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Drug – Drug interactions 8 th Advanced HIV course, Montpellier, France September 10, 2010 David M. Burger Ass. Professor in Clinical Pharmacology Radboud University Nijmegen Medical Centre [email protected]

Drug – Drug interactions 8 th Advanced HIV course, Montpellier, France September 10, 2010 David M. Burger Ass. Professor in Clinical Pharmacology Radboud

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Page 1: Drug – Drug interactions 8 th Advanced HIV course, Montpellier, France September 10, 2010 David M. Burger Ass. Professor in Clinical Pharmacology Radboud

Drug – Drug interactions

8th Advanced HIV course, Montpellier, FranceSeptember 10, 2010

David M. Burger

Ass. Professor in Clinical Pharmacology

Radboud University Nijmegen Medical Centre

[email protected]

Page 2: Drug – Drug interactions 8 th Advanced HIV course, Montpellier, France September 10, 2010 David M. Burger Ass. Professor in Clinical Pharmacology Radboud

Outline (30 minutes)

1.  Basic pharmacology of ARVs2.  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

Page 3: Drug – Drug interactions 8 th Advanced HIV course, Montpellier, France September 10, 2010 David M. Burger Ass. Professor in Clinical Pharmacology Radboud

http://www.hiv-druginteractions.org/

Page 4: Drug – Drug interactions 8 th Advanced HIV course, Montpellier, France September 10, 2010 David M. Burger Ass. Professor in Clinical Pharmacology Radboud

Basic pharmacology of ARVs

Drug class Drug Substrate Inhibitor Inducer

NRTIs ABC, ZDV UGT - -

NNRTIs EFVNVP

CYP2B6CYP2B6, CYP3A

- CYP3A, UGT

PIs RTV CYP3A CYP3A, CYP2D6

CYP1A2, CYP2C9, UGT

Other CYP3A CYP3A -

Integrase inh RAL UGT - -

CCR5 inh MRV CYP3A - -

Page 5: Drug – Drug interactions 8 th Advanced HIV course, Montpellier, France September 10, 2010 David M. Burger Ass. Professor in Clinical Pharmacology Radboud

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

Page 6: Drug – Drug interactions 8 th Advanced HIV course, Montpellier, France September 10, 2010 David M. Burger Ass. Professor in Clinical Pharmacology Radboud

Interactions among ARVs (1): TDF +ATV/r

AUC -25%

Taburet et al. AAC 2004

Page 7: Drug – Drug interactions 8 th Advanced HIV course, Montpellier, France September 10, 2010 David M. Burger Ass. Professor in Clinical Pharmacology Radboud

Interactions among ARVs (2): TDF + ddI

AUC +48-60%

Pecora et al. Ann Pharmacother 2003

Page 8: Drug – Drug interactions 8 th Advanced HIV course, Montpellier, France September 10, 2010 David M. Burger Ass. Professor in Clinical Pharmacology Radboud

Interactions among ARVs (3): ATV/r + NNRTIs

Cmin –82%

Poirier et al. AIDS 2006

Recommendation: ATV/r 400/200mg QD

Page 9: Drug – Drug interactions 8 th Advanced HIV course, Montpellier, France September 10, 2010 David M. Burger Ass. Professor in Clinical Pharmacology Radboud

Interactions among ARVs (4): LPV/r + NNRTIs

AUC –19%

Recommendation: LPV/r 500/125mg or600/150mg BD

Efavirenz + PIs (n=153):65% received a dose adjustmentVirological response in patients WITH dose adjustment was better than in patients WITHOUT dose adjustment (p=0.05)

Page 10: Drug – Drug interactions 8 th Advanced HIV course, Montpellier, France September 10, 2010 David M. Burger Ass. Professor in Clinical Pharmacology Radboud

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

Page 11: Drug – Drug interactions 8 th Advanced HIV course, Montpellier, France September 10, 2010 David M. Burger Ass. Professor in Clinical Pharmacology Radboud

Interactions among ARVs (6): ATV + Raltegravir

Iwamoto et al. Clin Inf Dis 2008AUC: + 72%

Page 12: Drug – Drug interactions 8 th Advanced HIV course, Montpellier, France September 10, 2010 David M. Burger Ass. Professor in Clinical Pharmacology Radboud

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

Page 13: Drug – Drug interactions 8 th Advanced HIV course, Montpellier, France September 10, 2010 David M. Burger Ass. Professor in Clinical Pharmacology Radboud

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%

Nelfinavir 1250mg 2dd -43%

Saquinavir/rtv 1000/100mg 2dd

400/400mg 2dd

1600/100mg 1dd

-19%

-32%

+3%

Tipranavir/rtv 500/200mg 2dd -48%

Non-nucleoside reverse

transcriptase inhibitors

Efavirenz 600mg 1dd -57%

-52%

Etravirine 100mg 2dd +8%

Nevirapine 200mg 2dd

200mg 2dd

400mg 1dd

-41%

-53%

-49%

Page 14: Drug – Drug interactions 8 th Advanced HIV course, Montpellier, France September 10, 2010 David M. Burger Ass. Professor in Clinical Pharmacology Radboud

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 > H2 antagonist > antacids

• Dose of PPI and timing of H2 antagonist are relevant too

Page 15: Drug – Drug interactions 8 th Advanced HIV course, Montpellier, France September 10, 2010 David M. Burger Ass. Professor in Clinical Pharmacology Radboud

Interactions between ARVs and PPIs (2)

Klein et al. J Clin Pharmacol 2008

AUC: - 62% AUC: - 48%

Page 16: Drug – Drug interactions 8 th Advanced HIV course, Montpellier, France September 10, 2010 David M. Burger Ass. Professor in Clinical Pharmacology Radboud

PPIs and raltegravir: a positive interaction

AUC: + 212%

Page 17: Drug – Drug interactions 8 th Advanced HIV course, Montpellier, France September 10, 2010 David M. Burger Ass. Professor in Clinical Pharmacology Radboud

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

Page 18: Drug – Drug interactions 8 th Advanced HIV course, Montpellier, France September 10, 2010 David M. Burger Ass. Professor in Clinical Pharmacology Radboud

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 anti-epileptic drug levels (both ↑ and ↓)

• Avoid these older drugs as much as possible; if not possible: TDM of both ARVs and antiepileptics

• Alternatives: lamotrigine, levetiracetam

Page 19: Drug – Drug interactions 8 th Advanced HIV course, Montpellier, France September 10, 2010 David M. Burger Ass. Professor in Clinical Pharmacology Radboud

Pharmacodynamics of ARVs

• Brain

• Genital tract

Page 20: Drug – Drug interactions 8 th Advanced HIV course, Montpellier, France September 10, 2010 David M. Burger Ass. Professor in Clinical Pharmacology Radboud

Cerebrospinal fluid / brain

• Blood – brain barrier protects brain from toxic substances

• Characteristics of drugs that are able to penetrate:

• Small molecule (low Mw)

• Lipophilic

• Low protein binding

• No substrate of efflux transporters

Page 21: Drug – Drug interactions 8 th Advanced HIV course, Montpellier, France September 10, 2010 David M. Burger Ass. Professor in Clinical Pharmacology Radboud

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?

Page 22: Drug – Drug interactions 8 th Advanced HIV course, Montpellier, France September 10, 2010 David M. Burger Ass. Professor in Clinical Pharmacology Radboud
Page 23: Drug – Drug interactions 8 th Advanced HIV course, Montpellier, France September 10, 2010 David M. Burger Ass. Professor in Clinical Pharmacology Radboud

Three criteria to assess CSF penetration effectiveness (CPE) score

• Chemical and pharmacological properties

• CSF concentrations above IC50

• Clinical studies demonstrating CSF viral load response 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

Page 24: Drug – Drug interactions 8 th Advanced HIV course, Montpellier, France September 10, 2010 David M. Burger Ass. Professor in Clinical Pharmacology Radboud

CPE scores

Page 25: Drug – Drug interactions 8 th Advanced HIV course, Montpellier, France September 10, 2010 David M. Burger Ass. Professor in Clinical Pharmacology Radboud
Page 26: Drug – Drug interactions 8 th Advanced HIV course, Montpellier, France September 10, 2010 David M. Burger Ass. Professor in Clinical Pharmacology Radboud

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

Page 27: Drug – Drug interactions 8 th Advanced HIV course, Montpellier, France September 10, 2010 David M. Burger Ass. Professor in Clinical Pharmacology Radboud

CPE scores (updated 2010)

Letendre et al. CROI 2010 (#430)

Page 28: Drug – Drug interactions 8 th Advanced HIV course, Montpellier, France September 10, 2010 David M. Burger Ass. Professor in Clinical Pharmacology Radboud

CPE ≥ 8 appears important, but none of the preferred 1st line regimens achieves that score…

Letendre et al. CROI 2010 (#430)

Page 29: Drug – Drug interactions 8 th Advanced HIV course, Montpellier, France September 10, 2010 David M. Burger Ass. Professor in Clinical Pharmacology Radboud

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

Page 30: Drug – Drug interactions 8 th Advanced HIV course, Montpellier, France September 10, 2010 David M. Burger Ass. Professor in Clinical Pharmacology Radboud

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%)

Page 31: Drug – Drug interactions 8 th Advanced HIV course, Montpellier, France September 10, 2010 David M. Burger Ass. Professor in Clinical Pharmacology Radboud

Lowe et al. AIDS 2004; 18: 1353-62

3.3

Page 32: Drug – Drug interactions 8 th Advanced HIV course, Montpellier, France September 10, 2010 David M. Burger Ass. Professor in Clinical Pharmacology Radboud

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

Page 33: Drug – Drug interactions 8 th Advanced HIV course, Montpellier, France September 10, 2010 David M. Burger Ass. Professor in Clinical Pharmacology Radboud

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

Page 34: Drug – Drug interactions 8 th Advanced HIV course, Montpellier, France September 10, 2010 David M. Burger Ass. Professor in Clinical Pharmacology Radboud
Page 35: Drug – Drug interactions 8 th Advanced HIV course, Montpellier, France September 10, 2010 David M. Burger Ass. Professor in Clinical Pharmacology Radboud
Page 36: Drug – Drug interactions 8 th Advanced HIV course, Montpellier, France September 10, 2010 David M. Burger Ass. Professor in Clinical Pharmacology Radboud

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?

Page 37: Drug – Drug interactions 8 th Advanced HIV course, Montpellier, France September 10, 2010 David M. Burger Ass. Professor in Clinical Pharmacology Radboud

Newer ARVs penetrate well into CVF

Talameh et al. J Chrom B 2009Dumond et al. J AIDS 2009

Raltegravir Maraviroc

Page 38: Drug – Drug interactions 8 th Advanced HIV course, Montpellier, France September 10, 2010 David M. Burger Ass. Professor in Clinical Pharmacology Radboud

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