Invasiveness Of Pharmacokinetics Studies In Children

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Pharmacokinetics Studies

Introduction

Pharmacokinetic studies generally should be performed to support formulation development and determine pharmacokinetic parameters in different age groups to support dosing recommendations. Relative bioavailability comparisons of pediatric formulations with the adult oral formulation typically should be done in adults. Definitive pharmacokinetic studies for dose selection across the age ranges of pediatric patients in whom the medicinal product is likely to be used should be conducted in the pediatric population.

Pharmacokinetic studies in the pediatric population are generally conducted in patients with the disease. This may lead to higher intersubject variability than studies in normal volunteers, but the data better reflect clinical use (Sonnichsen, 1995, pp. 99-107).

Discussion

Pharmacokinetic characteristics of an anti-neoplastic drug potentially influence its therapeutic and toxic effects in the individual patient by determining systemic exposure. Pharmacokinetic variability may partially account for inter individual differences in response. In fact, a correlation between drug disposition and toxicity or treatment outcome has been documented for a number of anti-neoplastic drugs with large inter individual pharmacokinetic variability. It is sensible to explore the possibilities of pharmacokinetically guided dosing of these drugs with the aim to achieve less toxicity and a better treatment outcome. Therapeutic drug monitoring after high-dose methotrexate infusion is a well-known example of successful application of pharmacokinetic information in standard clinical care. If the methotrexate concentration 48 h after infusion of high-dose methotrexate indicates an increased risk of toxicity, folinic acid rescue is intensified to prevent toxicity.

Analysis

In children with leukaemia and various solid tumours cyclophosphamide disappearance from plasma was mono-exponential with a median or mean elimination half-life between 3.2 and 4.1 h, and a median or mean total body clearance of 35.7 and 48.5 ml/(min m2), respectively, in different reports. Intra- and interindividual variability were large. A positive correlation between elimination half-life and dose was demonstrated in children, possibly caused by saturation of cyclophosphamide metabolism at higher drug concentrations. It should be noted that cyclophosphamide requires biotransformation to be activated to alkylating metabolites. Therefore pharmacokinetics of cyclophosphamide metabolites would be more relevant to know. However, pharmacokinetics of cyclophosphamide metabolites was only studied in a few children. Although a significant correlation between elimination half-life of cyclophosphamide and age could not be demonstrated within the paediatric population, half-life in children appeared to be shorter than previously reported in adults (Tasso, 1992, pp. 207-211).

Since cyclophosphamide has to be activated by biotransformation, an inverse correlation between cyclophosphamide systemic exposure and toxicity or response might be anticipated. However, studies on pharmacokinetic and pharmacodynamic correlations of cyclophosphamide in children have not been reported up till now. In adult women with metastatic breast carcinoma a smaller cyclophosphamide area under the concentration-time curve (AUC) was indeed associated with cardiotoxicity and longer duration of tumour response. In addition to the lack of data on pharmacokinetic and pharmacodynamic correlations of cyclophosphamide in children, there are no reports on pharmacokinetically guided, individualized dosing of cyclophosphamide in children (Table 1).

Table 1. Summary of pharmacokinetic considerations regarding alkylating agents

Clearance

Interactions that promote elimination

Interactions that inhibit elimination

Pharmacokinetic and -dynamic correlations

Individualized dosing

Cyclophosphamide

Primarily hepatic ...