• William C Zamboni, Sanjay Goel, Tahir Iqbal, Robert A Parise, Sandra Strychor, Trisha V W Repinski, Merrill J Egorin, and Sridhar Mani.
• Program of Molecular Therapeutics and Drug Discovery, University of Pittsburgh Cancer Institute, Pittsburgh, PA, 15213, USA. zamboniwc@upmc.edu
• Cancer Chemother. Pharmacol. 2006 May 1; 57 (5): 631-9.

Background9-Nitrocamptothecin (9NC) is an orally administered camptothecin analogue that has completed phase III trials for pancreatic cancer. In biological matrices, camptothecin analogues exist in equilibrium between the active-lactone (LAC) and inactive-hydroxy acid (HA) forms. 9NC has been administered on an empty stomach; however, it is unclear if food alters the absorption and disposition of 9NC and its 9-aminocamptothecin (9AC) active-metabolite. Thus, we evaluated the disposition of 9NC and 9AC after administration of 9NC under fasting conditions and after a standard meal.MethodsPatients were randomized to receive 9NC as a single oral dose at 1.5 mg/m(2) with 8 ounces (oz) of an acidic beverage under fasting conditions, or after a meal consisting of two eggs, 8 oz of orange juice, buttered toast, 8 oz of milk, and 4 oz of hash brown potatoes. Following a 72 h washout period, 9NC was administered with the alternative condition (i.e., with food or fasting). 9NC was then continued for 5 days of every week. Serial blood samples were obtained prior to and from 0.25 to 24 h after administration of 9NC. The total (sum of LAC + HA) of 9NC and 9AC were measured by an LC-MS/MS assay. Area under the plasma concentration versus time curve (AUC) for 9NC and 9AC total were calculated. After the pharmacokinetic section of the study, patients received 9NC 1.5 mg/m(2) orally under fasting conditions daily for 5 days per week for 8 weeks.ResultsSixteen patients with median (range) age 62 (47-83) years, diagnoses of colorectal (six patients), lung (two patients), and other (eight patients) malignancies, received 83 [median (range) 4 (2-9)] weeks of therapy. Patients with toxicities greater than grade 2: were diarrhea (1), nausea (2), vomiting (2), fatigue (2), anemia (3), neutropenia (3), and febrile neutropenia (2). Three patients (lung, unknown primary, and colon) had stable disease for eight weeks. The mean+/-SD of 9NC AUC(food) and 9NC AUC(fast) (n=9) were 330+/-182 and 558+/-379 ng/ml.h, respectively (P<0.05). The mean+/-SD of 9AC AUC(food) and 9AC AUC(fast) (n=9) were 244+/-60 and 256+/-101 ng/ml.h, respectively (P>0.05). The mean +/- SD ratio of 9NC AUC(food) to AUC(fasting) in individual patients (n=9) was 0.67+/-0.22. The mean +/- SD ratio of 9AC AUC(food) to AUC(fasting) in individual patients (n=9) was 1.14+/-0.61.ConclusionsCo-administration of 9NC with food reduces the oral absorption of 9NC; however, there was no difference in the exposure of 9AC. The is high interpatient variability in the effect of food on the absorption of 9NC and the interpatient variability in the effect of food on the disposition of 9AC is even greater when compared to 9NC.

22 keywords...

hide…