Transcript Drug – Drug interactions 8th Advanced HIV course, Montpellier

Drug – Drug interactions
8th Advanced HIV course, Montpellier, France
September 10, 2010
David M. Burger
Ass. Professor in Clinical Pharmacology
Radboud University Nijmegen Medical Centre
[email protected]
Outline (30 minutes)
1. Basic pharmacology of ARVs
2. Important interactions
Between ARV drugs/classes with special reference to new
drugs
Other important interactions
i. very practical, use examples specific to clinical practices
ii. Methadone
iii. PPIs
iv. OCP
v. Anti-epileptics
(How to improve drug exposure)
3. Basic pharmacodynamics
Brain
Genital tract
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http://www.hiv-druginteractions.org/
Basic pharmacology of ARVs
Drug class
Drug
Substrate
Inhibitor
Inducer
NRTIs
ABC, ZDV
UGT
-
-
NNRTIs
EFV
NVP
CYP2B6
CYP2B6, CYP3A
-
CYP3A, UGT
PIs
RTV
CYP3A
CYP3A,
CYP2D6
CYP1A2,
CYP2C9, UGT
Other
CYP3A
CYP3A
-
Integrase inh
RAL
UGT
-
-
CCR5 inh
MRV
CYP3A
-
-
Summary of expected interactions
• All ARVs can be subject to interactions
• NNRTIs reduce drug concentrations
• PIs increase drug concentrations
• With a few exceptions….
• Check Liverpool website and/or send e-mail to
[email protected] in case of questions
Interactions among ARVs (1): TDF +ATV/r
AUC -25%
Taburet et al. AAC 2004
Interactions among ARVs (2): TDF + ddI
AUC +48-60%
Pecora et al. Ann Pharmacother 2003
Interactions among ARVs (3): ATV/r + NNRTIs
Recommendation: ATV/r 400/200mg QD
Cmin –82%
Poirier et al. AIDS 2006
Interactions among ARVs (4): LPV/r + NNRTIs
Efavirenz + PIs (n=153):
65% received a dose adjustment
Virological response in patients WITH dose adjustment was better than in
patients WITHOUT dose adjustment (p=0.05)
AUC –19%
Recommendation: LPV/r 500/125mg or
600/150mg BD
Interactions among ARVs (5): Maraviroc (CYP3A substrate)
• Normal dose: 300mg BID
• With an inducer (e.g., EFV): 600mg BID
• With an inhibitor (e.g., LPV/r): 150mg BID
• With both an inducer AND inhibitor: 150mg BID
Interactions among ARVs (6): ATV + Raltegravir
AUC: + 72%
Iwamoto et al. Clin Inf Dis 2008
Interactions between ARVs and methadone (1)
• Mechanism: complex pharmacokinetics
• Stereoselective (R- and S-enantiomer)
• Protein binding
• CYP2B6, UGT enzymes involved
• Change in methadone exposure may have variable
effect in patients
Interactions between ARVs and methadone (2)
Drug Class
ARV
Dose of ARV
Effect on
methadon AUC
Protease inhibitors
Atazanavir
400mg 1dd
+3%
Darunavir/rtv
600/100mg 2dd
-16%
Fosamprenavir/rtv
700/100mg 2dd
-18%
Indinavir
800mg 3dd
-4%
Indinavir/rtv
800/100mg 2dd
0%
Lopinavir/rtv
400/100mg 2dd
-53%
-26%
Non-nucleoside reverse
Nelfinavir
1250mg 2dd
-43%
Saquinavir/rtv
1000/100mg 2dd
-19%
400/400mg 2dd
-32%
1600/100mg 1dd
+3%
Tipranavir/rtv
500/200mg 2dd
-48%
Efavirenz
600mg 1dd
-57%
transcriptase inhibitors
-52%
Etravirine
100mg 2dd
+8%
Nevirapine
200mg 2dd
-41%
200mg 2dd
-53%
400mg 1dd
-49%
Interactions between ARVs and PPIs (1)
• Acid secretion reducing agents are frequently used by
HIV patients, incl. OTC
• A few ARVs need gastric acid for solution: ddI, IDV, ATV
• Impact of gastric acid inhibition can be major (>50%)
• PPIs > H
2
antagonist > antacids
• Dose of PPI and timing of H
2
antagonist are relevant too
Interactions between ARVs and PPIs (2)
AUC: - 62%
AUC: - 48%
Klein et al. J Clin Pharmacol 2008
PPIs and raltegravir: a positive interaction
AUC: + 212%
Interactions between ARVs and oral contraceptive pills
• General mechanism: boosted PIs and NNRTIs induce
glucuronidation of estrogens and/or progestagens
• Lower levels of hormones are the result with possible
less reliable anticonception
• Evidence based exception: medroxyprogesterone i.m.
depot (Cohn et la. CPT 2007)
• Other advice: condom use, avoid sub-50 pill
Interactions between ARVs and anti-epileptics
• Older anti-epileptics (phenytoin, carbamazepine,
phenobarbital) are all known to be strong enzyme
inducers: reduce levels of PIs and NNRTIs
• Boosted PIs & NNRTIs can also have effects on antiepileptic drug levels (both ↑ and ↓)
• Avoid these older drugs as much as possible; if not
possible: TDM of both ARVs and antiepileptics
• Alternatives: lamotrigine, levetiracetam
Pharmacodynamics of ARVs
• Brain
• Genital tract
Cerebrospinal fluid / brain
• Blood – brain barrier protects brain from toxic
substances
• Characteristics of drugs that are able to penetrate:
• Small molecule (low M )
• Lipophilic
• Low protein binding
• No substrate of efflux transporters
w
Facts and fiction about CSF penetration
•
CSF = “easy” to collect, but ≠ brain tissue
• Neurocognitive impairment (= brain tissue damage) can never be
directly related to [ARV] in CSF
• Lipophilic drug (e.g. EFV) distributes from CSF to brain tissue
(another example: itraconazole in cryptococcal meningitis)
•
LPV has 98-99% protein binding in plasma = 1-2% is active. If
1% penetrates CSF then CSF/plasma ratio is 0.01 = OK
(because there is hardly any protein in CSF)
•
How many ARVs must penetrate CSF?
• 1 is enough (see AZT effect on HIV dementia)?
• >1 to prevent development of resistance?
Three criteria to assess CSF penetration effectiveness (CPE) score
• Chemical and pharmacological properties
• CSF concentrations above IC
• Clinical studies demonstrating CSF viral load response
50
or improvement in neurocognitive performance
Based on available information each ARV receives a CPE
score of 0, 0.5, or 1; CPE score of an ARV regimen is
sum of CPE scores
CPE scores
CPE scores of popular regimens
• d4T, 3TC, NVP = 2.0
• ZDV, 3TC, NVP = 2.5
• TDF, FTC, EFV = 1.0
• TDF, FTC, ATV/r = 1.0
• Please note:
• All regimens are ≥ 1.0
• No evidence that 2.5 is better than 1.0
CPE scores (updated 2010)
Letendre et al. CROI 2010 (#430)
CPE ≥ 8 appears important, but none of the preferred
1st line regimens achieves that score…
Letendre et al. CROI 2010 (#430)
HIV drugs and the male genital tract
• Relevant compartment for many reasons:
• Development of resistance (if ARVs do not penetrate)
• Transmission of HIV if not suppressed
• Transmission of HIV resistance
• Semen is “easy” to collect and is a surrogate for
distribution of ARVs into the male genital tract
ARV drugs and penetration into male genital tract
• Diffusion or active transport (cf. CSF)
• Lipid solubility
• Ionisation: pH prostate (6.6) is lower than in blood (7.4);
weak bases cumulate in prostate (“ion trapping”)
• Protein binding (< 90%)
3.3
Lowe et al. AIDS 2004; 18: 1353-62
Clinical relevance of differences in semen penetration?
• Clinical studies show >90% VL suppression in semen
• No large series of patients with isolated drug resistance
in semen
• Male genital tract most likely not a separate
compartment
HIV, drugs and the female genital tract
•
Like the male genital tract, it is a relevant compartment for many
reasons:
• Development of resistance (if ARVs do not penetrate)
• Transmission of HIV if not suppressed
• Transmission of HIV resistance
• Esp. important for pre- (and maybe post-) exposure prophylaxis
•
Cervicovaginal fluid (CVF) is “easy” to collect and is a surrogate for
distribution of ARVs into the female genital tract
Clinical relevance of differential PK of ARVs in CVF
• Only 1/34 women had detectable HIV-1 RNA in CVF
• She was known to be nonadherent on a ddI, 3TC, EFV regimen
• NRTIs penetrate well
• Sufficient for pre-exposure prophylaxis?
• Selective development of NRTI resistance in CVF?
• What about NRTI-sparing regimens?
Newer ARVs penetrate well into CVF
Raltegravir
Maraviroc
Talameh et al. J Chrom B 2009
Dumond et al. J AIDS 2009
Conclusions
• Basic knowledge of clinical pharmacology essential to
manage your patients
• Check Liverpool website and/or seek expert advice
• ARV penetration into compartments interesting to study;
clinical relevance yet unknown