Drug administration and blood sampling for pharmacokinetic studies in pediatric cancer patients

This thesis focuses on drug administration and blood sampling for pharmacokinetic studies in pediatric cancer patients. Only about one third of the drugs used to treat children have been adequately tested with sufficient information regarding safety and efficacy for pediatric patients. The European regulation has led to a focus on preclinical and clinical trials within the pediatric population. A prerequisite for a quality assurance of trials is a standardized drug administration and suitable blood sampling procedures.

We have shown that blood sampling from the central venous access can be used under certain circumstances for therapeutic drug monitoring of methotrexate. However, carefully evaluated standardized instructions regarding rinsing and flushing after drug administration is required if blood samples for drug concentrations should be withdrawn from the central venous access. The importance of minimizing the total discarded blood volume, i.e. waste volume and sampling volume when using the central venous access has to be emphasized.

A standardized routine for intravenous drug administration was developed enabling an exact time point for start and cessation of the intravenous infusion which is crucial when blood sampling is performed solely after the infusion. A standardized short time infusion was used for studying the pharmacokinetics of tobramycin which revealed that dosing of tobramycin based on body surface area appears to be more consistent than dosing based on body weight. Furthermore, our pharmacokinetic findings enable a possibility to adjust the dose to obtain a predetermined target values of systemic drug exposure (AUC) and AUC:MIC ratio. The influence of the infusion time of the maximum serum concentration of tobramycin can be predicted from the determined pharmacokinetic data with the possibility to control the peak concentration without affecting AUC.

The standardized drug administration enabled the possibility to develop a limited sampling strategy for estimation of the tobramycin AUC. One blood sample gives an accurate estimate of the AUC enabling a valuable tool in therapeutic drug monitoring and for pharmacokinetic studies in large groups of pediatric patients. The actual sampling time is of great importance while a minor deviation in the infusion time is of less significance for the estimation of AUC using the developed limited strategy.

Despite the importance of reducing painful procedures capillary blood sampling can be suitable for pharmacokinetic studies of doxorubicin using a limited sampling strategy based on one concentration measurement at each treatment occasion in pediatric patients. In summary, this thesis has highlighted important areas to be considered when performing pharmacokinetic studies in children.

List of scientific papers

I. Ritzmo C, Albertioni F, Cosic K, Söderhäll S, Eksborg S (2007). Therapeutic drug monitoring of methotrexate on the pediatric oncology ward: can blood sampling from central venous accesses substitute for capillary finger punctures? Ther Drug Monit. 29(4): 447-51
https://pubmed.ncbi.nlm.nih.gov/17667799

II. Ritzmo C, Söderhäll S, Eksborg S (2009). Pharmacokinetic studies in pediatric cancer patients standardization of intravenous drug administration. [Manuscript]

III. Ritzmo C, Eksborg S, Kalin M, Söderhäll S, Jakobson Å (2009). Pharmacokinetics of tobramycin after an intravenous short time infusion in paediatric cancer patients. [Submitted]

IV. Ritzmo C, Jakobson Å, Söderhäll S, Eksborg S (2009). Limited sampling strategy for estimation of the tobramycin area under the serum concentration versus time curve after an intravenous short time infusion. [Manuscript]

V. Palm C, Björk O, Björkholm M, Eksborg S (2001). Quantification of doxorubicin in plasma--a comparative study of capillary and venous blood sampling. Anticancer Drugs. 12(10): 859-64
https://pubmed.ncbi.nlm.nih.gov/11707655

VI. Ritzmo C, Söderhäll S, Karlén J, Nygren H, Eksborg S (2007). Pharmacokinetics of doxorubicin and etoposide in a morbidly obese pediatric patient. Pediatr Hematol Oncol. 24(6): 437-45
https://pubmed.ncbi.nlm.nih.gov/17710661