Pharmacology - Antiretroviral Drugs

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Nucleoside/-tide Reverse Transcriptase Inhibitors (NRTIs)

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- ZDV/AZT, Stavudine, Didanosine, Tenofovir, Lamivudine, Abacavir
- MOA: termination of DNA elongation
- PK: renally excreted
- AE: mainly b/c of inhibition of mitochondrial DNA poly.; if more than one given --> overlapping toxicities; Liver toxicity** (lactic acidosis, hepatomegaly w/ steatosis)

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Nucleoside/-tide Reverse Transcriptase Inhibitors (NRTIs) - Drug interactions / Resistance

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- Drug interactions: not many (except w/ ZDV + tenofovir)
- Resistance: most common mutation at viral codon 184: lamivudine (restores sensitivity to ZDV and Tenofovir)
- cross-resistance b/w agents of same analog class

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Zidovudine / 3'azido-3'deoxythymidine (ZDV, AZT)

-AE/CI

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- AE: bone marrow suppression (neutropenia, anemia), headaches; GI intolerance
- CI: toxicity potentiated by coadin of probenecid, acetaminophen, lorazepam, indomethacin, and cimetidine
- stavudine and ribavirin activated by same pathways
- Clinical app: prophylaxis in exposed and prevention of prenatal infection
- PK: absorbed well orally, BBB, glucuronylated by liver --> urine

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Stavudine (d4T)

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- strong inhibitor of beta and gamma DNA polymerases (decreases mitochondrial DNA synthesis --> toxicity)
- PK: completely absorbed orally, penetrates BBB
- AE: peripheral neuropathy

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Didanosine (ddl)

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- HIV adults/children in comb w/ other agents
- PK: absorption best if taken in fasting state (acid labile) or combined with antacid
- penetrates into CSF (less than AZT)
- AE: pancreatitis (can be fatal, monitor serum amylase); peripheral neuropathy
- CI: Stavudine (similar toxicities)

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Tenofovir (TDF)

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- PK: should be taken w/ food
- long half-life
- most of drug recovered unchanged in urine
- AE: GI (nausea, diarrhea, vomiting, flatulence)
- CI: ONLY NRTI W/ SIG DRUG INTERACTIONS (increases [ddl] --> dosage reductions required)
- DECREASES [atazanavir] --> boosted w/ ritonavir

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Lamivudine (3TC)

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- terminates synthesis of proviral DNA chain and inhibits HIV and HBV RT (DOES NOT AFFECT MITOCHONDRIAL DNA synt or BONE MARROW PRECURSOR CELLS)
- approved for tx of HIV in comb w/ AZT
- single amino acid substitution --> resistance
- few AE
- Emtricitabine (FTC) is a structural relative of 3TC

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Abacavir (ABC)

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- guanosine analog
- may be cross-resistant w/ strains resistant to AZT + 3TC
- AE: GI, headache, dizziness
- 5%: HS RXN
- SENSITIZED INDIV SHOULD NEVER BE RECHALLENGED (genetically screen)

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Nonnucleoside Reverse Trancriptase Inhibitors (NNRTIs)

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MOA - highly-selective, non-competitive inhibitors of HIV-1 RT
- DO NOT REQUIRE ACTIVATION BY CELLULAR ENZYMES
- Advantages = lack of effect on host blood-forming elements
= lack of cross resistance with NRTIs
- Disadvantages = cross-resistance w/ NNRTIs, drug interactions, high incidence of HS rxns
- Nevirapine, Efavirenz, Delavirdine (Never Ever Deliver nucleosides)

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Nevirapine (NVP)

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- used in comb w/ other anti-retrovirals for HIV-1 tx
- PK: well abs orally, wide tissue dist, BBB, excreted in urine as metabolites (CYP3A4 + CYP2B6)

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Nervirapine (NVP) - AE

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- potential severe hepatotoxicity (dont use in women with CD4+ counts > 250 cells/mm and men >400)
- RASH (16%)
- dermatologic effects (stevens-johnson syn + toxic epidermal necrolysis)

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Nevirapine (NVP) - CI / Resistance

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CI
- INDUCER OF CYP3A4 --> inc metabolism of PI's, OCP, ketoconazole, methadone, metronidazole, quinidine, theophylline, and warfarin

Resistance
- target site is HIV-1 specific and not essential to enzyme --> resistance develops rapidly

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Efavirenz (EFV)

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- preferred NNRTI on DHHS guidelines (results in inc CD4 counts and decrease in viral load)
- PK: well dist after oral admin (better w/ fatty meal); 99% bound to albumin; extensively metabolized to inactive products
- AE: mostly CNS - dizziness, headache, vivid dreams; resolve in few weeks
- RASH
- CI = PREGNANCY
- potent inducer of CYP450 enzymes

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Protease Inhibitors (PIs) - MOA

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- reversible inhibitors of HIV aspartyl protease (enzyme responsible for cleavage of viral polyprotein into RT, protease, and integrase)
- inhibition prevents maturation and results in production of non-infectious virions

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Protease Inhibitors (PIs) - PK

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- POOR oral bioavailability
- high fat meals can increase (nelfanvir and saquinavir) and decrease (indinavir) bioavailability
- SUBSTRATES FOR CYP3A4

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- Protease Inhibitors (PIs) - AE

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- parathesias, nausea, vomiting, diarrhea
- dist in lipid metabolism
- chronic admin --> fat redistribution

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- Protease Inhibitors (PIs) - Drug Interactions / Resistance

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Drug Interactions - Potent inhibitors of CYP isozymes **; eg: rhabdomyolysis (simvastatin or lovastatin), excessive sedation (midazolam or triazolam), resp depression (fentanyl)
- warfarin, sildenafil, and phenytoin --> dosage adjustments
- Rifampicin and st. johns wort --> CI

Resistance: acc of stepwise mutations of protease gene (can lead to high levels of resistance)

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- Ritonavir (RTV)

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- PK enhancer
- Booster of other PI's
- potent inhibitor of CYP3A4

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- Saquinavir (SQV)

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- given w/ low dose RTV
- high fat meals enhance abs

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- Indinavir (IDV)

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- given w/ RTV to inc abs
- least protein bound
- abs decreased with meals
- dosage reduced with hepatic insufficiency
- AE: nephrolithiasis + hyperbilirubinemia (adeq hydration imp)

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Nelfinavir (NFV)

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- CANNOT be boosted by RTV
- met by several CYPs
- can inhibit met of other drugs

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Fosamprenavir (fAPV)

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- given w/ RTV
- prodrug = amprenavir

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Lopinavir (LPVr)

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- one of the preferred PIs
- given w/ RTV
- POOR intrinsic bioavailability
- enzyme inducers (ex St. Johns Wort) should be avoided

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Atazanavir (ATV)

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- ATV + RTV are only once-daily preferred PIs
- structurally unrelated to other PIs
- well abs orally
- high protein bound
- PPI = CI
- competitive inhibitor of glucuronyl transferase (benign hyperbilirubinemia and jaundice)
- prolongs PR interval and slows heart

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Tipranavir (TPV)

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- inhibits HIV protease resistant to other PIs
- SEVERE and FATAL HEPATITIS
- FATAL and NONFATAL INTRACRANIAL HEMORRHAGES

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Darunavir (DRV)

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- Inhibits HIV protease ressitant to other PIs

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Inhibition of Viral Attachment

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Enfuvirtide (T-20)
- use in tx-experienced adults w/ evidence of HIV replication

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Enfuvirtide (T-20) - MOA

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- structurally similar to gp41 (HIV protein mediates membrane fusion)
- Prevents ability of virion to fuse membranes

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Enfuvirtide (T-20) - PK and AE

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PK: admin parenterally twice daily subcutaneously

AE: injection-related, HS rxns, Eosinophilia

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Inhibition of Viral Entry

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Maraviroc

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Maraviroc - MOA, PK, AE

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MOA: blocks CCR5 coreceptor that works w/ gp41 to facilitate HIV entry through cell membrane (only CCR5-expressing virus can be treated w/ maraviroc)

PK: orally, met by CYP3A4 (dose reduced when given w/ PIs)

AE: well tolerated, risk of hepatotoxicity

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Integrase Strand Transfer Inhibitor (INSTI)

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Raltegravir (RAL)
- in comb w/ other retrovirals is approved for tx-experienced and tx-naive pts w/ evidence of viral replication

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Raltegravir (RAL)

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- MOA: inhibits final step in integration of viral DNA into host cell DNA
- PK: metabolism - UGT1A1-mediated glucuronidation --> no interactions w/ CYP450 inducers, inhibitors, etc
- AE: well tolerated, nausea, headache, diarrhea

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Current Recc for tx of Naive pts- Goals

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- maximally and durably suppress viral load replication
- restore and preserve immunologic fxn
- reduce HIV-related morbidity and mortality

INCREASE QUALITY OF LIFE

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Current Recc for tx of Naive pts - Regimens

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1 of following
- NNRTI + 2 NRTI
- PI (preferably boosted w/ ritonavir) + 2NRTI
- INSTI + 2 NRTI

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Current recc for use of antiretroviral drugs in pregnancy

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Ritonavir-boosted lopinavir (2 daily) + Zidovudine/lamivudine