Dr. Molinelli CLN Ask the Expert November 2015

When is therapeutic drug monitoring (TDM) needed in pediatric cancer chemotherapy?

There are several scenarios in which TDM is most useful, such as when the drug of interest has a narrow therapeutic index, the potential for serious or life-threatening- toxicity, or exhibits substantial intra and/or inter-patient pharmacokinetic variability. Pediatric cancer chemotherapy agents meet many of these criteria, though TDM is only used for a small number of them.

What are some commonly measured pediatric cancer chemotherapy drugs?

Methotrexate is an antimetabolite used widely in pediatric oncology for treating both hematologic and non-hematologic malignancy. In the cancer chemotherapy setting, clinicians typically prescribe methotrexate at high doses that carry a risk for severe toxicities such as mucositis, myelosuppression, and renal and liver dysfunction. After a period of exposure the patient is rescued with leucovorin (folinic acid) to protect normal cells. TDM of methotrexate typically starts 24 hours after therapy starts, with the results used to adjust the leucovorin dose.

Another drug is busulfan, an alkylating agent used in combination with other drugs prior to bone marrow transplantation. Busulfan has a very narrow therapeutic index and exhibits large inter-patient variability. If the busulfan exposure is too high, the risk of sinusoidal obstruction syndrome rises; if the concentration is too low, there is an increased risk of relapse. Pharmacokinetically-guided dosing of busulfan is integral to preventing these adverse effects.

Other commonly measured drugs include the mercaptopurines (azathioprine, 6-mercaptopurine, and 6-thioguanine), which are used to treat several childhood malignancies. These drugs undergo a complex metabolic pathway that involves several enzymes including thiopurine methyltransferase (TPMT). TPMT exhibits inherited variability -affecting mercaptopurine clearance, so knowledge of the TPMT genotype can guide proper dose selection prior to initiation of therapy. Monitoring thiopurine metabolites (6-thioguanine- and 6-methyl mercaptopurine nucleotides) is useful for optimizing the proper dose.

How are pharmacokinetic parameters different in neonates and children compared to adults?

Many changes in pharmacokinetic parameters occur with maturation. For example, neonates have higher gastric pH than adults, which affects the absorption of drugs. Factors such as the amount of fat tissue and total body water also affect drug distribution. In addition, metabolic enzymes mature over the course of infancy and childhood, leading to potential differences in the clearance of many drugs. Elimination can also be affected by renal function, which is very low at birth but increases during the first 9 months of life.

Why isn’t TDM for pediatric cancer chemotherapy more common?

For most cancer chemotherapy agents, even those meeting the criteria for TDM, current dosing practices focus on body-surface area and standardized dosing instead of pharmacokinetically-guided dosing. The reason for this has historical roots as well as practical considerations, including an incomplete understanding of the pharmacology and pharmacokinetics of many anticancer drugs in children.

Performing clinical outcome studies is difficult due to the significant lag time between drug exposure and response (e.g. complete remission), and many chemotherapy agents are used in combination, complicating the study of any individual drug’s effect. There are also laboratory considerations such as the requirement of advanced analytical instrumentation, low testing volumes versus high costs, and the need for properly timed collections. However, as more studies examining the use of TDM and clinical outcomes are published, and as advanced analytical instrumentation becomes more common in clinical laboratories, we could see more chemotherapy agents being considered for TDM.

Alejandro R. Molinelli, PhD, NRCC-CC, is director of the clinical pharmacokinetics laboratory at St. Jude Children’s Research Hospital in Memphis, Tennessee. +Email: [email protected]