Docetaxel, cyclophosphamide, and epirubicin: application of PBPK modeling to gain new insights for drug-drug interactions.

The new adjuvant chemotherapy of docetaxel, epirubicin, and cyclophosphamide has been recommended for treating breast cancer. It is necessary to investigate the potential drug-drug Interactions (DDIs) since they have a narrow therapeutic window in which slight differences in exposure might result in significant differences in treatment efficacy and tolerability. To guide clinical rational drug use, this study aimed to evaluate the DDI potentials of docetaxel, cyclophosphamide, and epirubicin in cancer patients using physiologically based pharmacokinetic (PBPK) models. The GastroPlus™ was used to develop the PBPK models, which were refined and validated with observed data. The established PBPK models accurately described the pharmacokinetics (PKs) of three drugs in cancer patients, and the predicted-to-observed ratios of all the PK parameters met the acceptance criterion. The PBPK model predicted no significant changes in plasma concentrations of these drugs during co-administration, which was consistent with the observed clinical phenomenon. Besides, the verified PBPK models were then used to predict the effect of other Cytochrome P450 3A4 (CYP3A4) inhibitors/inducers on these drug exposures. In the DDI simulation, strong CYP3A4 modulators changed the exposure of three drugs by 0.71-1.61 fold. Therefore, patients receiving these drugs in combination with strong CYP3A4 inhibitors should be monitored regularly to prevent adverse reactions. Furthermore, co-administration of docetaxel, cyclophosphamide, or epirubicin with strong CYP3A4 inducers should be avoided. In conclusion, the PBPK models can be used to further investigate the DDI potential of each drug and to develop dosage recommendations for concurrent usage by additional perpetrators or victims.

Alginate Self-Crosslinking Ink for 3D Extrusion-Based Cryoprinting and Application for Epirubicin-HCl Delivery on MCF-7 Cells.

3D-printed hydrogels are particularly advantageous as drug-delivery platforms but their loading with water-soluble active compounds remains a challenge requiring the development of innovative inks. Here, we propose a new 3D extrusion-based approach that, by exploiting the internal gelation of the alginate, avoids the post-printing crosslinking process and allows the loading of epirubicin-HCl (EPI). The critical combinations of alginate, calcium carbonate and d-glucono-δ-lactone (GDL) combined with the scaffold production parameters (extrusion time, temperature, and curing time) were evaluated and discussed. The internal gelation in tandem with 3D extrusion allowed the preparation of alginate hydrogels with a complex shape and good handling properties. The dispersion of epirubicin-HCl in the hydrogel matrix confirmed the potential of this self-crosslinking alginate-based ink for the preparation of 3D-printed drug-delivery platforms. Drug release from 3D-printed hydrogels was monitored, and the cytotoxic activity was tested against MCF-7 cells. Finally, the change in the expression pattern of anti-apoptotic, pro-apoptotic, and autophagy protein markers was monitored by liquid-chromatography tandem-mass-spectrometry after exposure of MCF-7 to the EPI-loaded hydrogels.

An Application of Tumor-Associated Macrophages as Immunotherapy Targets: Sialic Acid-Modified EPI-Loaded Liposomes Inhibit Breast Cancer Metastasis.

Breast cancer metastasis is an important cause of death in patients with breast cancer and is closely related to circulating tumor cells (CTCs) and the metastatic microenvironment. As the most infiltrating immune cells in the tumor microenvironment (TME), tumor-associated macrophages (TAMs), which highly express sialic acid (SA) receptor (Siglec-1), are closely linked to tumor progression and metastasis. Furthermore, the surface of CTCs also highly expressed receptor (Selectin) for SA. A targeting ligand (SA-CH), composed of SA and cholesterol, was synthesized and modified on the surface of epirubicin (EPI)-loaded liposomes (EPI-SL) as an effective targeting delivery system. Liposomes were evaluated for characteristics, stability, in vitro release, cytotoxicity, cellular uptake, pharmacokinetics, tumor targeting, and pharmacodynamics. In vivo and in vitro experiments showed that EPI-SL enhanced EPI uptake by TAMs. In addition, cellular experiments showed that EPI-SL could also enhance the uptake of EPI by 4T1 cells, resulting in cytotoxicity second only to that of EPI solution. Pharmacodynamic experiments have shown that EPI-SL has optimal tumor inhibition with minimal toxicity, which can be ascribed to the fact that EPI-SL can deliver drugs to tumor based on TAMs and regulate TME through the depletion of TAMs. Our study demonstrated the significant potential of SA-modified liposomes in antitumor metastasis. Schematic diagram of the role of SA-CH modified EPI-loaded liposomes in the model of breast cancer metastasis.

Effect of low-energy shock wave therapy on intravesical epirubicin delivery in a rat model of bladder cancer.

OBJECTIVES: To study the efficacy of low-energy shock wave therapy (LESW) on enhancing intravesical epirubicin (EPI) delivery in a rat model of bladder cancer (BCa). MATERIALS AND METHODS: A total of 100 female Fischer rats were randomly allocated into five groups: control; BCa; LESW; EPI; and EPI plus LESW. After BCa induction by N-butyl-N-(4-hydroxybutyl)nitrosamine, EPI (0.6 mg/0.3 mL of EPI diluted in 0.3 mL saline) or saline (0.6 mL) was administered and retained in the bladders for 1 h with or without LESW treatment (300 pulses at 0.12 mJ/mm2 ). This was repeated weekly for 6 weeks. Survival was then calculated, rats were weighed and their bladders were harvested for bladder/body ratio estimation, histopathological examination, p53 immunostaining, miR-210, hypoxia-inducible factor (HIF)-1α, tumour necrosis factor (TNF)-α and interleukin (IL)-6 relative gene expression and fluorescence spectrophotometric drug quantification. Heart and blood samples were also collected for assessment of the safety profile and toxicity. RESULTS: The EPI plus LESW group had significantly lower mortality rates, loss of body weight and bladder/body ratio. Histopathological results in terms of grossly visible bladder lesions, mucosal thickness, dysplasia formation and tumour invasion were significantly better in the combined treatment group. The EPI plus LESW group also had statistically significant lower expression levels of p53 , miR-210, HIF-1α, TNF-α and IL-6. LESW increased urothelial concentration of EPI by 5.7-fold (P < 0.001). No laboratory variable exceeded the reference ranges in any of the groups. There was an improvement of the indicators of EPI-induced cardiomyopathy in terms of congestion, hyalinization and microvesicular steatosis of cardiomyocytes (P = 0.068, 0.003 and 0.046, respectively) in the EPI plus LESW group. CONCLUSIONS: The combined use of intravesical EPI and LESW results in less BCa invasion and less dysplasia formation, as LESW increases urothelial permeability of EPI and enhances its delivery into tumour tissues, without subsequent toxicity.

Use of a Glass Membrane Pumping Emulsification Device Improves Systemic and Tumor Pharmacokinetics in Rabbit VX2 Liver Tumor in Transarterial Chemoembolization.

PURPOSE: To evaluate the phamacokinetics of epirubicin in conventional transarterial chemoembolization using a developed pumping emulsification device with a microporous glass membrane in VX2 rabbits. MATERIALS AND METHODS: Epirubicin solution (10 mg/mL) was mixed with ethiodized oil (1:2 ratio) using the device or 3-way stopcock. Forty-eight rabbits with VX2 liver tumor implanted 2 weeks prior to transarterial chemoembolization were divided into 2 groups: a device group (n = 24) and a 3-way-stopcock group (n = 24). Next, 0.5 mL of emulsion was injected into the hepatic artery, followed by embolization using 100-300-µm microspheres. The serum epirubicin concentrations (immediately after, 5 minutes after, and 10 minutes after) and the tumor epirubicin concentrations (20 minutes after and 48 hours after) were measured after transarterial chemoembolization. Histopathologic evaluation was performed with a fluorescence microscope. RESULTS: The area under the curve and maximum concentrations of epirubicin in plasma were 0.45 ± 0.18 µg min/mL and 0.13 ± 0.06 µg/mL, respectively, in the device group and 0.71 ± 0.45 µg min/mL and 0.22 ± 0.17 µg/mL, respectively, in the 3-way-stopcock group (P = .013 and P = .021, respectively). The mean epirubicin concentrations in VX2 tumors at 48 hours in the device group and the 3-way-stopcock group were 13.7 ± 6.71 and 7.72 ± 3.26 µg/g tissue, respectively (P = .013). The tumor necrosis ratios at 48 hours were 62 ± 11% in the device group and 51 ± 13% in the 3-way-stopcock group (P = .039). CONCLUSIONS: Conventional transarterial chemoembolization using the pumping emulsification device significantly improved the pharmacokinetics of epirubicin compared to the current standard technique using a 3-way stopcock.

Intracellular tracking of drug release from pH-sensitive polymeric nanoparticles via FRET for synergistic chemo-photodynamic therapy.

BACKGROUND: Synergistic therapy of tumor is a promising way in curing cancer and in order to achieve effective tumor therapy with real-time drug release monitoring, dynamic cellular imaging and antitumor activity. RESULTS: In this work, a polymeric nanoparticle with Forster resonance energy transfer (FRET) effect and chemo-photodynamic properties was fabricated as the drug vehicle. An amphiphilic polymer of cyclo(RGDfCSH) (cRGD)-poly(ethylene glycol) (PEG)-Poly(L-histidine) (PH)-poly(ε-caprolactone) (PCL)-Protoporphyrin (Por)-acting as both a photosensitizer for photodynamic therapy (PDT) and absorption of acceptor in FRET was synthesized and self-assembled into polymeric nanoparticles with epirubicin (EPI)-acting as an antitumor drug for chemotherapy and fluorescence of donor in FRET. Spherical EPI-loaded nanoparticles with the average size of 150 ± 2.4 nm was procured with negatively charged surface, pH sensitivity and high drug loading content (14.9 ± 1.5%). The cellular uptake of EPI-loaded cRGD-PEG-PH-PCL-Por was monitored in real time by the FRET effect between EPI and cRGD-PEG-PH-PCL-Por. The polymeric nanoparticles combined PDT and chemotherapy showed significant anticancer activity both in vitro (IC50 = 0.47 µg/mL) and better therapeutic efficacy than that of free EPI in vivo. CONCLUSIONS: This work provided a versatile strategy to fabricate nanoassemblies for intracellular tracking of drug release and synergistic chemo-photodynamic therapy.

Preparation and pharmacokinetics of bifunctional epirubicin-loaded micelles.

In this study, micelles were designed to deliver an antitumor agent and a fluorescent marker to a tumor site. The micelles simultaneously encapsulated epirubicin (EPI) and polyethylene glycol (PEG)-modified graphene quantum dots (GQDs-PEG), and employed a PEG-polylactic acid block copolymer amphiphilic block polymer as a nanocarrier. Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy were used to characterize the functional groups in the synthesized GQDs-PEG. A Malvern particle size meter and transmission electron microscopy were used to show that the particle size of the GQDs-PEG is approximately 2-9 nm, and that of the bifunctional EPI-loaded micelles (EPI-FIDCR) is 19.59±1.21 nm, with zeta potential at -22.87±0.85 mV. The EE% and DL% for EPI in EPI-FIDCR are 74.02±0.55 % and 3.78±0.28 %, respectively. The IC50 values of EPI-FIDCR and EPI solution (EPI-Free) for tumor cells were 7.03 µg/mL and 5.54 µg/mL, showing that EPI-FIDCR still maintained strong cytotoxicity. Fluorescence micrographs of HeLa cells incubated with GQDs-PEG and EPI-FIDCR for 6 h, respectively, show that only EPI-FIDCR could enter the cells. In vitro cellular uptake assays and an inhibition study indicated that EPI-FIDCR could deliver both EPI and GQDs-PEG into tumor cells, while maintaining an inhibitory effect similar to that of unencapsulated EPI. A pharmacokinetic study showed that EPI-FIDCR could persist in the circulation for a significant period of time. The AUC0→t calculated for the EPI-FIDCR formulation was 159.5-fold compared with that of EPI-Free, based on its improved stability and prolonged blood circulation time. The EPI-FIDCR enables both fluorescence imaging and controlled drug-release, exhibits prolonged systematic circulation time and has potential for the treatment of cancer.

MUC1 aptamer-conjugated mesoporous silica nanoparticles effectively target breast cancer cells.

In the present study, we developed aptamer (Apt) conjugated mesoporous silica nanoparticles (MSNs) for specific delivery of epirubicin (EPI) to breast cancer cells. MSNs were synthesized and functionalized with 3-mercaptopropyltrimethoxysilane (3-MPTMS), followed by MUC1 aptamer conjugation through disulfide bonds. The nanoparticles were analyzed by transmission electron microscopy (TEM), particle size analyzer, zeta potential, elemental analysis (CHNS), aptamer conjugation efficiency, drug loading efficiency, and drug release profile. Cell uptake and in vitro cytotoxicity of different formulations were performed. The results of MSNs characterization confirmed spherical nanoparticles with thiol functional groups. Particle size of obtained nanoparticles was 163 nm in deionized water. After conjugation of MUC1 aptamer and EPI loading (MSN-MUC1-EPI), particle size increased to 258 nm. The aptamer conjugation to MSNs with disulfide bonds were confirmed using gel retardation assay. Cellular uptake studies revealed better cell uptake of MSN-MUC1-EPI compared to MSN-EPI. Moreover, cytotoxicity study results in MCF7 cell lines showed improved cytotoxicity of MSN-MUC1-EPI in comparison with MSN-EPI or EPI at the same concentration of drug. These results exhibited that MSN-MUC1-EPI has the potential for targeted drug delivery into MUC1 positive breast cancer cells to improve drug efficacy and alleviate side effects.

Labeling of epirubicin with technetium-99m: Optimization, biodistribution and scintigraphic imaging in tumor bearing mice.

Epirubicin is an antineoplastic agent of anthracycline antibiotic, used for treating a variety of tumor types such as lymphoma, cancer of the breast, lung, ovary and stomach. The objective of this work was to demonstrate direct radiolabeling of epirubicin with 99mTc, quality control, biological characterization and scientigraphic evaluation in tumor bearing mice. The 99mTc-epirubicin labeling was optimized by varying the amounts of ligand 100-350µg, stannous chloride dihydride 20-50µg and pH range 2-10 by using NaOH or HCl. The radiochemical purity of 99mTc-epirubicin was evaluated by chromatographic techniques (Whatman No. 3 paper and ITLC-SG). HPLC analyses were performed to check purity of epirubicin and radiochemical purity of labeled 99mTc- epirubicin. Biodistribution and scintigraphic imaging of 99mTc-epirubicin was performed in normal and tumor bearing mice at various time intervals. The optimum conditions ensuring 99mTc-epirubicin labeling yield as high as 99% by adding 35µg SnCl2.2H2O, 200µg of ligand at pH 6 for 30 min at room temperature (25°C±2°C). HPLC of 99mTc-epirubicin shows about 99% binding of the compound with technetium-99m. Electrophoresis study indicated the neutral nature of 99mTc-epirubicin. Biodistribution data and scintigraphic results showed that 99mTc-epirubicin accumulated in the liver as well as in tumor with significant uptake and excellent retention. 99mTc-epirubicin shows good stability in human serum. In vitro and in vivo studies revealed the significantly uptake of 99mTc-epirubicin in the tumor, and also indicating the efficiency of 99mTc-epirubicin as a tumor diagnostic agent.

A first-in-human Phase 1 study of epirubicin-conjugated polymer micelles (K-912/NC-6300) in patients with advanced or recurrent solid tumors.

Background K-912 also known as NC-6300 is a novel epirubicin pro-drug conjugate developed using micellar nanoparticle technology. We conducted a first-in-human, Phase 1, open-label, non-randomized dose escalation study to evaluate the safety, tolerability, efficacy, and pharmacokinetics of K-912 administered as monotherapy in patients with advanced or recurrent solid tumors. Methods Patients aged 41 to 72 years with histologically or cytologically confirmed advanced or recurrent malignant solid tumors either refractory to standard therapy or had no other viable treatment options were enrolled. K-912 was administered as a 10-min intravenous infusion every three weeks. Doses were increased in a step-wise manner based on a predetermined series: 15, 30, 60, 80, 100, 130, 170, and 225 mg/m2. The appropriateness of doses above 60 mg/m2 was assessed using a Bayesian continual reassessment model. Treatment-emergent adverse events and tumor response were evaluated according to internationally accepted criteria. Results Nineteen patients were treated with K-912. No additional adverse events expected with anthracyclines were observed. While the number of patients treated at the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D) were small, MTD and RP2D were established to be 170 mg/m2. Partial response was observed in one patient with breast cancer treated at 100 mg/m2, yielding an objective response rate of 5% (1/19). Stable disease was observed in 10 patients. The human pharmacokinetic profile of K-912 was consistent with that observed from nonclinical studies in rats and monkeys. Conclusions This study showed that K-912 was well tolerated in patients with various solid tumors and exhibited less toxicity than conventional epirubicin formulations.

[Chemotherapy for Malignancy During Pregnancy - Literature Review.]

In today's dynamic development of modern life, we can unfortunately see more and more often cases of malignant diseases during pregnancy. Therapy of these conditions in pregnant women is a challenge to the doctors, due to concerns for the mother's health, but also the possible risks for the foetus. An additional difficulty is the fact that there are no common algorithms for the treatment. Of great importance is the ges'tation period, because in its different parts, the risks vary in grade. It is believed that up to 10-12th ges.tation week chemotherapy should not be included. The optimal time for the last course is 35th gestation week or three weeks to the due date. The purpose of this review is to examine the benefits and risks of the treatment of malignant diseases during pregnancy for both the mother and the fetus.

Enhanced antitumor effect of anti-tissue factor antibody-conjugated epirubicin-incorporating micelles in xenograft models.

For the creation of a successful antibody-drug conjugate (ADC), both scientific and clinical evidence has indicated that highly toxic anticancer agents (ACA) should be conjugated to a monoclonal antibody (mAb) to administer a reasonable amount of ADC to patients without compromising the affinity of the mAb. For ordinary ACA, the conjugation of a mAb to ACA-loaded micellar nanoparticles is clinically applicable. Tissue factor (TF) is often overexpressed in various cancer cells and tumor vascular endothelium. Accordingly, anti-TF-NC-6300, consisting of epirubicin-incorporating micelles (NC-6300) conjugated with the F(ab')2 of anti-TF mAb was developed. The in vitro and in vivo efficacy and pharmacokinetics of anti-TF-NC-6300 were compared to NC-6300 using two human pancreatic cancer cell lines, BxPC3 (high TF expression) and SUIT2 (low TF expression), and a gastric cancer cell line, 44As3 (high TF expression). The intracellular uptake of epirubicin was faster and greater in BxPC3 cells treated with anti-TF-NC-6300, compared with NC-6300. Anti-TF-NC-6300 showed a superior antitumor activity in BxPC3 and 44As3 xenografts, compared with NC-6300, while the activities of both micelles were similar in the SUIT2 xenograft. A higher tumor accumulation of anti-TF-NC-6300 compared to NC-6300 was seen, regardless of the TF expression levels. However, anti-TF-NC-6300 appeared to be localized to the tumor cells with high TF expression. These results indicated that the enhanced antitumor effect of anti-TF-NC6300 may be independent of the tumor accumulation but may depend on the selective intratumor localization and the preferential internalization of anti-TF-NC-6300 into high TF tumor cells.

Stability, Pharmacokinetics, Biodistribution and Safety Assessment of Folate-Conjugated Pullulan Acetate Nanoparticles as Cervical Cancer Targeted Drug Carriers.

It is recognized that the stability and journey in the body of nanoparticles are important issues for drug formulations. In this study, we prepared folate-conjugated pullulan acetate nanoparticles (FPANs) and epirubicin loaded FPANs (FPA/EPI) using dialysis method. The storage stability of FPANs and FPA/EPI at 4 degrees C could be up to 3 months. Using folate receptor overexpressed Hela cells, dose dependent cellular uptake and receptor-mediated endocytosis of FPA/EPI were confirmed. From the in vivo pharmacokinetics test, compared to free EPI, half-life time (t½) of FPA/EPI was extended 1.57 times and the area under-the-curve (AUC) increased 3.95 times as well. In addition, biodistribution data showed that, EPI concentration in tumor in FPA/EPI group was 2.01 times higher than that in free EPI group after 96 h; The concentration of drug in liver treated by FPA/EPI was 5.7-11.6 times, while in heart, kidney, especially in stomach and intestine were much lower than those in free EPI group from 24 to 96 h. Furthermore, blank FPANs showed no apparent acute toxicity at dose up to 125 mg/kg. All results suggested that FPA/EPI showed a promising potential on treating cervical carcinoma and its metastatic hepatocellular carcinoma in future because of the high stability, less toxicity and tumor targeting.

The Use of a Liposomal Formulation Incorporating an Antimicrobial Peptide from Tilapia as a New Adjuvant to Epirubicin in Human Squamous Cell Carcinoma and Pluripotent Testicular Embryonic Carcinoma Cells.

This study aims to explore the effects and mechanisms of hepcidin, a potential antimicrobial peptide from Tilapia, and epirubicin (Epi), an antineoplastic agent, on the generation of reactive oxygen species (ROS) and link the ROS levels to the reversal mechanisms of multidrug resistance (MDR) by epirubicin and hepcidin in human squamous cell carcinoma SCC15 and human embryonal carcinoma NT2D1 cells. The cells, pretreated with hepcidin, epirubicin, or a combination of these compounds in PEGylated liposomes, were used to validate the molecular mechanisms involved in inhibiting efflux transporters and inducing apoptosis as evaluated by cytotoxicity, intracellular accumulation, mRNA levels, cell cycle distribution, and caspase activity of this combination. We found that hepcidin significantly enhanced the cytotoxicity of epirubicin in liposomes. The co-incubation of epirubicin with hepcidin in liposomes intensified the ROS production, including hydrogen peroxide and superoxide free radicals. Hepcidin significantly increased epirubicin intracellular uptake into NT2D1 and SCC15 cells, as supported by the diminished mRNA expressions of MDR1, MDR-associated protein (MRP) 1, and MRP2. Hepcidin and/or epirubicin in liposomes triggered apoptosis, as verified by the reduced mitochondrial membrane potential, increased sub-G1 phase of cell cycle, incremental populations of apoptosis using annexin V/PI assay, and chromatin condensation. As far as we know, this is the first example showing that PEGylated liposomal TH1-5 and epirubicin gives rise to cell death in human squamous carcinoma and testicular embryonic carcinoma cells through the reduced epirubicin efflux via ROS-mediated suppression of P-gp and MRPs and concomitant initiation of mitochondrial apoptosis pathway. Hence, hepcidin in PEGylated liposomes may function as an adjuvant to anticancer drugs, thus demonstrating a novel strategy for reversing MDR.

Effect of combined treatment with the epirubicin-incorporating micelles (NC-6300) and 1,2-diaminocyclohexane platinum (II)-incorporating micelles (NC-4016) on a human gastric cancer model.

Anticancer agent-incorporating polymeric micelles accumulate effectively in tumors via the enhanced permeability and retention effect to exert potent antitumor effects. However, combined use of such micelles has not been elucidated. We compared the effect of combining the epirubicin-incorporating micelle NC-6300 and 1,2-diaminocyclohexane platinum (II) (oxaliplatin parent complex)-incorporating micelle NC-4016 (NCs) with that of epirubicin and oxaliplatin (E/O) in 44As3Luc cells using the combination index method. The in vivo antitumor activities of NCs and E/O were evaluated in mice bearing 44As3Luc xenografts. Pharmacokinetic analysis was performed by high-performance liquid chromatography and mass spectrometry. Cardiotoxicity of NC-6300 and epirubicin was assessed by echocardiography. Neurotoxicity of NC-4016 and oxaliplatin was evaluated by examining the paw withdrawal response to noxious mechanical stimuli. NCs showed a highly synergistic activity equivalent to E/O. In vivo, NCs exhibited higher antitumor activity in the subcutaneous tumor model and longer overall survival in the orthotopic tumor model than E/O (p < 0.001, p = 0.015, respectively). The intratumor concentrations of epirubicin and platinum were significantly higher following NCs than following E/O administration. Moreover, the micelles showed lower cardiotoxicity and neurotoxicity than the corresponding conventional drugs. The combined use of the micelles was associated with remarkable efficacy and favorable toxicities in the human gastric cancer model, and warrants the conduct of clinical trials.

Optimizing anticancer drug treatment in pregnant cancer patients: pharmacokinetic analysis of gestation-induced changes for doxorubicin, epirubicin, docetaxel and paclitaxel.

BACKGROUND: Pregnant patients with cancer are increasingly treated with anticancer drugs, although the specific impact of pregnancy-induced physiological changes on the pharmacokinetics (PK) of anticancer drugs and associated implications for optimal dose regimens remains unclear. Our objectives were to quantify changes in PK during pregnancy for four frequently used anticancer agents doxorubicin, epirubicin, docetaxel and paclitaxel, and to determine associated necessary dose adjustments. PATIENTS AND METHODS: A pooled analysis of PK data was carried out for pregnant (Pr) and nonpregnant (NPr) patients for doxorubicin (n = 16 Pr/59 NPr), epirubicin (n = 14 Pr/57 NPr), docetaxel (n = 3 Pr/32 NPr) and paclitaxel (n = 5 Pr/105 NPr). Compartmental nonlinear mixed effect models were used to describe the PK and gestational effects. Subsequently, we derived optimized dose regimens aiming to match to the area under the concentration-time curve (AUC) in nonpregnant patients. RESULTS: The effect of pregnancy on volumes of distribution for doxorubicin, epirubicin, docetaxel and paclitaxel were estimated as fold-change of <1.32, <2.08, <1.37 and <4.21, respectively, with adequate precision [relative standard error (RSE) <37%]. For doxorubicin, no gestational effect could be estimated on clearance (CL). For epirubicin, docetaxel and paclitaxel, a fold-change of 1.1 (RSE 9%), 1.19 (RSE 7%) and 1.92 (RSE 21%) were, respectively, estimated on CL. Calculated dose adjustment requirements for doxorubicin, epirubicin, docetaxel and paclitaxel were +5.5%, +8.0%, +16.9% and +37.8%, respectively. Estimated changes in infusion duration were marginal (<4.2%) except for paclitaxel (-21.4%). CONCLUSION: Clinicians should be aware of a decrease in drug exposure during pregnancy and should not a priori reduce dose. The decrease in exposure was most apparent for docetaxel and paclitaxel which is supported by known physiological changes during pregnancy. The suggested dose adaptations should only be implemented after conduct of further confirmatory studies of the PK during pregnancy.

Pharmacokinetics of gelatin sponge microparticles in a rabbit VX2 liver tumor model of hepatic arterial chemoembolization.

The objective of this study is to investigate pharmacokinetics of gelatin sponge microparticles (GSMs) combined with epirubicin in a rabbit VX2 liver tumor model of hepatic arterial chemoembolization (TACE). Eighteen successful models of VX2 in New Zealand white rabbits was established, which were divided into three groups randomly: HAI group (n = 6), the epirubicin solution (epirubicin 10 mg mixed with saline 10 ml into the hepatic artery); GSMs-TACE group (n = 6), GSMs (20 mg) mixed with epirubicin solution (1 mg/ml); c-TACE group (n = 6), epirubicin (10 mg) mixed with lipiodol (10 ml). Each rabbit was administrated epirubicin at dose adjusted for a 1 mg/kg. Samples were collected from femoral vein at 5, 10, 20, 30, 40, 60, 90, and 120 min after therapy after 120 min; rabbit was killed, and tumor and peritumoral normal liver tissue was cised. Epirubicin concentrations in plasma and tumor were measured. The epirubicin concentration in plasma was significantly lower in GSMs-TACE group than in HAI group. C max in there groups after administration was 28.77 ± 7.15 µg/ml in c-TACE group, 83.84 ± 32.28 µg/ml in GSMs-TACE group, and 238.46 ± 23.44 µg/ml in HAI group at 5 min, respectively. The epirubicin concentration in tumor tissue was 53.06 ± 16.9 µg/g in c-TACE group, 44.49 ± 16.80 µg/g in the GSMs-TACE group, and 18.32 ± 8.30 µg/g in HAI group, respectively. Epirubicin concentration of GSMs-TACE group was significantly higher than that of HAI group (P < 0.05). The area under the curve (AUC) at 0-120 min in c-TACE, GSMs-TACE, and HAI groups were 1,815 ± 889.88, 3,416 ± 799.90, and 11,899 ± 2,717.17 µg min/ml, respectively. The AUC was lower in GSMs-TACE group than in HAI group (P < 0.05). Compared with HAI, GSMs-TACE has higher epirubicin concentrations in tumor and lower concentrations in plasma. The results show that GSMs-TACE has a feature of slow drug release-it may be one of the mechanisms of GSMs-TACE for HCC.

Characterization of endogenous G-CSF and the inverse correlation to chemotherapy-induced neutropenia in patients with breast cancer using population modeling.

PURPOSE: Neutropenia is a severe adverse-event of chemotherapeutics. Neutrophils (ANC) are mainly regulated by granulocyte colony stimulating factor (G-CSF). The aim was to characterize the dynamics between endogenous G-CSF and ANC over time following chemotherapy. METHODS: Endogenous G-CSF and ANC were monitored in forty-nine breast cancer patients treated with sequential adjuvant 5-fluorouracil-epirubicin-cyclophosphamide and docetaxel. RESULTS: During treatment courses ANC was transiently decreased and was reflected in an endogenous G-CSF increase, which was well described by a semi-mechanistic model including control mechanisms; when G-CSF concentrations increased the proliferation rate increased and the bone maturation time reduced for ANC. Subsequently, ANC in the circulation increased leading to increased elimination of G-CSF. Additionally, a non-specific elimination for G-CSF was quantified. The ANC-dependent elimination contributed to 97% at baseline and 49% at an ANC of 0.1 · 10(9)/L to the total G-CSF elimination. CONCLUSION: The integrated G-CSF-myelosuppression model captured the initial rise in endogenous G-CSF following chemotherapy-induced neutropenia and the return to baseline of G-CSF and ANC. The model supported the self-regulatory properties of the system and may be a useful tool for further characterization of the biological system and in optimization of chemotherapy treatment.

Construction and application of biotin-poloxamer conjugate micelles for chemotherapeutics.

Biotin was conjugated on poloxamer to prepare biotin-poloxamer (BP) conjugate micelles for chemotherapeutics. Epirubicin (EPI) was encapsulated in BP micelles. The EPI-loaded BP micelles were characterized in terms of size, ζ-potential, morphology, drug loading, drug encapsulation and drug release. Marrow leukemic HL-60 cells were used for evaluating the in vitro cytotoxicity of EPI-loaded BP micelles. Nude mice were axillainoculated subcutaneously HL-60 cells to establish tumour model for investigating the inhibition effects of EPI-loaded BP micelles. From the results, the sizes of these nanoparticles were about 100 nm. Fluorescence microscope observation supported the enhanced cellular uptake of the micelles. The order of the inhibition on tumour volume growth was: EPI-loaded BP micelles >EPI-loaded MATP micelles >EPI-loaded poloxamer micelles >EPI. BP micelles showed significant antitumour activity and low toxicity, compared with the non-targeted micelles. With the advantage of EPR effect and tumour-targeting potential, BP conjugate micelles might be developed as a new system for chemotherapeutics.

Evaluation of epirubicin in thermogelling and bioadhesive liquid and solid suppository formulations for rectal administration.

Temperature sensitive Pluronic (Plu) and pH-sensitive polyacrylic acid (PAA) were successfully mixed in different ratios to form in situ gelling formulations for colon cancer therapy. The major formulations were prepared as the liquid and solid suppository dosage forms. Epirubicin (Epi) was chosen as a model anticancer drug. In vitro characterization and in vivo pharmacokinetics and therapeutic efficacy of Epi in six Plu/PAA formulations were evaluated. Our in vitro data indicate that Epi in Plu 14%/PAA 0.75% of both solid and liquid suppositories possess significant cytotoxicity, strong bioadhesive force, long-term appropriate suppository base, sustained release, and high accumulation of Epi in rat rectums. These solid and liquid suppositories were retained in the upper rectum of Sprague-Dawley (SD) rats for at least 12 h. An in vivo pharmacokinetic study using SD rats showed that after rectal administration of solid and liquid suppositories, Epi had greater area under the curve and higher relative bioavailability than in a rectal solution. These solid and liquid suppositories exhibited remarkable inhibition on the tumor growth of CT26 bearing Balb/c mice in vivo. Our findings suggest that in situ thermogelling and mucoadhesive suppositories demonstrate a great potential as colon anticancer delivery systems for protracted release of chemotherapeutic agents.