Download Guidelines for predicting toxic doses of pharmaceuticals

Guidelines for predicting toxic
doses of pharmaceuticals for
children
Steve Tomlin
Project Team
Guy’s & St Thomas’
NHS Foundation Trust, London, UK
Medical Toxicology Unit
Bara V, Bates N, Edwards N,
Volans G, Wiseman H.
Pharmacy
Tomlin S
Hypothesis
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All medicines have the potential to cause harm in
children
This potential varies between different medicines
and is dose-related
If this potential can be assessed, the information
can be used to advise on the safety packaging of
medicines
Objectives
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To assess the feasibility of predicting a toxic dose
of a drug in children
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To assess the feasibility of deciding the need for
child- resistant packaging on the basis of the
toxicity
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To assess sources of information on therapeutic
and toxic doses of solid medications in children
under 5 years
– Infants under 6 months were not considered
Method
Study group evaluated:
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Usefulness of case reports from Poison Centres
and literature
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Usefulness of drug information from clinical trials
– e.g. maximum therapeutic dose
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Influence of paediatric pharmacology, product
formulation, and clinical factors
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Methods for extrapolating paediatric doses from
adult doses
Reasons why the guidelines aim to
determine a safe dose rather than a
toxic dose
I.
Greater effectiveness as a preventive measure.
2.
The potentially variable response to a toxic
dose.
3.
There are too few case reports.
Procedure for predicting the “No
Treatment Dose” - 1
1. Use the Maximum Tolerated Dose determined in
clinical trial
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The most suitable proxy measure for a safe dose
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The MTD is the highest dose that is safe to
administer to patients.
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There is unlikely to be an MTD for children
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Evaluating the reliability of case data:
factors to consider
Have doses been estimated?
Is the exact age or weight stated?
Is there laboratory data to confirm ingestion or dose?
How does the report compare with previous reports?
Could other toxins have influenced the clinical effects?
Are the clinical effects due to the medication?
Is the reporter reliable?
Are the clinical effects quantified? (eg heart rate)
Could underlying medical conditions have affected
response?
Procedure for predicting the “No
Treatment Dose” - 2
2. If the Maximum Tolerated Dose has not been
defined look for human case reports
Sources of data:
 Poison centres.
 Published literature.
 Sources of mortality data.
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If sufficient information is not available for the
drug under review, use case reports for structurally
and pharmacologically similar drugs.
Procedure for predicting the “No
Treatment Dose” - 3
3. If no other information is available, use the
normal Single Treatment Dose
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Single Treatment Dose (STD) is the highest single
starting dose.
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It does not depend on the indication or whether
subsequent doses would normally be titrated up or
down.
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If a paediatric STD is not available, then
extrapolate from the adult STD.
Assessment for Safe Packaging
Calculate the No Treatment Dose for a 6 month old.
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The dose that is safe for the lowest age group
being considered should be used.
– Average weight for a 6 month child is 7.5 kg.
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The outcome from this procedure is a mg/kg dose
estimated to be the maximum dose below which
medical intervention is not needed (NTD).
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Compare this dose with the size of solid dose
units available to decide the specific packaging
required.
Feasibility of predicting doses by
extrapolation from adult doses
The Weight Method
Adult dose (mg) = mg/kg dose
70kg
The Surface Area Method
Surface area of child (m2) x 100 = % of adult dose
1.73m2
Drug May Be Toxic
MTD in children
NTD
MTD in adults
NTD
Expert evaluation
paediatric data
MTD adult
70
NTD
Expert evaluation
adult data
MTD adult
70
NTD
structure & pharmacology
like other medicines *
STD in children
NTD
STD in adults
NTD
No Treatment Dose
Max Tolerated Dose
Single Treatment Dose
Example 1 - Olanzapine
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Adult MTD from Phase 1 trials = 20mg
in mg/kg is 20mg/70kg
= 0.28mg/kg
For child aged > 6months = 0.28mg/kg x 7.5kg = 2.1mg
One case report was found.
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10 mg Olanzapine in a 17kg produced pronounced CNS
depression. This amount is about 0.6mg/kg and is obviously well
above the MTD (NPIS London).
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Therefore the proposed NTD = 2.1mg
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Dose Units Available = 2.5mg, 5mg, 7.5mg and 10mg.
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One dose unit of any strength contains more than the NTD and is
potentially toxic to this age group.
Example 2 - Nifedipine
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No MTD has been established in children or adults
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Reviews of cases of more than 200 children (Belson et al., Droy
et al.,NPIS [London] case data) suggest 2mg/kg is likely to be a
realistic NTD in children.
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Proposed NTD for nifedipine = 2mg/kg.
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>6 months the NTD = 2mg/kg x 7.5kg = 15mg
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Dose units available = 10mg, 20mg, 30mg, 40mg, 60mg.
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Two 10mg dose unit or one of any of the higher strength dose units
would be above the NTD - potentially toxic
Conclusion
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It is feasible to assess the need for safety
packaging based on the maximum safe dose of a
drug.
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Data needs to be sought from a number of sources.
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Case reports from poisons centres are a key source
of information.
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Reliability of the data needs to be carefully
assessed by a panel of experts in clinical
toxicology and paediatric pharmacology.
Acknowledgement
This study was commissioned by
ANEC
European Association for Coordination of
Consumer Representation in Standardisation
ANEC Project Advisor
Dr Franz Fiala