Estimating Pediatric Doses of Drugs Metabolized by Cytochrome P450 (CYP) Isozymes, Based on Physiological Liver Development and Serum Protein Levels

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We established a method for estimating pediatric doses of drugs metabolized by cytochrome P450 (CYP) isozymes, using the free fraction of drug in plasma (fu), serum protein level (P), liver volume (LV), and CYP activity (Vmax/Km) as indices of physiological and biochemical development in children up to 15 years old. This method allows the child/adult dose ratio (DC/DA)=child/adult oral clearance ratio (CL(PO)C/CL(PO)A) of drugs mainly metabolized in the liver to be estimated by the following equation: \\[ \\frac{D_C}{D_A} \\cong \\left( \\frac{1}{fu_A + (1 - fu_A) \\frac{P_C}{P_A}} \\right) \\cdot \\left( \\frac{BSA_C}{BSA_A} \\right)^{1.176} \\cdot \\left( \\frac{Vmax_C/Km_C}{Vmax_A/Km_A} \\right) \\] Major metabolism of drugs was ascribed to CYP1A2 for theophylline and caffeine, and CYP1A2 and CYP2D6 for propranolol and mexiletine. For theophylline and caffeine, CL(PO)C/CL(PO)A calculated from the child/adult body surface area ratio (BSA ratio) and the value calculated by our method were compared, using CL(PO)C/CL(PO)A calculated from the clearance ratio based on population pharmacokinetics (PPK ratio) as a reference. For all drugs, pediatric doses calculated from the Crawford equation and our equation were compared, with predetermined doses as the reference. For theophylline and caffeine, the relative accuracy of our method was significantly higher than that of BSA-based estimation when the PPK ratio was used for reference. For theophylline, caffeine, and propranolol, the relative accuracy of our method was significantly higher than that of BSA-based estimation when predetermined doses were used for reference. These findings indicate the validity of our method which considers the physiological and biochemical development (i.e., fu, P, LV, and CYP activity) for pediatric dose estimation.

Estimating Pediatric Doses of Drugs Metabolized by Cytochrome P450 (CYP) Isozymes, Based on Physiological Liver Development and Serum Protein Levels

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