Abstract Purpose: Dactinomycin (actinomycin D) is an antitumor antibiotic used routinely to treat certain pediatric and adult cancers. Despite concerns over the incidence of toxicity, little is known about the pharmacology of dactinomycin. A study was done to investigate dactinomycin pharmacokinetics in children. Experimental Design: Dactinomycin was administered to 31 patients by bolus i.v. infusion, at doses of 0.70 to 1.50 mg/m2. Plasma concentrations were determined by liquid chromatography-mass spectrometry up to 24 hours after drug administration and National Cancer Institute Common Toxicity Criteria was assessed. Results: Pharmacokinetic data analysis suggested that a three-compartment model most accurately reflected dactinomycin pharmacokinetics. However, there was insufficient data available to fully characterize this model. A median peak plasma concentration (Cmax) of 25.1 ng/mL (range, 3.2-99.2 ng/mL) was observed at 15 minutes after administration. The median exposure (AUC0-6), determined in 16 patients with sampling to 6 hours, was 2.67 mg/L.min (range, 1.12-4.90 mg/L.min). After adjusting for body size, AUC0-6 and Cmax were positively related to dose (P = 0.03 and P = 0.04, respectively). Patients who experienced any level of Common Toxicity Criteria grade had a 1.46-fold higher AUC0-6, 95% confidence interval (1.02-2.09). AUC0-6 was higher in patients <40 kg, possibly indicating a greater toxicity risk. Conclusions: Data presented suggest that dosing of dactinomycin based on surface area is not optimal, either in younger patients in whom the risk of toxicity is greater, or in older patients where doses are capped.
The impact of p53 status on cellular sensitivity to antifolate drugs has been examined in seven human cell lines (A549, MCF7, T-47D, CCRF-CEM, COR-L23, A2780, and HCT-116) and p53 nonfunctional counterparts of two of the cell lines (HCT-116/N7 and A2780/CP70). p53 status was determined by sequencing and functional assays. The sensitivities of the cell lines to growth inhibition (sulphorhodamine B assay) produced by four antifolate drugs (Alimta, methotrexate, raltitrexed, and lometrexol) were studied. There was no clear relationship between functional p53 status and sensitivity to methotrexate or lometrexol, whereas a functional p53 status was possibly associated with resistance to Alimta- and raltitrexed-induced growth inhibition. In contrast, in the two pairs of related human tumor cell lines (HCT-116 and HCT-116/N7 and A2780 and A2780/CP70) cells with functional p53 were more sensitive to Alimta- and raltitrexed-induced growth inhibition (P = 0.002). Detailed studies were performed with the A2780 cell lines, and in the parental cells sensitivity to Alimta- and raltitrexed-induced cytotoxicity (clonogenic assay) was similar to the sensitivity determined in the sulphorhodamine B assay. However, in A2780/CP70 cells, 1 microM of drug resulted in only 40-60% growth inhibition yet > or = 85% cytotoxicity. After Alimta and raltitrexed exposure for < or = 72 h, there were no differences between the A2780 and A278/CP70 cell lines in cell cycle phase distribution, absolute cell number, or the induction of apoptosis. However, the cellular protein content of the A2780/CP70 cells was 3-6-fold higher than in A2780 cells after Alimta and raltitrexed treatment, suggesting that cells without functional p53 can maintain protein synthesis in the absence of cell division (unbalanced cell growth). In conclusion, the apparent impact of functional p53 status on sensitivity to antifolate drugs may depend upon the phenotypic/genotypic background as well as the assay used to measure cellular sensitivity.
Abstract 13-cis-retinoic acid (13cisRA) is now an established part of the clinical treatment of high-risk neuroblastoma. However, the efficacy observed with the current regimen contrasts with a lack of clinical benefit reported with low dose 13cisRA, suggesting that drug exposure may be a key factor determining response. We have previously published data showing significant interpatient variation in 13cisRA pharmacokinetics and extensive drug metabolism, with many patients achieving potentially sub-therapeutic plasma concentrations. The current study was carried out to investigate the feasibility of 13cisRA pharmacokinetic dose individualisation to achieve peak plasma concentrations >2µM in all patients. 13cisRA (80 mg/m2 b.d. or 5.33 mg/kg/day for children <12kg) was administered orally to 30 children and plasma concentrations of parent drug and metabolites determined by HPLC analysis at 0,1,2,4 and 6h on day 14 of course 1 of treatment. Dose increases of 25% and 50% were implemented on course 2 for patients who achieved peak plasma concentrations of <2 µM and <1µM, respectively. Where dose increases were implemented, plasma concentrations were again analysed on day 14 of course 2 at the increased dose level. 13cisRA was extracted from capsules and administered with food in 15 patients and by nasogastric tube in 9 patients. The remaining 6 patients were able to swallow the capsules. Peak plasma concentrations determined on course 1 ranged from 0.6 – 11.2 µM, with a total of 10 patients (33%) achieving peak plasma concentrations below the target level of 2µM. Dose increases were carried out in 9 of these 10 patients, with peak plasma concentrations >2µM achieved on course 2 in 7 patients (78%) and following a further dose increase on course 3 in an additional patient. The remaining patient did not achieve plasma concentrations >2 µM despite several dose increases. The patient cohort included a total of 8 infant patients, with 7 (88%) of these patients failing to achieve peak plasma concentrations >2µM at a reduced dose level of 5.33mg/kg. Dose increases implemented in all 7 of these patients led to plasma concentrations >2µM on course 2 of treatment, with increased doses well tolerated in all cases. All 6 patients who swallowed 13cisRA capsules achieved plasma concentrations >2µM, as compared to 8/15 (53%) and 6/9 patients (67%) when the drug was extracted and mixed with food or administered via nasogastric tube, respectively. These data indicate the feasibility of 13cisRA pharmacokinetic dose individualisation and suggest that reduced dosing should not be implemented for children <12kg. Individualisation of dosing may be particularly beneficial for children unable to swallow capsules, who require the drug to be extracted and mixed with food prior to administration. This study will continue to recruit patients to investigate the potential long-term clinical benefit of 13cisRA pharmacokinetic dose individualisation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4348. doi:10.1158/1538-7445.AM2011-4348
Background: BT1718 is a novel bicyclic peptide anticancer drug targeting membrane type I matrix metalloproteinase to release its toxic payload DM1. A LC–MS/MS method was validated to quantify DM1 generated from BT1718 in a Phase I/IIa clinical trial. Materials & methods: Plasma samples underwent a reduction reaction to artificially cleave BT1718 into DM1 and its bicycle components. An alkylation step was carried out to stabilize the reaction products, and plasma proteins extracted using acetonitrile. LC–MS/MS analysis utilized a C18 column and Agilent 6460 triple quadrupole mass spectrometer (Agilent, Cheshire, UK). Results: The method was fully validated over a linear range of 200–50,000 ng/ml BT1718, with overall precision ≤10% and accuracy 89–102%. Conclusion: A novel method for quantifying DM1 yielded from BT1718 has been validated and is now being utilized clinically.
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