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

Pharmacological InteractionsPharmacological Interactionswithwith Antiretroviral DrugAntiretroviral Drugss

Gilles PEYTAVINPharmD, PhD

GHU X Bichat-Cl Bernard - APHPParis - France

Aims & ObjectivesAims & 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

Drug – Drug Interactions (DDI)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

Results of the Swiss HIV Cohort on DDI Results of the Swiss HIV Cohort on DDI prevalence (n=1497 patients)prevalence (n=1497 patients)

Marzolini C et al, EACs, Abst. PS12/5

PK Drug-Drug interactionsPK Drug-Drug interactions

Mainly metabolicMainly metabolic Multiple and reciprocalMultiple and reciprocal Intricate and unexpectedIntricate and unexpected Quantitatively difficult to predictQuantitatively difficult to predict Interpretation complexInterpretation complex

Clinical relevance ?Clinical relevance ?

Class Effect ? Class Effect ?

Pharmacological Intervention ? Pharmacological Intervention ?

Pharmacokinetic of Antiretroviral DrugsPharmacokinetic of Antiretroviral Drugs

1 to 2 daily drug intakes depending the combinations and drugs

Wide between patients variability

Intestinal absorption

Metabolism Elimination Drug-drug interaction

NRTIs & NtRTIs

++ Intracellular

(Prodrugs)

Urine +

(Intra & extra cellular)

PIs ++ Liver

+++

Bile +++

NNRTIs ++ Liver

+++

Urine/bile +++

Enfuvirtide -

(SC)

Liver

+

Urine -

CCR5 inhibitors

+ Liver

++

Bile +++

Integrase inhibitors

++ Liver

++ (CYP450)

+ (UGT1A1)

Bile

Urine

+++

+

Mechanisms for PK DDIMechanisms 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

Activation of Nucleoside AnaloguesActivation of Nucleoside Analogues

Guanosine

ABC- MP

CBV-MP

CBV-DP

CBV-TP

ABCAdenosine

Phosphotransferase

Cytosolic Enzyme

Kinase

Kinase

Thymidine

ZDV-MP

ZDV

ZDV-DP

d4T

d4T-MP

d4T-DP

Thymidylate Kinase

NDP Kinase

Thymidine Kinase

ZDV-TP d4T-TP

Cytidine

ddC 3TC

ddC-MP

ddC-DP

3TC-MP

3TC-DP

NDP Kinase

CMP/dCMP Kinase

Deoxycytidine Kinase

ddC-TP 3TC-TP

Adenosine

ddI - MP

ddA-MP

ddA-DP

ddI

5’ Nucleotidase

Adenylate Synthetase& Adenylate Lyase

Adenylate Kinase &PRPP Synthetase

Adenylate Kinase &PRPP Synthetase

ddA-TP

Tenofovir

TFV-MP

Tenofovir DF

Diester Hydrolysis

AMP Kinase

NDP Kinase

TFV-DP

Activation of Nucleoside AnaloguesActivation of Nucleoside Analogues

Guanosine

ABC- MP

CBV-MP

CBV-DP

CBV-TP

ABCAdenosine

Phosphotransferase

Cytosolic Enzyme

Kinase

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

NDP Kinase

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

Adenylate Kinase &PRPP Synthetase

ddA-TP

Tenofovir

TFV-MP

Tenofovir DF

Diester Hydrolysis

AMP Kinase

NDP Kinase

TFV-DP

ProposedProposed Mechanisms 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.

Interaction between tenofovir and ddIInteraction between tenofovir and ddI

mitochondrial toxicity !!!

Entero-hepatic efflux transportersEntero-hepatic efflux transporters

Faber KN et al, Adv Drug Deliv Rev, 2003

Adapted from Hosoyamada et al., Am. J. Physiol. (1999)And Rollot F, CID, 2003

Izzedine H et al, AIDS 2010

Renal interactions with TFV

K+ATPase

SDCT2

Na+

DC2-

DC2-

Organic Anions & tenofovir, adefovir,

cidofovir

hOAT1

NaDC-1Na+

Proximal tubular Cell

Apical Side

DC2-

MRP2

oatp

OAT-K1

X

OAT-K2

OrganicAnions

Basolateral Side

HIV ProteaseInhibitors ?

Probenecid

_

DDI in GI tractDDI in GI tract

• RAL and and Proton Pump Inhibitors or H2-Receptor antagonist : RAL ASC0-12h (Isentress® Prescribing information)

• DTG (S/GSK1349572) 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

CYP450 enzymes in Hepatic Drug CYP450 enzymes in Hepatic Drug MetabolismMetabolism

RELATIVE HEPATIC CONTENT OF CYP450 ENZYMES

% DRUGS METABOLIZED BY CYP450 ENZYMES

Restrictively Metabolized Drugs : Effect of Cirrhosis on CLint

Restrictively Metabolized Drugs : Effect of Cirrhosis on CLint

MILDMILD MODERATEMODERATE SEVERESEVERE

GLUCURONIDATIONGLUCURONIDATION(UGT…)(UGT…)

CYP2D6CYP2D6

CYP3A4CYP3A4

CYP2C19CYP2C19

Degree of liver function impairmentDegree of liver function impairment

00

2020

4040

6060

8080

100100

% Normal Intrinsic Clearance% Normal Intrinsic Clearance

CYP 450 System DefinitionsCYP 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

Importance of Enzyme Inhibition Importance of Enzyme Inhibition and Enzyme Inductionand Enzyme Induction

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

IC50 (mM)

0.03720.0372 0.218 0.675 1.310.218 0.675 1.31 3.083.08

RTVRTV ATVATV > IDV IDV = LPV = LPV NFV APV = DRVNFV APV = DRV SQVSQV

THE MOSTTHE MOSTPOTENTPOTENT

INHIBITORINHIBITOR

THE LESSTHE LESSPOTENTPOTENT

INHIBITORINHIBITOR

Pharmacokinetic Principle of PI combination Pharmacokinetic Principle of PI combination with ritonavir (RTV)with ritonavir (RTV)

Potent inhibitory effect of RTV on CYP450 3A4Potent inhibitory effect of RTV on CYP450 3A4

oral bioavailability consecutive tooral bioavailability consecutive to pre-systemic (enterocytes & hepatocytes) metabolismpre-systemic (enterocytes & hepatocytes) metabolism

hepatic clearancehepatic clearance& & elimination half-lifeelimination half-life

oof the associated PI,f the associated PI,

or or on RTV pharmacokineticon RTV pharmacokinetic

““Cmax” or “Half-life” RTV boostingCmax” or “Half-life” RTV boosting

Time

Interval between 2 daily doses

IC95

IC50

Cmin

CmaxP

lasm

a C

on

c

SQV, LPV, TPV

Cmax

APV, ATV, DRV, IDV

T1/2

Non boosted PIHalf-life boostingCmax boosting

Plasma PK Profiles of LPV after a unique dose of Plasma PK Profiles of LPV after a unique dose of 400 mg administered to healthy volunteers400 mg administered to healthy volunteers

± RTV combination± RTV combination

+ 50 mg RTV

+ 200 mg RTV

AUC(mg h/l)

0.854

105

122+ 100 mg RTV

400 mg LPV alone

Time (Hours)

0 6 12 18 24 30 36 42 480.0001

0.001

0.01

0.1

1

10

ECEC5050**

+ RTV 50mg+ RTV 50mg

+ RTV 100mg+ RTV 100mgLPV aloneLPV alone

+ RTV 200mg+ RTV 200mg

* EC50 with 50% of human serum

Plasma Concentrations (mg/l)

0 2 4 6 8 10 12

IDV Plasma Concentration (ng/mL)

10 000

800/100 Light meal 800/100 High-fat meal

IDV q8h (mg):

400/400 Light meal 400/400 High-fat meal

800 Fasted

IDV/RTV q12h (mg):

IC 90

Modified fromSaah et al, ICAAC, 1999

Mean Plasma Concentrations Mean Plasma Concentrations of of indinavir ± ritonavirindinavir ± ritonavir

1000

10

100

400/100 (GHOSN J, AIDS, 2003)

Time (hours)

Drug-Drug InteractionsDrug-Drug Interactions

CYP 3A4CYP 3A4

CYP 2C19CYP 2C19 CYP 2C9CYP 2C9CYP 2D6CYP 2D6

CYP 1A2CYP 1A2 CYP 2E1CYP 2E1 CYP 2A6CYP 2A6 CYP 2B6CYP 2B6 CYP 2C8CYP 2C8

Enzymatic Enzymatic InhibitionInhibition

Enzymatic Enzymatic InductionInduction

RTV, NFVRTV, NFVEFV, NVPEFV, NVPAPV, LPVAPV, LPVTPV +++TPV +++

RTV, NFV RTV, NFV IDV, APV, DRVIDV, APV, DRVSQV, DLVSQV, DLV

Modified from Fichtenbaum et al, Clin Pharmacokinet, 2002

DLVDLVRTV, NFVRTV, NFV

LPV ?LPV ?

RTVRTVDLV, EFVDLV, EFV

RTV,RTV,NFV ?NFV ?EFV EFV NVPNVP

RTV Cmin in association with TPV, SQV,LPV or APV (BI.1182.51 study)

RTV Cmin in association with TPV, SQV,LPV or APV (BI.1182.51 study)

• 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 10 000

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 ?

Sabo J, 7th IWCPHT 2006; abs. 43

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)*

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)*

*Mean ± SD ; n

Ritonavir Cmin (µg/ml)D

en

sité

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9

0

2

4

6

8

10

12

14

0

2

4

6

8

10

12

14

0

1

2

3

4

5

6

7

02468

10

1416

12

DDI between antineoplastic and antiretroviral drugs (1)DDI between antineoplastic and antiretroviral drugs (1)

Peytavin G, ARV & AntiK, Lyon 19 nov 2010

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, CYP2B6Tyrosine kinase InhibitorsImatinib (Glivec*) 2

Erlotinib (Tarceva*)Sumatinib (Sutent*)Sorafenib (Nexavar*)ThiotepaTamoxifène (Novaldex*)Exemestane (Aromasine*)Bortezomib (Velcade*) CYP3A4 et 2C19Corticosteroides :Prednisone (Solupred*)Methyl prednisolone (Solumedrol*)Dexamethasone

Peytavin G, ARV & AntiK, Lyon 19 nov 2010

Antinéoplastic drugs Main elimination pathway Effect of antiretroviral on antineoplastic drugs

Cyclophosphamide (Endoxan*) Dacarbazine (Déticène*)Bendamustine

Other CYPCYP 2B6, 3A4,

CYP1A2>CYP2E1CYP1A2

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.)

MethotrexateFluoro-uracile (Fluorouracile* and per os Capécitabine*)CisplatineCarboplatineOxaliplatineLenalidomide (Revlimide)

Renal elimination (inchanged)

Low Probability of DDI

(efflux transporters ?)

DDI between antineoplastic and antiretroviral drugs (2)DDI between antineoplastic and antiretroviral drugs (2)

Drug-Drug interactions outcomeDrug-Drug interactions outcome

EnzymaticEnzymaticInhibitionInhibition

ANTIVIRAL

EFFICACY

INDUCTION

ADVERSE EFFECTS

EnzymaticInduction

VIRAL FAILURE

VIRAL RESISTANCES

Evaluation of Steady-State Interaction between ATVEvaluation of Steady-State Interaction between ATV(400 mg qd) and EFV (600 mg qd) in 31 Healthy Subjects (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)

Steady-State Pharmacokinetic Interaction Study of ATVSteady-State Pharmacokinetic Interaction Study of ATV(400 mg qd) with EFV (600 mg qd) and RTV (200 mg qd)(400 mg qd) with EFV (600 mg qd) and RTV (200 mg qd)

ATV

ATV+EFV+RTV

Cmax ATV x 2.2 AUCss ATV x 3.4

(O’Mara E, Poster 444-W, 9th CROI 2002, Seattle)

MVC DDI and dose adjustementsMVC DDI and dose adjustements

• 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 CYP3A4Inhibiteurs puissants du CYP3A4 ( ketoconazole, itraconazole, clarithromycine, telithromycine)

Semi-dose Maraviroc

150 mg 150 mg

• Etravirine• Efavirenz• Inducteurs CYP3A4CYP3A4 (rifampicine)

Double dose Maraviroc

2 x 300 mg 2 x 300 mg

Celsentri® 2008

Maraviroc (Morning dose)

Maraviroc (Evening dose)

Associated Drugs

PK Interaction between MVC & DRV/rPK Interaction between MVC & DRV/r

Abel S et al, Poster 55, 8th IWCPHIVT, 2007

Summary :• DRV/r MVC AUC012hr and Cmax by 405% (294-559%) and 229% (146-359%), 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.

PK interactions on raltegravir (MK-0518) in healthy volunteers

[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

-4%

77%

-55%-61%

-21%

3%

-16%

24%

-18%

-38% -36%

64%

-24%

41%

-24%

-40%-36%

49%

-80%

-60%

-40%

-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(600 mg qd)

(SD) [5]

TDF (300 mg qd)

(SS) [3]

*Geometric Mean Ratio

Cmin*

Cmax*

AUC0-12H*

Legend :

SD : Single DoseSS : Steady State

Rilpivirine (TMC278) and PK DDI

Back D, BHIVA 2010

DDI PreventionDDI 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 www.hiv-druginteractions.org

• Notified case report

• Use of TDM

Many thanks for your attention !Many thanks for your attention !