20 PHARMACOLOGY

Intermittent administration of tretinoin advantageous

Administering tretinoin [all-trans-retinoic acid; ATRA] according to an intermittent schedule 'appears to circumvent the low plasma drug exposure that is a result of the sustained upregulation of metabolism when this drug is administered on a chronic daily schedule', note researchers from the US.

33 patients aged ~ 21 years who had cancer refractory to conventional antineoplastic therapy were followed in this study. They received SC interferon-cx-2a 3 x 1()6 U/m2/day for 5 consecutive days per week and oral tretinoin 60 mglm2/day (increased to a maximum of 120 mglm2/day) for 3 consecutive days per week. The total duration of therapy was 4 weeks.

IntenniHent schedule advantageous The researchers note that there was considerable

interpatient variability in tretinoin concentrations across all dose levels. AUC appeared to increase in a dose-dependent fashion. By day 3 of tretinoin administration, the plasma tretinoin AUC had declined to 6% of the day 1 AUC. However, by day 1 of each subsequent week of tretinoin therapy, the AUC had returned to the initial value.

The researchers add that 'there appears to be a pharmacokinetic advantage to this intermittent ATRA administration schedule, because it allows for periodic exposure to high concentrations of ATRA '.

Four patients experienced dose-limiting neurotoxicity. One patient achieved an objective response and 2 patients experienced stabilisation of disease. Another patient also appeared to have disease stabilisation, and was found to have hamartoma indicative of a differentiated Wilms' tumour. Adamson PC, Reaman G, Finldestein rz.. Feusner J, Bo-g S1., et aI. I'Ilase I trial and pharmacokinetic study of aJI-trans-retinoic acid administered on an intermittent

schedule in combinaIion with intcrfcmn-a2a in pediatric patients with refractory cancer. Journal ofOinical Oncology 15: 3330-3337. Nov 1997 """""'"

Inphanna-20 Dec 1887 No. 111. 1173-832419711118-0002OIS01 .rxf' Adlalntemetlonal Limited 1887. All rlghta-*