Antiretroviral Antiretroviral PharmacologyPharmacology

Dr Njagi Lilian, M.B.Ch.B, Dr Njagi Lilian, M.B.Ch.B,

MSc. TID 2009MSc. TID 2009

UONUON

INTRODUCTIONINTRODUCTION

Retroviruses; Retroviruses; A A retrovirusretrovirus is an is an RNA virus that is that is replicated in a host cell via the enzyme replicated in a host cell via the enzyme reverse transcriptase to produce DNA from its RNA genome. The DNA is then to produce DNA from its RNA genome. The DNA is then incorporated into the host's genome by an into the host's genome by an integrase enzyme. enzyme. The virus thereafter replicates as part of the host cell's DNA. The virus thereafter replicates as part of the host cell's DNA. Retroviruses are Retroviruses are enveloped viruses that belong to the viral that belong to the viral family family RetroviridaeRetroviridae..

General characteristics;General characteristics;

Envelope::

RNA: Two single-strand linear RNA molecules per virion : Two single-strand linear RNA molecules per virion

Proteins: gag, : gag, protease(PR), pol and env. (PR), pol and env.

Reverse transcriptase Reverse transcriptase (RNA to DNA); (RNA to DNA);

Virus classification

Group: Group VI (Group: Group VI (ssRNA-RT))

Family: Family: RetroviridaeRetroviridaeGenera Genera SubfamilySubfamily: : OrthoretrovirinaeOrthoretrovirinae

Alpharetrovirus Betaretrovirus Gammaretrovirus Deltaretrovirus Epsilonretrovirus Lentivirus

SubfamilySubfamily: : SpumaretrovirinaeSpumaretrovirinae Spumavirus

Antiretroviral ClassesAntiretroviral Classes

NRTIsNRTIs (Nucleoside (Nucleoside OROR Nucleotide Reverse Nucleotide Reverse Transcriptase Inhibitors)Transcriptase Inhibitors)

Reverse Transcriptase Inhibitors)Reverse Transcriptase Inhibitors) NNRTIs NNRTIs (Non-(Non-Nucleoside Nucleoside

PIsPIs (Protease Inhibitors)(Protease Inhibitors)

Fusion InhibitorsFusion Inhibitors Chemokine Receptor Chemokine Receptor

AntagonistsAntagonists Integrase InhibitorsIntegrase Inhibitors

Mechanism of Action of ARVs

NNRTI

NRTI

Protease Inhibitor

Illustration by David Klemm

Fusion Inhibitor &ChemokineReceptor Antagonist

Integrase Inhibitor

Antiretroviral Drug Approval:Antiretroviral Drug Approval:1987 - 20071987 - 2007

0

5

10

15

20

1987 1991 1993 1995 1997 1999 2001 2003 2006

AZTddI

ddCd4T

3TCSQV

RTVIDVNVP

NFVDLV

EFVABC

APVLPV/r

TDF

T-20ATVFTCFPV

TPV

DRV

MaravirocRaltegravir

NRTIsNRTIsMechanism of ActionMechanism of Action

Nucleoside analogs (like AZT below)Nucleoside analogs (like AZT below) Analog of thymidine, cytosine, adenine, or guanineAnalog of thymidine, cytosine, adenine, or guanine Triphosphorylated inside lymphocytes to active compoundTriphosphorylated inside lymphocytes to active compound Incorporate into the growing HIV viral DNA strand by reverse Incorporate into the growing HIV viral DNA strand by reverse

transcriptase(competitively inhibits reverse transcriptase).transcriptase(competitively inhibits reverse transcriptase). Nucleotide analogNucleotide analog

Currently only tenofovir (TDF)Currently only tenofovir (TDF) Does Does NOTNOT need to be tri-phosphorylated only di-phosphorylated need to be tri-phosphorylated only di-phosphorylated

to active compoundto active compound

After incorporation of After incorporation of the NRTI, viral DNA the NRTI, viral DNA synthesis will be synthesis will be terminated.terminated.

NRTI Class ToxicitiesNRTI Class ToxicitiesLactic AcidosisLactic Acidosis– Damage to mitochondria in cellsDamage to mitochondria in cells– Elevated lactate, low pH/bicarbonate, N/V, Elevated lactate, low pH/bicarbonate, N/V,

shortness of breath, if untreated can lead to shortness of breath, if untreated can lead to deathdeath

Hepatomegaly with SteatosisHepatomegaly with Steatosis– Build up of fat droplets Build up of fat droplets inside liver cellsinside liver cells– Enlarged liverEnlarged liver

NRTIsNRTIs

Drug Standard Dose* Dosage forms Common Side Effects

Metabolism/

Elimination

Zidovudine (ZDV/AZT) Retrovir

300mg bid* 300mg tab, 100mg cap, iv, oral soln

Fatigue, malaise, HA myalgia, anemia, GI

Renal

Lamivudine (3TC) Epivir

150mg bid* or 300mg qd

150, 300mg tab, oral soln Well tolerated Renal

Emtricitabine(FTC) Emtriva

200mg qd* 200mg cap Well tolerated Renal

Didanosine (ddI) Videx

400mg EC qd ( 60kg)250mg EC qd (<60kg)*

125,200,250, 400mg cap, pwdr for soln

Pancreatitis, peripheral neuropathy, LA/HS

Renal

*dose reduce for renal dysfunction

•Note: Lactic acidosis can occur with any NRTIs

NRTIsNRTIs

Drug Standard Dose* Dosage forms Common Side Effects

Metabolism/Elimination

Stavudine (d4T) Zerit IR

40mg bid ( 60kg) 30mg bid

(<60kg) *

15,20,30,40 mg cap,oral soln

Peripheral neuropathy,

Pancreatitis, LA/HS,Lipoatrophy, facial

wasting

Renal

Abacavir (ABC) Ziagen

300mg bid, 600mg qd

300mg tabs, oral soln

hypersensitivity Hepatic by alcohol

dehydrogenase and glucuronyl

transferase

Tenofovir(TDF) Viread

300mg qd* 300mg tabs Few SEs, renal toxicity

Renal

*dose reduce for renal dysfunction

NRTI CombinationsNRTI Combinations

Drug Standard Dose* Dosage forms

Lamivudine/Zidovudine (COM) Combivir

1 Tablet bid * 150/300mg tabs

Abacavir/Lamivudine/Zidovudine (TZV) Trizivir

1 Tablet bid* 300/150/300mg tabs

Tenofovir/EmtricitabineTruvada

1 Tablet qd* 300/200mg tabs

Abacavir/LamivudineEpzicom

1 Tablet qd* 600/300mg tabs

Tenofovir/Emtricitabine/EfavirenzAtripla

1 Tablet qd* 300/200/600 mg tabs

*dose reduce for renal dysfunction

Non-nucleoside Reverse Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)Transcriptase Inhibitors (NNRTIs)

These agents These agents directly bind to reverse directly bind to reverse transcriptasetranscriptase to inhibit transcriptionto inhibit transcription

NNRTIs do not NNRTIs do not

require require

phosphorylation phosphorylation

to be activeto be active

RT

X

NNRTIsNNRTIs

Drug Standard Dose

Dosage forms Common AEs

Metabolism

Delavirdine (DLV) Rescriptor

400 mg tid 100mg tab, 200mg cap

Rash Potent CYP3A inhibitor; 3A4 substrate

Nevirapine (NVP) Viramune

200 mg qd x 14 d then200 mg bid

200mg tabs, Oral susp

Rash (SJ), hepatotoxicity

CYP3A inducer, auto inducer; 3A4, 2B6 substrate

Efavirenz* (EFV) Sustiva

600 mg qhs 50, 100, 200mg cap, 600mg tab

Vivid dreams, drowsiness or insomnia, rash (SJ), hyperlipidemia

CYP3A, 2B6 inducer; 2B6, 3A4 substrate

*Pregnancy Class D

Second Generation NNRTIs

ETRAVIRINE (ETR)

Diaminopyrimidine (DAPY) compound; flexible chemical structureIn vitro EC50 1.4-4.8 nM (wild-type HIV-1); 3.5 uM (HIV-2)In vitro activity against NNRTI-resistant virusMetabolism: inducer + substrate of CYP 3A4 and othersDrug interactions: do NOT use with other NNRTI, unboosted PI, ATV/r, FPV/r, TPV/r, RIF, antisz meds; use with caution LPV/r; OK with DRV/r, SQV/r, methadone Package Insert 2008 FDA approved 1/08

Progress on 2ng gen NNRTI (11/08/08 xvii international Aids conference)

TMC278 (rilpivirine; Tibotec),Most advanced stage of development(phase2b). Very few patients experienced virologic failure with resistance-associated mutations.Most commonly observed mutations were 184V and 134k but not sure how many mutations are sufficient to confer resistance to TMC287.IDX899 ; Potent in vitro activity for both wild-type and NNRTI-resistant HIV-1, has a high barrier to resistance.RDEA806 phase 2a data presented on this NNRTI with an in vitro high barrier to resistance and activity against isolates resistant to current NNRTIs. It may be important that its metabolic pathway does not appear to have any significant effect on other drugs. Previous work in healthy volunteers had shown good bioavailability and tolerability.

Protease Inhibitors (PIs):Protease Inhibitors (PIs):Mechanism of ActionMechanism of Action

Protease enzyme cleaves Protease enzyme cleaves HIV precursor proteins HIV precursor proteins (gag/pol polyproteins) into (gag/pol polyproteins) into active proteins that are active proteins that are needed to assemble a needed to assemble a new, mature HIV virus. new, mature HIV virus.

PIs bind to protease PIs bind to protease preventing the cleavage preventing the cleavage and inhibiting the and inhibiting the assembly of new HIV assembly of new HIV virusesviruses

PI

HIV-1 Protease

XHIV

Lipids, Insulin Resistance Lipids, Insulin Resistance (Lypodystrophy)(Lypodystrophy)

HypercholesterolemiaHypercholesterolemia– Usually hypertriglyceridemia, can have Usually hypertriglyceridemia, can have

increased LDL and decreased HDLincreased LDL and decreased HDL– Treat with Fibric acid derivatives and certain Treat with Fibric acid derivatives and certain

HMGCoA reductase inhibitors HMGCoA reductase inhibitors

Insulin ResistanceInsulin Resistance– Treat with diet/exercise, metformin, TZDs, Treat with diet/exercise, metformin, TZDs,

insulin, sulfonylureasinsulin, sulfonylureas

Lipodystrophy IllustrationsLipodystrophy Illustrations

“Buffalo hump”

“Protease paunch”

“Facial wasting”

Use of Ritonavir as a P450 Inhibitor Use of Ritonavir as a P450 Inhibitor with PIswith PIs

Protease InhibitorsProtease InhibitorsStandard

DoseDosage Forms Metabolism Common AEs**

Saquinavir(Invirase) (1)

1000/ rtv 100 bid or 1600/ rtv 100 qd

200mg caps, 500mg tabs

3A, Pgp substrate; weak 3A inhibitor

GI intolerance

Nelfinavir (Viracept) (1)

1250 bid, 750mg tid 250mg, 625mg tabs, 50mg/g oral pwdr

2C19 (M83A) substrate; weak 3A inhibitor

Diarrhea

Lopinavir/ritonavir(Kaletra) (1,2)

400/100 bid 200/50 mg tabs, 80/20mg/5mL soln

3A, Pgp substrate; 3A inhibitor; 2C9, 2C19 inducer

Dyspepsia, Nausea, vomiting, diarrhea, flatulence

Indinavir(Crixivan) (1-when taken with rtv)

800/ rtv 100 bid, 800mg tid

100, 200, 333, 400mg caps

3A, Pgp substrate; weak 3A inhibitor

Nephrolithiasis Drink 7-8 glasses of water per day; hyperbilirubinemia

(1) Take with Food(2) Must be refrigerated** All PIs except atazanavir can increase lipids and cause insulin resistance

Protease InhibitorsProtease InhibitorsStandard

DoseDosage Forms Metabolism Common

AEs**

Atazanavir (Reyataz) (1)

400qd or 300/ rtv 100qd

100, 150, 200mg caps

3A substrate; 3A and UGT1A1 inhibitor

Hyperbilirubinemia, PR prolongation

Fosamprenavir (Lexiva) (1)

1400mg bid; 700/100 RTV mg bid; 1400/200 RTV mg qd

700mg tabs (Agenerase-APV liq available)

3A4, Pgp substrate; 3A4 inducer/Inhibitor

Rash, GI intolerance, caution with sulfur allergy

Tipranavir(Aptivus) (1,2)

500/200 RTV mg bid

250mg caps 3A4, Pgp substrate; 3A4, inducer/inhibitor??; Pgp inducer

Hepatotoxicity, Increased bleedingcaution with sulfur allergy

Darunavir(Prezista) (1)

600/100 RTV mg bid

300mg tabs 3A4 substrate;3A4 inhibitors

Diarrhea, nausea, HA, nasopharyngitis

Ritonavir(Norvir) (1,2)

Used as a PK booster 100-200mg

100mg caps; 80mg/mL

2D6, 3A4, Pgp substrate; 3A4, Pgp inhibitor

Nausea, vomiting, diarrhea, GI upset

(1) Take with Food (2) Must be refrigerated** All PIs except atazanavir can increase lipids and cause insulin resistance

Dose adjustments to considerDose adjustments to considerRenally-eliminatedRenally-eliminated

NRTIs (except Abacavir)NRTIs (except Abacavir)

Adjust for CrCl <50 ml/min Adjust for CrCl <50 ml/min or or dialysisdialysis

DidanosineDidanosine

EmtricitabineEmtricitabine

LamivudineLamivudine

StavudineStavudine

TenofovirTenofovir

ZidovudineZidovudine

Hepatic MetabolismHepatic Metabolism NNRTIsNNRTIs PIsPIs Adjust for certain inducers, Adjust for certain inducers,

substrates, or inhibitors of substrates, or inhibitors of P450 systemP450 system

Adjust for insufficiencyAdjust for insufficiencyIndinavirIndinavir

FosamprenavirFosamprenavirAtazanavirAtazanavir

AvoidAvoidAmprenavir oral solnAmprenavir oral soln

Foasmprenavir (+/- ritonavir)Foasmprenavir (+/- ritonavir)TipranavirTipranavir

New ARV Targets Against HIVNew ARV Targets Against HIV

Fusion InhibitorFusion InhibitorFuzeon (Enfuvirtide, T-20)Fuzeon (Enfuvirtide, T-20)

See Kilby and Eron, NEJM 2003;348:2228-38

Fuzeon : Enfuvirtide (T-20)Fuzeon : Enfuvirtide (T-20)

FDA-approved fusion inhibitor; 36 AA peptideFDA-approved fusion inhibitor; 36 AA peptide– Requires 106 steps to manufactureRequires 106 steps to manufacture

Dose: 90 mg sq bidDose: 90 mg sq bidside effects: side effects: – injection site rxn, hypersensitivity (rare)injection site rxn, hypersensitivity (rare)

resistance: changes in gp41 (cell surface resistance: changes in gp41 (cell surface protein) protein)

HIV TropismHIV Tropism

Chemokine Receptor AntagonistsChemokine Receptor AntagonistsMarviroc (SelzentryMarviroc (Selzentry®®))

CCR5 or CXCR4 receptors on cell surface CCR5 or CXCR4 receptors on cell surface

Virus will bind to one of the 2 receptors Virus will bind to one of the 2 receptors – Some patients’ virus will bind to either receptorSome patients’ virus will bind to either receptor

Marviroc blocks viral entry at CCR5Marviroc blocks viral entry at CCR5

Dosed 300mg BIDDosed 300mg BID– 150mg BID with P450 inhibitors150mg BID with P450 inhibitors– 600mg BID with P450 inducers600mg BID with P450 inducers

Integrase InhibitorsIntegrase Inhibitors

Raltegravir (Isentress™)Raltegravir (Isentress™)

Dosed 400mg BID (1 tab BID)Dosed 400mg BID (1 tab BID)

No induction or inhibition on CYP450 No induction or inhibition on CYP450 enzymes or Pgpenzymes or Pgp

Metabolized by UGT1A1 (glucuronidation)Metabolized by UGT1A1 (glucuronidation)– Only affected by drugs that inhibit or induce Only affected by drugs that inhibit or induce

UGTs (ie, rifampin)UGTs (ie, rifampin)

Drug InteractionsDrug Interactions

Antiretroviral Metabolism, Antiretroviral Metabolism, Induction, and InhibitionInduction, and Inhibition

DrugDrug SubstrateSubstrate InhibitsInhibits InducesInduces

EfavirenzEfavirenz 2B6, 3A42B6, 3A4 3A43A4 3A4, 2B63A4, 2B6

NevirapineNevirapine 3A4, 2B63A4, 2B6 3A43A4

RitonavirRitonavir 2D6, 3A4, Pgp2D6, 3A4, Pgp 3A4, 2D6, Pgp3A4, 2D6, Pgp 2D6 (at high 2D6 (at high doses only)doses only)

SaquinavirSaquinavir 3A4, Pgp3A4, Pgp 3A4 3A4

NelfinavirNelfinavir 2C19 (M82C19 (M83A4)3A4) 3A43A4

AmprenavirAmprenavir 3A4, Pgp3A4, Pgp 3A4 (in vitro)3A4 (in vitro) 3A4 (in vivo)3A4 (in vivo)

FosamprenavirFosamprenavir 3A4, Pgp3A4, Pgp 3A4 (in vitro)3A4 (in vitro) 3A4 (in vivo)3A4 (in vivo)

Lopinavir/ritonavirLopinavir/ritonavir 3A4, Pgp3A4, Pgp 3A43A4 2C9, 2C19, 1A22C9, 2C19, 1A2

AtazanavirAtazanavir 3A4, Pgp3A4, Pgp 3A4, UGT, 1A23A4, UGT, 1A2

TipranavirTipranavir 3A4, Pgp3A4, Pgp 3A43A4 Other enzymesOther enzymes

DarunavirDarunavir 3A4, Pgp3A4, Pgp 3A43A4

MaravirocMaraviroc 3A4, Pgp3A4, Pgp

Substrate Inhibitor Inducer

3A4 Macrolides,cyclosporine, CCB, statins, azoles, PDE5 inhibitors, aprepitant, midazolam, triazolam

Cimetidine, Macrolides, FQs, SSRIs, CCB, azoles, aprepitant

rifamycins, phenytoin, carbamazepine, St. John’s wort, aprepitant, garlic

2D6 Opiates, nortriptyline, amitriptyline, tramadol, trazodone, paroxetine, metoprolol, propranolol, carvedilol

Haldol, SSRIs, cimetidine, amiodarone

rifamycins, phenytoin, CBZ, St. John’s wort

1A2 Amitriptyline, clozapine, caffeine, clozapine, imipramine, R-warfarin, theophylline, proprnaolol

FQs, azoles, macrolides, rifamycins, phenytoin, CBZ, smoking, St. John’s wort

2C19 Omeprazole, phenytoin SSRIs, azoles, fluvastatin, omeprazole, topiramate

rifamycins, CBZ, phenytoin

2C9 S-warfarin, sulfonylureas, phenytoin, carvedilol

Amiodarone, SSRIs, azoles, amiodarone

Phenytoin, CBZ, rifammycins, aprepitant

Cytochrome P450: Non-Antiretrovirals

Protease Inhibitors and Acid Protease Inhibitors and Acid SuppressionSuppression

Do Not combine Do Not combine Atazanavir Atazanavir and and Proton Pump Proton Pump InhibitorsInhibitors– May Combine May Combine ATVATV and and Famotidine Famotidine but dose but dose

adjustments are REQUIREDadjustments are REQUIRED

May use May use Indinavir Indinavir with with PPIs PPIs but ONLY if but ONLY if coadministered with coadministered with RTVRTV

May use Fosamprenavir with EsomeprazoleMay use Fosamprenavir with Esomeprazole– Separate FPV from H2 blockers if used concomitantlySeparate FPV from H2 blockers if used concomitantly

Dose Adjustments Between ARVsDose Adjustments Between ARVsDrug ADrug A Drug BDrug B RecommendationRecommendation

TenofovirTenofovir DidanosineDidanosine Dose ddI as 250mg Dose ddI as 250mg QD with TDF 300mg QD with TDF 300mg QDQD

Tenofovir Tenofovir AtazanavirAtazanavir Use RTV 100mg QD Use RTV 100mg QD with ATV + TDFwith ATV + TDF

EfavirenzEfavirenz

(Nevirapine)(Nevirapine)

AtazanavirAtazanavir Use RTV 100mg QD Use RTV 100mg QD with ATV + EFVwith ATV + EFV

EfavirenzEfavirenz

(Nevirapine)(Nevirapine)

FosamprenavirFosamprenavir Use RTV with FPVUse RTV with FPV

EfavirenzEfavirenz

(Nevirapine)(Nevirapine)

Lopinavir/ritonavirLopinavir/ritonavir Increase LPV/RTV to Increase LPV/RTV to 3 tabs BID3 tabs BID

Important Drug InteractionsImportant Drug InteractionsDo NOT use Do NOT use Simvastatin, Lovastatin, Antiarrthymics, Midazolam, Simvastatin, Lovastatin, Antiarrthymics, Midazolam, Triazolam, Ergot derivatives, Rifamin, St. Johns Wort, or Garlic Triazolam, Ergot derivatives, Rifamin, St. Johns Wort, or Garlic with with most most PIs or DLVPIs or DLVDo NOT combine Do NOT combine RifampinRifampin with with PIsPIs– LPV/RTV may be dose increased and combined with RifampinLPV/RTV may be dose increased and combined with Rifampin– Conflicting data with EFV and NVPConflicting data with EFV and NVP

Use other Use other P450 inducersP450 inducers with CAUTION when combining with with CAUTION when combining with PIs PIs and NNRTIsand NNRTIsDo NOT use Do NOT use Fluticasone Fluticasone or or AlfuzosinAlfuzosin with with RitonavirRitonavirCaution with Caution with Azoles, Clarithromycin, Oral Contraceptives, Phenytoin, Azoles, Clarithromycin, Oral Contraceptives, Phenytoin, Carbamazepine, Phenobarbital, Methadone, PDE5 inhibitors, Carbamazepine, Phenobarbital, Methadone, PDE5 inhibitors, Atorvastatin, Beta blockers, Atorvastatin, Beta blockers, when combined with PIswhen combined with PIsAvoid Herbal Products with Known or Suspected InteractionsAvoid Herbal Products with Known or Suspected InteractionsWhen combining Protease Inhibitors, Often Dose Adjustments are When combining Protease Inhibitors, Often Dose Adjustments are NecessaryNecessary

Therapeutic Drug MonitoringTherapeutic Drug Monitoring

Not widely used in the USNot widely used in the US

Recommended in certain situations for PIs Recommended in certain situations for PIs and NNRTIsand NNRTIs

What makes a drug a good candidate for What makes a drug a good candidate for TDM?TDM?

When should TDM be performed for When should TDM be performed for antiretrovirals?antiretrovirals?