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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 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 To assess the feasibility of predicting a toxic dose of a drug in children To assess the feasibility of deciding the need for child- resistant packaging on the basis of the toxicity 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: Usefulness of case reports from Poison Centres and literature Usefulness of drug information from clinical trials – e.g. maximum therapeutic dose Influence of paediatric pharmacology, product formulation, and clinical factors 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 The most suitable proxy measure for a safe dose The MTD is the highest dose that is safe to administer to patients. There is unlikely to be an MTD for children 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. 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 Single Treatment Dose (STD) is the highest single starting dose. It does not depend on the indication or whether subsequent doses would normally be titrated up or down. 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. 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. The outcome from this procedure is a mg/kg dose estimated to be the maximum dose below which medical intervention is not needed (NTD). 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 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. 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). Therefore the proposed NTD = 2.1mg Dose Units Available = 2.5mg, 5mg, 7.5mg and 10mg. One dose unit of any strength contains more than the NTD and is potentially toxic to this age group. Example 2 - Nifedipine No MTD has been established in children or adults 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. Proposed NTD for nifedipine = 2mg/kg. >6 months the NTD = 2mg/kg x 7.5kg = 15mg Dose units available = 10mg, 20mg, 30mg, 40mg, 60mg. Two 10mg dose unit or one of any of the higher strength dose units would be above the NTD - potentially toxic Conclusion It is feasible to assess the need for safety packaging based on the maximum safe dose of a drug. Data needs to be sought from a number of sources. Case reports from poisons centres are a key source of information. 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