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)
 Antifungal (2)
 Antiprotozoal (4)
 Cytotoxics (12)
 Other antiinfectives (6)
 Anaesthetics (5)
 Miscellaneous (41)
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’.
What Constitutes a Clinically
Relevant Drug-Drug Interaction?
>20%, 30%, 50%, 70% change in PK?
PK-PD
Therapeutic Window
Change in steady state concentration:
Enzyme Induction
Drug Conc.
Decrease in steady state
Target for efficacy
Inducer
Time
Change in steady state concentration:
Enzyme Induction
Drug Conc.
Decrease in steady state
Target for efficacy
Inducer
Time
Change in steady state concentration:
Enzyme Inhibition
Drug Conc.
Increase in steady state
Concern re toxicity
Inhibiting Drug
Time
19
Change in steady state concentration:
Enzyme Inhibition
Increase in steady state
Drug Conc.
Concern re toxicity
Inhibiting Drug
Time
20
Most Drug-Drug Interaction
Studies are done in Healthy
Volunteers
Physiological changes (versus healthy
volunteers)
Parameter
HIV-infected
HCV-infected
HIV/HCV
co-infected
Albumin
↓1,2
↓*3
↓†4
α1-acid glycoprotein
↑5
↑6
↑
Gastric pH
↑7
↑8
↑
Cytochrome P450
↓
↓
↓
Cytokines
↑
↑
↑
*
Decreased albumin associated more with cirrhosis and significant liver damage
lower than HIV or HCV mono-infected patients
† Significantly
1Mehta
SH, et al. AIDS Res Human Retrovir 2006;22:14–21; 2Graham SM, et al. AIDS Res Human Retrovir 2007;23:1197–1200
3Nagao Y & Sata M. Virology Journal 2010;7:375; 4Monga HK, et al. Clin Infect Dis 2001;33:240–7
5
; Boffito M, et al. Drug Metab Dispos 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
PK differences (versus healthy volunteers)
Drug
HIV-infected
HIV/HCV
co-infected*
ATV
↓ (Reyataz SPC)
↑ (Regazzi et al. Ther Drug Monit 2011)
ATV/r
↓ (Reyataz SPC)
↔ (Di Biagio et al. J Infect Chemother 2012)
↔ (Regazzi et al. Ther Drug Monit 2011)
DRV/r
↑ (Prezista SPC)
↔† (Sekar et al. Clin Pharmacokinet 2010)
↑ RTV † (Sekar et al. Clin Pharmacokinet 2010)
↔ (Sekar et al. 11th EACS 2011)
↔ cirrhosis vs. historical controls (Curran et al. 13th WCPHT 2012)
LPV/r
↔ (Kaletra SPC)
↔ (Barreiro et al. J Infect Dis 2007)
↑ (Peng et al. J Clin Pharmacol 2006)
↑ RTV (Peng et al. J Clin Pharmacol 2006)
↔ (Canta et al. JAC 2005)
↔ but ↑ V/F (Molto et al. Clin Pharmacokinet 2007)
↑ RTV, ↓ CL/F V/F (Molto et al. Clin Pharmacokinet 2007)
↔ (Seminari et al. JAC 2005)
↓ (Dominguez et al. JAC 2010)
EFV
↓ (Mukonzo et al. Clin Pharmcokinet 2011)
(Ugandan study)
↓ (Dupont review report 1998)
(↔ Caucasian; ↓ Black)
↔ (Katsounas et al. Eur J Med Res 2007)
↔ (Pereira et al. BJCP 2008)
↑ cirrhosis versus no cirrhosis (Barreiro et al. J Infect Dis 2007)
↑ (Dominguez et al. JAC 2010)
RAL
↓ (Arab-Alameddine et al. AAC 2012 )
↔ (composite analysis, Merck)
↑ cirrhosis versus no cirrhosis (Hemandez-Novoa et al.
19th CROI 2012)
↔ Ұ (Iwamoto et al. AAC 2009)
to HIV mono-infected; †Healthy individuals with & without mild/moderate hepatic impairment
individuals with and without moderate hepatic impairment
*Compared
ҰHealthy
Interactions with nonoral drugs
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.
Corticosteroid metabolism and
formulations
Drug
Budesonide
CYP3A4
Dexamethasone
CYP3A4
Fludrocortisone
CYP3A4
Oral
Inhaled





Fluticasone
CYP3A4
Hydrocortisone
CYP3A4
Prednisolone
CYP3A4

Beclomethasone
Esterase to active met
Triamcinolone
CYP3A4
Mometasone
CYP3A4

Topical
Eye/ear
drops
Injection











 
 
Created from SmPCs for all included drugs. Available at: http://www.medicines.org.uk/emc/.

Rectal



Prevelance of Clinically
Significant Drug Interactions
in HIV Cohorts
Prevelance of DDIs
Clinically Significant Interactions in
HIV+ patients
Study
Year
Setting
N
CSDI
de Maat et al
2004
Netherlands
115
26%
105
23%
Screen
Tool
Adverse
Notes
Liverpool
site
NR
Pharmacy
screening
effective
Audit
Shah et al
2007
USA
(Medicaid)
571
30%
Liverpool
site
Micromedex
No VL
impact
Miller et al
2007
USA
(hospital)
153
41%
DHHS
SPC/PI
Micromedex
NR
Kigen et al
2009
Kenya
(hospital)
996
34%
Liverpool
site
NR
Marzolini et al
2009
Swiss Cohort
(hospital)
1497
40%
Liverpool
site
No VL or
CD4
impact
Evans Jones
et al
2009
UK
(hospital)
159
27%
Liverpool
site
NR
Patel et al
2011
USA
190
34%
Lexi-interact
Only 36%
CSDIs
identified
>5 non-HIV
meds
increase risk
Drug Interactions will be greater as
patients age
A
<<5050
years
years
50
B
< 50 years
< 50
years
?50 years
> 50 years
60
?50 years
>50 years
***
50
patients (%)
(%)
patients
patients (%)(%)
Patients
40
30
20
40
***
30
***
20
***
10
10
**
*** ***
**
*
0
0
1
2
3
4
5
6
7
>8
***
***
***
0
numberof
of co-medications
Number
co-medications
Marzolini C et al J Antimicrob Chemother 2011;66:2107
Numerous factors determine the
pharmacokinetic phenotype