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