Explore the vast range of titles available.

PurposeDoxorubicin is a widely used chemotherapeutic drug that can be administered intravenously as both a bolus infusion and a continuous infusion. The latter is believed to lower the risk of cardiotoxicity, which is a critical long-term complication of doxorubicin treatment. The local tissue concentrations of doxorubicin will be reflected in both treatment efficacy and toxicity, but very limited information is available. The aim of this study was to measure the concentration of doxorubicin after continuous and bolus infusion in tissue compartments around a typical location of a bone tumour.MethodsSixteen pigs (female, Danish Landrace, mean weight 77 kg) were randomized into two groups of eight. Both groups received an intravenous infusion of 150 mg doxorubicin; Group 1 received a bolus infusion (10–15 min) and Group 2 received a continuous infusion (6 h). Before infusion, microdialysis catheters were placed intravenously and in four bone tumour-relevant tissue compartments (cancellous bone, subcutaneous tissue, synovial fluid of the knee joint and muscle tissue). Sampling was done (n = 15) over 24 h, and venous blood samples were collected as a reference.ResultsArea under the concentration–time curve (AUC0–24 h) for plasma (total concentration) was significantly different between the two groups, while peak drug concentration (Cmax) was significantly higher in two compartments (plasma and synovial fluid of the knee joint) in Group 1 compared to Group 2. Overall, the unbound tissue concentrations were extremely low with values below 0.20 µg/mL.ConclusionThe pharmacokinetic profile for doxorubicin in the investigated tissues is very similar when comparing bolus and 6 h continuous infusion.

Purpose In a preclinical drug screen, mithramycin was identified as a potent inhibitor of the Ewing sarcoma EWS–FLI1 transcription factor. We conducted a phase I/II trial to determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and pharmacokinetics (PK) of mithramycin in children with refractory solid tumors, and the activity in children and adults with refractory Ewing sarcoma. Patients and methods Mithramycin was administered intravenously over 6 h once daily for 7 days for 28 day cycles. Adult patients (phase II) initially received mithramycin at the previously determined recommended dose of 25 µg/kg/dose. The planned starting dose for children (phase I) was 17.5 µg/kg/dose. Plasma samples were obtained for mithramycin PK analysis. Results The first two adult patients experienced reversible grade 4 alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevation exceeding the MTD. Subsequent adult patients received mithramycin at 17.5 µg/kg/dose, and children at 13 µg/kg/dose with dexamethasone pretreatment. None of the four subsequent adult and two pediatric patients experienced cycle 1 DLT. No clinical responses were observed. The average maximal mithramycin plasma concentration in four patients was 17.8 ± 4.6 ng/mL. This is substantially below the sustained mithramycin concentrations ≥50 nmol/L required to suppress EWS–FLI1 transcriptional activity in preclinical studies. Due to inability to safely achieve the desired mithramycin exposure, the trial was closed to enrollment. Conclusions Hepatotoxicity precluded the administration of a mithramycin at a dose required to inhibit EWS–FLI1. Evaluation of mithramycin in patients selected for decreased susceptibility to elevated transaminases may allow for improved drug exposure.

Purpose The primary objectives of this trial were aimed at exploring the pharmacokinetic profiles and the human bioequivalence of an intravenous liposomal injection of doxorubicin hydrochloride in comparison with a reference formulation in Chinese patients diagnosed with metastatic breast cancer. Methods To achieve these goals, the trial employed a randomized, open-label, two-formulation crossover dosing strategy among Chinese patients with metastatic breast cancer. Pharmacokinetic (PK) evaluation was conducted through the collection of blood samples, and the liquid chromatography tandem mass spectrometry (LC/MS/MS) method was leveraged to quantify plasma concentrations of both liposome-encapsulated doxorubicin and non-encapsulated doxorubicin in patients. Throughout the trial, all adverse events observed in the patients were meticulously assessed. Results The results indicated that the maximum concentration (Cmax), AUC from time zero to the last measurable concentration (AUC 0-t ), and AUC extrapolated to infinity (AUC 0-∞ ) of in vivo non-encapsulated doxorubicin after administration of both formulations fell within the 80.00%–125.00% range at a 90% confidence interval. Conclusion These findings strongly indicated that the tested formulations were bioequivalent to the reference formulation. The results also demonstrated that both formulations were well-tolerated, further establishing their safety profile in the context of metastatic breast cancer treatment. Trial registration Chinadrugtrials.org.cn Identifier: CTR20200878.

Purpose There is significant inter-patient variability in the pharmacokinetics of pegylated liposomal doxorubicin (PLD). Identification of factors affecting the pharmacokinetics of PLD would enable personalization of therapy. We previously reported that age, gender, body composition, and monocytes affect the clearance of other liposomal agents. Therefore, we evaluated how these factors affect the pharmacokinetics of PLD. Methods Pharmacokinetic studies of PLD were performed as part of phase I and II studies in 70 patients with solid tumors or Kaposi’s sarcoma. The effects of monocyte count, age, gender, and body composition on PLD clearance were examined. Results There was a 15.3-fold variability in PLD clearance. Body surface area-based dosing did not significantly reduce the variability in PLD clearance. The mean ± SD clearance for patients <60 years old and ≥60 years old were 54.6 ± 28.5 and 23.3 ± 10.8 mL/h/m 2 , respectively ( P  < 0.0001), and for female and male patients were 23.7 ± 18.8 and 55.6 ± 26.8 mL/h/m 2 , respectively ( P  < 0.0001). A reduction in pre-cycle monocyte count was associated with a greater reduction in PLD clearance. Conclusions Age, gender, and monocyte counts appear to correlate with PLD clearance. Further investigation of the association between these factors, PLD pharmacokinetics, and clinical outcomes (efficacy and toxicity) is warranted. These effects on the pharmacokinetics of PLD may be an approach for personalizing PLD therapy and may affect other pegylated liposomes and nanoparticle agents.

The rationale for combining anticancer drugs has not been applied consistently to use of intravesical agents for treatment of superficial bladder cancer, for which immunotherapeutic BCG and chemotherapeutic mitomycin seem to be a potentially effective combination. We aimed to do a prospective, randomised comparison of BCG alone with that of sequential BCG and electromotive mitomycin in patients with stage pT1 bladder cancer. After transurethral resection and multiple biopsies, 212 patients with stage pT1 bladder cancer were randomly assigned to: 81 mg BCG infused over 120 min once a week for 6 weeks (n=105); or to 81 mg BCG infused over 120 min once a week for 2 weeks, followed by 40 mg electromotive mitomycin (intravesical electric current 20 mA for 30 min) once a week as one cycle for three cycles (n=107). Complete responders underwent maintenance treatment: those assigned BCG alone had one infusion of 81 mg BCG once a month for 10 months, and those assigned BCG and mitomycin had 40 mg electromotive mitomycin once a month for 2 months, followed by 81 mg BCG once a month as one cycle for three cycles. The primary endpoint was disease-free interval; secondary endpoints were time to progression; overall survival; and disease-specific survival. Analyses were done by intention to treat. This trial has been submitted for registration at the US National Cancer Institute website http://clinicaltrials.gov. Median follow-up was 88 months (IQR 63–110). Patients assigned sequential BCG and electromotive mitomycin had higher disease-free interval than did those assigned BCG alone (69 months [95% CI 55–86] vs 21 months [15–54]; difference between groups 48 months [42–54], log-rank p=0·0012). Patients assigned sequential BCG and electromotive mitomycin also had lower recurrence (41·9% [32·7–51·5] vs 57·9% [48·7–67·5]; difference between groups 16·0% [2·7–29·3], log-rank p=0·0012); progression (9·3% [3·8–14·8] vs 21·9% [17·9–25·9]; difference between groups 12·6% [3·0–22·2], log-rank p=0·004); overall mortality (21·5% [13·5–29·5] vs 32·4% [23·4–41·4], difference between groups 10·9% [0·6–21·2], log-rank p=0·045); and disease-specific mortality (5·6% [1·2–10·0] vs 16·2% [6·1–23·3], difference between groups 10·6% [2·5–18·7], log-rank p=0·01). Side-effects were mainly localised to the bladder. BCG-induced inflammation might increase the permeability of the bladder mucosa such that mitomycin can reach the target tissue more easily and exert its anticancer effect.

Purpose There are no definitive data in humans on the dose dependence and/or cycle dependence of the pharmacokinetics (PK) of pegylated liposomal doxorubicin (PLD). This study examined the PK of PLD across a twofold dose variation and along 3 cycles. Methods Fifteen patients received PLD in successive doses of 60, 30, and 45 mg/m 2 (Arm A) and 30, 60, and 45 mg/m 2 (Arm B), every 4 weeks. Twelve patients, six on each arm, completed all three cycles and were fully evaluable. Plasma levels of doxorubicin were analyzed by HPLC and fluorimetry. PK analysis was done by non-compartmental method. Repeated measures ANOVA and paired tests were used for statistical analysis. Results There was no significant difference in the PK parameters examined when the dose was increased from 30 to 60 mg/m 2 . However, when we analyzed the effect of cycle number on the PK, we found a gradual and significant inhibition of clearance ( P  < 0.0001) from the 1st through the 3rd cycle of PLD, with a geometric mean increase of 43% in dose-normalized AUC ( P  = 0.0003). Dose-normalized C max and T½ mean values increased by 17 and 18%, respectively between the 1st and 3rd cycles, but only the increase in T½ was statistically significant ( P  = 0.0017). Conclusions While the PK of PLD is not dose-dependent within the dose range of 30–60 mg/m 2 , there is evidence of a cycle-dependent effect that results in inhibition of clearance when patients receive successive cycles of PLD. These results suggest the need for dose adjustments of PLD upon retreatment to minimize the risk of toxicity.

Purpose This study examines safety, efficacy, and pharmacokinetics of chemoembolization with loadable microspheres ≤100 μm for hepatocellular carcinoma. Materials and Methods A pilot safety study was performed in 19 patients with size and dose escalation and then 52 patients were enrolled prospectively and randomly assigned to chemoembolization with TANDEM™ loaded with 150 or 100 mg of doxorubicin. Results The mean diameter of the tumors was 7.28 ± 2.09 cm (range 4–12) and distribution dominant/multiple 51.9/48.1 %. Child A/B distribution was 32/20 (61.5/38.5 %) and etiology HBV/HCV/HBV/HCV-hemochromatosis was 61.6/9.6/9.6/15.4 %. Twenty-five patients were assigned in the low and 27 in the high loading group. There was 1.92 % thirty-day mortality due to lesion rupture. Biliary damage was seen in 3 patients (5.7 %) in the high loading. Mean maximum plasma concentration of doxorubicin C max  ± SD was 284.9 ± 276.2 ng/mL for the high and 108.5 ± 77.6 ng/mL for the low loading ( p  < 0.001). According to m-RECIST overall objective response after two sessions reached 61.22 and 63.82 % at 6 months. Notably, complete target lesion response (CR) after the second session was observed in 28.57 % and maintained in 23.40 % at 6 months. No statistical differences in the local response rates were observed between the two loading groups. Overall survival (OS) at 6 months, 1 , 2, and 3 years was 98.08, 92.3, 88.46, and 82.6 %, respectively. OS and Progression-Free Survival did not demonstrate statistical significance between the two loading groups. Conclusion Initial evidence shows that (a) TANDEM™ achieves high rates of local response and mid-term survival, (b) high loading provides no clinical benefit and is associated with biliary toxicity.

Purpose The present study aimed to investigate the role of expression of daunorubicin-metabolizing enzymes carbonyl reductase 1 and 3 ( CBR1 and CBR3 ) on the in vitro cytotoxicity of daunorubicin in primary acute myeloid leukemia (AML) cells and the effect of genetic variants in CBR1 and CBR3 on the plasma pharmacokinetics of daunorubicin and daunorubicinol (DOL) in AML patients. Methods RNA expression of CBR1 and CBR3 , intracellular daunorubicin and DOL levels, and in vitro cytotoxicity of daunorubicin were measured in bone marrow mononuclear cells of 104 adult AML patients. Plasma pharmacokinetics of daunorubicin and DOL was measured in 24 patients receiving daunorubicin-based induction chemotherapy for AML. Results Increased expression of CBR1 significantly reduced the in vitro cytotoxicity of daunorubicin and also positively correlated with intracellular DOL levels. Polymorphisms in CBR1 and CBR3 did not show any association with intracellular daunorubicin or DOL levels, but there was a trend towards significant increase in plasma daunorubicin systemic exposure in patients with a variant genotype for CBR1 polymorphism rs25678. Conclusions This pilot study suggests that CBR1 RNA expression may be helpful in identifying AML patients at risk of developing resistance or toxicity to daunorubicin due to increased formation of DOL. Further confirmation of these findings in a larger sample pool would be required to determine the applicability of these results. Inhibition of CBR1 can be an option to improve the efficacy and prevent toxicity related to the treatment. Influence of daunorubicin and DOL plasma levels on clinical outcome, if any, remains to be evaluated.

DNA nanostructures are promising drug carriers with their intrinsic biocompatibility, uniformity and versatility. However, rapid serum disintegration leads to low bioavailability at targeted sites following systemic administration, hindering their biomedical applications. Here we demonstrate transdermal delivery of framework nucleic acids (FNAs) through topical applications. By designing FNAs with distinct shapes and sizes, we interrogate their penetration on mice and human skin explant. Skin histology reveals size-dependent penetration, with FNAs ≤75 nm effectively reaching dermis layer. 17 nm-tetrahedral FNAs show greatest penetration to 350 µm from skin periphery. Importantly, structural integrity is maintained during the skin penetration. Employing a mouse melanoma model, topical application of doxorubicin-loaded FNAs accommodates ≥2-fold improvement in drug accumulation and tumor inhibition relative to topically-applied free doxorubicin, or doxorubicin loaded in liposomes and polymeric nanoparticles. Programmable penetration with minimal systemic biodistribution underlines FNA potential as localized transdermal drug delivery carriers. DNA nanostructures hold great promise for drug delivery, but systemic administration is problematic. Here, the authors demonstrate that framework nucleic acids (FNAs) improve drug accumulation in tumours in topical application and that penetration depth is controllable through adjusting FNA size.

Purpose This perisurgical phase 1 study evaluated the pharmacokinetics, pharmacodynamics, and safety of the mammalian target of rapamycin (mTOR) inhibitor ridaforolimus in patients ( N  = 10) with progressive or recurrent primary grade IV malignant glioma, who failed standard therapy. The primary objective of the study was to determine the maximum tolerated dose (MTD) of ridaforolimus. Methods Treatment was administered intravenously at doses of 12.5 mg ( N  = 7) or 15 mg ( N  = 3) once daily for 4 days prior to surgical resection, then resumed for 5 consecutive days every 2 weeks until disease progression or unacceptable toxicity, following a postsurgical recovery period. Results The MTD was not determined because the trial was suspended early due to slower than expected patient accrual and postsurgical drug administration challenges. Pharmacokinetic and pharmacodynamic analyses showed that ridaforolimus concentrations declined slowly during the 24-h dosing interval and remained detectable for 10 days after the last infusion in whole blood samples. In peripheral blood mononuclear cells, median levels of the mTOR downstream effector p4E-BP1 were reduced by >80% compared with baseline by 4 h after dosing. Resected brain specimens showed reduced levels of pS6, another mTOR downstream effector, while nuclear staining for p27 kip1 , a protein that functions as a cell cycle inhibitor, increased after treatment. No dose-limiting toxicities were observed, and the reported adverse events were consistent with the previously established safety profile for ridaforolimus. One of 3 patients evaluable for efficacy had stable disease as best response. Conclusion Results suggest that ridaforolimus can cross the blood–brain barrier in areas of tumor involvement, and may inhibit mTOR activity in advanced gliomas based on decreased pS6 levels. This perisurgical trial design should serve as a template for evaluating intratumoral pharmacokinetics and pharmacodynamics of other targeted agents in this patient population.