Toxicological Assessment of Herbal and Traditional Herbal Medicinal Products: New Developments Olaf...

Toxicological Assessment of Herbal and Traditional Herbal Medicinal Products: New DevelopmentsOlaf KelberHead, Medical Science and Clinical ResearchSteigerwald Arzneimittelwerk GmbH, Darmstadt, Germany

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Overview / Content

New Developments, Literature Overview From ICH to Tradition: New European Regulations in Toxicology The European Herbal Medicines Directive Could it have saved the lives of Romeo and Juliet?(Routlege PA, Drug safety : an international journal of medical toxicology and drug experience; VOL: 31 (5); p. 416-8 /2008)

The New HMPC Genotoxicity Guideline Which studies to conduct?

News from Herbal GenotoxicityThe Example of the Collaborative Genotoxicity Study Project of the Kooperation Phytopharmaka – a surprising success

Perspectives

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New developments - Literature Overview

New developments - view of the scientific literature

Search in DIMDI(All toxicological databases)

Query: herb? toxic? medic?from 2008-2009

Total No. 483 hits

Manual Check for relatedness 90 hits

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New developments - Literature Overview

Search in DIMDI, results:

Low number of papers, no dynamic field of research

Detallied view necessary

Theme Toxicology, general

Hepato-toxicity

Other ARs Heavy Metal toxicity

Sum

Number 36 28 19 7 90

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New developments - Literature Overview

Search in DIMDI, results:

Toxicology, general

- Preclinical and clinical toxicological studies - Includes reviews (e.g. on ginger), in vitro studies - Mainly Indian Medicine, TCM - Also products for veterinary use (dogs, chickens)

Theme Toxicology, general

Hepato-toxicity

Other ARs Heavy Metal toxicity

Sum

Number 36 28 19 7 90

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New developments - Literature Overview

Search in DIMDI, results:

Hepatotoxicity

- Mainly reviews, only few case reports or studies - Incl. TCM, Indian Medicine, Nutraceuticals, Slimming Aids, Contaminated products (e.g. by Bacteria), Insufficiently defined products and reactions

Theme Toxicology, general

Hepato-toxicity

Other ARs Heavy Metal toxicity

Sum

Number 36 28 19 7 90

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New developments - Literature Overview

Search in DIMDI, results:

Other Adverse Reactions

- Incl. reviews covering also chemically defined preparations

- Preparations from TCM, Korea, Singapore, Ayurveda - Incl. Nutraceuticals (e.g. caffeine intoxication), Kava, Aristolochic acid, Black cohosh, Pyrroizidine alkaloids

Theme Toxicology, general

Hepato-toxicity

Other ARs Heavy Metal toxicity

Sum

Number 36 28 19 7 90

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New developments - Literature Overview

Search in DIMDI, results:

Heavy Metal Toxicity

- Mainly reviews of contaminations - Preparations from India and the US

Theme Toxicology, general

Hepato-toxicity

Othter ARs Heavy Metal toxicity

Sum

Number 36 28 19 7 90

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New developments - Literature Overview

Search in DIMDI, results:

Summary

- Mainly reviews

- Mainly Non-European preparations

- No new trends or surprises

Theme Toxicology, general

Hepato-toxicity

Other ARs Heavy Metal toxicity

Sum

Number 36 28 19 7 90

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EU Commission Overview of risk assessment methodologies, Opinion paper published January 2009

New developments - Europe

Critical assessment of methods

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New developments - Europe

Also thematizes limitations of methods

EU Commission Overview of risk assessment methodologies, Opinion paper published January 2009

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From ICH to Tradition

The ICH Toxicity Guidelines

Framework for the study of NCEs Created for the development of NCEs Substances with unknown risk profile Toxicological studies precede the studies

“first in man” resp. the market launch

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From ICH to Tradition

ICH Guidelines

Safety Guidelines

S1 Carcinogenicity

S2 Genotoxicity

S3 Toxico-/Pharmacokinetics

S5 Reproductive Toxicity

S7 Pharmacology

S8 Immunotoxicology

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From ICH to Tradition

ICH Guideline M 3:

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From ICH to Tradition

Example for a toxicological assessment plan for a WEU preparation: High use of resources and time (e.g. 7 years),

no adequate improvement of benefit-risk ratio

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From ICH to Tradition

THMPs and WEU HMPs

Long-standing experience of use in the popu-lation

Often clinical studies, covering clinical endpoints (including acute and chronic tolerability in man)

Substances with (more or less) well known pharmacological and toxicological profile

Toxicological studies follow the use “first in man” resp. the market launch.

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The EU Herbal Medicines Directive

Aim: Enable free trade within the EU

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The EU Herbal Medicines Directive

Aim: Protection of public health

CONFERENCE PAPER Drug Safety 2008:31(5):416-418

The European HerbalMedicines Directive Could it Have Saved the Lives of Romeo and Juliet?

Philip A. Routledge

Department of Pharmacology, Therapeutics and Toxicology, Wales College of Medicine, Heath Park, Cardiff, UK .

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The EU Herbal Medicines Directive

Aim: Protection of public health

Conclusion: No, as in this case, not lack in toxicological data, but lack in communication was causative for death.

CONFERENCE PAPER Drug Safety 2008:31(5):416-418

The European HerbalMedicines Directive Could it Have Saved the Lives of Romeo and Juliet?

Philip A. Routledge

Department of Pharmacology, Therapeutics and Toxicology, Wales College of Medicine, Heath Park, Cardiff, UK .

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The EU Herbal Medicines Directive

Report on the experience acquired (from 29.9.2008)

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The EU Herbal Medicines Directive

Report on the experience acquired (from 29.9.2008)

Genotoxicity data on a case-by case basis

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The HMPC Genotoxicity Guideline

In effect 01.12.2008

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The HMPC Genotoxicity Guideline

Scope:“For many herbal substances/preparations, contained in well established or traditional herbal medicinal products (HMPs), an adequate safety profile may be confirmed by their documented history of medicinal use. However, the complete lack of some specific non-clinical studies (e.g. genotoxicity studies) may present a safety concern because important questions relating to product safety would remain unanswered.”

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The HMPC Genotoxicity Guideline

“Pragmatic framework on how to assess the potential genotoxicity of HMPs”,

Stepwise test strategy:

1. Ames test

2. In case of positive results: mammalian cell assay

3. In case of another positive result: in vivo genotoxicity tests.

Negative results progressing to the nexttest step is not required.

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The HMPC Genotoxicity Guideline

Step 1: The Ames Test

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The HMPC Genotoxicity Guideline

Step 2: The Mouse Lymphoma Assay

Assay in L5178Y mouse lymphoma cells

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The HMPC Genotoxicity Guideline

Step 3: The In Vivo Test

Mouse lymphoma assay in bone marrow or peripheral blood cells

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The HMPC Genotoxicity Guideline

Summary

• Pragmatic approach

• Tests not contributing to a risk reduction in the patient are minimized

• In case of lack of specific concern still without relevant benefit for the patient

• Still a considerable burden in case of herbs of low economic importance

Importance of a collaborative approach

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The HMPC Concept Paper on Genotoxicity Testing

Bracketing andMatrixing as approach to collaborativeresearch

Testing of extremes of extraction solvent polarity for covering the whole range of preparations

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Genotoxicity Testing: Collaborative Approach

Example:

Genotox Project initiated by

Kooperation PhytopharmakaBonn, Germany

Scientific Society active in the field of herbal medicines

www.koop-phyto.org

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Genotoxicity Testing: Collaborative Approach

Aim of the project:- To provide pharmaceutical companies with

state of the art genotoxicity data for registration of Herbal and Traditional Herbal Medicinal Products

- To provide an economic way of conducting trials, using the advantages of a bracketing and matrixing concept in a collaborative approach

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Genotoxicity Testing of Koop. Phyto.

Bracketing and matrixing concept:Example: Hops (Humuli lupuli strobuli)

Extracts tested:polar Water

Methanol 45 %Ethanol 90 %

unpolar HeptaneThese solvents cover the whole range of polarity. Extrapolation to the whole range of extracts Extrapolaton also to drug powder preparations

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Genotoxicity Tests of Koop. Phyto.

- Coordinated collaborative approach

- Conduction in cooperation with GLP certified toxicological laboratories

- Methods according to all current guidelines (including OECD, ICH, EMEA)

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Genotoxicity Tests of Koop. Phyto.

Step 1: Ames test- Bacterial reverse mutation test, developed by

Bruce Ames, Univ. of California, Berkeley, 1970ff.- Salmonella typhimurium strains with defects in

gene(s) involved in histidine synthesis Growth depends on external histidine

- Mutations lead to accidental repair of defect gene Histidine independent growth

- Mammalian hepatic metabolism is mimicked with S9 Mix (enzyme fraction from rat liver)

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Genotoxicity Tests of Koop. Phyto.

Ames testOECD Guideline 471: Conduction in 5 different strainsdiffering in susceptibility to different mutagens

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Genotoxicity Tests of Koop. Phyto.

Ames testFigure: Counting of colonies using the Petri Viewer Mk2 (Perceptive Instruments) and the software program Ames Study Manager

Control: Negative Positive

TA 100

TA 1535

E. coli

Photographs: A

. Sokolow

ski,H

arlan R

CC

, Ro

ßd

orf, G

erman

y

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Genotoxicity Tests of Koop. Phyto.

Step 1: Ames test- For several herbal preparations, positive results

in Ames tests could not be reproduced in mammalian cell assays or in vivo assays

- These false positive results have been attributed mainly to the quercetin content of these herbal preparations

- Therefore the usefulness of the Ames test for testing herbal preparations has been questioned.

(Okpanyi S.N. et al., Arzneim.-Forsch./Drug. Res. 1990, 40 (II)): 851-855)

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Genotoxicity Tests of Koop. Phyto.

Herbal drugs tested:- Artichoke- Bittersweet- Stinging nettle- Marshmallow- Gingko- Ginseng- Hops- St. John´s wort- Garlic- Caraway- Pumpkin oil- Pine oil

- Milk thistle- Melissa- Mistle- Passiflora- Primrose- Rosmary- Horse Chestnut- Liquorice- Thyme- Whitethorn leaves and flowers- Whitethorn fruits- Devils claw

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Genotoxicity Tests of Koop. Phyto.

Results, example:

Negative results for a St. John´s wort extract.

Validated by inde-pendent testing in a second laboratory.

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Genotoxicity Tests of Koop. Phyto.

Conclusions:The project has broadened the knowledge about the safety of important herbs used in Europe and allows to meet current regulatory requirements.

The project unexpectedly has also shown that the safety profile of some herbs, previously under discussion, has to be re-rated as safe when tested by modern validated methods.

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Perspectives

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Perspectives

Harmonization with the US?Wu et al., Food Chem Toxicol 2008, 46:2606-2610

2008: FDA authorizes its first HMP (Veregen®)

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Perspectives

Harmonization with the US?Wu et al., Food Chem Toxicol 2008, 46:2606-2610

Demands of FDA in large parts identical with ICH guidelines for NCEs

From an European perspective, adequate acceptance of traditional or well established use is questionable

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Perspectives

New developments in the assessment of toxicological data and case reports?• Dose as a key issue• Critical consideration of pharmaceutical quality• Priority for clinical data and in vivo toxicological data, use of in vitro data only where adequate• Approach of transparent pragmatism, respecting traditional and well established use also in sub- groups of patients (e.g. children), and by physicians

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Thank you for your attention!

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