Starting or Strengthening a Drug Bulletin - A Practical Manual
(2005; 165 pages) View the PDF document
Table of Contents
View the documentPreface
View the documentHow the manual was produced
View the documentAbout ISDB
View the documentExecutive summary
Open this folder and view contents1. Introduction
Open this folder and view contents2. Rational use of medicines
Open this folder and view contents3. What are drug bulletins?
Open this folder and view contents4. Defining aims, target and type of bulletin
Open this folder and view contents5. Planning resources
Open this folder and view contents6. Planning bulletin production: schedules and timing
Open this folder and view contents7. The editorial process
Open this folder and view contents8. Reviewing a new drug: is it a therapeutic advance?
Close this folderAnnexe to Chapter 8: Evaluating harm
View the document8.An-1 Talk about harm, not risk
View the document8.An-2 Assessment of causation of a harmful effect
Close this folder8.An-3 Assessing coherence with preclinical data
View the document8.An-3.1 General principles
View the document8.An-3.2 Chemical structure of new drugs
View the document8.An-3.3 Considering the profile of adverse effects
View the document8.An-3.4 Ratio of toxic and efficacy level in the same animal
View the document8.An-3.5 Extrapolation of animal toxicity (safety) level to humans
View the document8.An-4 References
Open this folder and view contents9. Design and production
Open this folder and view contents10. Dissemination
Open this folder and view contents11. Organizational and legal issues
Open this folder and view contents12. Evaluating quality and usefulness
Open this folder and view contents13. Partnership and collaboration
Open this folder and view contents14. Keeping records and creating a memory
Open this folder and view contentsAppendix: Electronic sources of information
 

8.An-3.5 Extrapolation of animal toxicity (safety) level to humans

a) Do not use mg/kg

b) Use Area Under the Curve (AUC)

c) If AUC is not available, then use mg/m2 (mg/kg factor 9 for mice, mg/kg factor 6 for rats).

AUC is considered the most comprehensive pharmacokinetic endpoint since it takes into account the plasma concentration of the compound and residence time in vivo (ICH-S1C7, 8,9). Search for AUC of the active ingredient (preferably the unbound agent) both in animals (at the maximum non-toxic dose) and humans (at the usual clinical dose). The ratio of the two is the most important safety parameter of the drug. If it is below 1 for subacute and/or chronic toxicity tests, the agent will probably be very harmful if it is used for more than three months (e.g. pioglitazone10 [see Box 8.13] - and gefitinib11). If the ratio is about 1 to 3 for subacute and/or chronic toxicity test, the drug may possibly be very harmful if it is used for more than three months (e.g. the ratio for cerivastatin was almost 2).

Box 8.13 How toxicity data from animals can be used to predict clinical effects (toxicity). Example 1: pioglitazone5, 10

1. In rats, the dose of pioglitazone causing hypoglycaemia (3.0mg/kg/day) is about the same as that causing chronic toxicity (3.6 mg/kg/day).

2. One of the most important findings is cardiotoxicity, including

• cardiac hypertrophy (safety level is 0.9 mg/kg/day and toxic level is 3.6 mg/kg/day)
• cardiomyopathy with focal necrosis, cardiac/pulmonary weight increase and/or lung haemorrhage (safety level is 3.6 mg/kg/day and toxic level is 14.5 mg/kg/day).


3. These findings are important in interpreting the adverse events of pioglitazone. Myocardial infarction and/or heart failure later emerged as one of the most important adverse reactions to pioglitazone.

Contributed by Rokuro Hama, Kusuri-no-Check, Japan [http://www.npojip.org].

In Japan, the data cited above can be found in the New Drug Approval Package (NAP) which may be available within a few months of approval of marketing of a drug. The data are available on the Internet (Japan Pharmacists Education Center: http://www.jpec.or.jp/) and/or can be read as a paper document (in Japanese only). Boxes 8.14 and 8.15 show two more examples of how toxicity data in animals may predict toxic effects in humans.

Box 8.14 How toxicity data from animals can be used to predict clinical effects (toxicity). Example 2: fluticasone12

We received important animal toxicity data showing that inhalation of 200 micrograms of fluticasone over 52 weeks induced adrenal atrophy in dogs. Inhalation of 200 micrograms of fluticasone by a dog weighing 12 kg is equivalent to 400 micrograms/day for a human, which is within the clinical dose range.

While only 13% of prescriptions for inhaled corticosteroids were for fluticasone, 94% of the patients with adrenal crisis had used fluticasone. It was concluded that clinical doses of fluticasone may induce adrenal insufficiency, although all the reported cases used more than the recommended dose.

A paediatrician on our advisory board had a case of adrenal insufficiency associated with use of inhaled fluticasone propionate (FP). He asked how to analyse the paper reporting the epidemiological study on adrenal crisis and inhaled corticosteroids. The paper shows a very close relationship between adrenal crisis and FP. We examined the pharmacokinetics of FP in animals and in humans and also the chronic inhalation toxicity tests. These data indicated that FP has binding affinity to corticosteroid receptors that is 18 times more potent than for dexamethasone; it has an elimination half-life about 2.4 - 3 times longer (14.4 vs. 5-6 hr.) and within the usual clinical dose (400 micrograms/day) induces histologically observed adrenal atrophy in dogs. The trough level of FP rose above the detection threshold after 1 week in the phase I study. Within 6 months, several patients treated with the usual clinical dose of inhaled FP became non-responders when tested with adrenocorticotropic hormone (ACTH).

Contributed by Rokuro Hama, Kusuri-no-Check, Japan [http://www.npojip.org].

Box 8.15 How toxicity data from animals can be used to predict clinical effects (toxicity). Example 3: tacrolimus13,14

There are no definite data for carcinogenicity in humans from using tacrolimus (Protopic) ointment, because no large long-term randomised controlled trials have yet been done. But we have a 2-year mouse carcinogenicity study using 0.03% and 0.1% tacrolimus with sham and vehicle-only control, with toxicokinetic data including area under the curve (AUC), and human pharmacokinetic data including AUC.

The lower concentration (0.03%) induced more cancer (all sites) than the vehicle-only control. So it could induce malignancy in long-term clinical use. It seems reasonable to think that small infants may be more affected than adults.

On 26 June 2003, the Advisory Committee to the Japanese Ministry of Health, Labour and Welfare decided to include warnings on a potential cancer risk associated with tacrolimus ointment use, in response to the petition by Kusuri-no-Check and The Informed Prescriber13 insisting that cancer development can be expected considering the animal carcinogenicity tests and concentration of tacrolimus in the patients treated with it.

On 10 March 2005, the U.S. Food and Drug Administration (FDA) advised health professionals to prescribe Elidel (pimecrolimus) and Protopic (tacrolimus) only as directed and only after other eczema treatments have failed to work because of a potential cancer risk associated with their use. In addition, the FDA is adding a black box warning to the health professional label for the two products and developing a medication guide for patients.

These actions follow the recommendations made by the FDA’s Pediatric Advisory Committee at its 15 February 2005 meeting,14 which reviewed findings of cancer in three different animal species. The data showed that the risk of cancer increased with the amount of the drug given, although only a few cancers had been reported in children and adults treated with Elidel or Protopic. Most of the cancers might be first apparent after several years of marketing.

On 18 May 2005, the EMEA also began to investigate the potential cancer risk of Elidel (pimecrolimus) and Protopic (tacrolimus).15

Contributed by Rokuro Hama, Kusuri-no-Check, Japan [http://www.npojip.org].

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