Outcomes from hematopoietic stem cell transplantation following treosulfan-based conditioning: A clinical and pharmacokinetic analysis.

BACKGROUND: The aims of this study are to report our experience with treosulfan-based conditioning regimens for patients with non-malignant hematologic conditions, correlating clinical outcomes at different time points post-transplant with treosulfan exposure (AUC). METHODS: This study was a single-center observational study investigating overall survival (OS), disease-free survival (DFS), and event-free survival (EFS) end-points post-transplant. The consequences of treosulfan AUC with respect to toxicity, correction of underlying disease, and long-term chimerism were also explored using pharmacokinetic analysis. RESULTS: Forty-six patients received 49 transplants with treosulfan and fludarabine-based conditioning between 2005 and 2023. Twenty-four patients also received thiotepa. Donor chimerism was assessed on either whole blood or sorted cell lines at different time points post-transplant. Thirty-nine patients received treosulfan pharmacokinetic assessment to evaluate cumulative AUC, with five infants receiving real-time assessment to facilitate daily dose adjustment. OS, DFS, and EFS were 87%, 81%, and 69%, respectively. Median follow-up was 32.1 months (range 0.82-160 months) following transplant. Lower EFS was associated with patient age (<1 year; p = .057) and lower cumulative treosulfan dose (<42 g/m2; p = .003). Stable donor chimerism in B-cell, NK-cell, and granulocyte lineages at 1-year post-transplant were more prevalent in patients receiving thiotepa conditioning. Two infants required daily dose adjustment to treosulfan to avoid high AUC. CONCLUSIONS: Excellent clinical outcomes and stable chimerism were observed in this patient series. The addition of thiotepa conferred no significant toxicity and trended toward sustained ongoing donor engraftment. Correlating treosulfan AUC with long-term patient outcomes is required.

Maximum a posteriori Bayesian methods out-perform non-compartmental analysis for busulfan precision dosing.

Dose personalization improves patient outcomes for many drugs with a narrow therapeutic index and high inter-individuality variability, including busulfan. Non-compartmental analysis (NCA) and model-based methods like maximum a posteriori Bayesian (MAP) approaches are two methods routinely used for dose optimization. These approaches vary in how they estimate patient-specific pharmacokinetic parameters to inform a dose and the impact of these differences is not well-understood. Using busulfan as an example application and area under the concentration-time curve (AUC) as a target exposure metric, these estimation methods were compared using retrospective patient data (N = 246) and simulated precision dosing treatment courses. NCA was performed with or without peak extension, and MAP Bayesian estimation was performed using either the one-compartment Shukla model or the two-compartment McCune model. All methods showed good agreement on real-world data (correlation coefficients of 0.945-0.998) as assessed by Bland-Altman plots, although agreement between NCA and MAP methods was higher during the first dosing interval (0.982-0.994) compared to subsequent dosing intervals (0.918-0.938). In dose adjustment simulations, both NCA and MAP estimated high target attainment (> 98%) although true simulated target attainment was lower for NCA (63-66%) versus MAP (91-93%). The largest differences in AUC estimation were due to different assumptions for the shape of the concentration curve during the infusion phase, followed by how the methods considered time-dependent clearance and concentration-time points collected in earlier intervals. In conclusion, although AUC estimates between the two methods showed good correlation, in a simulated study, MAP lead to higher target attainment. When changing from one method to another, or changing infusion duration and other factors, optimum estimated exposure targets may require adjusting to maintain a consistent exposure.

Temozolomide nano-in-nanofiber delivery system with sustained release and enhanced cellular uptake by U87MG cells.

OBJECTIVE: The study was aimed at formulating temozolomide (TMZ) loaded gelatin nanoparticles (GNPs) encapsulated into polyvinyl alcohol (PVA) nanofibers (TMZ-GNPs-PVA NFs) as the nano-in-nanofiber delivery system. The secondary objective was to explore the sustained releasing ability of this system and to assess its enhanced cellular uptake against U87MG glioma cells in vitro. SIGNIFICANCE: Nano-in-nanofibers are the emerging drug delivery systems for treating a wide range of diseases including cancers as they overcome the challenges experienced by nanoparticles and nanofibers alone. METHODS: The drug-loaded GNPs were formulated by one-step desolvation method. The Design of Experiments (DoE) was used to optimize nanoparticle size and entrapment efficiency. The optimized drug-loaded nanoparticles were then encapsulated within nanofibers using blend electrospinning technique. The U87MG glioma cells were used to investigate the uptake of the formulation. RESULTS: A 32 factorial design was used to optimize the mean particle size (145.7 nm) and entrapment efficiency (87.6%) of the TMZ-loaded GNPs which were subsequently ingrained into PVA nanofibers by electrospinning technique. The delivery system achieved a sustained drug release for up to seven days (in vitro). The SEM results ensured that the expected nano-in-nanofiber delivery system was achieved. The uptake of TMZ-GNPs-PVA NFs by cells was increased by a factor of 1.964 compared to that of the pure drug. CONCLUSION: The nano-in-nanofiber drug delivery system is a potentially useful therapeutic strategy for the management of glioblastoma multiforme.

Exploring temozolomide encapsulated PEGylated liposomes and lyotropic liquid crystals for effective treatment of glioblastoma: in-vitro, cell line, and pharmacokinetic studies.

Temozolomide (TMZ) is one of the best choices for treating glioblastoma. However, due to the short plasma half-life, only 20-30 % brain bioavailability can be achieved using traditional formulations. In the present study, PEGylated liposomes and lyotropic liquid crystals (LLCs) were developed and investigated to prolong the plasma circulation time of TMZ. Industrially feasible membrane extrusion and modified hot melt emulsification techniques were utilized during the formulation. Liposomes and LLCs in the particle size range of 80-120 nm were obtained with up to 50 % entrapment efficiency. The nanocarriers were found to show a prolonged release of up to 72 h. The cytotoxicity studies in glioblastoma cell lines revealed a âˆ¼1.6-fold increased cytotoxicity compared to free TMZ. PEGylated liposomes and PEGylated LLCs were found to show a 3.47 and 3.18-fold less cell uptake in macrophage cell lines than uncoated liposomes and LLCs, respectively. A 1.25 and 2-fold increase in the plasma t1/2 was observed with PEGylated liposomes and PEGylated LLCs, respectively, compared to the TMZ when administered intravenously. Extending plasma circulation time of TMZ led to significant increase in brain bioavailability. Overall, the observed improved pharmacokinetics and biodistribution of TMZ revealed the potential of these PEGylated nanocarriers in the efficient treatment of glioblastoma.

Melphalan: Recent insights on synthetic, analytical and medicinal aspects.

Cancer is an uncontrolled expansion of atypical cells in the body. These unusual cells are labelled as cancerous or malignant cells. Melphalan, an anticancer drug which is imperatively recognized under the class of alkylating agents. It exhibits broad spectrum antitumor activity, as observed in ovarian cancer, breast cancer, etc. However, it is mainly utilized in the management of multiple myeloma. Several studies across the globe suggest that resistance to melphalan is the major concern that leads to relapsed myeloma. In the present paper, several pivotal approaches to compensate resistance associated with melphalan have been discussed. Numerous chemical and formulation developments concerning melphalan to enhance its salient characteristics and targeted profile have also been portrayed. The rationale of the current article also summarizes the recent analytical methods, structure-activity relationship, pharmacokinetics, interactions, potential adverse effects along with medicinal updates of melphalan. Special attention is also laid on their synthetic developments viz. melphalan derivatives, conjugates and prodrugs along with encouraging insights and research findings.

Association study of candidate DNA-repair gene variants and acute graft versus host disease in pediatric patients receiving allogeneic hematopoietic stem-cell transplantation.

Acute Graft versus Host Disease (aGvHD) grades 2-4 occurs in 15-60% of pediatric patients undergoing allogeneic haematopoietic stem-cell transplantation (allo-HSCT). The collateral damage to normal tissue by conditioning regimens administered prior to allo-HSCT serve as an initial trigger for aGvHD. DNA-repair mechanisms may play an important role in mitigating this initial damage, and so the variants in corresponding DNA-repair protein-coding genes via affecting their quantity and/or function. We explored 51 variants within 17 DNA-repair genes for their association with aGvHD grades 2-4 in 60 pediatric patients. The cumulative incidence of aGvHD 2-4 was 12% (n = 7) in the exploratory cohort. MGMT rs10764881 (G>A) and EXO rs9350 (c.2270C>T) variants were associated with aGvHD 2-4 [Odds ratios = 14.8 (0 events out of 40 in rs10764881 GG group) and 11.5 (95% CI: 2.3-191.8), respectively, multiple testing corrected p ≤ 0.001]. Upon evaluation in an extended cohort (n = 182) with an incidence of aGvHD 2-4 of 22% (n = 40), only MGMT rs10764881 (G>A) remained significant (adjusted HR = 2.05 [95% CI: 1.06-3.94]; p = 0.03) in the presence of other clinical risk factors. Higher MGMT expression was seen in GG carriers for rs10764881 and was associated with higher IC50 of Busulfan in lymphoblastoid cells. MGMT rs10764881 carrier status could predict aGvHD occurrence in pediatric patients undergoing allo-HSCT.

Triolein emulsion enhances temozolomide brain delivery: an experimental study in rats.

PURPOSE: To evaluate the enhancement of temozolomide (TMZ) delivery in the rat brain using a triolein emulsion. MATERIALS AND METHODS: Rats were divided into the five groups as following: group 1 (negative control), group 2 (treated with triolein emulsion and TMZ 20 mg/kg), and group 3 (TMZ 20 mg/kg treatment without triolein), group 4 (treated with triolein emulsion and TMZ 10 mg/kg), and group 5 (TMZ 10 mg/kg treatment without triolein). Triolein emulsion was infused into the right common carotid artery. One hour later, the TMZ concentration was evaluated quantitatively and qualitatively using high-performance liquid chromatography (HPLC-MS) and desorption electrospray ionization mass spectrometry (DESI-MS) imaging, respectively. The concentration ratios of the ipsilateral to contralateral hemisphere in each group were determined and the statistical analysis was conducted using an unpaired t-test. RESULTS: Quantitatively, the TMZ concentration ratio of the ipsilateral to the control hemisphere was 2.41 and 1.13 in groups 2 and 3, and were 2.49 and 1.14 in groups 4 and 5, respectively. Thus, the TMZ signal intensities of TMZ in group 2 and 4 were statistically high in the ipsilateral hemispheres. Qualitatively, the signal intensity of TMZ was remarkably high in the ipsilateral hemisphere in group 2 and 4. CONCLUSIONS: The triolein emulsion efficiently opened the blood-brain barrier and could provide a potential new strategy to enhance the therapeutic effect of TMZ. HPLC-MS and DESI-MS imaging were shown to be suitable for analyses of enhancement of brain TMZ concentrations.

First-principles studies on two-dimensional B3O3 adsorbent as a potential drug delivery platform for TEPA anticancer drug.

The remarkable properties of pristine B3O3 nanosheet as a nanocarrier for adsorption and desorption of TEPA anticancer drug for designing potential drug delivery platform were investigated using periodic DFT calculations. We studied the adsorption energy of all stable complexes formed between the drug molecule and B3O3 in gas and aqueous phases along with electronic structure analysis of complexes. Different adsorption configurations were studied for drug/B3O3 complexes, including the interaction of the C atom of the triangular ring, O atom in the TEPA drug with the B atom in B3O3, and indirect drug interaction the middle of the R1 ring cavity of the B3O3 nanosheet. The take-up of TEPA prompts a substantial change of 68.13% in the band gap (Eg) of the B3O3 nanosheet in the most stable complex. The present study results affirmed the application of B3O3 nanosheet as a potential vehicle for TEPA drugs in the treatment of cancerous tissues.

A natural protein based platform for the delivery of Temozolomide acid to glioma cells.

Glioblastoma is one of the most difficult to treat cancers with poor prognosis and survival of around one year from diagnosis. Effective treatments are desperately needed. This work aims to prepare temozolomide acid (TMZA) loaded albumin nanoparticles, for the first time, to target glioblastoma (GL261) and brain cancer stem cells (BL6). TMZA was loaded into human serum albumin nanoparticles (HSA NPs) using the desolvation method. A response surface 3-level factorial design was used to study the effect of different formulation parameters on the drug loading and particle size of NPs. The optimum conditions were found to be: 4 mg TMZA with 0.05% sodium cholate. This yielded NPs with particle size and drug loading of 111.7 nm and 5.5% respectively. The selected formula was found to have good shelf life and serum stability but with a relatively fast drug release pattern. The optimized NPs showed excellent cellular uptake with âˆ¼ 50 and 100% of cells were positive for NP uptake after 24 h incubation with both GL261 and BL6 glioblastoma cell lines, respectively. The selected formula showed high cytotoxicity with Ì´ 20% cell viability at 1 mM TMZA after 72 h incubation time. Finally, the fluorescently labelled NPs showed co-localization with the bioluminescent syngeneic BL6 intra-cranial tumour mouse model after intravenous administration.

Improving temozolomide biopharmaceutical properties in glioblastoma multiforme (GBM) treatment using GBM-targeting nanocarriers.

Glioblastoma multiforme (GBM) is the most common primary brain cancer. GBM has aggressive development, and the pharmacological treatment remains a challenge due to GBM anatomical characteristics' (the blood-brain barrier and tumor microenvironment) and the increasing resistance to marketed drugs, such as temozolomide (TMZ), the first-line drug for GBM treatment. Due to physical-chemical properties such as short half-life time and the increasing resistance shown by GBM cells, high doses and repeated administrations are necessary, leading to significant adverse events. This review will discuss the main molecular mechanisms of TMZ resistance and the use of functionalized nanocarriers as an efficient and safe strategy for TMZ delivery. GBM-targeting nanocarriers are an important tool for the treatment of GBM, demonstrating to improve the biopharmaceutical properties of TMZ and repurpose its use in anti-GBM therapy. Technical aspects of nanocarriers will be discussed, and biological models highlighting the advantages and effects of functionalization strategies in TMZ anti-GBM activity. Finally, conclusions regarding the main findings will be made in the context of new perspectives for the treatment of GBM using TMZ as a chemotherapy agent, improving the sensibility and biological anti-tumor effect of TMZ through functionalization strategies.

Precision dosing of intravenous busulfan in pediatric hematopoietic stem cell transplantation: Results from a multicenter population pharmacokinetic study.

Busulfan (Bu) is a common component of conditioning regimens before hematopoietic stem cell transplantation (HSCT) and is known for high interpatient pharmacokinetic (PK) variability. This study aimed to develop and externally validate a multicentric, population PK (PopPK) model for intravenous Bu in pediatric patients before HSCT to first study the influence of glutathione-s-transferase A1 (GSTA1) polymorphisms on Bu's PK in a large multicentric pediatric population while accounting for fludarabine (Flu) coadministration and, second, to establish an individualized, model-based, first-dose recommendation for intravenous Bu that can be widely used in pediatric patients. The model was built using data from 302 patients from five transplantation centers who received a Bu-based conditioning regimen. External model validation used data from 100 patients. The relationship between body weight and Bu clearance (CL) was best described by an age-dependent allometric scaling of a body weight model. A stepwise covariate analysis identified Day 1 of Bu conditioning, GSTA1 metabolic groups based on GSTA1 polymorphisms, and Flu coadministration as significant covariates influencing Bu CL. The final model adequately predicted Bu first-dose CL in the external cohort, with 81% of predicted area under the curves within the therapeutic window. The final model showed minimal bias (mean prediction error, -0.5%; 95% confidence interval [CI], -3.1% to 2.0%) and acceptable precision (mean absolute prediction error percentage, 18.7%; 95% CI, 17.0%-20.5%) in Bu CL prediction for dosing. This multicentric PopPK study confirmed the influence of GSTA1 polymorphisms and Flu coadministration on Bu CL. The developed model accurately predicted Bu CL and first doses in an external cohort of pediatric patients.

Cyclophosphamide bioactivation pharmacogenetics in breast cancer patients.

PURPOSE: Genetic variation in the activation of the prodrug cyclophosphamide (CP) by cytochrome P450 (CYP) enzymes has been shown to influence outcomes. However, CYP are also subject to phenoconversion due to either the effects of comedications or cancer associated down-regulation of expression. The aim of this study was to assess the relationship between CP bioactivation with CYP2B6 and CYP2C19 genotype, as well as CYP2C19 phenotype, in breast cancer patients. METHODS: CP and the active metabolite levels were assessed in breast cancer patients (n = 34) at cycle 1 and cycle 3 of treatment. Patients were genotyped for a series of SNP known to affect CYP2B6 and CYP2C19 function. The activity of CYP2C19 was also assessed using a probe drug. RESULTS: We found a significant linear gene-dose relationship with CYP2B6 coding SNP and formation of 4-hydroxycyclophosphamide. A possible association with CYP2C19 null genotype at cycle 1 was obscured at cycle 3 due to the substantial intra-individual change in CP bioactivation on subsequent dosing. CONCLUSION: Comedications may be the cause for this inter-occasion variation in bioactivation of cyclophosphamide and the ensuing phenoconversion may account for the conflicting reports in the literature about the relationship between CYP2C19 genotype and CP bioactivation pharmacokinetics. Trial registration ANZCTR363222 (6/11/2012, retrospectively registered).

Melphalan Flufenamide (Melflufen): First Approval.

Melphalan flufenamide (melflufen, Pepaxto®) is a peptide conjugated alkylating drug developed by Oncopeptides for the treatment of multiple myeloma (MM) and amyloid light-chain amyloidosis. It is an ethyl ester of a lipophilic dipeptide consisting of melphalan and para-fluoro-L-phenylalanine. Due to its lipophilicity, melphalan flufenamide is rapidly transported across the cell membrane and almost immediately hydrolyzed by aminopeptidases in the cytoplasm to yield more hydrophilic alkylating molecules, such as melphalan and desethyl-melflufen. Like other nitrogen mustard drugs, melphalan flufenamide exerts antitumor activity through DNA crosslinking. In February 2021, melphalan flufenamide, in combination with dexamethasone, received its first approval in the USA for the treatment of adults with relapsed or refractory (r/r) MM who have received at least four prior lines of therapy and whose disease is refractory to at least one proteasome inhibitor (PI), one immunomodulatory agent, and one CD38-directed monoclonal antibody. A multinational clinical study of melphalan flufenamide in amyloid light-chain amyloidosis is underway across several countries, and preclinical studies for various haematological and solid cancers are underway. This article summarizes the milestones in the development of melphalan flufenamide leading to this first approval.

Evaluation of two software using Bayesian methods for monitoring exposure and dosing once-daily intravenous busulfan in paediatric patients receiving haematopoietic stem cell transplantation.

AIM: To assess the ability of model-based personalised dosing tools to estimate busulfan exposure (i) in comparison to clinically used intensive sampling exposure estimation procedure, (ii) using limited sampling strategies and (iii) to predict changes in busulfan clearance during busulfan treatment. METHODS: Data on intravenous busulfan dosing for patients with 4 consecutive days were entered into Bayesian forecasting software, InsightRX and NextDose. Prediction of busulfan cumulative exposure was compared to current clinical practice estimation, aiming for pre-defined individualised target of cumulative exposure. Estimation performance was tested given several limited sampling strategies. RESULTS: Thirty-two paediatric patients (0.2-16.5 years) provided a total of 103 daily exposure measurements estimated using 7 samples taken per day (full sampling), with 19 patients having sampling following all doses administered. Both software tools utilising Bayesian methods provided acceptable relative bias and precision of cumulative exposure estimations under the tested sampling scenarios. Relative bias ranged from median RE of 0.1-14.6% using InsightRX and from 3.4-7.8% using NextDose. Precision ranged from median RMSE of 0.19-0.32 mg·h·L-1 for InsightRX and 0.08-0.1 mg·h·L-1 for NextDose. A median reduction in busulfan clearance from day 1 to day 4 was observed in the clinical data (-10.9%), when using InsightRX (-18.6%) and with NextDose (-14.7%). CONCLUSION: Bayesian methods were shown to have relatively low bias and precisely estimate busulfan exposure using intensive sampling and several limited sampling strategies, which provides evidence for prospective studies to evaluate these tools in clinical practice. A trend to overestimation of exposure using Bayesian methods was observed compared to clinical practice. Reduction of busulfan clearance from day 1 to 4 of once daily dosing was confirmed and should be considered when adjusting doses.

Dual Encapsulated Dacarbazine and Zinc Phthalocyanine Polymeric Nanoparticle for Photodynamic Therapy of Melanoma.

PURPOSE: Melanoma is an invasive and very aggressive skin cancer due to its multi-drug resistance that results in poor patient survival. There is a need to test new treatment approaches to improve therapeutic efficacy and reduce side effects of conventional treatments. METHODS: PLA/PVA nanoparticles carrying both Dacarbazine and zinc phthalocyanine was produced by double emulsion technique. The characterization was performed by dynamic light scattering and atomic force microscopy. In vitro photodynamic therapy test assay using MV3 melanoma cells as a model has been performed. In vitro cell viability (MTT) was performed to measure cell toxicity of of nanoparticles with and without drugs using human endothelial cells as a model. The in vivo assay (biodistribution/tissue deposition) has been performed using radiolabeled PLA/PVA NPs. RESULTS: The nanoparticles produced showed a mean diameter of about 259 nm with a spherical shape. The in-vitro photodynamic therapy tests demonstrated that the combination is critical to enhance the therapeutic efficacy and it is dose dependent. The in vitro cell toxicity assay using endothelial cells demonstrated that the drug encapsulated into nanoparticles had no significant toxicity compared to control samples. In-vivo results demonstrated that the drug loading affects the biodistribution of the nanoparticle formulations (NPs). Low accumulation of the NPs into the stomach, heart, brain, and kidneys suggested that common side effects of Dacarbazine could be reduced. CONCLUSION: This work reports a robust nanoparticle formulation with the objective to leveraging the synergistic effects of chemo and photodynamic therapies to potentially suppressing the drug resistance and reducing side effects associated with Dacarbazine. The data corroborates that the dual encapsulated NPs showed better in-vitro efficacy when compared with the both compounds alone. The results support the need to have a dual modality NP formulation for melanoma therapy by combining chemotherapy and photodynamic therapy.

Phase I clinical trial of temozolomide and methoxyamine (TRC-102), an inhibitor of base excision repair, in patients with advanced solid tumors.

Temozolomide (TMZ) generates DNA adducts that are repaired by direct DNA and base excision repair mechanisms. Methoxyamine (MX, TRC-102) potentiates TMZ activity by binding to apurinic and apyrimidinic (AP) sites after removal of N3-methyladenine and N7-methylguanine, inhibiting site recognition of AP endonuclease. We conducted a phase I trial to determine the maximum tolerated dose and dose-limiting toxicities (DLTs) of intravenous MX when given with oral TMZ. Patients with advanced solid tumors and progression on standard treatment were enrolled to a standard 3 + 3 dose escalation trial assessing escalating doses of TMZ and MX. Tumor response was assessed per RECIST and adverse events (AEs) by CTCAEv3. Pharmacokinetics (PK) of MX and COMET assays on peripheral blood mononuclear cells were performed. 38 patients were enrolled-median age 59.5 years (38-76), mean number of cycles 2.9 [1-13]. No DLTs were observed. Cycle 1 grade 3 AEs included fatigue, lymphopenia, anemia, INR, leukopenia, neutropenia, allergic reaction, constipation, psychosis and paranoia. Cycle 2-13 grade 4 AEs included thrombocytopenia and confusion. A partial response was seen in 1 patient with a pancreatic neuroendocrine tumor (PNET) and six additional patients, each with different tumor types, demonstrated prolonged stable disease. MX PK was linear with dose and was not affected by concomitant TMZ. TMZ 200 mg/m2 daily × 5 may be safely administered with MX 150 mg/m2 intravenously once on day 1 with minimal toxicity. Further studies assessing this drug combination in select tumor types where temozolomide has activity may be warranted.

Bioequivalence study of 20-mg and 100-mg temozolomide capsules (TOZ309 and Temodal®) in glioma patients in China.

BACKGROUND: Temozolomide is an alkylating agent approved by the U.S. Food and Drug Administration in 1999 for the treatment of patients with primary brain tumors. The aim of this study was to confirm the bioequivalence and safety of two strengths (20-100 mg) of generic temozolomide in the form of TOZ039 and Temodal® capsules administered to brain tumor patients. STUDY DESIGN: An open-label, randomized, two-phase, two-period, crossover pharmacokinetic study was performed in a single institution. The reference and test drugs were prescribed at a dose of 150 mg/m2 daily from days 1 to 5 of a 28-day cycle in the first phase; in the second phase, either a 150- or 200-mg/m2 dose was prescribed, depending on patient tolerance. On days 1 and 2 of each phase, a fixed 200-mg dose was administered either as ten 20-mg capsules in the first cycle or two 100-mg capsules in the second cycle. Drug administration in the first two days was randomized, i.e., if TOZ309 was administered on day 1, Temodal® was administered on day 2, and vice versa. The rest of the prescribed dose was administered in the form of Temodal® and spread equally over days 3-5. Blood samples were obtained for pharmacokinetic evaluation on days 1 and 2. Bioequivalence was demonstrated if the geometric means ratio of the three main pharmacokinetic parameters (mean maximum plasma concentration (Cmax), area under the concentration-time curve (AUC) 0-t, AUC 0-∞) fell within the equivalence boundary of 80-125%. RESULTS: Twenty-nine glioblastoma multiforme or anaplastic astrocytoma patients were enrolled and dosed with the test and reference formulations under fasting conditions. The 90% confidence interval of the geometric means ratio for Cmax (91.08%, 106.18%), AUC0-t (98.62%,102.18%), and AUC0-∞ (98.65%, 102.21%) was well within the 80%-125% range for the 20-mg capsule, as was the Cmax (90.49%, 113.32%), AUC0-t (99.89%, 104.63%) and AUC0-∞ (99.99%, 104.67%) for the 100-mg capsule drug product. Additionally, all the secondary pharmacokinetic parameters were not significantly different. After two cycles of treatment, there was no mortality among the 29 patients, treatment-related severe adverse events, or events that would require study discontinuation; however, one significant adverse effect (life-threatening seizures) occurred and was related to disease progression. Adverse events were reported in 82.8% (24/29) patients, and treatment emergent adverse events were reported in 72.4% (21/29) patients. CONCLUSION: It can be concluded that 20-mg and 100-mg capsules of TOZ309 are bioequivalent to Temodal® capsules of the same strength under fasting conditions. TRIAL REGISTRATION: https://www.chinadrugtrials.org.cn/index.html , CTR2017 0122.

Thymoquinone-Loaded Soluplus®-Solutol® HS15 Mixed Micelles: Preparation, In Vitro Characterization, and Effect on the SH-SY5Y Cell Migration.

Thymoquinone (TQ) is the main active ingredient of Nigella sativa essential oil, with remarkable anti-neoplastic activities with anti-invasive and anti-migratory abilities on a variety of cancer cell lines. However, its poor water solubility, high instability in aqueous solution and pharmacokinetic drawbacks limits its use in therapy. Soluplus® and Solutol® HS15 were employed as amphiphilic polymers for developing polymeric micelles (SSM). Chemical and physical characterization studies of micelles are reported, in terms of size, homogeneity, zeta potential, critical micelle concentration (CMC), cloud point, encapsulation efficiency (EE%), load capacity (DL), in vitro release, and stability. This study reports for the first time the anti-migratory activity of TQ and TQ loaded in SSM (TQ-SSM) in the SH-SY5Y human neuroblastoma cell line. The inhibitory effect was assessed by the wound-healing assay and compared with that of the unformulated TQ. The optimal TQ-SSM were provided with small size (56.71 ± 1.41 nm) and spherical shape at ratio of 1:4 (Soluplus:Solutol HS15), thus increasing the solubility of about 10-fold in water. The entrapment efficiency and drug loading were 92.4 ± 1.6% and 4.68 ± 0.12, respectively, and the colloidal dispersion are stable during storage for a period of 40 days. The TQ-SSM were also lyophilized to obtain a more workable product and with increased stability. In vitro release study indicated a prolonged release of TQ. In conclusion, the formulation of TQ into SSM allows a bio-enhancement of TQ anti-migration activity, suggesting that TQ-SSM is a better candidate than unformulated TQ to inhibit human SH-SY5Y neuroblastoma cell migration.

Pharmacokinetics, safety, and activity of trabectedin as first-line treatment in elderly patients who are affected by advanced sarcoma and are unfit to receive standard chemotherapy: A phase 2 study (TR1US study) from the Italian Sarcoma Group.

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.

Population pharmacokinetic approach for evaluation of treosulfan and its active monoepoxide disposition in plasma and brain on the basis of a rat model.

PURPOSE: Efficacy of treosulfan, used in the treatment of marrow disorders, depends on the activity of its monoepoxy-(EBDM) and diepoxy compounds. The study aimed to describe the pharmacokinetics of treosulfan and EBDM in the rat plasma and brain by means of mixed-effects modelling. METHODS: The study had a one-animal-per-sample design and included ninty-six 10-week-old Wistar rats of both sexes. Treosulfan and EBDM concentrations in the brain and plasma were measured by an HPLC-MS/MS method. The population pharmacokinetic model was established in NONMEM software with a first-order estimation method with interaction. RESULTS: One-compartment pharmacokinetic model best described changes in the concentrations of treosulfan in plasma, and EBDM concentrations in plasma and in the brain. Treosulfan concentrations in the brain followed a two-compartment model. Both treosulfan and EBDM poorly penetrated the blood-brain barrier (ratio of influx and efflux clearances through the blood-brain barrier was 0.120 and 0.317 for treosulfan and EBDM, respectively). Treosulfan plasma clearance was significantly lower in male rats than in females (0.273 L/h/kg vs 0.419 L/h/kg). CONCLUSIONS: The developed population pharmacokinetic model is the first that allows the prediction of treosulfan and EBDM concentrations in rat plasma and brain. These results provide directions for future studies on treosulfan regarding the contribution of transport proteins or the development of a physiological-based model.