Download Lopinavir/ritonavir

Antiretroviral
Combinations
James A Zachary MD
LSU Health Sciences Center
HIV Outpatient Clinic
December 13, 2004
http://HIVManagement.org
Objectives
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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
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Improved adherence
Decrease pill burden
 Decrease dosing frequency
 Decrease meal dependence
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Improve efficacy
Improved adherence
 Improved levels of protease inhibitors
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Levels out interindividual variations
 Compensates for the effects of inducers
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Problems of Boosting
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Multiple drug-drug interactions
Increased serum lipid & fat redistribution side effects
Increased side effects
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Abdominal pain
Diarrhea
Nausea
Hepatitis
Perioral paresthesia
Increased number of prescribed medications
Need to refrigerate medication (ritonavir)
Pharmacology
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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
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P-450
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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
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P-450
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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
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P-450
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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
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Other Mechanisms
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P-glycoprotein
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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 protease inhibitors,
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.
P-450
inhibition
Increase
PI Levels
Decrease
PI Levels
P-450
induction
X
X
P-gly
inhibition
HRP 1+2
inhibition
X
X
ritonavir
indinavir
saquinavir
P450
inhibition
P450
induction
P-gly
inhibition
HRP 1+2
inhibition
X
X
X
X
X
X
nelfinavir
lopinavir
amprenavir
X
X
nevirapine
efavirenz
X
X
X
X
X
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
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 Soft
gel caps (Fortovase) better absorbed but
more GI upset
Boosted Saquinavir
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Saquinavir hard gel caps (Invirase)
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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
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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
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Boosting decreases dosing frequency and meal
dependence
Overcomes nevirapine or efavirenz problems
Boosted Atazanavir
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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
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Unboosted fosamprenavir 2 x 700 mg bid
Boosted regimens:
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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
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Nevirapine: a P-450 inducer
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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
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Increase dosage or boost: indinavir,
lopinavir/ritonavir
Increase nelfinavir
Boost fosamprenavir, saquinavir
↓
Nevirapine Effect on PIs
PI
Cmin
Increase
Dose?
Boosting
Effective?
Yes
Yes
AUC
Cmax
lopinavir with
ritonavir
73%
50%
indinavir
72%
Yes
Yes
fosamprenavir
67%
No
Yes
nelfinavir
68%
Yes
No
saquinavir
73%
No
Yes
atazanavir
?
?
Theoretical
PI – NNRTI Interactions
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Efavirenz: a P-450 inducer/inhibitor
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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
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Increase dosage or boost: indinavir, lopinavir/ritonavir
No change in nelfinavir
Boost fosamprenavir, saquinavir?, atazanavir
Efavirenz Effect on PIs
Cmax
Cmin
Increase
Dose?
Boosting
Effective?
61%
Yes
Yes
Yes
Yes
No
Yes
PI
AUC
lopinavir /
ritonavir
81%
indinavir
69%
fosamprenavir
64%
nelfinavir /
nelfinavir
metabolite
120%/
63%
121%/
60%
No
Need
No
Need
saquinavir
38%
50%
No
?
atazanavir
79%
No
Yes
84%
Tenofovir Interactions
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Nucleotide antiretroviral
Atazanavir
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Lopinavir/ritonavir
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Decreases atazanavir levels
Levels of tenofovir increased by atazanavir
Compensate by using boosted atazanavir and observe for
tenofovir toxicity
Levels of tenofovir increased: observe for toxicity
Didanosine
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Levels of didanosine increased (144-160% AUC)
Compensate by decreasing dose of didanosine
PI-PI interactions
Lopinavir - fosamprenavir/amprenavir
Poorly tolerated
 Slightly decreased lopinavir and moderately
decreased amprenavir levels
 Adding extra ritonavir further reduces
amprenavir!!!
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PI-PI Interactions
saquinavir - atazanavir - ritonavir
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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 halflife 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
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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
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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
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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
 Atazanavir
- nevirapine
 Lopinavir/ritonavir - atazanavir
Adverse PI Interactions
Many Overcome By Boosting
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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
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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
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Lopinavir/ritonavir
Efavirenz
Tenofovir
Didanosine
Patient 1
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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
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Lopinavir/ritonavir: levels decreased by efavirenz
Efavirenz
Tenofovir
Didanosine
Patient 1
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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
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Lopinavir/ritonavir
Efavirenz
Tenofovir: levels increased by renal failure and lopinavir/rtv
Didanosine
Patient 1
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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
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Lopinavir/ritonavir
Efavirenz
Tenofovir
Didanosine: levels increased by low weight, renal failure,
and tenofovir
Patient 1
Considerations
Drug
lopinavir/ritonavir
tenofovir
efavirenz
didanosine
Dosage
Patient 1
Considerations
Low weight
Renal failure [Ccr= 48 cc/min]
Drug interactions
Drug
Dosage
lopinavir/ritonavir
tenofovir
efavirenz
didanosine
Patient 1
Considerations
Low weight
Renal failure [Ccr= 48 cc/min]
Drug interactions
Drug
Dosage
lopinavir/ritonavir
4 caps bid
tenofovir
efavirenz
didanosine
Patient 1
Considerations
Low weight
Renal failure [Ccr= 48 cc/min]
Drug interactions
Drug
Dosage
lopinavir/ritonavir
4 caps bid
tenofovir
300 mg every 48 hours*
efavirenz
didanosine
Patient 1
Considerations
Low weight
Renal failure [Ccr= 48 cc/min]
Drug interactions
Drug
Dosage
lopinavir/ritonavir
4 caps bid
tenofovir
300 mg every 48 hours*
efavirenz
600 mg daily
didanosine
Patient 1
Considerations
Low weight
Renal failure [Ccr= 48 cc/min]
Drug interactions
Drug
Dosage
lopinavir/ritonavir
4 caps bid
tenofovir
300 mg every 48 hours*
efavirenz
600 mg daily
didanosine
100 – 125 mg daily?
Final Recommendations
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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