Transcript Dangers in Herbs-Drug Interactions Understanding Mechanisms to

Dangers in Herbs-Drug
Interactions
Understanding mechanisms
to inform management
Andrew McLachlan
Centre for Education and Research on Ageing
Concord RG Hospital
Australia
Faculty of Pharmacy
University of Sydney
Australia
This presentation
 Complementary medicines use
 People most at risk
 Investigating herb-drug interactions
 Understanding and applying the findings
Complimentary medicines
Complementary medicines
Complementary medicine
Complementary medicines
Complementary medicines
Alternative
medicines
Australian trends in the use of
supplements
CAM
Vitamins (but not
calcium or iron)
Herbal medicines
Mineral supplements
Soy products
Chinese medicines
Homeopathic medicines
Total CAM user (at least
one product)
1993*
38 %
2000*
36 %
2004*
39 %
10 %
9%
2%
4%
49 %
13 %
11%
3%
4%
52 %
21 %
14 %
4%
2%
2%
52 %
*data shown as percent respondents who have used these medicines within the last 12 months.
MacLennan AH, Myers SP, Taylor AW.The continuing use of complementary and
alternative medicine in South Australia: costs and beliefs in 2004. Med J Aust. 2006;184:27-31.
US trends in the use of supplements
13% used at
least 1
herbal
supplements
in the last 12
months
n=5860
aged above 65
years
Bruno JJ, Ellis JJ. Herbal use among US elderly: 2002 National
Health Interview Survey. Ann Pharmacother. 2005
The issue
 50% of people who reported that they used
complementary and alternative therapies also used
conventional medicines on the same day
 57% did not report the use of complementary
therapies to their doctor.
MacLennan AH, Myers SP, Taylor AW.The continuing use of complementary and
alternative medicine in South Australia: costs and beliefs in 2004. Med J Aust. 2006;184:27-31.
Herb-drug interactions: potentially
important but woefully under
researched
E. Ernst
Eur J Clin Pharmacol 2000: 56: 523-524
 Why have only so few cases of suspected herb-drug
interactions been reported in the medical literature?
 Truly rare events?
 Significant unreporting?
http://www.pharma.unibas.ch/bio/img/Humor_now_and_then/Humor_Herbal_Medicine_2.jpg
Clinical risk management of
herb-drug interactions
 Risk identification and assessment
 Development and implementation of risk reduction
strategies
 Evaluation of risk reduction strategies
De Smet, PAGM. Br J Clin Pharmacol 2006
Clinical significance of
herb-drug Interactions
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Patient characteristics
Nature of pharmacodynamic response
Mechanism of interaction
Safety margin of the interacting herb and drug
Quality of the product
Size of the dose
Duration of therapy
Time course of drug interaction
Order and timing of administration
PD Coxeter, AJ McLachlan, CC Duke, BD Roufogalis. Herb-drug interactions:
an evidence based approach. Current Medicinal Chemistry 2004;11:1513-25
Understanding the mechanism of a herb-drug
interaction allows the
prediction of other interactions
 assessment of clinical significance
 guide risk minimisation strategies
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Study designs used to assess
herb-drug interactions
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Controlled trials in patients
Controlled trials in healthy subjects
Case reports or series
Animal studies
In vitro studies
Adverse event data
Theoretical
PD Coxeter, AJ McLachlan, CC Duke, BD Roufogalis. Herb-drug interactions:
an evidence based approach. Current Medicinal Chemistry 2004;11:1513-25
Investigating drug interactions
Type of
study
Enzyme, Cells
or microsomes
Animals
Healthy
subjects
Patients
Mechanism
Cost
Clinical
Relevance
Ethical
Issues
The need to establish quality
CONSORT guidelines for reporting
Gagnier JJ et al, Reporting Randomized, Controlled Trials of Herbal Interventions:
An Elaborated CONSORT Statement. Ann Intern Med. 2006;144:364-367.
The need to establish quality of herbal
medicine product
 Herbal medicine product name
 Characteristics of herbal product
(including part of plant used)
 Dose and qualitative description
 Quantitative analysis of HMP
(including procedures and
standardisation)
Gagnier JJ et al, Reporting Randomized, Controlled Trials of Herbal Interventions:
An Elaborated CONSORT Statement. Ann Intern Med. 2006;144:364-367.
Herb-drug interactions with warfarin
o To investigate the potential herbaldrug interactions with warfarin
o To examine the effect of herbal
medicines on clotting status
o Commonly used herbal medicines
o St Johns wort, Asian ginseng
o ginkgo biloba, ginger
o cranberry juice, garlic
Jiang et al, Brit J Clin Pharmacol 2004, 2005
Herb-drug interactions with warfarin
o To investigate the potential herbaldrug interactions with warfarin
o To examine the effect of herbal
medicines on clotting status
o Commonly used herbal medicines
o St Johns wort
I will focus on these
herbal medicines
o cranberry juice
Jiang et al, Brit J Clin Pharmacol 2004, 2005
St John’s Wort
 In vitro study: inhibit human CYP2D6, CYP3A4
and CYP2C9
Budzinski et al, Phytomedicine 2000
 In vivo study in healthy subjects: induce human
CYP3A4, CYP2E1, CYP1A2 and P-glycoprotein
 Case reports: reduce the efficacy of warfarin
Fugh-Berman & Ernst, Br J Clin Pharmacol 2001
Comparison of German St John’s Wort Products according
to hyperforin and total hypericin content
Wurglics et al, J Am Pharm Assoc 2001
St John’s wort dose and preparation on herb-drug
interaction with digoxin
Mueller et al, Clin Pharmacol Ther 2004
TLC of Proprietary St John’s Wort Products
-A
-B
-C
A: Hypericin;
B: Pseudohypercin;
C: Hyperoside;
D: Rutin;
No. 5: Use in the trial
-D
1
2
3
4
5
6
TLC of different commercial St
John’s wort
(British Pharmacopoeia 2001)
Study Design
randomised, open label, three-treatment, threesequence, crossover design
14-day washout period
single 25 mg dose of warfarin
with or without treatment with herbal medicines
Blood samples collected at -48, -24, 0 and up to
168 h
Mechanisms of drug interactions
PHARMACOKINETIC
PHARMACEUTICAL
PHARMACODYNAMIC
CYP2C9
S-warfarin
S-7-hydroxywarfarin
Park et al, 1998
Effect of St John’s wort and Asian ginseng on
the Pharmacodynamics of Warfarin
Warfarin+GS
Warfarin only
Warfarin+SJW
4
INR
3
*
2
1
0
-48
0
48
96
Time (h)
144
192
*P<0.05
Jiang et al, Brit J Clin Pharmacol 2004
St John's wort - Warfarin interaction
90% CI of log-transformed ratio
1.8
1.6
1.4
1.2
1
0.8
0.6
0.4
0.2
0
Cmax
CL/F
V/F
AUC of INR
PK and PD parameters
S-warfarin PK data shown
Jiang et al, Br J Clin Pharmacol 2004
St John's wort - Warfarin interaction
90% CI of log-transformed ratio
1.8
1.6
1.4
1.2
1
0.8
0.6
0.4
0.2
0
Cmax
CL/F
V/F
AUC of INR
PK and PD parameters
S-warfarin PK data shown
Jiang et al, Br J Clin Pharmacol 2004
Mortality and INR
Oden and Fahlen, BMJ 2002
St John’s wort can reduce the
effectiveness of many medicines
Pretreatment with SJW
significantly
Mills E et al. Interaction of St
John's wort with conventional
drugs: systematic review of
clinical trials. BMJ. 2004;329:2730.
St John’s wort can reduce the
effectiveness of many medicines
Pretreatment with SJW
significantly
Jiang X et al. Effect of St John's wort and
ginseng on the pharmacokinetics and
pharmacodynamics of warfarin in healthy
subjects. Br J Clin Pharmacol. 2004
Mills E et al. Interaction of St
John's wort with conventional
drugs: systematic review of
clinical trials. BMJ. 2004;329:2730.
Rindone and Murphy, Warfarin-Cranberry Juice Interaction Resulting in Profound
Hypoprothrombinemia and Bleeding. Am J Ther 13, 283–284 (2005)
Warfarin-cranberry interaction
INR response
(AUC of INR over 168 h)
160
*
140
33%
increase
in INR
response
120
100
80
60
40
20
0
Warfarin alone
Warfarin and Cranberry
* p =0.017
Randomsied cross-over clinical trial
12 healthy male subjects
25 mg warfarin dose +/- 2 weeks treatment with cranberry juice extract
MI Mohammed Abdul et al, 2006
Effect of Cranberry Juice Extract on
warfarin response
180
INR response (INR AUC over 7 days)
160
140
120
100
80
60
40
20
0
1
2
1= Warfarin only; 2 = Warfarin + cranberry
MI Mohammed
Abdul et al,
2006
Cranberry - warfarin interaction
1.6
90% CI of log-transformed ratio
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
Cmax
CL/F
V/F
PK and PD Parameters
AUC of INR
MI Mohammed Abdul et al, 2006
Pharmacodynamic Endpoint
AUC of INR
Log transformed INRAUC ratio
1.8
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
St John's
wort
Ginseng
Ginkgo
Ginger
Cranberry
Garlic
Jiang et al, Br J Clin Pharmacol 2004, 2005
MI Mohammed Abdul et al, 2006
Challenges with evidence related
to herb-drug interactions
 Many published studies lack rigorous design
 May not reflect how complementary medicines are
used in practice
 Not conducted in the patient group of interest
 Product quality and variability is a key concern
 Ginkgo biloba (based on EGb 761)
 St John’s wort (hyperforin content)
 Lack of surveillance on use (esp in combination)
Avoiding clinical significant herb-drug
interactions
o
o
o
o
comprehensive history is essential
review and assess evidence
appreciate health
monitor when herbs or drugs are started and
stopped
o …or doses increased
o understanding the likely time course of an
interaction
In conclusion….
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Complementary medicine use is increasing
Consider the patient perspective
Clinical risk management
Focus on the people most at risk
Investigating herb-drug interactions
 Understanding mechanisms
 Evidence of quality
 Quality of evidence
 Informed application of the evidence
Acknowledgments
HMREC
Prof Basil Roufogalis
Peter Coxeter
Dr Xuemin Jiang
Mohammed Abdul Mohi Iqbal
Dr Colin Duke
Dr Alaina Ammit
Dr Gray Peng
Cathy Rich
Claudia Kohlert-Schutt
St Vincent's Hospital
Sydney
Prof Ric Day
A/Prof Kenneth Williams
Dr Winston Liauw
Clinical trials staff
Vincent Fairfax Family Foundation
The National Health and Medical Research Council (NHMRC)
The University of Sydney
over 150 years of tradition
in education and research
“Show me a drug with no side effects and
I’ll show you a drug with no actions”
Sir Derrick Dunlop
Chairman, Committee on Safety of Drugs, UK founder of
the Yellow Card System 1964