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Antiretroviral
Pharmacology
Dr Njagi Lilian, M.B.Ch.B,
MSc. TID 2009
UON
INTRODUCTION
Retroviruses; A retrovirus is an RNA virus that is
replicated in a host cell via the enzyme reverse
transcriptase to produce DNA from its RNA genome. The
DNA is then incorporated into the host's genome by an
integrase enzyme. The virus thereafter replicates as part
of the host cell's DNA. Retroviruses are enveloped
viruses that belong to the viral family Retroviridae.
General characteristics;
Envelope:
RNA: Two single-strand linear RNA molecules per virion
Proteins: gag, protease(PR), pol and env.
Reverse transcriptase (RNA to DNA);
Virus classification
Group: Group VI (ssRNA-RT)
Family: Retroviridae
Genera Subfamily: Orthoretrovirinae
Alpharetrovirus Betaretrovirus
Gammaretrovirus Deltaretrovirus
Epsilonretrovirus Lentivirus
Subfamily: Spumaretrovirinae
Spumavirus
Antiretroviral Classes
 NRTIs (Nucleoside OR Nucleotide Reverse
Transcriptase Inhibitors)
 Reverse Transcriptase Inhibitors)
Nucleoside
 PIs (Protease Inhibitors)
 Fusion Inhibitors
 Chemokine Receptor
Antagonists
 Integrase Inhibitors
NNRTIs (Non-
Mechanism of Action of ARVs
Integrase
Inhibitor
Fusion
Inhibitor &
Chemokine
Receptor
Antagonist
NNRTI
NRTI
Illustration by David Klemm
Protease
Inhibitor
Antiretroviral Drug Approval:
Maraviroc
1987 - 2007 FPV DRVRaltegravir
FTC
ATV TPV
T-20
20
15
RTV
IDV
NVP
3TC
SQV
10
EFV
TDF
LPV/r
ABC
NFV APV
DLV
d4T
5
AZT
ddI
ddC
0
1987
1991
1993
1995
1997
1999
2001
2003
2006
NRTIs
Mechanism of Action
 Nucleoside analogs (like AZT below)
 Analog of thymidine, cytosine, adenine, or guanine
 Triphosphorylated inside lymphocytes to active compound
 Incorporate into the growing HIV viral DNA strand by reverse
transcriptase(competitively inhibits reverse transcriptase).
 Nucleotide analog
 Currently only tenofovir (TDF)
 Does NOT need to be tri-phosphorylated only di-phosphorylated
to active compound
 After incorporation of
the NRTI, viral DNA
synthesis will be
terminated.
NRTI Class Toxicities
Lactic Acidosis
– Damage to mitochondria in cells
– Elevated lactate, low pH/bicarbonate, N/V,
shortness of breath, if untreated can lead to
death
Hepatomegaly with Steatosis
– Build up of fat droplets
inside liver cells
– Enlarged liver
NRTIs
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
•Note: Lactic acidosis can occur with any NRTIs
*dose reduce for renal dysfunction
NRTIs
Drug
Standard Dose*
Dosage forms
Common
Side Effects
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
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
Metabolism/
Elimination
Renal
NRTI 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/Emtricitabine
Truvada
1 Tablet qd*
300/200mg
tabs
Abacavir/Lamivudine
Epzicom
1 Tablet qd*
600/300mg
tabs
Tenofovir/Emtricitabine/Efavirenz
Atripla
1 Tablet qd*
300/200/600
mg tabs
*dose reduce for renal dysfunction
Non-nucleoside Reverse
Transcriptase Inhibitors (NNRTIs)
 These agents directly bind to reverse
transcriptase to inhibit transcription
 NNRTIs do not
require
phosphorylation
to be active
RT
NNRTIs
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 then
200 mg bid
200mg tabs,
Oral susp
Rash (SJ),
hepatotoxicity
CYP3A inducer,
auto inducer; 3A4,
2B6 substrate
50, 100, 200mg
cap, 600mg tab
Vivid dreams,
drowsiness or
insomnia, rash
(SJ),
hyperlipidemia
CYP3A, 2B6
inducer; 2B6, 3A4
substrate
Efavirenz*
600 mg qhs
(EFV) Sustiva
*Pregnancy Class D
Second Generation NNRTIs
ETRAVIRINE (ETR)
Diaminopyrimidine (DAPY) compound;
flexible chemical structure
In vitro EC50 1.4-4.8 nM (wild-type HIV-1); 3.5 uM (HIV2)
In vitro activity against NNRTI-resistant virus
Metabolism: inducer + substrate of CYP 3A4 and others
Drug 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):
Mechanism of Action
 Protease enzyme cleaves
HIV-1 Protease
HIV precursor proteins
(gag/pol polyproteins) into
active proteins that are
needed to assemble a
new, mature HIV virus.
 PIs bind to protease
preventing the cleavage
and inhibiting the
assembly of new HIV
viruses
PI
X
HIV
Lipids, Insulin Resistance
(Lypodystrophy)
Hypercholesterolemia
– Usually hypertriglyceridemia, can have
increased LDL and decreased HDL
– Treat with Fibric acid derivatives and certain
HMGCoA reductase inhibitors
Insulin Resistance
– Treat with diet/exercise, metformin, TZDs,
insulin, sulfonylureas
Lipodystrophy Illustrations
“Buffalo hump”
“Protease paunch”
“Facial wasting”
Use of Ritonavir as a P450 Inhibitor
with PIs
Protease Inhibitors
Standard
Dose
Dosage 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
(M83A)
substrate;
weak 3A
inhibitor
Diarrhea
Lopinavir/
400/100 bid
ritonavir
(Kaletra) (1,2)
200/50 mg tabs,
80/20mg/5mL soln
3A, Pgp
substrate; 3A
inhibitor; 2C9,
2C19 inducer
Dyspepsia, Nausea,
vomiting, diarrhea,
flatulence
Indinavir
800/ rtv 100 bid,
(Crixivan)
800mg tid
(1-when
taken with rtv)
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 Inhibitors
Standard
Dose
Dosage Forms
Metabolism
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 bleeding
caution 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
Common
AEs**
Dose adjustments to consider
Renally-eliminated
NRTIs (except Abacavir)
Adjust for CrCl <50 ml/min or
dialysis
Didanosine
Emtricitabine
Lamivudine
Stavudine
Tenofovir
Zidovudine
Hepatic Metabolism
 NNRTIs
 PIs
Adjust for certain inducers,
substrates, or inhibitors of
P450 system
Adjust for insufficiency
Indinavir
Fosamprenavir
Atazanavir
Avoid
Amprenavir oral soln
Foasmprenavir (+/- ritonavir)
Tipranavir
New ARV Targets Against HIV
Fusion Inhibitor
Fuzeon (Enfuvirtide, T-20)
See Kilby and Eron, NEJM 2003;348:2228-38
Fuzeon : Enfuvirtide (T-20)
FDA-approved fusion inhibitor; 36 AA peptide
– Requires 106 steps to manufacture
Dose: 90 mg sq bid
side effects:
– injection site rxn, hypersensitivity (rare)
resistance: changes in gp41 (cell surface
protein)
HIV Tropism
Chemokine Receptor Antagonists
Marviroc (Selzentry®)
CCR5 or CXCR4 receptors on cell surface
Virus will bind to one of the 2 receptors
– Some patients’ virus will bind to either receptor
Marviroc blocks viral entry at CCR5
Dosed 300mg BID
– 150mg BID with P450 inhibitors
– 600mg BID with P450 inducers
Integrase Inhibitors
Raltegravir (Isentress™)
Dosed 400mg BID (1 tab BID)
No induction or inhibition on CYP450
enzymes or Pgp
Metabolized by UGT1A1 (glucuronidation)
– Only affected by drugs that inhibit or induce
UGTs (ie, rifampin)
Drug Interactions
Antiretroviral Metabolism,
Induction, and Inhibition
Drug
Substrate
Inhibits
Efavirenz
2B6, 3A4
Nevirapine
3A4, 2B6
Ritonavir
2D6, 3A4, Pgp
3A4, 2D6, Pgp
Saquinavir
3A4, Pgp
3A4
Nelfinavir
2C19 (M83A4)
3A4
Amprenavir
3A4, Pgp
3A4 (in vitro)
3A4 (in vivo)
Fosamprenavir
3A4, Pgp
3A4 (in vitro)
3A4 (in vivo)
3A4
2C9, 2C19, 1A2
Lopinavir/ritonavir 3A4, Pgp
3A4
Induces
3A4, 2B6
3A4
Atazanavir
3A4, Pgp
3A4, UGT, 1A2
Tipranavir
3A4, Pgp
3A4
Darunavir
3A4, Pgp
3A4
Maraviroc
3A4, Pgp
2D6 (at high
doses only)
Other enzymes
Cytochrome P450: Non-Antiretrovirals
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
SSRIs, azoles, fluvastatin,
omeprazole, topiramate
rifamycins, CBZ,
phenytoin
2C19 Omeprazole, phenytoin
2C9
S-warfarin,
Amiodarone, SSRIs,
sulfonylureas, phenytoin, azoles, amiodarone
carvedilol
Phenytoin, CBZ,
rifammycins,
aprepitant
Protease Inhibitors and Acid
Suppression
Do Not combine Atazanavir and Proton Pump
Inhibitors
– May Combine ATV and Famotidine but dose
adjustments are REQUIRED
May use Indinavir with PPIs but ONLY if
coadministered with RTV
May use Fosamprenavir with Esomeprazole
– Separate FPV from H2 blockers if used concomitantly
Dose Adjustments Between ARVs
Drug A
Drug B
Recommendation
Tenofovir
Didanosine
Dose ddI as 250mg
QD with TDF 300mg
QD
Tenofovir
Atazanavir
Use RTV 100mg QD
with ATV + TDF
Efavirenz
(Nevirapine)
Atazanavir
Use RTV 100mg QD
with ATV + EFV
Efavirenz
(Nevirapine)
Fosamprenavir
Use RTV with FPV
Efavirenz
(Nevirapine)
Lopinavir/ritonavir
Increase LPV/RTV to
3 tabs BID
Important Drug Interactions
Do NOT use Simvastatin, Lovastatin, Antiarrthymics, Midazolam,
Triazolam, Ergot derivatives, Rifamin, St. Johns Wort, or Garlic with
most PIs or DLV
Do NOT combine Rifampin with PIs
– LPV/RTV may be dose increased and combined with Rifampin
– Conflicting data with EFV and NVP
Use other P450 inducers with CAUTION when combining with PIs
and NNRTIs
Do NOT use Fluticasone or Alfuzosin with Ritonavir
Caution with Azoles, Clarithromycin, Oral Contraceptives, Phenytoin,
Carbamazepine, Phenobarbital, Methadone, PDE5 inhibitors,
Atorvastatin, Beta blockers, when combined with PIs
Avoid Herbal Products with Known or Suspected Interactions
When combining Protease Inhibitors, Often Dose Adjustments are
Necessary
Therapeutic Drug Monitoring
Not widely used in the US
Recommended in certain situations for PIs
and NNRTIs
What makes a drug a good candidate for
TDM?
When should TDM be performed for
antiretrovirals?