Pharmacokinetics and pharmacogenetics of 13-cis-retinoic acid in the treatment of neuroblastoma.
There are a number of factors relating to the clinical pharmacology of 13-cis-Retinoic Acid (13-cisRA) which, taken together, provide a strong case for the potential benefit of a therapeutic monitoring approach to ensure that uniform plasma concentrations of 13-cisRA are achieved in all patients. Firstly, low dose, continuous use of 13-cisRA has been shown to provide limited or no clinical benefit in neuroblastoma patients, whereas a high-dose, intermittent regimen resulted in a significant improvement in event-free survival. This suggests that dose levels and therefore plasma concentrations of drug are important determinants of 13-cisRA efficacy. Secondly, the currently used 13-cisRA dosing regimen of 160 mg/m(2)/day results in a >10-fold variation in plasma concentrations, with plasma concentrations observed in a significant percentage of patients below those required for activity in neuroblastoma cells in vitro. Importantly, there would appear to be limited intra-patient variation in 13-cisRA plasma concentrations, i.e. those patients with lower 13-cisRA plasma concentrations following a single dose of 13-cisRA are likely to have similarly low concentrations following all doses of 13-cisRA on subsequent courses. As 13-cisRA is given as chronic treatment, those patients experiencing lower plasma concentrations on the current dosing regimen will potentially be exposed to sub-therapeutic concentrations of drug for the entire 6 month treatment period. While this type of pharmacokinetic monitoring approach may prove to be beneficial in the short term, an increased knowledge of pharmacogenetic factors influencing to the metabolism of 13-cisRA may ultimately allow us to identify patients who may be less likely to benefit from treatment due to an increased rate of parent drug metabolism. In this respect, pharmacogenetic studies assessing the relative expression levels or mutations in enzymes such as cytochrome P450 (CYP) and particularly CYP26 are needed to assess any potential association with rate of metabolism in vivo.
Veal
Gareth
G
Northern Institute for Cancer Research, Newcastle University, Framington Place, Newcastle upon Tyne, United Kingdom.
Rowbotham
Sophie
S
Boddy
Alan
A
D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D015474:Isotretinoin / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy / Q000235:genetics; D009447:Neuroblastoma / Q000188:drug therapy* / Q000235:genetics; D010597:Pharmacogenetics
D000970:Antineoplastic Agents; D015474:Isotretinoin