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Drug-Drug Interaction Satellite Workshop

Drug-Drug Interaction Satellite Workshop. David Back University of Liverpool UK. How the Drug Interactions web site started. Launched – July 2012. There is always room for improvement. Web site Improvement: Add WHO Essential Medicines. Anthelminics (11) Anti-TB (5) Antibiotics (15)

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Drug-Drug Interaction Satellite Workshop

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  1. Drug-Drug Interaction Satellite Workshop David Back University of Liverpool UK

  2. How the Drug Interactions web site started

  3. Launched – July 2012

  4. There is always room for improvement

  5. Web site Improvement:Add WHO Essential Medicines • Anthelminics (11) • Anti-TB (5) • Antibiotics (15) • Antifungal (2) • Antiprotozoal (4) • Cytotoxics (12) • Other antiinfectives (6) • Anaesthetics (5) • Miscellaneous (41)

  6. Web Site Improvement:Amber Project • Amber Project! Re-visit amber designations in the data base and re-classify if the interaction has a high likelihood of not being ‘clinically relevant’.

  7. What Constitutes a Clinically Relevant Drug-Drug Interaction? >20%, 30%, 50%, 70% change in PK? Therapeutic Window PK-PD

  8. Change in steady state concentration:Enzyme Induction Decrease in steady state Drug Conc. Target for efficacy Inducer Time

  9. Change in steady state concentration:Enzyme Induction Decrease in steady state Drug Conc. Target for efficacy Inducer Time

  10. Change in steady state concentration:Enzyme Inhibition Increase in steady state Drug Conc. Concern re toxicity Inhibiting Drug Time

  11. Change in steady state concentration:Enzyme Inhibition Increase in steady state Concern re toxicity Drug Conc. Inhibiting Drug Time

  12. Most Drug-Drug Interaction Studies are done in Healthy Volunteers

  13. Physiological changes (versus healthy volunteers) * Decreased albumin associated more with cirrhosis and significant liver damage † Significantly lower than HIV or HCV mono-infected patients 1Mehta SH, et al. AIDS Res Human Retrovir 2006;22:14–21; 2Graham SM, et al. AIDS Res Human Retrovir 2007;23:1197–12003Nagao Y & Sata M. Virology Journal 2010;7:375; 4Monga HK, et al. Clin Infect Dis 2001;33:240–7; 5Boffito M, et al. Drug MetabDispos 2002;30:859–60; 6Ozeki T, et al. Br J Exp Path 1988;69:589–95 7Welage LS, et al. Clin Infect Dis 1995;21:1431–38; 8Nam YJ, et al. Korean J Hepatol 2004;10:216–22

  14. PK differences (versus healthy volunteers) *Compared to HIV mono-infected; †Healthy individuals with & without mild/moderate hepatic impairment ҰHealthy individuals with and without moderate hepatic impairment

  15. Interactions with non-oral drugs

  16. Corticosteroids • Case report of Cushing’s syndrome and adrenal suppression in a patient on ATV/r and dexamethasone 0.1% eye drops1 • Cushing’s syndrome reported with the use of intra articular triamcinolone injections in patients on boosted PIs2–4 • Cushing’s syndrome and adrenal suppression in patients on budesonide and ritonavir (paediatrics) or boosted PIs5,6 • Several cases of Cushing’s syndrome with fluticasone and ritonavir7 1. Molloy A, et al. AIDS. 2011;25:1337–9. 2. Dort K, et al. AIDS Res Ther. 2009;6:10. 3. Danaher PJ, et al. Orthopedics 2009;32:450. 4. Ramanathan R, et al. Clin Infect Dis. 2008;47:e97–9. 5. Gray D, et al. S Afr Med J. 2010;100:296–7. 6. Frankel JK, & Packer CD. Ann Pharmacother. 2011;45:823–4. 7. Foisy MM, et al. HIV Medicine 2008;9:389–96.

  17. Corticosteroid metabolism and formulations                           Created from SmPCs for all included drugs. Available at: http://www.medicines.org.uk/emc/.

  18. Prevelance of Clinically Significant Drug Interactions in HIV Cohorts

  19. Prevelance of DDIs

  20. Clinically Significant Interactions in HIV+ patients

  21. B B < 50 years < 50 years A A 60 60 < 50 years < 50 years ? 50 years 50 50 *** *** *** 50 years ? >50 years 50 50 40 40 40 40 *** *** *** 30 30 patients (%) patients (%) 30 30 Patients (%) patients (%) 20 20 *** *** *** 20 20 *** *** *** *** *** *** *** *** *** ** ** ** ** ** ** *** *** *** 10 10 10 10 *** *** *** *** *** *** * * * 0 0 0 0 0 0 1 1 2 2 3 3 4 4 5 5 6 6 7 7 >8 >8 diuretics hormones analgesics methadone CNS agents antilipidemics ACE inhibitors Beta blockers anti-infectives Number of co-medications diuretics number of co-medications insulin/antidiabetics hormones analgesics methadone cardiovascular drugs gastrointestinal drugs angiotensin II inhibitors CNS agents antilipidemics ACE inhibitors Betablockers anti-infectives calcium channel inhibitors antiplatelets/anticoagulants insulin/antidiabetics angiotensin II inhibitors cardiovascular drugs gastrointestinaldrugs calciumchannelinhibitors antiplatelets/anticoagulants Drug Interactions will be greater as patients age > 50 years Marzolini C et al J AntimicrobChemother 2011;66:2107

  22. Numerous factors determine the pharmacokinetic phenotype

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