Optimization by design of etoposide loaded solid lipid nanoparticles for ocular delivery: Characterization, pharmacokinetic and deposition study.

The present study was to develop etoposide loaded solid lipid nanoparticles (SLN) and optimize it for effective ocular delivery to the posterior eye. SLN were prepared by melt-emulsification and ultrasonication technique. Etoposide loaded SLN were optimized by using three-factor three levels Box-Behnken design to establish the functional relationships between variables on responses of particle size, polydispersity index (PDI) and entrapment efficiency (EE). SLN were characterized for size & surface morphology, entrapment efficiency and in vitro release. Further the pharmacokinetic study of optimized formulation after intravitreal administration was evaluated in Wister rats. The deposition in the ocular tissues was checked by scintigraphic analysis in Albino rabbits. Histology was also done to evaluate morphological changes if any occur after treatment. The particle size, PDI and EE obtained for the optimized formulation (Z15) were 239.43 ±â€¯2.35 nm, 0.261 ±â€¯0.001 and 80.96 ±â€¯2.21% respectively. Single intravitreal administrations of SLN were able to give sustained etoposide concentration in the vitreous for 7 consecutive days which was also supported by the results of Gamma scintigraphic study. Histology of posterior ocular tissues do not showed any serious toxic effect. Therefore it can concluded that etoposide loaded SLN was able to maintain vitreous concentration of drug without any serious toxic effect to the surrounding ocular tissues after an intravitreous administration in rat eye.

Accurate Prediction of Initial Busulfan Exposure Using a Test Dose With 2- and 6-Hour Blood Sampling in Adult Patients Receiving a Twice-Daily Intravenous Busulfan-Based Conditioning Regimen.

This study aimed to predict the area under the curve (AUC) of the initial busulfan dose using a test dose with the sparse sampling scheme in adult patients who underwent hematopoietic cell transplant. A test dose of 0.8 mg/kg busulfan was used 2 days before twice-daily intravenous busulfan-based conditioning regimens were administered. The AUC and the clearance (CL) were calculated for both the test dose and the first dose (AUCT , CLT , AUC1, and CL1 ) by noncompartmental analysis. The sparse sampling schemes of the test dose were developed by Bayesian method based on the population pharmacokinetic model. The optimal sparse sampling schemes were determined by evaluating the mean prediction error, the root mean square error, the absolute mean prediction error, and Bland-Altman plot. The mean AUC1 was 7.20 ± 1.48 mg • h/L, which ranged from 4.70 to 9.46 mg • h/L. The AUC1 was below the therapeutic concentration of 7.38 mg • h/L in 45% (9 of 20) of the patients. The CLT of 3.05 ± 0.56 mL/min/kg was not significantly different with the CL1 of 3.03 ± 0.69 mL/min/kg (P = .901). A sampling scheme at 2 and 6 hours after the test dose was developed to predict the AUCT (mean prediction error of 1.64%, root mean square error of 6.17%, and absolute mean prediction error of 4.94%). Additionally, the Bland-Altman plot showed that the 2-sampling scheme provided an acceptably accurate prediction of the AUC1 . A test dose with a 2-sampling scheme was sufficient to personalize the initial busulfan dosing in hematopoietic cell transplant recipients.

Au/Pd@rGO nanocomposite decorated with poly (L-Cysteine) as a probe for simultaneous sensitive electrochemical determination of anticancer drugs, Ifosfamide and Etoposide.

The simultaneous measurement of the concentration of anticancer drugs with a fast, sensitive and accurate method in biological samples is a challenge for better monitoring of drug therapy and better determine the pharmacokinetics. An electrochemical sensor was developed for the simultaneous determination of anticancer drugs, Ifosfamide (IFO) and Etoposide (ETO) based on pencil graphite electrode modified with Au/Pd@rGO nanocomposite decorated with poly (L-Cysteine). Cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) were utilized to study the properties of the modified electrode. The electrochemical behavior of IFO and ETO on the Au/Pd@rGO@p(L-Cys) modified electrode was investigated by cyclic voltammetry and differential pulse voltammetry (DPV) techniques and the obtained results confirmed its efficiency for the individual and simultaneous sensing of IFO and ETO. After optimization of electrochemical parameters, the fabricated sensor presented excellent performance in simultaneous determination of IFO and ETO with a wide linear range from 0.10 to 90.0 µM and 0.01 to 40.0 µM and low detection limits (3 Sb/m) of 9.210 nM and 0.718 nM, respectively. In addition, this study proved that the constructed sensor could be useful to simultaneous analysis of IFO and ETO in biological samples and pharmaceutical compounds.

Polysorbate 20 alters the oral bioavailability of etoposide in wild type and mdr1a deficient Sprague-Dawley rats.

The aim of the present work was to investigate the ability of nonionic surfactants to increase the oral absorption of the P-glycoprotein substrate etoposide in vitro and in vivo. Intestinal absorption was investigated by studying bidirectional permeability of etoposide across filter-grown Caco-2 and MDCKII MDR1 cell monolayers. The oral absorption of etoposide was investigated in wild type (WT) and mdr1a deficient (KO) Sprague-Dawley rats. In cell cultures, polysorbate 20 (PS20) decreased P-glycoprotein mediated efflux of etoposide. When PS20 and etoposide were co-administered to WT rats, the oral absorption of etoposide increased significantly in the presence of 5 and 25% (v/v) PS20. However, in KO rats, the exposure of etoposide after oral co-administration with 5% PS20 was similar to control. Unexpectedly, co-administration of etoposide with 25% PS20 significantly reduced the absorption fraction of etoposide in mdr1a KO rats. In vitro dialysis studies performed on PS20-containing etoposide solutions suggested that the reduced bioavailability may be due to etoposide retention in PS20 micelles and/or through increased viscosity. In conclusion, PS20 increases oral bioavailability of etoposide through inhibition of P-glycoprotein. However, the use of the excipient may be challenged by etoposide retention at higher concentrations.

Validated UHPLC-MS/MS assay for quantitative determination of etoposide, gemcitabine, vinorelbine and their metabolites in patients with lung cancer.

A fully valid UHPLC-MS/MS method was developed for the determination of etoposide, gemcitabine, vinorelbine and their metabolites (etoposide catechol, 2',2'-difluorodeoxyuridine and 4-O-deacetylvinorelbine) in human plasma. The multiple reaction monitoring mode was performed with an electrospray ionization interface operating in both the positive and negative ion modes per compound. The method required only 100 µL plasma with a one-step simple de-proteinization procedure, and a short run time of 7.5 min per sample. A Waters ACQUITY UPLC HSS T3 column (2.1 × 100 mm, 1.8 µm) provided chromatographic separation of analytes using a binary mobile phase gradient (A, 0.1% formic acid in acetonitrile, v/v; B, 0.1% formic acid in water, v/v). Linear coefficients of correlation were >0.995 for all analytes. The relative deviation of this method was <10% for intra- and inter-day assays and the accuracy ranged between 86.35% and 113.44%. The mean extraction recovery and matrix effect of all the analytes were 62.07-105.46% and 93.67-105.87%, respectively. This method was successfully applied to clinical samples from patients with lung cancer.

Development of a Limited Sampling Strategy for the Estimation of Exposure to High-Dose Etoposide After Intravenous Infusion in Pediatric Patients.

BACKGROUND: Etoposide (VP-16), a podophyllotoxin derivative, is used in conditioning regimens before allogeneic hematopoietic stem cell transplantation in children with acute lymphoblastic leukemia. The aim of this study was to develop a limited sampling strategy (LSS) suitable for the prediction of exposure to VP-16 defined as area under time-concentration curve (AUC). METHODS: The study included 28 pediatric patients with acute lymphoblastic leukemia, who were administered a 4-hour infusion of 60 mg/kg VP-16. VP-16 concentrations were determined in samples collected 4-124 hours after the beginning of infusion. On obtaining the pharmacokinetic (PK) profiles, a population PK model was developed in NONMEM (ICON Development Solutions, Hanover, MD) with first-order conditional estimation with interaction algorithm. LSSs were chosen by means of a multivariate regression analysis and cross-validated with a leave-one-out approach. Predictive performance of LSSs was assessed by calculating relative prediction error (PE), mean PE, mean absolute PE, and root mean squared PE for model-predicted and observed AUC. RESULTS: VP-16 PKs was best described by a 2-compartment first-order model, and a large variability in the PK parameters was observed. A 3-sample strategy allowed the estimation of VP-16 with highest accuracy and precision (mean relative PE = 0.18%, 95% confidence interval, 1.73%-2.09%; mean absolute relative PE = 3.47%, 95% confidence interval, 2.28%-4.66%; root mean squared PE = 4.43%). The final equation was AUC = 6.85 × C6 h + 3.88 × C12 h + 46.11 × C28 h + 282.0 (adjusted R = 0.9540). CONCLUSIONS: In conclusion, developed LSS allows accurate and precise estimation of VP-16 AUC and might be useful for therapeutic drug monitoring.

Transdermal Delivery of Etoposide Phosphate II: In Vitro In Vivo Correlations (IVIVC).

A dependable in vitro in vivo correlation (IVIVC) is a vital tool to optimize drug formulation and expedite product development time. Although many IVIVC examples are available for oral delivery systems, IVIVC for transdermal delivery is far less common, especially for electrical-assisted delivery. The objective of this study was to develop an IVIVC for the iontophoretic delivery of the anticancer drug etoposide. Iontophoresis was performed at 4 current densities (100, 200, 300, and 400 µA/cm(2)) both in vitro using a standard Franz-cell apparatus with excised porcine skin as membrane, and in vivo in a rabbit model. There was strong correlation between the in vitro % permeated across porcine skin and in vivo absorption (AUC, Cmax) in the range 100-300 µA/cm(2). The correlation between in vitro flux and in vivo input rate (R0) permitted to predict the R0 from a different set of in vitro data (external validation). Convolution of such input rate accurately predicted in vivo plasma profiles (PE% <15) in the absorption phase, whereas the elimination phase was slightly under-predicted (PE% >20). In vivo absorption profiles obtained with deconvolution did not overlap directly with the in vitro profiles; however, correction for the lag time and the application of a scaling factor estimated from Levy' s plots resulted in excellent correlation.

Transdermal Delivery of Etoposide Phosphate I: In Vitro and In Vivo Evaluation.

Cancer chemotherapy frequently requires long periods of multiple intravenous infusions that often results in patients opting out of treatment. The main purpose of this study was to investigate the feasibility of delivering one of these anticancer agents: etoposide phosphate (ETP) transdermally using iontophoresis and a combination of iontophoresis/microporation. The iontophoresis conditions for ETP were first optimized in vitro then tested in vivo in a rabbit model. Both ETP and its active form etoposide (VP) were quantified in dermis (via microdialysis sampling) and in plasma, with a specially developed high-performance liquid chromatography method. In vitro, the amount of total etoposide permeated and the steady state flux increased (p < 0.05) with increase in iontophoretic current densities (100-400 µA/cm(2)). At 300 µA/cm(2), microporation/iontophoresis further improved both parameters by 2- and 2.8-fold, respectively. In vivo, exposure increased proportionally to current density in plasma, whereas dermal concentration dropped significantly at the highest current density. Microporation led to a 50% increase in Cmax and AUClast values in both skin and plasma. In conclusion, a mild current density (300 µA/cm(2)) and a small surface area (10.1 cm(2)) achieved and maintained the minimum effective concentration for the entire duration of electrical current delivery; microporation further increased the plasma concentrations at the same current density.

Population Pharmacokinetic Modeling of Etoposide Free Concentrations in Solid Tumor.

PURPOSE: This study aimed to determine free etoposide (ETO) concentrations in two regions of Walker-256 (W256) solid tumor using microdialysis and to establish a population pharmacokinetic (popPK) model to describe simultaneously free tumor and total plasma concentrations. METHODS: W256 tumor-bearing Wistar rats received ETO 10 or 20 mg/kg i.v. bolus. Free ETO concentrations were sampled from central and peripheral regions of the tumor via CMA/20 probes for up to 7 h, whereas blood samples were collected via carotid artery cannulation. Total plasma and free tumor concentration-time profiles were analyzed by non-compartmental approach using WinNonlin® v. 5.3. PopPK modeling was conducted using MONOLIX v.4.3.3. RESULTS: ETO penetration was higher in the periphery (61 ± 15% and 61 ± 29%) than in tumor center (34 ± 6% and 28 ± 11%) following 10 and 20 mg/kg doses, respectively (ANOVA, α = 0.05). A 4-compartment model fitted ETO concentration-time profiles in all sampling compartments. CONCLUSIONS: The popPK model allowed the simultaneous fitting of plasma and tumor concentrations and a better understanding of ETO distribution in solid tumors. ETO plasma concentrations are not a good surrogate for tumoral exposure, emphasizing the importance of knowing intratumoral concentrations to predict drug response.

A simple dried blood spot method for clinical pharmacological analyses of etoposide in cancer patients using liquid chromatography and fluorescence detection.

BACKGROUND: Therapeutic drug monitoring of etoposide is not part of the routine clinical practice, however, measuring etoposide plasma concentration may be useful to prevent chemotherapy related adverse drug reactions. This paper describes the development and validation of a dried blood spot (DBS) assay for the determination of etoposide in blood samples of lung cancer patients. METHODS: The whole blood spot was cut out of the DBS card followed by sonication assisted liquid drug extraction. Extraction solution was evaporated and re-dissolved. A high-performance-liquid-chromatography method with fluorimetric detection ( λex=230nm; λem=330nm) was used. RESULTS: Method met the validation criteria in terms of selectivity, linearity (0.5-20.0µg/mL), accuracy (≥96.1%), precision (≤10.1%) and stability (long term 4weeks at room temperature and 40°C). Haematocrit did not influence DBS etoposide concentration. Good correlation between measured plasma and DBS concentrations was observed. The equation considering only haematocrit value was used for conversion of DBS to plasma concentration. CONCLUSIONS: DBS sampling method showed comparable results to plasma samples. Therefore, it can be concluded that the developed and validated DBS method, which is more patient-friendly and requires less sample handling, is a reliable alternative to conventional plasma methods for measuring etoposide concentration in clinical pharmacological analyses.

Etoposide pharmacokinetics impact the outcomes of lymphoma patients treated with BEAM regimen and ASCT: a multicenter study of the LYmphoma Study Association (LYSA).

BACKGROUND: Relationships between pharmacokinetic (PK) parameters of etoposide and toxicity survivals were reported in cancer patients treated at standard doses. The clinical impact of PK variations of etoposide high doses has never been explored in lymphoma patients. PATIENTS AND METHODS: The primary objective of LYMPK study was to prospectively assess the impact of etoposide PK parameters on outcomes in lymphoma patients receiving high-dose chemotherapy regimen (carmustine, cytarabine, etoposide and melphalan) followed by autologous stem cell transplant (ASCT). Individual etoposide PK parameters were estimated with a previously reported bi-compartment model using NONMEM(®) program. The impact of PK parameters on toxicity and survival was assessed using univariate/multivariate analyses. RESULTS: A total of 91 patients with malignant lymphoma [non-Hodgkin's lymphoma (NHL): 79; Hodgkin's lymphoma: 12] at first line (n = 49) or relapse (n = 42) were enrolled in five centers. Large inter-individual variabilities in individual PK values were found for the same administration doses. In NHL patients, cumulative higher trough concentrations over the eight administrations of the first cycle (TotC min, categorized by the median 58.71 mg/L) had significant prognostic value regarding the 5-year progression-free survival (PFS: 73.6 vs 46.5 %, P = 0.015) and 5-year overall survival (OS: 74.0 vs 52.2 %, P = 0.034). Using a Cox model analysis, integrating disease settings (first line vs recurrent disease), simplified IPI and other prognostic factors, TotC min was the only significant independent prognostic factor influencing PFS, disease-specific survival and OS. CONCLUSION: This prospective study suggests survival of NHL patients treated with BEAM regimen and ASCT might be improved by increasing etoposide administration dose, or plasma concentration-based adjustment.

Bioequivalence study of two formulations of etoposide in advanced lung cancer patients.

INTRODUCTION: The present randomized, two-period, cross-over bioequivalence study compared two soft capsules of etoposide (test and reference formulations), in treating 18 advanced lung cancer patients. MATERIALS AND METHODS: The pharmacokinetic parameters were determined based on the concentrations of etoposide, using HPLC with fluorescence detector. In each of the two study periods, a single dose of test or reference product was administered. The pharmacokinetic parameters assessed included area under the plasma concentration-time curve (AUC(0-12h)) from 0 to 12 hours, AUC(0-T) from time zero to infinity, the peak plasma concentration of the drug (C(max)), time to achieve C(max), and the elimination half-life. RESULTS: Comparison of the test and reference products containing etoposide showed that geometric mean ratios (90% confidence interval (CI)) of AUC(0-T), AUC(0-∞)ž, and C(max) were 99.7% (92.1 - 103.7%), 99.4% (92.3 - 105.2%), and 101.5% (94.2 - 109.6%), respectively. Both AUC and C(max) ratio 90% CI of test and reference formulations were within its acceptable range for bioequivalence. The values of tmax and t1/2 were not found to have a statistically significant difference between the test and the reference drug (p > 0.05). No adverse events occurred in this bioequivalence study. CONCLUSION: The two etoposide soft capsules (the test and reference formulations) were bioequivalent.

HPLC-UV method for quantifying etoposide in plasma and tumor interstitial fluid by microdialysis: application to pharmacokinetic studies.

A simple and sensitive bioanalytical method was developed and validated for determination of etoposide in plasma and microdialysis samples of Walker-256 tumor-bearing rats. A microdialysis probe was implanted in the center of a subcutaneous tumor and Ringer's solution was used as perfusion medium. Chromatographic separation was conducted on a Shimadzu CLC-C8 column using a mobile phase consisting of water-acetonitrile (70:30; v/v) adjusted to pH 4.0 ± 0.1 with formic acid at a gradient flow rate of 1.0-0.6 mL/min, an injection volume of 30 µL and UV detection at 210 nm. Microdialysate samples were analyzed without processing and plasma samples (100 µL) were spiked with phenytoin as internal standard (IS) (1 µg/mL) followed by extraction with tert-butyl methyl ether. The organic layer was evaporated and reconstituted with 100 µL of mobile phase before injection. The methods for plasma and microdialysate were linear in the ranges of 25-10,000 ng/mL and of 10-1500 ng/mL, respectively. All the validation parameters such as intra- and inter-day precision and accuracy and stability were within the limits established by international guidelines. The present method was successfully applied in the investigation of etoposide pharmacokinetics in rat plasma and microdialysate tumor samples following a single 15 mg/kg intravenous dose.

Quantification of target analytes in various biofluids using a postcolumn infused-internal standard method combined with matrix normalization factors in liquid chromatography-electrospray ionization mass spectrometry.

Liquid chromatography-electrospray ionization mass spectrometry (LC-ESI-MS) has become one of the most widely used methods in pharmaceutical laboratories. Although LC-ESI-MS provides high sensitivity and high specificity for quantifying target analytes in complicated biofluids, the associated severe matrix effects (MEs) generally result in large quantification errors. Here, we propose a novel strategy for correcting MEs in various biofluids using a postcolumn infused-internal standard (PCI-IS) method in combination with matrix normalization factors (MNFs). We used the MNFs to normalize the encountered MEs in various biofluids to the MEs encountered in standard solutions. The use of a postcolumn infused-internal standard also corrects the MEs for individual samples. When using the PCI-IS method in combination with MNFs, the calibration curve generated from standard solutions can be applied to quantify the target analytes in various biofluids. We applied this new approach to quantify etoposide and etoposide catechol in plasma and CSF. The accuracy of the test results showed that over 93% of the data have quantification errors less than 20% and that 99% of the data have quantification errors less than 30%. The successful application of this method to evaluate real clinical samples revealed that our proposed MNFs in combination with the PCI-IS method largely simplifies the entire method development and validation processes, saves a great deal of time and cost without sacrificing quantification accuracy, and provides a simple means of quantifying target analytes in various biofluids. This method will be particularly useful in fields in which the same target analytes need to be quantified in various types of matrices, including bioanalysis, forensic toxicology, environmental studies, and food safety control.

A phase I study of AT-101 with cisplatin and etoposide in patients with advanced solid tumors with an expanded cohort in extensive-stage small cell lung cancer.

BACKGROUND: A phase I, dose-escalation study of AT-101 with cisplatin and etoposide was conducted to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), safety and pharmacokinetics in patients with advanced solid tumors, with an expanded cohort in patients with extensive-stage small cell lung cancer (ES-SCLC) to assess preliminary activity. METHODS: In the dose escalation portion, increasing doses of AT-101 were administered orally BID on days 1-3 along with cisplatin on day 1 and etoposide on days 1-3 of a 21 day cycle. At the RP2D, an additional 7 patients with untreated ES-SCLC were enrolled. RESULTS: Twenty patients were enrolled in the dose-escalation cohort, and 7 patients with ES-SCLC were enrolled in the expanded cohort. The MTD/RP2D was established at AT-101 40 mg BID days 1-3 with cisplatin 60 mg/m2 and etoposide 120 mg/m2 on day 1 of a 21 day cycle with pegfilgrastim support. Two DLTs of neutropenic fever were seen at dose level 1. After the addition of pegfilgrastim, no additional DLTs were observed. Grade 3/4 treatment-related toxicities included: diarrhea, increased AST, neutropenia, hypophosphatemia, hyponatremia, myocardial infarction and pulmonary embolism. No apparent PK interactions were observed between the agents. Preliminary activity was observed with PRs in patients with ES-SCLC, high-grade neuroendocrine tumor, esophageal cancer and NSCLC. CONCLUSIONS: AT-101 with cisplatin and etoposide is well tolerated with growth factor support. Anti-tumor activity was observed in a variety of cancers including ES-SCLC, supporting further investigation with BH-3 mimetics in combination with standard chemotherapy for ES-SCLC.

Pharmacokinetic assessment of absorptive interaction of oral etoposide and morphine in rats.

Etoposide and morphine are well known P-glycoprotein (P-gp) substrates. The pharmacokinetic effect of morphine on plasma etoposide concentration after the oral concomitant use of etoposide and morphine in rats was assessed using a population analysis approach. A P-gp substrate quinidine and the anticholinergic drug propantheline were also administered with etoposide to compare with the effects of morphine. Plasma etoposide concentration after oral administration was well described using a linear 2-compartment open model with first-order kinetic absorption from the intestine, although a flip-flop phenomenon was shown. After administration of etoposide with morphine, an increased concentration and extended time at maximum concentration were observed compared with the administration of etoposide alone. However, coadministered quinidine significantly increased the maximum concentration without changing the time of the peak concentration of etoposide. Coadministered propantheline significantly extended the time at maximum concentration, although no changes in the peak concentration of etoposide were observed. These coadministered drugs resulted in different pharmacokinetic parameters of etoposide and acted as a significant covariate. That is, morphine and quinidine significantly increased the bioavailability of etoposide believed to be due to competitive P-gp inhibition in the intestine. In contrast, morphine and propantheline decreased the absorption rate constant and were associated with the suppression of enterokinesis. These results indicate that it is necessary to understand the effects on P-gp as well as have information on other effects on the gastrointestinal tract, such as enterokinesis suppression, and to appropriately assess the pharmacokinetic interactions of the combined oral use of P-gp substrate drugs.

Enhanced intestinal absorption of etoposide by self-microemulsifying drug delivery systems: roles of P-glycoprotein and cytochrome P450 3A inhibition.

Etoposide is recognized as a dual P-glycoprotein (P-gp) and cytochrome P450 3A (CYP3A) substrate drug with poor water-solubility. To improve its solubility and bioavailability, three novel self-microemulsifying drug delivery systems (SMEDDS) contained the known P-gp and CYP3A inhibitory surfactants, Cremophor RH40, Cremophor EL, or Polysorbate 80, were prepared. This work aims to evaluate the enhanced intestinal absorption of etoposide SMEDDS as well as to explore the roles of P-gp and CYP3A inhibition in the absorption process. Etoposide SMEDDS were orally administered to rats for in vivo bioavailability investigation. In situ single-pass intestinal perfusion with mesenteric vein cannulation was employed to study the drug permeability and intestinal metabolism. In vitro Caco-2 cell models were applied to study the effects of P-gp and CYP3A inhibition by SMEDDS on the cellular accumulation of etoposide. It was found that the bioavailability and in situ intestinal absorption were significantly enhanced by SMEDDS with the order of Polysorbate 80-based SMEDDS>Cremophor EL-based SMEDDS>Cremophor RH40-based SMEDDS. In addition, there was a dramatically high linear correlation between the AUC0-t values and the apparent permeability coefficient values based on the appearance of the drug in mesenteric vein blood. Cellular uptake studies demonstrated that P-gp inhibition by SMEDDS played an important role in etoposide uptake. Moreover, etoposide metabolism was demonstrated to be dramatically inhibited by the three kinds of SMEDDS. These finding may assist in the improvement of the intestinal absorption of P-gp and/or CYP3A substrate drugs.

Self-nanoemulsifying lipid carrier system for enhancement of oral bioavailability of etoposide by P-glycoprotein modulation: in vitro cell line and in vivo pharmacokinetic investigation.

The purpose of this work is intended to investigate the potential of self-nanoemulsifying (SNE) drug delivery system for enhanced oral bioavailability of etoposide by P-glycoprotein (P-gp) modulation. The components of SNE formulation were optimized by their solubilization and emulsification efficiency. The ternary phase diagrams provided nanoemulsion existence ranges and the corresponding formulations were developed and evaluated via thermodynamic and dispersibility tests. The successful formulations were characterized for various parameters including time required for self-emulsification, percentage transmittance, droplet size, surface morphology, zeta potential and in vitro release. The etoposide loaded SNE9 formulation showed 2.6- and 11-fold higher permeability coefficient in apical to basolateral direction across Caco-2 monolayers as compared to the Etosid and plain drug solution, respectively. The etoposide loaded SNE9 formulation showed a higher cytotoxicity at the highest tested concentration compared to the blank SNE9 formulation and the free etoposide. Furthermore, an in vivo pharmacokinetic study of etoposide in SNE9 formulation showed 3.2- and 7.9-fold increase in relative oral bioavailability compared with that of etoposide in Etosid and drug suspension, respectively. Thus, the developed SNE drug delivery system could be a valuable tool for the effective oral delivery of etoposide.

Accelerated blood clearance of PEGylated PLGA nanoparticles following repeated injections: effects of polymer dose, PEG coating, and encapsulated anticancer drug.

PURPOSE: To investigate accelerated blood clearance (ABC) induction upon repeated injections of PLGA-PEG nanoparticles as a commonly used polymeric drug carrier. METHODS: Etoposide-loaded PLGA-PEG NPs were developed and administered as the test dose to rats pre-injected with various NP treatments at certain time intervals. Pharmacokinetic parameters of etoposide and production of anti-PEG IgM antibody were evaluated. RESULTS: A notable ABC effect was induced by a wide range of polymer doses (0.1 to 20 mg) of empty NPs, accompanied by IgM secretion. However, a further increase in polymer dose resulted not only in the abrogation of the observed ABC induction but also in distinctly a higher value for AUC of the NPs relative to the control. The data from the PEG-negative group verified the fundamental role of PEG for ABC induction. The first injection of etoposide-containing PEGylated nanoparticles (a cell cycle phase-specific drug) produced a strong ABC phenomenon. Three sequential administrations of etoposide-loaded NPs abolished ABC, although a high level of IgM was still detected, which suggests saturation with insignificant poisoning of immune cells. CONCLUSION: The presented results demonstrate the importance of clinical evaluations for PLGA-PEG nanocarriers that consider the administration schedule in multiple drug delivery, particularly in cancer chemotherapy.