CLINICAL PHARMACOKINETICS OF IRINOTECAN

This article reviews the clinical pharmacokinetics of a water-soluble analogue of camptothecin, irinotecan {CPT-11 or peridino)-1-piperidino ]-carbonyloxy-camptothecin}. Irinotecan, and its more potent metabolit e SN-38 (7-ethyl-10-hydroxy-camptothecin), interfere with mammalian DN A topoisomerase I and cancer cell death appears to result from DNA str and breaks caused by the formation of cleavable complexes. The main cl inical adverse effects of irinotecan therapy are neutropenia and diarr hoea. Irinotecan has shown activity in leukaemia, lymphoma and the fol lowing cancer sites: colorectum, lung, ovary, cervix, pancreas, stomac h and breast,Following the intravenous administration of irinotecan at 100 to 350 mg/m(2) mean maximum irinotecan plasma concentrations are within the 1 to 10 mg/L range. Plasma concentrations can be described using a 2- or 3-compartment model with a mean terminal half-life rangi ng from 5 to 27 hours. The volume of distribution at steady-state (V-S S) ranges from 136 to 255 L/m(2) and the total body clearance is 8 to 21 L/h/m(2). Irinotecan is 65% bound to plasma proteins. The areas und er the plasma concentration-time curve (AUG) of both irinotecan and SN -38 increase proportionally to the administered dose, although interpa tient variability is important. SN-38 levels achieved in humans are ab out 100-fold lower than corresponding irinotecan concentrations, but t hese concentrations are potentially important as SN-38 is 100- to 1000 -fold more cytotoxic than the parent compound. SN-38 is 95% bound to p lasma proteins. Maximum concentrations of SN-38 are reached about 1 ho ur after the beginning of a short intravenous infusion. SN-38 plasma d ecay follows closely that of the parent compound with an apparent term inal half-life ranging from 6 to 30 hours. In human plasma at equilibr ium, the irinotecan lactone form accounts for 25 to 30% of the total a nd SN-38 lactone for 50 to 64%. Irinotecan is extensively metabolised in the liver. The bipiperidinocarbonylxy group of irinotecan is first removed by hydrolysis to yield the corresponding carboxylic acid and S N-38 by carboxyesterase. SN-38 can be converted into SN-38 glucuronide by hepatic UDP-glucuronyltransferase. Another recently identified met abolite is 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-cnrbo nyloxy-camptothecin (APC). This metabolite is a weak inhibitor of KB c ell growth and a poor inducer of topoisomerase I DNA-cleavable complex es (100-fold less potent than SN-38). Numerous other unidentified me t abolites have been detected in bile and urine. The mean 24-hour irinot ecan urinary excretion represents 17 to 25% of the administered dose. Recovery of SN-38 and its glucuronide in urine is low and represents I to 3% of the irinotecan dose. Cumulative biliary excretion is 25% for irinotecan, 2% for SN-38 glucuronide and about 1% for SN-38. The phar macokinetics of irinotecan and SN-38 are not influenced by prior expos ure to the parent drug. The AUC of irinotecan and SN-38 correlate sign ificantly with leuco-neutropenia and sometimes with the intensity of d iarrhoea. Certain hepatic function parameters have been correlated neg atively with irinotecan total body clearance. rt was noted that most t umour responses were observed at the highest doses administered in pha se I trials, which indicates a dose-response relationship with this dr ug. In the future, these pharmacokinetic-pharmacodynamic relationships will undoubtedly prove useful in minimising the toxicity and maximise the likelihood of tumour response in patients.