Development of docetaxel-loaded intravenous formulation, Nanoxel-PM™ using polymer-based delivery system.

Nanoxel-PM™, docetaxel-loaded methoxy-poly(ethylene glycol)-block-poly(d,l-lactide) (mPEG-PDLLA) micellar formulation was prepared in an effort to develop alternative, less toxic and efficacious Tween 80-free docetaxel formulation, and its pharmacokinetics, efficacy, and toxicity were evaluated in comparison with Taxotere® in preclinical studies. The mean diameter of the Nanoxel-PM™ was 10-50 nm and the polydispersity of samples exhibited a narrow size distribution and monodisperse unimodal pattern. Pharmacokinetic study in mice, rats and beagle dogs revealed that Nanoxel-PM™ exhibited similar pharmacokinetic profiles (C(max), AUC, t(1/2), CL, V(ss)) to Taxotere, and the relative mean AUC(t) and C(max) of Nanoxel-PM™ to Taxotere® were within 80-120%. Furthermore, excretion study in rats demonstrated that there was no statistically significant difference in the amount excreted in feces or urine as an unmetabolized docetaxel between Nanoxel-PM™ and Taxotere®. Its pharmacokinetic bioequivalence resulted in comparable anti-tumor efficacy to Taxotere® in human lung cancer xenografts H-460 in nude mice as well as in lung, ovary and breast cancer cell lines. Several animal toxicity studies on Nanoxel-PM™ compared with Taxotere® were carried out. In single dose rat and dog model and repeated dose mouse model, both Nanoxel-PM™ and Taxotere® exhibited similar toxic effects on hematology and body weight gain. On the other hand, vehicle related hypersensitivity reactions and fluid retentions were not observed when Nanoxel-PM™ was administered, unlike Taxotere®, in the beagle dog study. Based on these results, it is expected that Nanoxel-PM™ can reduce side effects of hypersensitivity reactions and fluid retention while retaining antitumor efficacy in cancer patients. Currently, Nanoxel-PM™ is under evaluation for bioequivalence with Taxotere® in a multi-center, open-label, randomized, crossover study.

Pharmacokinetic/pharmacodynamic modeling of the cardiovascular effects of beta blockers in humans.

Pharmacokinetic-pharmacodynamic (PK/PD) analysis is useful study in clinical pharmacology, also PK/PD modeling is major tools for PK/PD analysis. In this study, we sought to characterize the relationship between the cardiovascular effects and plasma concentrations of the beta blocker drugs carvedilol and atenolol using PK/PD modeling in healthy humans. One group received oral doses of atenolol (50 mg) and the other group received oral doses of carvedilol (25 mg). Subsequently, blood samples were taken, and the effects of the drugs on blood pressure were determined. Plasma concentrations of drugs were measured by HPLC, and PK/PD modeling performed by applied biophase model, plasma drug concentrations were linked to the observed systolic blood pressure (SBP) and diastolic blood pressure (DBP) via an effect compartment. The model parameters were estimated using the ADAPT II program. In PK/PD analysis, it was observed the time delay between plasma concentration and effect and the time delay between SBP and DBP. The two time delays were properly explained by PD parameter "Keo" in applied biophase model. As conclusion, the biophase PK/PD model described the relationship between the plasma concentrations of the drugs and the cardiovascular effects, including the time delay between systolic blood pressure and diastolic blood pressure.

Bioequivalence and pharmacokinetics of 70 mg alendronate sodium tablets by measuring alendronate in plasma.

The bioequivalence and pharmacokinetics of alendronate sodium tablets were examined by determining the plasma concentration of alendronate. Two groups, consisting of 24 healthy volunteers, each received a 70 mg reference alendronate sodium tablet and a test tablet in a 2x2 crossover study. There was a 6-day washout period between doses. The plasma alendronate concentration was monitored for 7 h after the dose, using HPLC-Fluorescence Detector (FD). The area under the plasma concentration-time curve from time 0 to the last sampling time at 7 h (AUC(0-7h) was calculated using the linear-log trapezoidal rule. The maximum plasma drug concentration (Cmax) and the time to reach Cmax (Tmax) were derived from the plasma concentration-time data. Analysis of variance was performed using logarithmically transformed AUC(0-7h) and Cmax, and untransformed Tmax. For the test medication versus the reference medication, the AUC(0-7h) were 87.63 +/- 29.27 vs. 102.44 +/- 69.96 ng x h x mL(-1) and the Cmax values were 34.29 +/- 13.77 vs. 38.47 +/- 24.39 ng x mL(-1), respectively. The 90% confidence intervals of the mean differences of the logarithmic transformed AUC(0-7h) and Cmax values were log 0.8234-log 1.1597 and log 0.8222-log 1.1409, respectively, satisfying the bioequivalence criteria guidelines of both the U.S. Food and Drug Administration and the Korea Food and Drug Administration. The other pharmacokinetic parameters for the test drug versus reference drug, respectively, were: t(1/2), 1.87 +/- 0.62 vs. 1.77 +/- 0.54 h; V/F, 2061.30 +/- 986.49 vs. 2576.45 +/- 1826.05 L; CL/F, 835.32 +/- 357.35 vs. 889.48 +/- 485.87 L x h(-1); K(el), 0.42 +/- 0.14 vs. 0.40 +/- 0.18 h(-1); Ka, 4.46 +/- 3.63 vs. 3.80 +/- 3.64 h(-1); and Tlag, 0.19 +/- 0.09 vs. 0.18 +/- 0.06 h. These results indicated that two alendronate formulations (70-mg alendronate sodium) were biologically equivalent and can be prescribed interchangeably.

High-performance liquid chromatography method for determining alendronate sodium in human plasma by detecting fluorescence: application to a pharmacokinetic study in humans.

A high-performance liquid chromatographic (HPLC) method was developed using diethylamine (DEA) solid-phase extraction (SPE), 9-fluorenylmethyl derivative (FMOC) and fluorescence detection for quantifying alendronate in human plasma. Sample preparation involved a manual protein precipitation with trichloroacetic acid, a manual coprecipitation of the bisphosphonate with calcium phosphate and derivatization with 9-fluorenylmethyl chloroformate in citrate buffer at pH 11.9. Liquid chromatography was performed on a Capcell Pak C(18) column (4.6 mm x 150 mm, 5 microm particles), using a gradient method starting with mobile phase acetonitrile/methanol-citrate/pyrophosphate buffer (32:68, v/v). The total run time was 25 min. The fluorometric detector was operated at 260 nm (excitation) and 310 nm (emission). Pamidronate was used as the internal standard. The limit of quantification was 1 ng/ml using 3 ml of plasma. The intra- and inter-day precision expressed as the relative standard deviation was less than 15%. The assay was applied to the analysis of samples from a pharmacokinetic study. Following the oral administration of 70 mg of alendronate sodium to volunteers, the maximum plasma concentration (C(max)) and elimination half-life were 40.94 +/- 19.60 ng/ml and 1.67 +/- 0.50 h, respectively. The method was demonstrated to be highly feasible and reproducible for pharmacokinetic studies including bioequivalence test of alendronate sodium in humans.

Pharmacokinetics and bioequivalence of haloperidol tablet by liquid chromatographic mass spectrometry with electrospray ionization.

The purpose of this study is to investigate the bioequivalence of two haloperidol 5 mg tablets, Myung In haloperidol (Myung In Pharm. Co., Ltd., test drug) and Peridol (Whanin Pharm. Co., Ltd., reference drug), and also to estimate the pharmacokinetic parameters of haloperidol in Korean volunteers. The bioavailability and pharmacokinetics of haloperidol tablets were examined on 24 healthy volunteers who received a single oral dose of each preparation in the fasting state in a randomized balanced 2 way crossover design. After an oral dosing, blood samples were collected for a period of 60 h. Plasma concentrations of haloperidol were determined using a liquid chromatographic electrospray mass spectrometric (LC-MS) method. The pharmacokinetic parameters were calculated with noncompartmental pharmacokinetic analysis. The geometric means of AUC0-60h and Cmax between test and reference formulations were 17.21 +/- 8.26 ng x h/mL vs 17.31 +/- 13.24 ng x h/mL and 0.87 +/- 0.74 ng/mL vs 0.85 +/- 0.62 ng/mL, respectively. The 90% confidence intervals of mean difference of logarithmic transformed AUC0-60h and Cmax were log0.9677 - log1.1201 and log0.8208-log1.1981, respectively. It shows that the bioavailability of test drug is equivalent with that of reference drug. The geometric means of other pharmacokinetic parameters (AUCinf, t1/2, Vd/F, and CL/F) between test drug and reference drug were 21.75 +/- 8.50 ng x h/mL vs 21.77 +/- 15.63 ng x h/mL, 29.87 +/- 8.25 h vs 29.60 +/- 7.56 h, 11.51 +/- 5.45 L vs 12.90 +/- 6.12 L and 0.26 +/- 0.09 L/h vs 0.31 +/- 0.17 L/h, respectively. These observations indicate that the two formulation for haloperidol was bioequivalent and, thus, may be clinically interchangeable.