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We have conducted a clinical and pharmacokinetic trial of the novel podophyllotoxin derivative NK611 administered orally for 21 consecutive days. The treatment was repeated every 35 days. Eighteen patients were included into the study, all of whom were eligible. Due to early progression of tumor disease in two patients, 16 patients were evaluable for toxicity [7 female, 9 male, median age 64 years (range: 44 to 73)]. Dose escalation steps were 5 mg/day [105 mg per cycle (pc)], 10 mg/day (210 mg pc), 12.5 mg/day (265 mg pc) and 15 mg/day (315 mg pc). A total of 37 courses was administered. Toxicity was evaluated using NCI-CTC criteria. Granulocytopenia was the main hematologic toxicity. Other hematologic toxicities were sporadic. Non-hematologic toxicities were mild and consisted of grade 1 nausea and grade 2 alopecia. Pharmacokinetic analyses were performed in six patients each treated with 10 mg/day and 12.5 mg per day, and in one patient treated with 15 mg/day. Using a two-compartment model, t1/2 alpha ranged from 0.47 to 1.54 h and t1/2 beta from 2.0-11.6 h. Mean values for Cmax and AUC were 1.47 +/- 0.331 microgram/ml and 13.67 +/- 3.81 micrograms/ml.h. No objective tumor responses were observed. However, one patient with metastatic breast cancer had stable disease for twelve months. We conclude that the Maximum Tolerated Dose of NK611 administered daily for 21 consecutive days is 12.5 mg/day. The Dose-Limiting Toxicity is granulocytopenia. The recommended dose for further clinical Phase II studies is 10 mg/day.

Background and Objectives The pharmacokinetics of polyethylene glycol-conjugated asparaginase (PEG-ASNase) are characterized by an increase in elimination over time, a marked increase in ASNase activity levels from induction to reinduction, and high inter- and intraindividual variability. A population pharmacokinetic (PopPK) model is required to estimate individual dose intensity, despite gaps in monitoring compliance. Methods In the AIEOP-BFM ALL 2009 trial, two PEG-ASNase administrations (2500 U/m2 intravenously) during induction (14-day interval) and one administration during reinduction were administered in children with acute lymphoblastic leukemia. ASNase activity levels were monitored weekly. A PopPK model was used for covariate modeling and external validation. The predictivity of the model in case of missing data was tested for observations, as well as for the derived parameters of the area under the concentration time curve (AUC0-∞) and time above different thresholds. Results Compared to the first administration in induction (1374 patients, 6069 samples), the initial clearance and volume of distribution decreased by 11.0% and 15.9%, respectively, during the second administration during induction and by 41.2% and 28.4% during reinduction. Furthermore, the initial clearance linearly increased for children aged > 8 years and was 7.1% lower for females. The model was successfully externally validated (1253 patients, 5523 samples). In case of missing data, > 52% of the predictions for observations and > 82% for derived parameters were within ± 20% of the nominal value. Conclusion A PopPK model that describes the complex pharmacokinetics of PEG-ASNase was successfully externally validated. AUC0−∞ or time above different thresholds, which are parameters describing dose intensity, can be estimated with high predictivity, despite missing data. (www.clinicaltrials.gov, NCT01117441, first submitted date: May 3, 2010). Supplementary Information The online version contains supplementary material available at 10.1007/s13318-021-00670-8.

Background Although elderly patients (≥70 years) represent 30% of new diagnoses of soft tissue sarcoma (STS), they are underrepresented in clinical trials and are often unfit to receive standard anthracycline-based chemotherapy. Trabectedin is registered as a second-line treatment for advanced STS and is characterized by a favorable safety profile. Methods The aim of this single-arm, phase 2 study was to investigate trabectedin (scheduled dose, 1.3-1.5 mg/m2 ) as a first-line treatment in elderly patients with advanced stage STS who are inoperable and are unfit to receive standard anthracycline-based chemotherapy. The coprimary endpoints were progression-free survival at 3 months (PFS3) and the rate of clinically limiting toxicities (CLTs). We also conducted an ancillary study on pharmacokinetics. Results Twenty-four patients (12 men and 12 women) with a median age of 79 years (interquartile range [IQR], 74-83 years) were enrolled. The histological subtype was leiomyosarcoma in 46%, liposarcoma in 33%, and other histotypes in 21%. The median number of trabectedin courses was 4 (IQR, 3-6), with 7 patients (29%) receiving ≥6 cycles. Eight patients (33%) required dose reductions. The most frequent grade 3/4 adverse events were neutropenia in 9 patients (38%), fatigue in 5 patients (21%), and aminotransferase elevation in 5 patients (21%). PFS3, median PFS, and overall survival were 71% (80% CI, 57%-81%), 4 months, and 12 months, respectively. Ten patients (42% [80% CI, 28%-57%]) experienced CLTs. Trabectedin Cmax , half-life, clearance, and distribution volume were 1.28 ng/mL (standard deviation [SD], 0.58 ng/mL), 26.70 hours (SD, 9.09 hours), 39.98 L/h/m2 (SD, 14.08 L/h/m2 ), and 1460 L/m2 (SD, 561 L/m2 ), respectively. Conclusion Trabectedin can be administered safely to elderly patients with STS who are unfit to receive anthracyclines. Pharmacokinetics in the elderly population was superimposable to historical data.

Rationale: Optimal intratumor distribution of an anticancer drug is fundamental to reach an active concentration in neoplastic cells, ensuring the therapeutic effect. Determination of drug concentration in tumor homogenates by LC-MS/MS gives important information about this issue but the spatial information gets lost. Targeted mass spectrometry imaging (MSI) has great potential to visualize drug distribution in the different areas of tumor sections, with good spatial resolution and superior specificity. MSI is rapidly evolving as a quantitative technique to measure the absolute drug concentration in each single pixel. Methods: Different inorganic nanoparticles were tested as matrices to visualize the PARP inhibitors (PARPi) niraparib and olaparib. Normalization by deuterated internal standard and a custom preprocessing pipeline were applied to achieve a reliable single pixel quantification of the two drugs in human ovarian tumors from treated mice. Results: A quantitative method to visualize niraparib and olaparib in tumor tissue of treated mice was set up and validated regarding precision, accuracy, linearity, repeatability and limit of detection. The different tumor penetration of the two drugs was visualized by MSI and confirmed by LC-MS/MS, indicating the homogeneous distribution and higher tumor exposure reached by niraparib compared to olaparib. On the other hand, niraparib distribution was heterogeneous in an ovarian tumor model overexpressing the multidrug resistance protein P-gp, a possible cause of resistance to PARPi. Conclusions: The current work highlights for the first time quantitative distribution of PAPRi in tumor tissue. The different tumor distribution of niraparib and olaparib could have important clinical implications. These data confirm the validity of MSI for spatial quantitative measurement of drug distribution providing fundamental information for pharmacokinetic studies, drug discovery and the study of resistance mechanisms.

Background An increasing number of anticancer agents has been proposed in recent years with the attempt to overcome treatment-resistant cancer cells and particularly cancer stem cells (CSC), the major culprits for tumour resistance and recurrence. However, a huge obstacle to treatment success is the ineffective delivery of drugs within the tumour environment due to limited solubility, short circulation time or inconsistent stability of compounds that, together with concomitant dose-limiting systemic toxicity, contribute to hamper the achievement of therapeutic drug concentrations. The synthetic retinoid Fenretinide (4-hydroxy (phenyl)retinamide; 4-HPR) formerly emerged as a promising anticancer agent based on pre-clinical and clinical studies. However, a major limitation of fenretinide is traditionally represented by its poor aqueous solubility/bioavailability due to its hydrophobic nature, that undermined the clinical success of previous clinical trials. Methods Here, we developed a novel nano-micellar fenretinide formulation called bionanofenretinide (Bio-nFeR), based on drug encapsulation in an ion-pair stabilized lipid matrix, with the aim to raise fenretinide bioavailability and antitumour efficacy. Results Bio-nFeR displayed marked antitumour activity against lung, colon and melanoma CSC both in vitro and in tumour xenografts, in absence of mice toxicity. Bio-nFeR is suitable for oral administration, reaching therapeutic concentrations within tumours and an unprecedented therapeutic activity in vivo as single agent. Conclusion Altogether, our results indicate Bio-nFeR as a novel anticancer agent with low toxicity and high activity against tumourigenic cells, potentially useful for the treatment of solid tumours of multiple origin. Electronic supplementary material The online version of this article (10.1186/s13046-019-1383-9) contains supplementary material, which is available to authorized users.

Asparagine levels in cerebrospinal fluid and serum asparaginase activity were monitored in children with acute lymphoblastic leukemia treated with pegylated-asparaginase. The drug was given intravenously at a dose of 2,500 IU/m2 on days 12 and 26. Serum and cerebrospinal fluid samples obtained on days 33 and 45 were analyzed centrally. Since physiological levels of asparagine in the cerebrospinal fluid of children and adolescents are 4-10 μmol/L, in this study asparagine depletion was considered complete when the concentration of asparagine was ≤0.2 μmol/L, i.e. below the lower limit of quantification of the assay used. Over 24 months 736 patients (AIEOP n=245, BFM n=491) and 903 cerebrospinal fluid samples (n=686 on day 33 and n=217 on day 45) were available for analysis. Data were analyzed separately for the AIEOP and BFM cohorts and yielded superimposable results. Independently of serum asparaginase activity levels, cerebrospinal fluid asparagine levels were significantly reduced during the investigated study phase but only 28% of analyzed samples showed complete asparagine depletion while relevant levels, ≥1 μmol/L, were still detectable in around 23% of them. Complete cerebrospinal fluid asparagine depletion was found in around 5-6% and 33-37% of samples at serum asparaginase activity levels

One of the goals of the pharmaceutical sciences is the amelioration of targeted drug delivery. In this context, nanocarrier-dependent transportation represents an ideal method for confronting a broad range of human disorders. In this study, we investigated the possibility of improving the selective release of the anti-cancer drug paclitaxel (PTX) in the gastro-intestinal tract by encapsulating it into the biodegradable nanoparticles made by FDA-approved poly(lactic-co-glycolic acid) (PLGA) and coated with polyethylene glycol to improve their stability (PLGA-PEG-NPs). Our study was performed by combining the synthesis and characterization of the nanodrug with in vivo studies of pharmacokinetics after oral administration in mice. Moreover, fluorescent PLGA-nanoparticles (NPs), were tested both in vitro and in vivo to observe their fate and biodistribution. Our study demonstrated that PLGA-NPs: (1) are stable in the gastric tract, (2) can easily penetrate inside carcinoma colon 2 (CaCo2) cells, (3) reduce the PTX absorption from the gastrointestinal tract, further limiting systemic exposure, (4) enable PTX local targeting. At present, the oral administration of biodegradable nanocarriers is limited because of stomach degradation and the sink effect played by the duodenum. Our findings, however, exhibit promising evidence towards our overcoming these limitations for a more specific and safer strategy against gastrointestinal disorders.

Background: Hyperthermic intraperitoneal chemotherapy (HIPEC) is advised as a treatment option for epithelial ovarian cancer (EOC) with peritoneal carcinomatosis. This study was designed to define the pharmacokinetics of cisplatin (CDDP) and paclitaxel (PTX) administered together during HIPEC. Methods: Thirteen women with EOC underwent cytoreductive surgery (CRS) and HIPEC, with CDDP and PTX. Blood, peritoneal perfusate and tissue samples were harvested to determine drug exposure by high-performance liquid chromatography and matrix-assisted laser desorption ionization imaging mass spectrometry (IMS). Results: The mean maximum concentrations of CDDP and PTX in perfusate were, respectively, 24.8 ± 10.4 μg ml-1 and 69.8 ± 14.3 μg ml-1; in plasma were 1.87 ± 0.4 μg ml-1 and 0.055 ± 0.009 μg ml-1. The mean concentrations of CDDP and PTX in peritoneum at the end of HIPEC were 23.3 ± 8.0 μg g-1 and 30.1 ± 18.3 μg-1 g-1, respectively. The penetration of PTX into the peritoneal wall, determined by IMS, was about 0.5 mm. Grade 3-4 surgical complications were recorded in four patients, five patients presented grade 3 and two patients presented grade 4 hematological complications. Conclusions: HIPEC with CDDP and PTX after CRS is feasible with acceptable morbidity and has a favorable pharmacokinetic profile: high drug concentrations are achieved in peritoneal tissue with low systemic exposure. Larger studies are needed to demonstrate its efficacy in patients with microscopic postsurgical residual tumours in the peritoneal cavity.

A HPLC assay was developed to determine IDN 5390, a new paclitaxel analogue, in mouse plasma. The method involves solid-phase extraction from cyano cartridges (recovery >80%), HPLC separation on Symmetry C(18) (4.6 x 150 mm), on isocratic mobile phase of water-acetonitrile-acetic acid (49:50:1) and detection at 227 nm. Retention times of IDN 5390 and IDN 5517 (internal standard, I.S.) were 9.1 and 10.5 min, respectively. The assay was linear from 0.05 to 5 micro g/ml (r(2)>or=0.995), showed intra- and inter-day precision within 1.0 and 6.2%, and accuracy of 94.7-106.8%. LOQ was 0.050 micro g/ml. Using this method IDN 5390 pharmacokinetics was determined in mice.

E-3810 is a novel small molecule that inhibits VEGF receptor-1, -2, and -3 and fibroblast growth factor receptor-1 tyrosine kinases at nmol/L concentrations currently in phase clinical II. In preclinical studies, it had a broad spectrum of antitumor activity when used as monotherapy in a variety of human xenografts. We here investigated the activity of E-3810 combined with different cytotoxic agents in a MDA-MB-231 triple-negative breast cancer xenograft model. The molecule could be safely administered with 5-fluorouracil, cisplatin, and paclitaxel. The E-3810–paclitaxel combination showed a striking activity with complete, lasting tumor regressions; the antitumor activity of the combination was also confirmed in another triple-negative breast xenograft, MX-1. The activity was superior to that of the combinations paclitaxel+brivanib and paclitaxel+sunitinib. Pharmacokinetics studies suggest that the extra antitumor activity of the combination is not due to higher paclitaxel tumor levels, which in fact were lower in mice pretreated with all three kinase inhibitors, and the paclitaxel plasma levels excluded reduced drug availability. Pharmacodynamic studies showed that E-3810, brivanib, and sunitinib given as single agents or in combination with paclitaxel reduced the number of vessels, but did not modify vessel maturation. Reduced tumor collagen IV and increased plasma collagen IV, associated with increased matrix metalloproteinases (MMP), particularly host MMP-9, indicate a proteolytic remodeling of the extracellular matrix caused by E-3810 that in conjunction with the cytotoxic effect of paclitaxel on the tumor cells (caspase-3/7 activity) may contribute to the striking activity of their combination. These data support the therapeutic potential of combining E-3810 with conventional chemotherapy. Mol Cancer Ther; 12(2); 131–40. ©2012 AACR.

Introduction: Plasma protein binding is an important factor for many drugs that can influence the tissue distribution and pharmacokinetics. α1-acid glycoprotein (AGP) is an acute-phase protein that can increase in plasma of patients with several pathological conditions including cancer. Studies performed in cultured cells indicate that paclitaxel cytotoxicity is reduced by adding AGP and the sensitivity to paclitaxel is restored by displacing its binding to AGP with clindamycin, resulting in an increased paclitaxel cell uptake. The purpose of this study was to evaluate whether clindamycin modifies paclitaxel pharmacokinetics also in cancer patients. Patients and methods: Sixteen patients with advanced ovarian cancer, previously treated with surgery and chemotherapy were enrolled in this study. A pharmacokinetic study of paclitaxel was performed in the first three cycles of the consolidation therapy (paclitaxel and carboplatin) in each patient. In these cycles paclitaxel was administered alone and with two different doses (600 and 1,200 mg) of concurrent clindamycin. The sequence of the three treatments was randomly assigned in each patient in order to avoid the same order of treatments. Results: Paclitaxel pharmacokinetics were partly modified by the concurrent administration of clindamycin. C max and AUC0–last of paclitaxel were significantly higher when the drug was given alone than when it was coadministered with 1,200 mg clindamycin. Moreover, AGP concentrations seem to have a small but statistically significant influence on paclitaxel pharmacokinetic, since AUC0–last showed a positive significant correlation with AGP plasma concentration when paclitaxel was given alone. The linear relation was lost when paclitaxel was coadministered with 1,200 mg clindamycin. Toxicity was not influenced by the coadministration of clindamycin. Conclusion: The hypothesis that clindamycin could affect paclitaxel pharmacokinetics seems to be verified with this study. Nevertheless, changes induced by giving the combination of the two drugs are minimal and thus of questionable clinical relevance.

A sensitive, specific, accurate and reproducible high-performance liquid chromatography (HPLC) analytical method was developed and validated for the quantification of the novel oral taxane analogue BAY59-8862 in mouse plasma and tissue samples. A fully automated solid-phase extraction procedure was applied to the plasma after internal standard (IS) addition, with only 0.2 mL volume of the sample loaded on a CN-Sep-pak cartridge. In the case of the tissues a very simple acetonitrile extraction was used to recover BAY59-8862 and its internal standard from liver. The procedure for the quantification of BAY59-8862 and its IS (IDN5127) is based on high-performance liquid chromatography/ion spray-tandem mass spectrometry, operating in selected ion monitoring mode. The retention times of BAY and IS were 7.21 and 10.36 min, respectively. In both plasma and tissue specimens the assay was linear in the range 50-5000 ng/mL (ng/g). The overall precision and accuracy were assessed on three different days. The results for plasma were within 6.1% (precision) and between 99 and 112% (accuracy), and for the liver samples within 7.3% and between 104 and 118%, respectively. The LOD was 5 ng/mL and 20 ng/g in the plasma and liver, respectively. In addition, the biliary excretion of the compound in rats was studied. The study showed that an oxidative chemical reaction was the preferred metabolic pathway for biliary excretion, and two sets of mono- and dihydroxylated metabolites were detected by LC/ISP-MS/MS experiments. With this method, BAY59-8862 pharmacokinetic was determined in mice. The combined results demonstrate that the methodology can be considered a valid approach to conduct pharmacokinetic and metabolic studies during preclinical and clinical investigations.

The pharmacokinetics of cis-diamminedichloro platinum(II) (cisplatin), given as a continuous infusion with concurrent radiotherapy to patients with locally advanced inoperable non-small-cell lung carcinoma, was investigated in 16 cases. The regimen, repeated for 6 consecutive weeks, consisted of weekly 10-Gy radiotherapy given in five fractions from Monday to Friday, and concurrent 100-h infusion of cisplatin delivered at a daily dose of 4 mg/m(2) by a central venous catheter and a portable pump. Throughout the weeks of therapy the platinum levels were determined in plasma and in ultrafiltered plasma by respectively inductively coupled plasma atomic emission spectrometry and inductively coupled plasma mass spectrometry. Mean levels of platinum in plasma ([Pt](tot)) increased from the 1st to the 6th week of infusion, while mean levels of platinum in ultrafiltered plasma ([Pt](uf)), 110 mu g/l, showed no marked variation throughout the therapy. [Pt](uf) ranged from 16% to 22% of the total Pt. Mean levels of Pt in ultrafiltered plasma were of the same order of magnitude as those found to be active invitro as radiopotentiators. Pt decay levels were measured for 24 h at the end of the 1st and 5th weeks of infusion, allowing the calculation of the Pt half-life and the area under the decay curves. The mean value of the area under the decay curve, plotting [Pt](tot) against time (AUG), in the range 0-24 h from the end of the 5th week of infusion, was about twice that from the end of the Ist week; by contrast, the mean AUC values did not vary for the [Pt](uf) against time curves. The mean values of the alpha half-life of Pt in the ultrafiltered plasma were in accordance with those published in the literature; however, an unexpected very long beta half-life was found (more than 100 h). Thus it was suggested that Pt species other than free cisplatin were present in the ultrafiltered plasma; such species probably involve metal bound to low-molecular-mass proteins. Throughout the therapy, the toxic effects in all patients were negligible, and 75% of them had an objective locoregional reduction of disease. In only 2 cases was progression of disease observed within the irradiated area. On the basis of these data, it can be concluded that cisplatin at a level of 110 mu g/l in the ultrafiltered plasma, in the reported scheme of continuous intravenous infusion, has an enhancing effect on radiation and avoids concentration peaks of platinum not bound to protein.

Summary Aims To evaluate antitumour activity, toxicity, pharmacokinetics, and the pharmacodynamic relationship with neutropenia of low-dose oral etoposide (E) in patients (pts) with epithelial cancer of the ovary previously treated with cisplatin. Patients and methods Eighteen pts receiving 50 mg daily of oral E for 21 days every 4 weeks. CBC with differential repeated every week. E plasma levels determined by HPLC method (sensitivity limit: 0.1 μg/ml) with evaluation during the first cycle of bioavailability and weekly 24-hour drug concentrations. Results Among 17 evaluable pts, 1 partial remission of 9 months. Dose-limiting neutropenia of high inter-patient variability. Mean bioavailability value of 75%, ranging from 44% to 100%. No correlation between mean 24-hour E plasma levels and ANC nadir or relative decrease of ANC during the first cycle. Conclusions Low-dose oral E is ineffective as salvage treatment in epithelial cancer of the ovary. The large variability of neutropenia requires a careful hematological monitoring to avoid severe myelosuppression.