Antiretroviral combinations
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Antiretroviral Combinations. James A Zachary MD LSU Health Sciences Center HIV Outpatient Clinic December 13, 2004 http://HIVManagement.org. Objectives. Review rationale for combinations Review basis of protease inhibitor interactions Review specific combinations (mainly PI)

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Antiretroviral combinations

Antiretroviral Combinations

James A Zachary MDLSU Health Sciences CenterHIV Outpatient ClinicDecember 13, 2004

http://HIVManagement.org


Objectives

Objectives

  • Review rationale for combinations

  • Review basis of protease inhibitor interactions

  • Review specific combinations (mainly PI)

  • Review what is not known

  • Final recommendations


Benefits of boosting

Benefits of Boosting

  • Improved adherence

    • Decrease pill burden

    • Decrease dosing frequency

    • Decrease meal dependence

  • Improve efficacy

    • Improved adherence

    • Improved levels of protease inhibitors

      • Levels out interindividual variations

      • Compensates for the effects of inducers


Problems of boosting

Problems of Boosting

  • Multiple drug-drug interactions

  • Increased serum lipid & fat redistribution side effects

  • Increased side effects

    • Abdominal pain

    • Diarrhea

    • Nausea

    • Hepatitis

    • Perioral paresthesia

  • Increased number of prescribed medications

  • Need to refrigerate medication (ritonavir)


Pharmacology

Pharmacology

  • Protease inhibitors and NNRTIs are primarily metabolized via cytochrome P-450 family of enzymes

  • P-450 enzymes

    • Primarily in liver but also in apical enterocytes

    • Multiple metabolic pathways by which these drugs are metabolized, with the most significant being CYP3A4


P 450

P-450

  • Inhibition

    • Inhibition can lead to increases in drug levels of agents that are normally metabolized through CYP450

    • Can occur after the first dose of an enzyme inhibitor

    • Ritonavir > saquinavir = lopinavir = indinavir > amprenavir

    • A flavinoid component which is peculiar to grapefruit (narangin or narangenin) blocks CYP4503A4 metabolism at the enzyme level


P 4501

P-450

  • Induction

    • Leads to a decrease in serum concentrations in drug levels with the time frame for maximal induction being about 2 weeks

    • Ritonavir, nelfinavir, and lopinavir


P 4502

P-450

  • Mixed induction-inhibition

    • Complex drug interactions

    • Difficult to predict

    • Changes over the first 2 week period

    • Drugs can induce themselves and thus counter the inhibitory effects of induction itself

    • Drug interaction studies necessary

    • Ritonavir, lopinavir


Other mechanisms

Other Mechanisms

  • P-glycoprotein

    • Transmembrane ATP-dependent, efflux membrane transport protein that is widely distributed in the GI tract, liver, and kidney

    • Absorption of the drugs, such as the proteaseinhibitors, may be decreased, leading to variations in bioavailability

    • Inhibition of p-glycoprotein may increase penetration/absorption

    • Inhibited by ritonavir and probenecid

  • Multidrug resistance proteins 1 and 2

  • Inhibition of these proteins increases penetration of protease inhibitors into CNS, seminal fluid, etc.


Boosted saquinavir

Boosted Saquinavir

  • First boosted regimen employed: saquinavir hard gel caps (Invirase) 400 mg + ritonavir 400 mg bid with food

    • Higher levels of saquinavir than could be achieved

    • Increased toxicity: GI upset, hepatitis, hyperlipidemia, fat redistribution

  • Soft gel caps (Fortovase) better absorbed but more GI upset


Boosted saquinavir1

Boosted Saquinavir

  • Saquinavir hard gel caps (Invirase)

    • Twice a day: SQV 5 x 200 mg + RTV 100 mg, both bid taken together, optimally with food

    • Once a day: SQV 8x200 mg + RTV 100-200 mg, both once a day, optimally with food

    • Less GI upset, hepatitis, hyperlipidemia

    • Decreases meal dependence, dosing frequency and increases levels of SQV

    • Eliminates need to refrigerate soft gel caps

    • Can overcome decreased levels due to nevirapine or efavirenz interactions


Boosted indinavir

Boosted Indinavir

  • Indinavir dosing normally q8hours on an empty stomach

  • Regimens

    • Indinavir 2 x 400 mg + ritonavir 100-200 bid with or without food

    • Indinavir 400 mg + ritonavir 200 mg bid with or without food

  • Boosting decreases dosing frequency and meal dependence

  • Overcomes nevirapine or efavirenz problems


Boosted atazanavir

Boosted Atazanavir

  • Atazanavir approved 2003

  • Atazanavir levels decreased by tenofovir, efavirenz

  • Unboosted regimen: atazanavir 2 x 200 mg caps q24h

  • Boosted Regimen: atazanavir 2 x 150-200 mg once a day with food + 100 mg ritonavir once a day

  • Boosting increases incidence of hyperlipidemia and possibly of jaundice

  • Studies suggest that boosted atazanavir may be a useful salvage strategy similar to lopinavir/ritonavir


Boosted fosamprenavir

Boosted Fosamprenavir

  • Unboosted fosamprenavir 2 x 700 mg bid

  • Boosted regimens:

    • Fosamprenavir 1 x 700 mg + ritonavir 100 mg, both bid

    • Fosamprenavir 2 x 700 mg + ritonavir 2 x 100 mg, both once a day – recommended for naïve patients only

  • Probably best used as first line boosted PI

  • May be able to overcome some PI resistance

  • Well tolerated

  • Increased hyperlipidemia with boosted regimen

  • May overcome nevirapine and efavirenz interactions


Pi nnrti interactions

PI – NNRTI Interactions

  • Nevirapine: a P-450 inducer

    • Decreases lopinavir/ritonavir levels (27% AUC, 50% dec Cmin)

    • Decreases indinavir levels (28% dec AUC)

    • Decreases fosamprenavir levels (33% dec AUC)

    • Decreases nelfinavir levels (32% dec Cmin)

    • Decreases saquinavir levels (27% dec AUC)

    • Unknown: atazanavir

    • Compensate for P-450 induction

      • Increase dosage or boost: indinavir, lopinavir/ritonavir

      • Increase nelfinavir

      • Boost fosamprenavir, saquinavir


Nevirapine effect on pis

Nevirapine Effect on PIs


Pi nnrti interactions1

PI – NNRTI Interactions

  • Efavirenz: a P-450 inducer/inhibitor

    • Decreases lopinavir/ritonavir levels (19% dec AUC, 39% dec Cmin)

    • Decreases indinavir levels (31% AUC, 16% dec Cmax)

    • Decreases fosamprenavir levels (36% dec AUC)

    • No significant nelfinavir interaction (20% inc AUC, 37% dec in AUC metabolite)

    • Decreases saquinavir levels (62% dec AUC, 50 dec Cmax)

    • Decreases atazanavir levels (21% dec AUC)

    • Compensate for P-450 induction/inhibition

      • Increase dosage or boost: indinavir, lopinavir/ritonavir

      • No change in nelfinavir

      • Boost fosamprenavir, saquinavir?, atazanavir


Efavirenz effect on pis

Efavirenz Effect on PIs


Tenofovir interactions

Tenofovir Interactions

  • Nucleotide antiretroviral

  • Atazanavir

    • Decreases atazanavir levels

    • Levels of tenofovir increased by atazanavir

    • Compensate by using boosted atazanavir and observe for tenofovir toxicity

  • Lopinavir/ritonavir

    • Levels of tenofovir increased: observe for toxicity

  • Didanosine

    • Levels of didanosine increased (144-160% AUC)

    • Compensate by decreasing dose of didanosine


Pi pi interactions lopinavir fosamprenavir amprenavir

PI-PI interactionsLopinavir - fosamprenavir/amprenavir

  • Poorly tolerated

  • Slightly decreased lopinavir and moderately decreased amprenavir levels

  • Adding extra ritonavir further reduces amprenavir!!!


Pi pi interactions saquinavir atazanavir ritonavir

PI-PI Interactionssaquinavir - atazanavir - ritonavir

  • Normal atazanavir levels

  • Boosted the trough levels of saquinavir 112% over baseline, peak levels by 42%, area under the curve by 60% and extended the saquinavir half-life by 17%

  • Atazanavir reduced the trough levels of ritonavir by 28% and the half-life by 17% (this latter result was not statistically significant); but peak levels were boosted by 58% and AUC by 41%.


Pi pi interactions lopinavir ritonavir saquinavir

PI-PI InteractionsLopinavir/ritonavir – saquinavir

  • Synergistic against viruses resistant to LPV but still sensitive to SQV

  • Limited data on interactions

  • Dosing

    • Standard lopinavir/ritonavir 400/100 bid

    • Invirase 800-1000 bid


Pi pi interactions lopinavir ritonavir indinavir

PI-PI InteractionsLopinavir/ritonavir – indinavir

  • Indinavir (600 mg twice daily) when coadministered with Kaletra (400/100 mg twice daily) may produce a similar AUC and higher Cmin relative to the established clinical dosing regimen

  • 11 subjects


Pi pi interactions indinavir saquinavir

PI-PI Interactionsindinavir - saquinavir

  • Coadministration of indinavir (800 mg three times daily) and a single dose of the soft gel formulation of saquinavir (800 or 1200 mg single dose)

  • N = 6

  • 800 mg saquinavir dose showed a 620% increase in AUC and a 551% increase in Cmax.

  • 1200 mg saquinavir dose showed a 364% increase in AUC and a 299% increase in Cmax.

  • There were no apparent clinically relevant changes to indinavir pharmacokinetics when coadministered with the soft gel formulation of saquinavir.


Unknown interactions

Unknown Interactions

  • Atazanavir - nevirapine

  • Lopinavir/ritonavir - atazanavir


Adverse pi interactions many overcome by boosting

Adverse PI InteractionsMany Overcome By Boosting

  • Lopinavir + amprenavir or fosamprenavir

  • Saquinavir + nevirapine or efavirenz

  • Atazanavir + tenofovir

  • Atazanavir + efavirenz

  • Atazanavir + efavirenz + tenofovir

  • Atazanavir + nevirapine

  • Indinavir + nevirapine or efavirenz

  • Fosamprenavir + nevirapine or efavirenz


Patient 1

Patient 1

  • 22 y/o man with AIDS CD4 122 VL > 750k DMAC

  • 122 lbs

  • Cr 1.4

  • Resistance testing: M184V, 215, 219, 82, 84

  • Proposed regimen

    • Lopinavir/ritonavir

    • Efavirenz

    • Tenofovir

    • Didanosine


Patient 11

Patient 1

  • 22 y/o man with AIDS CD4 122 VL > 750k DMAC

  • 122 lbs, 69 in

  • Nephropathy Cr 1.9

  • Resistance testing: M184V, 215, 219, 82, 84

  • Proposed regimen

    • Lopinavir/ritonavir: levels decreased by efavirenz

    • Efavirenz

    • Tenofovir

    • Didanosine


Patient 12

Patient 1

  • 22 y/o man with AIDS CD4 122 VL > 750k DMAC

  • 122 lbs

  • Cr 1.4

  • Resistance testing: M184V, 215, 219, 82, 84

  • Proposed regimen

    • Lopinavir/ritonavir

    • Efavirenz

    • Tenofovir: levels increased by renal failure and lopinavir/rtv

    • Didanosine


Patient 13

Patient 1

  • 22 y/o man with AIDS CD4 122 VL > 750k DMAC

  • 122 lbs

  • Cr 1.6

  • Resistance testing: M184V, 215, 219, 82, 84

  • Proposed regimen

    • Lopinavir/ritonavir

    • Efavirenz

    • Tenofovir

    • Didanosine: levels increased by low weight, renal failure, and tenofovir


Patient 14

Patient 1


Patient 15

Patient 1


Patient 16

Patient 1


Patient 17

Patient 1


Patient 18

Patient 1


Patient 19

Patient 1


Final recommendations

Final Recommendations

  • Look up all interactions using a computer or PDA

  • Avoid using drugs together which have not been studied

  • Pay close attention to body weight, hepatic and renal impairment

  • Follow liver enzymes and renal function closely


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