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Pharmacological Interactions with Antiretroviral Drugs

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1 Pharmacological Interactions with Antiretroviral Drugs
Gilles PEYTAVIN PharmD, PhD GHU X Bichat-Cl Bernard - APHP Paris - France

2 Aims & Objectives To understand the clinical importance of DDI
To understand the concept of PK enhancement and particularly the role of RTV “boosting” To retrieve DDI data Hartshorn, EA, Tatro, DS. Drug Interactions, 2003, Facts and Comparisons, St. Louis, MO

3 Drug – Drug Interactions (DDI)
“…phenomena that occurs when the effects (pharmacodynamics) or pharmacokinetics (PK) of a drug are altered by prior administration or co-administration of a second drug” (Hartshom EA et al, 2003) A change (in a positive or negative way) in blood concentration causes a change in the drug’s effect In the HIV Therapeutic era, DDI are PK interactions PK DDI continue to expand with - availability of new drugs - more complex combination - increasing age-related co-morbidities Hartshorn, EA, Tatro, DS. Drug Interactions, 2003, Facts and Comparisons, St. Louis, MO

4 Results of the Swiss HIV Cohort on DDI prevalence (n=1497 patients)
Marzolini C et al, EACs, Abst. PS12/5

5 PK Drug-Drug interactions
Mainly metabolic Multiple and reciprocal Intricate and unexpected Quantitatively difficult to predict Interpretation complex Clinical relevance ? Class Effect ? Pharmacological Intervention ?

6 Pharmacokinetic of Antiretroviral Drugs
Intestinal absorption Metabolism Elimination Drug-drug interaction NRTIs & NtRTIs ++ Intracellular (Prodrugs) Urine + (Intra & extra cellular) PIs Liver +++ Bile NNRTIs Urine/bile Enfuvirtide - (SC) CCR5 inhibitors Integrase inhibitors ++ (CYP450) + (UGT1A1) 1 to 2 daily drug intakes depending the combinations and drugs Wide between patients variability

7 Mechanisms for PK DDI Altered drug absorption and tissue distribution
pH, P-gp (efflux proteins or drug transporters) Altered drug metabolism Induction/inhibition, GT,P-gp Reduced renal excretion (P-gp) Altered intracellular activation Impairment of phosphorylation (D4T, ZDV) The outcome of these interactions could be additive/synergistic, antagonistic/opposing PK drug interactions may involve: Changes in gastric pH and drug absorption: absorption is sometimes dependent upon acidity of the gut – e.g. ketoconazole requires an acid pH for adequate absorption (drugs and food may change the acidity of the gut and decrease absorption). E.g. fluroquinolones must be taken at least 2 hours prior to antacids or 6 hours after antacids to avoid formation of insoluble complex (chelation). Changes in tissue distribution: protein binding displacement – temporary increase in free drug – also results in greater clearance of drug. Altered drug metabolism mediated by induction or inhibition of CYP450, glucuronyl transferase (GT) or modulation of P glycoprotein (P-gp), an efflux protein. P-gp transports substances from cells to intestinal lumen, urine or bile for destruction. P-gp is present in intestinal epithelial cells, in the liver and kidneys, and at various blood-tissue barriers. Normal P-gp activity protects the brain from excessive accumulation of toxic drugs and metabolites, e.g. selective reduction of CNS adverse effects. P-gp can have undesirable effects, e.g. decreasing the activity of antiretrovirals within the brain. Some drugs may inhibit P-gp resulting in decreased elimination. Ritonavir has been shown to inhibit p-gp mediated transport in renal proximal tubules. Some drugs may induce P-gp (St. John’s Wort) resulting in increased elimination PIs ritonavir, nelfinavir, and amprenavir may strongly induce P-gp expression. Fluctuation in intracellular drug concentrations of active drug (D4T, ZDV) is due to impairment of phosphorylation, which is needed to change the drug to its active state. D4T and ZDV should NEVER be used together. They are antagonistic (PK). Changes in renal elimination may result in increased drug concentrations in the blood.

8 Activation of Nucleoside Analogues
Thymidine Cytidine Guanosine Adenosine ZDV d4T ddC 3TC ABC ddI Tenofovir DF Deoxycytidine Kinase Thymidine Kinase Adenosine Phosphotransferase 5’ Nucleotidase Diester Hydrolysis ABC- MP ddI - MP Tenofovir ZDV-MP d4T-MP ddC-MP 3TC-MP Adenylate Synthetase & Adenylate Lyase AMP Kinase Cytosolic Enzyme Thymidylate Kinase CMP/dCMP Kinase CBV-MP ddA-MP TFV-MP ZDV-DP d4T-DP ddC-DP 3TC-DP Kinase Adenylate Kinase & PRPP Synthetase NDP Kinase NDP Kinase NDP Kinase CBV-DP ddA-DP TFV-DP Kinase Adenylate Kinase & PRPP Synthetase ZDV-TP d4T-TP ddC-TP 3TC-TP CBV-TP ddA-TP

9 Activation of Nucleoside Analogues
Guanosine ABC- MP CBV-MP CBV-DP CBV-TP ABC Adenosine Phosphotransferase Cytosolic Enzyme Kinase Thymidine F-ZDV-MP F-ZDV F- ZDV-DP d4T d4T-MP d4T-DP Thymidylate Kinase NDP Kinase Thymidine Kinase F-ZDV-TP d4T-TP Cytidine Reverset FTC Rvt-MP Rvt-DP FTC-MP FTC-DP CMP/dCMP Kinase Deoxycytidine Kinase Rvt-TP FTC-TP Adenosine ddI - MP ddA-MP ddA-DP ddI 5’ Nucleotidase Adenylate Synthetase & Adenylate Lyase Adenylate Kinase & PRPP Synthetase ddA-TP Tenofovir TFV-MP Tenofovir DF Diester Hydrolysis AMP Kinase TFV-DP

10 Interaction between tenofovir and ddI
Proposed Mechanisms A metabolic route for ddI clearance is its breakdown by purine nucleoside phosphorylase (PNP). It was further established that the mono- and diphosphate forms of TNF were inhibitors of PNP-dependent degradation of ddI. The level of systemic exposure to ddI is increased 40 to 300% when it is coadministered with allopurinol, ganciclovir, or TNF.  mitochondrial toxicity !!!

11 Summary of DDI between NRTIs and RBV
ABC (QD) ZDV (BID) ddI d4T 3TC FTC RBV TDF ABC (QD) QD/BID ddI fasted conditions Metabolism via ADH ICell Kinase Competition ICell ZDV-TP Hb sg ICell ddA-TP  toxicity  toxicity ddI fasted conditions ddI fasted conditions  ddI Cpl  toxicity  ICell d4T-TP ICell Kinase Competition Legend: Adequate ICell & Cpl Cpl to survey inadequate ICell

12 Entero-hepatic efflux transporters
Faber KN et al, Adv Drug Deliv Rev, 2003

13 Renal interactions with TFV
Basolateral Side Proximal tubular Cell Apical Side K+ DC2- ATPase NaDC-1 Na+ Na+ HIV Protease Inhibitors ? SDCT2 DC2- DC2- Organic Anions & tenofovir, adefovir, cidofovir hOAT1 MRP2 _ oatp Probenecid Organic Anions OAT-K1 OAT-K2 X Adapted from Hosoyamada et al., Am. J. Physiol. (1999)And Rollot F, CID, 2003 Izzedine H et al, AIDS 2010

14 DDI in GI tract RAL and and Proton Pump Inhibitors or H2-Receptor antagonist :  RAL ASC0-12h (Isentress® Prescribing information) DTG (S/GSK ) and Maalox® :  74 % DTG ASC0-24h (Song I, ICAAC 2009, Abs A1-1305) IDV or ATV and Proton Pump Inhibitors or H2-Receptor antagonist :  IDV or ATV ASC0-24h (Crixivan® and Reyataz® Prescribing information) RPV and antiacids or H2-Receptor antagonist :  75 % RPV ASC0-24h (Edurant® Complera® Prescribing information)  Recommendations for IDV, ATV, DTG and RPV : Coadministration of TMC278 with H2-receptor antagonists and antacids is possible with timed separation in dosing

15 CYP450 enzymes in Hepatic Drug Metabolism

16 Human Drug Metabolizing CYPs Located in Extrahepatic Tissues
CYP450 Enzymes Tissue 1A1 Lung, kidney, GI tract, skin, placenta, others 1B1 Skin, kidney, prostate, mammary, others 2A6 Lung, nasal membrane, others 2B6 GI tract, lung 2C GI tract (small intestine mucosa) larynx, lung 2D6 GI tract 2E1 Lung, placenta, others 2F1 Lung, placenta 2J2 Heart 3A GI tract, lung, placenta, fetus, uterus, kidney 4B1 4A11 Kidney Red indicates enzymes important in drug metabolism S. Rendic & F.J. DiCarlo, Drug Metab Rev, 1997

17 Factors Influencing Activity and Level of CYP450 Enzymes
Nutrition 1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4-5 Smoking 1A1, 1A2, 2E1 Alcohol 2E1 Drugs 1A1, 1A2, 2A6, 2B6, 2C, 2D6, 3A3, 3A4-5 Environment 1A1,1A2, 2A6, 1B, 2E1, 3A3, 3A4-5 Genetic Polymorphism 1A, 2A6, 2C9, 2C19, 2D6, 2E1 Red indicates enzymes important in drug metabolism Adapted from S Rendic Drug Metab Rev, 2002

18 Restrictively Metabolized Drugs : Effect of Cirrhosis on CLint
% Normal Intrinsic Clearance 100 CYP2D6 GLUCURONIDATION (UGT…) 80 60 40 CYP3A4 20 CYP2C19 MILD MODERATE SEVERE Degree of liver function impairment

19 CYP 450 System Definitions
Substrate: Drug is metabolized by the enzyme system Inducer: Drug that will increase the synthesis of CYP450 enzymes generating  associated Drug Plasma exposure &  risk of failure Inhibitor: Drug that will decrease the metabolism of a substrate generating  drug plasma exposure &  risk of toxicity

20 Importance of Enzyme Inhibition and Enzyme Induction

21 In vitro Inhibition of CYP 450 3A3/4 (N-demethylase Erythromycine breath test)

22 Pharmacokinetic Principle of PI combination with ritonavir (RTV)
Potent inhibitory effect of RTV on CYP450 3A4 ì oral bioavailability consecutive to î pre-systemic (enterocytes & hepatocytes) metabolism î hepatic clearance & ì elimination half-life of the associated PI, î or ì on RTV pharmacokinetic

23 “Cmax” or “Half-life” RTV boosting
Plasma Conc Cmax Non boosted PI SQV, LPV, TPV   Cmax Half-life boosting Cmax boosting APV, ATV, DRV, IDV   T1/2 IC95 Cmin IC50 Time Interval between 2 daily doses

24 * EC50 with 50% of human serum
Plasma PK Profiles of LPV after a unique dose of 400 mg administered to healthy volunteers ± RTV combination + 50 mg RTV + 200 mg RTV AUC (mg h/l) 0.8 54 105 122 + 100 mg RTV 400 mg LPV alone Time (Hours) 6 12 18 24 30 36 42 48 0.0001 0.001 0.01 0.1 1 10 EC50* + RTV 50mg + RTV 100mg LPV alone + RTV 200mg * EC50 with 50% of human serum Plasma Concentrations (mg/l)

25 Mean Plasma Concentrations of indinavir ± ritonavir
IDV Plasma Concentration (ng/mL) 10 000 IDV/RTV q12h (mg): 800/100 Light meal 800/100 High-fat meal 1000 400/400 Light meal 400/400 High-fat meal 400/100 (GHOSN J, AIDS, 2003) 100 IDV q8h (mg): IC 90 800 Fasted 10 2 4 6 8 10 12 Modified from Saah et al, ICAAC, 1999 Time (hours)

26 Drug-Drug Interactions
CYP 3A4 CYP 2C19 CYP 2C9 CYP 2D6 CYP 1A2 CYP 2E1 CYP 2A6 CYP 2B6 CYP 2C8 Enzymatic Inhibition Induction RTV, NFV EFV, NVP APV, LPV TPV +++ IDV, APV, DRV SQV, DLV Modified from Fichtenbaum et al, Clin Pharmacokinet, 2002 DLV LPV ? RTV DLV, EFV RTV, NFV ? EFV NVP

27 RTV Cmin in association with TPV, SQV, LPV or APV (BI.1182.51 study)
*Mean ± SD ; n 219 HIV infected patients, D1-D14, OT with TPV/r or SQV/r or LPV/r or APV/r Complete PK at steady state (D7 & D14), RTV Cmin Distribution study (bootstrap on re-samplings) RTV Cmin : SQV > LPV > TPV > APV Wide inter-patient variability, especially with SQV, Despite the RTV double dose (200 mg bid), RTV Cmin were lower than those with SQV & LPV Resulting of the TPV inducer effect, Favourable on the GI tolerance ? 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 2 4 6 8 10 12 14 1 3 5 7 16 SQV/r (1000/100 mg bid) (0,589 ± 0,451 mg/l; 57)* LPV/r (400/100 mg bid) (0,324 ± 0,232 mg/l; 59)* Densité TPV/r (500/200 mg bid) (0,247 ± 0,230 mg/l; 49)* APV/r (600/100 mg bid) (0,183 ± 0,206 mg/l; 54)* Ritonavir Cmin (µg/ml) Sabo J, 7th IWCPHT 2006; abs. 43

28 DDI between antineoplastic and antiretroviral drugs (1)
Antinéoplastic drugs Main elimination pathway Effect of antiretroviral on antineoplastic drugs Docetaxel (Taxotère*) 1 Paclitaxel (Taxol*) 2 Mainly CYP 3A Association with PI/r : AUC and toxicity   doses of cytotoxic drugs Association with NNRTI : AUC and efficacy of cytotoxic drugs Need to be evaluated !! Vincristine (Oncovin*) Vinblastine (Velbé*) Vinorelbine (Navelbine*) Vindésine (Eldésine*) Etoposide, VP16 (Vépéside*) Irinotecan (Campto*) 3 Ifosfamide (Holoxan*) 2 CYP3A4, CYP2B6 Tyrosine kinase Inhibitors Imatinib (Glivec*) 2 Erlotinib (Tarceva*) Sumatinib (Sutent*) Sorafenib (Nexavar*) Thiotepa Tamoxifène (Novaldex*) Exemestane (Aromasine*) Bortezomib (Velcade*) CYP3A4 et 2C19 Corticosteroides : Prednisone (Solupred*) Methyl prednisolone (Solumedrol*) Dexamethasone Peytavin G, ARV & AntiK, Lyon 19 nov 2010

29 DDI between antineoplastic and antiretroviral drugs (2)
Antinéoplastic drugs Main elimination pathway Effect of antiretroviral on antineoplastic drugs Cyclophosphamide (Endoxan*) Dacarbazine (Déticène*) Bendamustine Other CYP CYP 2B6, 3A4, CYP1A2>CYP2E1 CYP1A2 Association with PI/r : AUC and toxicity   doses of cytotoxic drugs Association with NNRTI : AUC and efficacy of cytotoxic drugs Need to be evaluated !! Melphalan (Alkeran*) Doxorubicine (Adriamycine*) Mitomycine (Ametycine*) Mitoxantrone (Novantrone*) Bleomycine (Bleomycine*) Other (conjugaison etc.) Methotrexate Fluoro-uracile (Fluorouracile* and per os Capécitabine*) Cisplatine Carboplatine Oxaliplatine Lenalidomide (Revlimide) Renal elimination (inchanged) Low Probability of DDI (efflux transporters ?) Peytavin G, ARV & AntiK, Lyon 19 nov 2010

30 Drug-Drug interactions outcome

31 Evaluation of Steady-State Interaction between ATV
(400 mg qd) and EFV (600 mg qd) in 31 Healthy Subjects ATV+EFV ATV  Cmax ATV de 59%  AUCss ATV de 74 % (S. Preston et al, Poster 443-W, 9th CROI 2002, Seattle)

32 Steady-State Pharmacokinetic Interaction Study of ATV
(400 mg qd) with EFV (600 mg qd) and RTV (200 mg qd) ATV+EFV+RTV ATV  Cmax ATV x 2.2  AUCss ATV x 3.4 (O’Mara E, Poster 444-W, 9th CROI 2002, Seattle)

33 MVC DDI and dose adjustements
Maraviroc (Morning dose) Maraviroc (Evening dose) Associated Drugs INTIs, Raltegravir Nevirapine Tipranavir/r Fosamprenavir/r No dose adjustement 300 mg 300 mg IPs (other than TPV/r ou FPV/r) Inhibiteurs puissants du CYP3A4 ( ketoconazole, itraconazole, clarithromycine, telithromycine) Semi-dose Maraviroc This flow chart simplifies the dose modification needed when combining Celsentri® with ARVs and other commonly used drugs. 150 mg 150 mg Etravirine Efavirenz Inducteurs CYP3A4 (rifampicine) Double dose Maraviroc 2 x 300 mg 2 x 300 mg Celsentri® 2008

34 PK Interaction between MVC & DRV/r
Summary : DRV/r  MVC AUC012hr and Cmax by 405% ( %) and 229% ( %), respectively. Neither modification of MVC Tmax nor DRV or RTV plasma exposure, A decrease of MVC daily dose (150 mg qd ?) is recommended in association with DRV/r. Abel S et al, Poster 55, 8th IWCPHIVT, 2007

35 PK interactions on raltegravir (MK-0518) in healthy volunteers
Cmin* Cmax* AUC0-12H* Legend : SD : Single Dose SS : Steady State -4% 77% -55% -61% -21% 3% -16% 24% -18% -38% -36% 64% -24% 41% -40% 49% -80% -60% -20% 0% 20% 40% 60% 80% 100% RTV (100 mg qd) (SD) [5] ATV/r (300/100 mg qd) (SS) [1] TPV/r (500/200 mg bid) (SS) [4] RFP (600 mg qd) (SD) [2] EFV TDF (300 mg qd) (SS) [3] *Geometric Mean Ratio [1] MISTRY GC et al, GLASGOW 2006 [2] IWAMOTO M, GLASGOW 2006 [3] WENNING LA ; ICAAC 2006 ; A-375 [4] WENNING LA, ICAAC 2006 ; A-374 [5] IWAMOTO M, ICAAC 2006 ; A-373

36 Rilpivirine (TMC278) and PK DDI
Back D, BHIVA 2010

37 DDI Prevention HIV infected patients are high-risk patients
Taking ≥ 2 medications Cardiovascular risk factors Hepatitis, TB, Cancer… co-morbidities Auto-medication (GI tract) …. Consult Summary characteristics of Products (EMA, FDA etc.) National Guidelines (?) Consult pharmacists or drug info specialists Check up-to-date drug interactions charts Notified case report Use of TDM It is impossible to remember all of the drug interactions that can occur. One compendium lists over 300 drugs that are thought to interact with warfarin. It is therefore important to develop a stepwise approach to preventing adverse reactions due to drug interactions. First, taking a good medication history is essential. The “AVOID Mistakes” mnemonic presented on the next slide can help health care practitioners to develop good habits when performing this task. Second, it is essential that physicians develop an understanding of which patients are at risk for drug interactions. Of course, any patient taking two or more medications is at some risk. Studies show that the rate of adverse drug reactions increases exponentially in patients taking four or more medications.1 Importantly, some categories of drugs are especially at high risk for interactions. These categories include anticonvulsants, antibiotics, and certain cardiac drugs such as digoxin, warfarin, and amiodarone. Third, any time a patient is taking multiple drugs, we recommend that the first step be to check a readily available pocket reference, recognizing that the interaction may not be listed and a more complete search may be required. We recommend the list available from Fourth, consult other members of the health care team. Depending upon the practice setting, this may be a hospital pharmacist, a Drug Information Center, a specially trained office staff nurse or the nearby pharmacist in community practice. Fifth, use one of the several computerized databases available. Up-to-date databases are maintained by,, and many others. Many of these can be placed on a hand-held computer and can be configured to automatically update each time you synchronize with the desktop computer. Also, the Medical Letter Drug Interaction Program is inexpensive and updated quarterly. 1. Jacubeit T, Drisch D, Weber E. Risk factors as reflected by an intensive drug monitoring system. Agents Actions Suppl 1990; 29:

38 Many thanks for your attention !

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