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Re: Pharmacogenomic can give children safer medicines

Dear Editor

I read with great interest Clarkson and Choonara’s paper on the fatal suspected adverse drug reactions (ADRs) in the UK, and I strongly agree with their conclusions, namely that an evidence-based approach to drug therapy is needed to minimise fatalities due to drug toxicity in children.[1] However, recent evidence also suggests that we are now ready for a gene based approach to drug therapy allowing to further minimise the occurrence and the severity of adverse drug reactions.[2] Increasingly complex genetic knowledge can be already used to elucidate mechanisms underlying the adverse events of drugs, to identify biomarkers for physiological events, and potentially even to predict adverse events before human exposure.[3] In a recently published systematic review, the authors found that more than half of the drugs cited in ADR studies are metabolized by at least one enzyme with a variant allele known to cause poor metabolism, suggesting that genetic variability in drug metabolizing enzymes is likely to be an important contributor to the incidence and severity of ADRs.[4] In the Clarkson and Choonara’s paper it is reported that anticonvulsants was the group of drugs most frequently associated with fatal ADRs. Anticonvulsants are indeed among the drugs mostly concerned by enzymes with variant alleles associated with poor metabolism. A number of polimorfisms in the cytocrome P450 enzimes (CYPs), important in the metabolism of anticonvulsants have been reported. For example, the enzyme CYPIA2, which is one important metabolic pathway for carbamazepine and phenitoin, has only one identified variant allele with poor metabolism, but there is a significant prevalence of poor metabolisers for CYPIA2 among the general population. Other common polymorphisms concern the enzyme CYP2C19, resulting in altered metabolism of both phenobarbital and phenitoin.[5] Substantial investments are being made within the pharmaceutical and biotechnology industries to use genomic strategies for the development of therapeutic agents targeted for specific subgroups of the population. Such pharmacogenomic studies also permit a more rational and safer use of existing therapies. It is my hope that this translation of functional genomics into rational therapeutics will not neglect the right of children to receive safer and more efficient pharmacotherapy, and that the pace of this transformation will not be limited by the lack of adequate pharmacogenomic information to practicing paediatricians.

References

(1) Clarkson A, Choonara I. Surveillance for fatal suspected adverse drug reactions in the UK. Arch Dis Child 2002;87:462-7.

(2) Varmus H. Getting ready for Gene-Based Medicine. N Engl J Med 2002;347:1526-7.

(3) Meyer UA. Pharmacogenetics and adverse drug reactions. Lancet 2000;356:1667-71.

(4) Phillips KA, Veenstra DL , Oren E, et al. Potential Role of pharmacogenomics in reducing adverse drug reactions: a systematic review JAMA 2001;286:2270-9.

(5) Holmes L. The interface of preclinical evaluation with clinical testing of antiepileptic drugs: role of pharmacogenomics and pharmacogenetics. Epilepsy Research 2002 50;1-2:41-54.