabolism reflects CYP2C9, CYP2C10, CYP2C18, and CYP2C19

8 Interplay of transport, metabolism & regulation
of proteins by transcription factors

9 Variabilité pharmacocinétique
Age Status génétique Pathologies associées Observance Sexe Formulation / Galénique  Débit sanguin  Activités enzymtiques  Activité des transporteurs  Fonction rénale  Fonction hépatique  Fonctions digestives Co-médications Environnement Dénutrition/ Régimes/carences Tabac/alcool Galénique/schéma thérapeutique/ posologie Pharmacocinétique

10 DDIs & Adverse Events Poly pharmacy Ageing

11 Due to co-morbidities polypharmacy is common in HIV patients – more so as patients age!
OIs Hypertension Erectile dysfunction Hyperlipidemia Malignancies Hepatitis Diabetes Transplantation Neuro- psychiatric illnesses Opioid dependency TB

12 Principaux mécanismes
Alteration de l’absorption et de la distribution tissulaire Chélation, pH, P-gp (protrines d’efflux ou transporteurs) Alteration des processus métaboliques Induction/inhibition, GT, P-gp Diminution de l’excrétion rénale (P-gp) Altération de l’activation intracellulaire Compétition phosphorylation (D4T, ZDV) Les interactions peuvent aussi être d’ordre pharmacodynamique

13 Interactions Pharmacodynamiques
Les interactions PD conduiront à des effets soit additifs, soit synergique ou encore antagonistes. Un exemple d’effet additif: Toxicité hématologique (moëlle osseuse) de l’association AZT + GCV Un exemple d’effet antagonistes: indinavir et saquinavir à fortes dose in vitro (Piscitelli NEJM 2001)

14 Principes de base pour évaluer une interaction
L’index thérapeutique décide de la pertinence clinique La fraction de clairance du médicament induit ou inhibé La puissance de l’inducteur ou de l’inhibiteur Profils possibles de la clairance

15 Pharmacocinétique des Antiretroviraux
Absorption Intestinale Métabolisme Elimination Interaction médicamenteuse INTIs & INtTIs ++ Intracellulaire (Prodrogues) Urine + (Intra & extracellulaires) INNTIs Foie +++ Urine/bile IPs Bile Enfuvirtide - (SC) Inhibiteurs d’entrée

16 Metabolic Characteristics of ARVs
This is a summary slide of the effects of ARVs on CYP450 for reference. Remember that in general, the NNRTIs are inducers of 3A4 and the PIs are inhibitors of 3A4, to varying degrees. However, some ARV have mixed effects on different enzymes which may make it difficult to predict drug interactions, and may require close clinical monitoring. Source: Antoniuo T. and A.L. Tseng. Annals of Pharmacotherapy 2002:36:

17 CYP P450 Drug-Drug Interactions
Pharmacologic action of drug is altered by coadministration of second drug effect (eg. ritonavir + saquinavir; ritonavir + simvastatin) Drug B New effect (eg. ritonavir + amitriptyline) Drug A Drug-drug interactions can result in a therapeutically desired effect, a negative drug-interaction, a new side effect of a drug, or no consequence at all. The pharmacologic action of one drug is altered by co-administration of second drug. Co administration of the interacting drug may increase the known effect, resulting in increased therapeutic effect or increased toxicity. Co-administration of ritonavir and saquinavir results in a significant increase in saquinavir levels, providing a beneficial interaction and a desired therapeutic effect. Alternatively, lovastatin and simvastatin undergo extensive first-pass metabolism by CYP3A4 and inhibitors of 3A4 (ritonavir) increase the risk of myopathy, in some cases leading to rhabdomyolysis and acute renal failure. The patient should be alert for evidence of myopathy (muscle pain or weakness) and dark urine. Co administration of the interacting drug also may result in a new effect not previously observed with either drug alone. An example: ritonavir is an inhibitor of CYP2D6 and 3A4 and the antidepressant amitriptyline is a substrate of both enzymes. Ritonavir can increase the levels of amitriptyline resulting in elevated concentrations (causing dry mouth, urinary retention, blurred vision, constipation, tachycardia and postural hypotension) and possibly a new side effect: cardiac arrhythmia (due to prolonged QT interval). If used together, amitriptyline should be started at the lowest possible dose and closely monitored. Co administration of the interacting drug may decrease the known effect, resulting in a decreased therapeutic effect of the target drug. For example, rifampin induces the metabolism of PIs, thereby reducing their concentrations and the antiretroviral effect of these drugs. Rifampin gradually reduces the response to oral anticoagulants, the effect may occur as early as a few days to a week with rifampicin and the offset usually takes 2-3 weeks. Consider the increased risk of impaired anticoagulant control and the increased need for monitoring and counseling for signs or symptoms of lack of anticoagulation control. effect (eg. rifampin + protease inhibitors, rifampin + coumadin) No Consequences

18 Quand se préoccuper d’une éventuelle interaction?
Au début d’un nouveau traitement Lors d’un "switch" tant au sein d’une même classe que pour une autre classe Ajout d’un médicament au potentiel d’interaction connu Interruptions de TRT avec un médicament à potentiel d’interaction Patients suivis par plusieurs médecins (et pharmaciens).

19 Principles of Drug Interaction Studies
Understanding drug interactions is critical to the benefit/risk assessment. An in vitro and in vivo integrated approach may reduce the number of studies needed and optimize knowledge. Appropriately designed studies are critical. Clinical significance should be interpreted based on well-defined exposure-response data and analyses. Classification of CYP inhibitors and substrates can aid in study design and cross labeling. Information should be appropriately placed in the labeling. Huang SS et al. Clin Pharmacol Ther 2007;81:

20 Clinical Significance of Drug-Drug Interactions
The clinical significance of a drug-drug interaction can only be determined or confirmed through a clinical study. In the absence of (or pending) clinical trial data, well defined exposure-response data provide a basis to predict the significance of a drug-drug interaction; however, there will be settings where the existing data are not informative as to PK and PD of the interaction. Exercise a measure of caution in managing drug interactions where no confirmatory clinical data exist.

21 Rosuvastatin and Lopinavir/ritonavir
Rosuvastatin Concentration (ng/mL) Time (hours) In 15 healthy volunteers receiving ROS, 20 mg/d, LPV/r caused a: 4.7-fold increase in ROS Cmax, 2.1-fold increase in ROS AUC; Cmin unchanged Half-life unchanged; argues against CYP-mediated interaction Closed squares ROS alone, Open circles ROS + LPV/RTV Kiser JJ, et al. JAIDS 2008; 47: 21

22 Rosuvastatin and LPV/RTV: statin effect
Phase III ROS + LPV/RTV ROS + LPV/RTV Baseline ROS LPV/RTV Baseline ROS LPV/RTV Change - 27% 21% (P = .03) - 31% 26% (P = .01) Kiser JJ, et al. JAIDS 2008; 47: 22

23 Antirétroviraux et Alimentation
A prendre avec repas: Lopinavir (capsules or solution):  % Saquinavir: 7 fold  (fatty meal) Nelfinavir: 2-3 fold  Ritonavir: 15%  Itraconazole caps Atazanavir 70 %  Ganciclovir  up to 5% atovaquone 24%  A prendre hors repas: Amprenavir:  23% with high fat meal (regular food OK) Indinavir: 77%  with high fat meal (light snack OK) ddI: 47%  with meal Efavirenz:  79% high fat meal increases toxicity Rifampin: food may  levels Itraconazole liquid Isoniazid Medications are recommended to be taken with food for one of two reasons: To ensure optimal absorption. e.g., Nelfinavir is best absorbed if it is taken with a meal or snack. In some instances, fat content of a meal may be an important factor affecting drug bioavailability. With lipid-soluble agents, ingestion of dietary fat results in formation of an oil or emulsion phase, which improves solubility. Ingesting a fatty meal also promotes secretion of gastric fluids, which in turn may lower gastric pH, delay stomach emptying, and decrease GI transit rates. e.g. Absorption of SQV is significantly increased when taken within 2 hours of a high-fat meal. Itraconazole caps can be taken with food or cola to increase absorption. Administration of a single 400 mg dose of ATZ with a light meal resulted in a 70% increase in AUC. Ganciclovir is poorly absorbed, if taken with food, levels are increased at best 5%. Atovaquone must be taken with a fatty meal to ensure absorption (23 g fat: 610 kcal). Amprenavir can be taken with or without meals; avoid a high fat meal which may decrease levels. IDV levels are reduced if taken with fat or high protein and should be taken on an empty stomach (at least 1 hour prior or 2 hours after a meal) or with a light, low-fat snack such as cereal with skim milk, toast and jam, fresh fruit, yogurt. ddI is destroyed by stomach acid, and therefore ddI tablets contain an antacid buffer. ddI tabs and EC caps should always be taken on an empty stomach since the presence of food interfere with action of the buffers. To reduce SE involving the stomach. Zidovudine does not need to be taken with food for adequate absorption. However, food may prevent or minimize the risk of stomach upset or nausea. INH should be taken on an empty stomach to attain peak concentration, however, it can be taken with food to decrease GI upset.

24 Interactions dans le VIH: que sait-on?
Certaines interactions sont favorables et utilisées volontairement:  effet " booster" D’autres sont tellement marquées qu’elles sont non recommandées ou contre-indiquées:  induction/inhibition par un ARV  induction/inhibition par un médicament associé Certaines peuvent êtres contrôlées par STP et adaptation posologiques  Maraviroc: posologie varie selon l’association  STP pour les interactions impactant IPs et/ou INNTIs  Connues comme : statines, méthadone, warfarine…

25 Principe pharmacocinétique du boost par le ritonavir (RTV)
Effet inhibiteur puissant du RTV sur CYP450 3A4  ì biodisponibilité orale consécutive à î métabolisme pré-systémique (entérocytes & hépatocytes) î clearance hépatique & ì demi-vie d’élimination de l’IP associé, et Légère modification de la PK du RTV ( avec SQV et IDV et ↓ avec LPV et APV)

26 PK Parameter elevation by ritonavir boosting

27 “Cmax” ou “T1/2” boosting du RTV
Concentration plasmatique Cmax IP non boosté SQV, LPV,NFV M8   Cmax Boost de la demi-vie Boost de la Cmax APV, IDV,M8, ATV   T1/2 CI95 Surface sous courbe de réplication potentielle Cmin CI50 Temps Intervalle entre 2 doses quotidiennes

28 Interactions dans le VIH: que sait-on?
Certaines interactions sont favorables et utilisées volontairement:  effet " booster" D’autres sont tellement marquées qu’elles sont non recommandées ou contre-indiquées:  induction/inhibition par un ARV  induction/inhibition par un médicament associé Certaines peuvent êtres contrôlées par STP et adaptation posologiques  Maraviroc: posologie varie selon l’association  STP pour les interactions impactant IPs et/ou INNTIs  Connues comme : statines, méthadone, warfarine…

29 Traitement anti-VIH Objectif thérapeutique Efficacité maximale
Toxicité minimale et Objectif thérapeutique Une interaction médicamenteuse peut modifier l’efficacité ou la toxicité du traitement

30 Impact de l’induction et de l’inhibition enzymatiques
Intervalle thérapeutique T + Inhibiteur + Inducteur Traitement optimisé Induction enzymatique sous-dosage : échec Inhibition enzymatique surdosage : toxicité

31 Traitement anti-VIH Objectif thérapeutique Efficacité maximale et
Toxicité minimale Objectif thérapeutique Association d’un inhibiteur Association d’un inducteur

32

33 Essai de classification selon l’impact potentiel (FDA)
CYP/ autres enzymes Puissants Inhibiteurs augmentation de l’AUC ≥ 5 Inhibiteurs modérés de l’AUC >2 et < 5 Faibles de l’AUC >1.25 et < 2 Inducteurs diminution de l’AUC ≥ 80% Inducteurs modérés diminution de l’AUC >50% mais < 80% diminution de l’AUC >20% mais < 50%

34 Raltegravir and Rifampin
If combining RAL with rifampin, increase the RAL dose to 800 mg twice daily. Raltegravir [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.: February 2009 34

35 Quelques médicaments contre indiqués en association
aux IPs qui inhibent leur métabolisme Médicament antirétroviral Atazanavir/rtv Darunavir/rtv Lopinavir/rtv Sivastatine Lovastatine Amiodarone Astémizole Halofantrine Midazolam Cisapride 

36 Pravastatine et IPs Cmax AUC Cmin
SQV/RTV (400/400 BID) plus pravastatin, 40 mg/day Effect on PRAV 0.58 0.50 N/A LPV/RTV (400/100 BID) plus 20 mg/day dose of pravastatin 1.26 (0.87, 1.83) 1.33 (0.91, 1.94) DRV/RTV (600/100 BID) plus 40 mg single dose of pravastatin 1.63 (0.95, 2.8) 1.81 (1.23, 2.66) Fichtenbaum C, AIDS 2002;16: Lopinavir/ritonavir [package insert]. North Chicago, Ill: Abbott Laboratories; Darunavir [package insert]. Raritan, NJ: Tibotec Therapeutics; 2008. 36

37 Principles of Drug Interaction Studies
Understanding drug interactions is critical to the benefit/risk assessment. An in vitro and in vivo integrated approach may reduce the number of studies needed and optimize knowledge. Appropriately designed studies are critical. Clinical significance should be interpreted based on well-defined exposure-response data and analyses. Classification of CYP inhibitors and substrates can aid in study design and cross labeling. Information should be appropriately placed in the labeling. Huang SS et al. Clin Pharmacol Ther 2007;81:

38 Protease inhibitor interactions with Statins
Lovastatin & simvastatin extensively metabolised by CYP3A4 and plasma levels significantly increased by boosted PI . Contraindicated; use alternative.

39 TPV/r in combination with CYP450 substrates – concentrations increase
TPV (a CYP3A4 inducer) … but with RTV is inhibitory….so Rifabutin AUC  2.9-fold (active metabolite  20-fold)1 Overall AUC of Rifabutin + metabolite  4.3-fold Dosing schedule of Rifabutin should be 3 x weekly or every other day2 POSTER #A-455 Open-label single-arm Phase I study of 12 healthy HIV-negative men. Each received TPV/RTV 500 mg/200 mg BID for a total of 13 doses. Steady state achieved by Day 7. 4.4% excreted renally as glucuronide; TPV/RTV dose adjustments unlikely in renal insufficiency. 82.3% excreted via biliary excretion, primarily as parent compound. POSTER #A-456 Coadministration of single-dose rifabutin (RFB) and steady-state TPV results in significant  in AUC, Cmax and C12 for RFB and its major metabolite (p<0.001). Requires reduction in RFB dose to 150 mg 3 x/week and careful monitoring for toxicity. POSTER #A-457 Single-dose and steady-state TPV/RTV in combination with clarithromycin (CLR) assessed in 24 healthy volunteers. TPV/RTV results in  exposure to CLR as the parent compound and inhibits conversion to major metabolite (14-OH-clari). Coadministration of steady-state CLR 500 mg BID increased steady-state TPV AUC0-12 (by 59%), Cmax (by 43%) and C12 (by 112%). No dose alteration with normal renal function. May require dose adjustment of CLR in renal impairment. Near-complete inhibition of metabolite (14-OH-CLR), which is more active against some pathogens (H. influenzae) than CLR itself. 1. van Heeswijk R, et al. 44th ICAAC, Washington 2004, #A-456; 2. CDC MMWR Guidelines

40 TPV/r in combination with CYP450 substrates – concentrations increase
TPV (a CYP3A4 inducer) … but with RTV is inhibitory….so Atorvastatin AUC  9-fold1 Clinically relevant; start with the lowest possible dose of atorvastatin with close monitoring. POSTER #A-455 Open-label single-arm Phase I study of 12 healthy HIV-negative men. Each received TPV/RTV 500 mg/200 mg BID for a total of 13 doses. Steady state achieved by Day 7. 4.4% excreted renally as glucuronide; TPV/RTV dose adjustments unlikely in renal insufficiency. 82.3% excreted via biliary excretion, primarily as parent compound. POSTER #A-456 Coadministration of single-dose rifabutin (RFB) and steady-state TPV results in significant  in AUC, Cmax and C12 for RFB and its major metabolite (p<0.001). Requires reduction in RFB dose to 150 mg 3 x/week and careful monitoring for toxicity. POSTER #A-457 Single-dose and steady-state TPV/RTV in combination with clarithromycin (CLR) assessed in 24 healthy volunteers. TPV/RTV results in  exposure to CLR as the parent compound and inhibits conversion to major metabolite (14-OH-clari). Coadministration of steady-state CLR 500 mg BID increased steady-state TPV AUC0-12 (by 59%), Cmax (by 43%) and C12 (by 112%). No dose alteration with normal renal function. May require dose adjustment of CLR in renal impairment. Near-complete inhibition of metabolite (14-OH-CLR), which is more active against some pathogens (H. influenzae) than CLR itself. 1. van Heeswijk R, et al. 5th International Workshop on Clinical Pharmacology in HIV Therapy, Rome 2004, #5.2

41 TPV/r in combination with CYP450 substrates – concentrations increase
TPV (a CYP3A4 inducer) … but with RTV is inhibitory….so Clarithromycin AUC  20%1 No dosage adjustment needed for patients with normal renal function. POSTER #A-455 Open-label single-arm Phase I study of 12 healthy HIV-negative men. Each received TPV/RTV 500 mg/200 mg BID for a total of 13 doses. Steady state achieved by Day 7. 4.4% excreted renally as glucuronide; TPV/RTV dose adjustments unlikely in renal insufficiency. 82.3% excreted via biliary excretion, primarily as parent compound. POSTER #A-456 Coadministration of single-dose rifabutin (RFB) and steady-state TPV results in significant  in AUC, Cmax and C12 for RFB and its major metabolite (p<0.001). Requires reduction in RFB dose to 150 mg 3 x/week and careful monitoring for toxicity. POSTER #A-457 Single-dose and steady-state TPV/RTV in combination with clarithromycin (CLR) assessed in 24 healthy volunteers. TPV/RTV results in  exposure to CLR as the parent compound and inhibits conversion to major metabolite (14-OH-clari). Coadministration of steady-state CLR 500 mg BID increased steady-state TPV AUC0-12 (by 59%), Cmax (by 43%) and C12 (by 112%). No dose alteration with normal renal function. May require dose adjustment of CLR in renal impairment. Near-complete inhibition of metabolite (14-OH-CLR), which is more active against some pathogens (H. influenzae) than CLR itself. 1. van Heeswijk et al., 2004; 44th ICAAC Abs A-457.

42 Interactions dans le VIH: que sait-on?
Certaines interactions sont favorables et utilisées volontairement:  effet " booster" D’autres sont tellement marquées qu’elles sont non recommandées ou contre-indiquées:  induction/inhibition par un ARV  induction/inhibition par un médicament associé Certaines peuvent êtres contrôlées par STP et adaptation posologiques  Maraviroc: posologie varie selon l’association  STP pour les interactions impactant IPs et/ou INNTIs  Connues comme : statines, méthadone, warfarine…

43 Métabolisme des anti-CCR5
Substrats de CYP450 & P-gp Interactions avec nourriture et autres molécules Etudes réalisées Références Aplaviroc (GSK) 3A4 (2C9; 2C19) In vitro/in vivo Nourriture LPV/r Adkinson K, Poster 665, 12th CROI, Boston 2005 Song I, Poster 6.1, 6th IWCPHT, Québec 2005 Maraviroc (Pfizer) P-gp Midazolam (cocktail) KTZ, SQV, ATV, LPV ± RTV*, EFV*, NVP , ddI, TDF, 3TC Abel S, Poster 6.2, 6th IWCPHT, Québec 2005 Vicriviroc (Schering) LPV/RTV**, EFV**, TDF, 3TC, ZDV Sansone A, Poster 6.4, 6th IWCPHT, Québec 2005 * Ajustement de Dose recommandé ** Contre-indiqué

44 Impact de l’association ETR +/-DRV/r sur
la PK du à Maraviroc J Davis et al, EACS 2007

45 Summary of Dose Modifications with Maraviroc
Concomitant treatment Morning dose Evening dose Includes a potent CYP3A4 inhibitor For example: Protease inhibitors* ± ritonavir (except tipranavir) Elvitegravir, delavirdine Ketoconazole, itraconazole, clarithromycin, telithromycin, nefazadone, telithromycin YES 150 mg 150 mg Regardless of other agents in the regimen NO Includes a CYP3A4 inducer For example: Efavirenz, etravirine Rifampicin YES 300 mg 300 mg 300 mg 300 mg NO 300 mg NO CYP3A4 inhibitors or inducers For example: NRTIs, also nevirapine, tipranavir/r 300 mg *including darunavir Davis J, et al. 11th EACS; Madrid, Spain; October 24-27, P4.3/02; Mcfadyen M, et al. Ibid. P4.1/06 45

46 Recommendations posologiques pour la Maraviroc
en présence d’ Etravirine ± Inhibiteurs des CYP Etravirine ± Inhibiteurs des CYP Posologie du Maraviroc Etravirine + IP “boosté” (ex: DRV/rtv) Maraviroc 150 mg bid per os Etravirine sans inhibiteur de CYP Maraviroc 600 mg bid per os J Davis et al, EACS 2007

47 Effect of ART on Methadone and Buprenorphine
Methadone levels decreased by PI/r and NNRTIs Monitor for withdrawal signs and symptoms Some patients may require increase in methadone dose Complicated by differential effect on the inactive S(-) and the active R(-) methadone Buprenorphine (BUP) BUP levels decreased by NVP & EFV: Use standard dose BUP and titrate to effect For PIs BUP levels increased so may need decrease in BUP dose.

48 Interactions dans le VIH: que sait-on?
Certaines se traduisent par une modification de l’efficacité et de la toxicité: ex: TDF + DDI Certains ont un effet clinique mal défini: ex: TDF + IPs

49 Activation intracellulaire des INTI
Thymidine ZDV-MP ZDV ZDV-DP d4T d4T-MP d4T-DP Thymidylate Kinase 5’NDP Kinase Thymidine Kinase ZDV-TP d4T-TP Cytidine FTC 3TC FTC-MP FTC-DP 3TC-MP 3TC-DP 5’NDP Kinase dCMP Kinase Deoxycytidine Kinase FTC-TP 3TC-TP Guanosine ABC- MP CBV-MP CBV-DP CBV-TP ABC Adénosine Phosphotransférase Adénosine MP Déaminase Guanylate Kinase 5’NDP Kinase Adénosine ddI - MP ddA-MP ddA-DP ddI 5’ Nucleotidase Adénosine MP Déaminase Adénosine MP Kinase ddA-TP Ténofovir DF Estérase cellulaire PMPA AMP Kinase PMPA-MP 5’NDP Kinase PMPA-DP 5’NDP Kinase Anderson PL et al. Clin Infect Dis 2004; 38:

50 Association ténofovir et ddI : mécanisme d’interaction
ddi + TDF Toxicité ddI ( ddATP et dGTP) Pancréatite, hyperglycémie lipoatrophie, hyperlactatémie... Barrière génétique faible (K65R) Même nucléoside- cible = adénosine-TP  compétition TDF-ddI Echec virologique Inhibition de la Purine Nucléoside Phosphorylase (PNP) Déplétion en CD4+ Interaction PK surdosage ddI Association non recommandée, particulièrement chez les patients avec CV élevée et faible taux de CD4. D’une manière générale ne pas associer 2 IN ayant la même voie métabolique Barreiro P et al. AIDS Reviews 2004; 6: Dictionnaire Vidal 2006.

51 Etravirine, Maraviroc and Raltegravir
ETV substrate: CYP3A, CYP2C9, CYP2C19 and UGT inducer: CYP3A, UGT(1A1); and inhibitor: CYP2C9 and CYP2C19 MVC substrate: CYP3A and P-gp RAL substrate: UGT1A1 and P-gp 51

52 Etravirine, Maraviroc and Raltegravir Effects of Trough Concentration (2 way interaction studies)
References: 1. Antimicrob Agents Chemo 2008;52: 2. 11th EACS, Poster P4.3/02. Madrid, Spain, October 2007. 3. Br J Clin Pharmacol 2010;69:51-7. 52

53 Etravirine and PI/r Drug Interactions
Etravirine Prescribing Information. Tibotec, Inc. Feb 23, 2010. 53

54 Median (95% CI) Prediction of Likelihood of Failure as a Function of Cmin and Cavg
McFadyen L, et al. PAGE. 2007, Abstract P4-13.

55 Etravirine, Maraviroc and Raltegravir
ETV MVC RAL Best “educated” guess for a combination regimen of ETV, MVC and RAL: ETV: usual dose of 200 mg BID MVC: increase dose to 600 mg BID RAL: consider dose increase to 800 mg BID 55

56 Etravirine, Maraviroc and Raltegravir PK in HIV-Infected Persons
37 treatment-experienced persons received: ETV, 200 mg twice daily; MVC, 600 mg twice daily; and RAL, 400 mg twice daily. Mean trough concentrations were: ETV: 515 ng/mL, 90%CV MVC: 91.4 ng/mL, 80%CV; trough concentrations were < 50 ng/mL in 37% of the samples RAL: 442 ng/mL, 100%CV ETV conc are consistent with the usual dose; MVC conc at 2x the usual dose are consistent with the usual dose but a high percent of patients had conc below threshold value; RAL conc at usual dose are higher than expected with lower variability. Calcagno A, et al. 11th IWCPHT. Sorrento, Italy, April 2010

57 Etravirine-Raltegravir Interaction: 4 Case Reports in HIV-infected persons
RAL Ctrough (nM) Case 1: pre ETV with ETV Case 2: with ETV 62 after RAL inc to /d 139 Case 3: with ETV Case 4: with ETV 60.1 RAL Ctrough Ratio Menard A, et al. AIDS 2009;23:

58