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Andrew McLachlanFaculty of Pharmacy University of Sydney
Australia
Centre for Education and Research on AgeingConcord RG Hospital
Australia
Dangers in Herbs-Drug Interactions
Understanding mechanisms to inform management
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
52 %52 %49 %Total CAM user (at least one product)
2 %4 %4 %Homeopathic medicines2 %3 %2 %Chinese medicines4 %--Soy products
14 % 11% 9 %Mineral supplements21 %13 % 10 %Herbal medicines
39 %36 %38 %Vitamins (but not calcium or iron)
2004*2000*1993*CAM
*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.
Bruno JJ, Ellis JJ. Herbal use among US elderly: 2002 National Health Interview Survey. Ann Pharmacother. 2005
13% used at least 1 herbal supplements in the last 12 months
n=5860 aged above 65 years
US trends in the use of supplements
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 researchedE. ErnstEur 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
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
Study designs used to assess herb-drug interactions
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
Healthysubjects
Patients
Mechanism Cost Clinical Relevance
Ethical Issues
The need to establish qualityCONSORT 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.
o To investigate the potential herbal-drug interactions with warfarin
o To examine the effect of herbal medicines on clotting status
o Commonly used herbal medicineso St Johns wort, Asian ginsengo ginkgo biloba, gingero cranberry juice, garlic
Herb-drug interactions with warfarin
Jiang et al, Brit J Clin Pharmacol 2004, 2005,
o To investigate the potential herbal-drug interactions with warfarin
o To examine the effect of herbal medicines on clotting status
o Commonly used herbal medicineso St Johns wort
o cranberry juice
Herb-drug interactions with warfarin
Jiang et al, Brit J Clin Pharmacol 2004, 2005,
I will focus on these herbal medicines
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 warfarinFugh-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
Mueller et al, Clin Pharmacol Ther 2004
St John’s wort dose and preparation on herb-drug interaction with digoxin
TLC of Proprietary St John’s Wort Products
A: Hypericin; B: Pseudohypercin; C: Hyperoside; D: Rutin;No. 5: Use in the trial
-A
-B
-D
-C
TLC of different commercial St John’s wort
1 2 3 4 5 6(British Pharmacopoeia 2001)
Study Design
randomised, open label, three-treatment, three-sequence, crossover design
14-day washout periodsingle 25 mg dose of warfarin with or without treatment with herbal medicinesBlood samples collected at -48, -24, 0 and up to
168 h
Mechanisms of drug interactions
PHARMACOKINETIC
PHARMACODYNAMIC
PHARMACEUTICAL
S-warfarin S-7-hydroxywarfarin
Park et al, 1998
CYP2C9
Effect of St John’s wort and Asian ginseng on the Pharmacodynamics of Warfarin
0
1
2
3
4
-48 0 48 96 144 192Time (h)
INR
Warfarin+GS Warfarin only Warfarin+SJW
*P<0.05
*
Jiang et al, Brit J Clin Pharmacol 2004
St John's wort - Warfarin interaction
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
Cmax CL/F V/F AUC of INR
PK and PD parameters
90
% C
I of
log
-tra
ns
form
ed
ra
tio
S-warfarin PK data shown Jiang et al, Br J Clin Pharmacol 2004
St John's wort - Warfarin interaction
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
Cmax CL/F V/F AUC of INR
PK and PD parameters
90
% C
I of
log
-tra
ns
form
ed
ra
tio
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;329:27-30.
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;329:27-30.
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
Rindone and Murphy, Warfarin-Cranberry Juice Interaction Resulting in ProfoundHypoprothrombinemia and Bleeding. Am J Ther 13, 283–284 (2005)
Warfarin-cranberry interaction
0
20
40
60
80
100
120
140
160
Warfarin alone Warfarin and Cranberry
INR
resp
onse
(AUC
of I
NR o
ver 1
68 h
)
Randomsied cross-over clinical trial12 healthy male subjects25 mg warfarin dose +/- 2 weeks treatment with cranberry juice extract
MI Mohammed Abdul et al, 2006
* p =0.017
*33% increase in INR response
Effect of Cranberry Juice Extract on warfarin response
0
20
40
60
80
100
120
140
160
180
1 2
1= Warfarin only; 2 = Warfarin + cranberry
INR
resp
onse
(IN
R A
UC
ove
r 7 d
ays)
MI Mohammed Abdul et al, 2006
Cranberry - warfarin interaction
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
Cmax CL/F V/F AUC of INR
PK and PD Parameters
90%
CI
of
log
-tra
nsfo
rmed
rati
o
MI Mohammed Abdul et al, 2006
AUC of INR
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
St John'swort
Ginseng Ginkgo Ginger Cranberry Garlic
Lo
g t
ran
sfo
rmed
INR
AU
C r
atio
Pharmacodynamic Endpoint
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 comprehensive history is essentialo review and assess evidenceo appreciate health o monitor when herbs or drugs are started and
stoppedo …or doses increasedo understanding the likely time course of an
interaction
In conclusion….
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
HMRECProf Basil Roufogalis
Peter CoxeterDr Xuemin Jiang
Mohammed Abdul Mohi IqbalDr Colin Duke
Dr Alaina AmmitDr Gray Peng
Cathy RichClaudia Kohlert-Schutt
Vincent Fairfax Family Foundation
The National Health and Medical Research Council (NHMRC)
St Vincent's Hospital
Sydney
Prof Ric Day
A/Prof Kenneth Williams
Dr Winston LiauwClinical trials staff
The University of Sydneyover 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 DunlopChairman, Committee on Safety of Drugs, UK
founder of the Yellow Card System 1964