Optimization of immunosuppressive drug monitoring in children.
BACKGROUND
The metabolism of drugs in children differs from adults, although pediatric pharmacokinetic (PK) studies remain scarce. Many of the drugs are metabolized by polymorphically expressed enzymes (cytochrome P450 [CYP450]; glucuronyl transferase [GT]) and/or transported by drug transporters (ABC and SLC families). In children, there is added complexity because of the age dependency of drug metabolism. This review addresses the age dependency of drug metabolism in childhood on the basis of routine PK monitoring.


METHODS
Standard pharmacokinetic studies in pediatric renal transplant recipients were analyzed to study drug-drug interactions between mycophenolic acid and cyclosporine on the one hand, and tacrolimus and sirolimus on the other hand. The exposure was compared with age. We also studied sirolimus metabolites, both by mass spectrometry as well as using human liver microsomes.


RESULTS
We demonstrated age dependency for MPA exposure. Independent of the concomitant medication, infants required approximately twice as much drug for the same exposure. The drug-drug interaction between sirolimus and tacrolimus demonstrated age dependency. Sirolimus metabolites showed a remarkably different pattern in children. Whereas 39-O-desmethyl sirolimus is the most prevalent metabolite in adults, we found 77.5% hydroxylated metabolites in children. Similarly, pediatric human liver microsomes produced 86.1% hydroxylated metabolites.


CONCLUSIONS
Our long-term objective is to develop evidence-based guidelines for age-appropriate drug dosing of all drugs commonly used during childhood and adolescence, based on pharmacokinetically/pharmacogenetically determined drug exposure to maximize therapeutic yield while minimizing toxicity. The potential need for lifelong medications warrants efforts to minimize toxicity in chronically ill pediatric patients.
Filler
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Department of Paediatrics, Children's Hospital of Western Ontario, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada. guido.filler@lhsc.on.ca
D000367:Age Factors; D002648:Child; D002851:Chromatography, High Pressure Liquid; D016572:Cyclosporine / Q000493:pharmacokinetics; D004347:Drug Interactions; D016903:Drug Monitoring / Q000379:methods*; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D009173:Mycophenolic Acid / Q000493:pharmacokinetics; D020123:Sirolimus / Q000493:pharmacokinetics; D016559:Tacrolimus / Q000493:pharmacokinetics
D007166:Immunosuppressive Agents; D016572:Cyclosporine; D009173:Mycophenolic Acid; D020123:Sirolimus; D016559:Tacrolimus