Stability of acetylsalicylic acid in human blood collected using volumetric absorptive microsampling (VAMS) under various drying conditions

Acetylsalicylic acid (ASA) is one of the most commonly used medications in global market, with a risk of intoxication in certain patients. However, monitoring blood drug concentration often requires frequent hospital visits; hence there is an unmet need to increase patientcentricity by conducting blood sampling at home. Volumetric absorptive microsampling (VAMS) is a device that allows collection of homogenous and accurate volume of blood without venipuncture, and can be utilized by patients who are not in hospital settings; but because ASA is prone to hydrolysis and stabilizing reagents cannot be added to VAMS samples, a way to improve sample stability must be developed. The objective of this study was to identify the cause of instability with ASA samples collected by VAMS, and to evaluate ways to improve sample stability. A liquid chromatography with tandem mass spectrometry (LC-MS/MS) was used for analysis of ASA concentration in whole blood. Samples collected with VAMS were kept under different drying conditions (desiccator, pressurized, nitrogen gas and household vacuum sealer) and were compared to the control samples collected by conventional venous sampling. The recovery of ASA was about 31% of the control when VAMS sample was dried at room temperature, whereas VAMS samples under humidity controlled conditions showed more than 85% of recovery. Our results suggest that adequate level of humidity control was critical to ensure sample stability of ASA, and this humidity control could also be achieved at home using household vacuum sealer, thus enabling patient-centric clinical trials to be conducted.

Validation of LC-MS/MS method for determination of rosuvastatin concentration in human blood collected by volumetric absorptive microsampling (VAMS)

In light of the shift toward patient-centric clinical trials, a measure of simplifying blood collection process and minimizing the volume of blood samples is on the rise. Volumetric absorptive microsampling (VAMS) is a microsampling device developed for blood sampling in non-hospital settings, which enables accurate hematocrit-independent collection of 10 or 20 µL of whole blood with a simple finger prick. In this study, liquid chromatography (LC)-tandem mass spectrometry workflow for quantification of rosuvastatin after VAMS sampling was developed and validated. The VAMS sample was stabilized by matrix drying and the optimum LC conditions and extraction methods were used to reach adequate sensitivity with lower limit of quantification verified at 1 ng/mL in 10 µL of blood. The bioanalytical method to quantify rosuvastatin from 1 to 100 ng/mL in VAMS sample was qualified by specificity, carryover, linearity, within-run and between-run reproducibility and stability. Inaccuracy was less than ± 6% and imprecision was less than 10% after analyzing the samples on 5 different days at all concentration levels. In addition, the feasibility of delivery to the analytical laboratory after home sampling during the guaranteed stability period of 10 days at room temperature was confirmed by evaluating concentration changes after VAMS sampling without adding pH buffer. Our results suggest that VAMS sampling did not have an effect on the stability of rosuvastatin, and it is a viable option for simple and accurate blood collection at home.

Pharmacokinetic properties and bioequivalence of gefitinib 250 mg in healthy Korean male subjects

Gefitinib is an anti-cancer drug used to treat non-small cell lung cancer. The objective of this study was to compare the pharmacokinetics and evaluate the bioequivalence of 2 orally administered gefitinib 250 mg tablets in healthy Korean subjects. A randomized, openlabel, single-dose, crossover bioequivalence study was conducted. A total of 50 healthy male volunteers were randomized into 2 sequence groups. During each treatment, the subjects received the test or reference formulation of 250 mg gefitinib with a washout period of 21 days. The plasma samples were collected at pre-dose and up to 144 hours post-dose, and plasma drug concentrations were measured using validated liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were calculated, and the formulations were considered as bioequivalent if the 90% confidence intervals (CIs) of the geometric mean ratios were within the bioequivalence limits of 0.8 to 1.25. Forty-one subjects completed the study and were included in the pharmacokinetic analysis. The 90% CIs of the geometric mean ratios of the test formulation to the reference formulation were 0.8115 to 0.9993 for maximum plasma concentration and 0.9119 to 1.0411 for area under the plasma concentration versus time curve from dosing to the last measurable concentration. There were no serious or unexpected adverse events during the study. In healthy Korean adult subjects, the test and reference formulations of gefitinib 250 mg had similar pharmacokinetic parameters and similar plasma concentration-time profiles. The test formulation of gefitinib met the regulatory criteria for assuming bioequivalence. Both formulations were safe and well-tolerated.

Comparative pharmacokinetics between tenofovir disoproxil phosphate and tenofovir disoproxil fumarate in healthy subjects

Tenofovir is the representative treatment for human immunodeficiency virus and hepatitis B virus infection. This study was conducted to assess the pharmacokinetics (PKs) and safety characteristics after a single administration of tenofovir disoproxil phosphate compared to tenofovir disoproxil fumarate in healthy male subjects. An open-label, randomized, single administration, two-treatment, two-sequence crossover study was conducted in 37 healthy volunteers. Serial blood samples were collected up to 72 hours. Non-compartmental analysis was used to calculate the PK parameters. The 90% confidence intervals (90% CIs) of the geometric mean ratio (GMR) were calculated for comparing tenofovir disoproxil phosphate to tenofovir disoproxil fumarate. Safety assessments were performed including clinical laboratory tests, adverse events, etc. during the study. The GMR and 90% CIs were 1.0514 (0.9527–1.1603) for C max and 1.0375 (0.9516–1.1311) for AUC last , respectively, and both fell within the conventional bioequivalence range of 0.8–1.25. Both tenofovir salt forms were tolerable. This study demonstrated that tenofovir disoproxil phosphate (292 mg) was bioequivalent to tenofovir disoproxil fumarate (300 mg).

Pharmacokinetics comparison of solifenacin tartrate and solifenacin succinate: a randomized, open-label, single-dose, 2-way crossover study in healthy male volunteers

Solifenacin is a muscarinic antagonist indicated for the treatment of overactive bladder with symptoms. Solifenacin tartrate is a newly developed salt formulation of solifenacin. This study compared the pharmacokinetic and safety properties after single-dose administration of solifenacin tartrate (test formulation) and solifenacin succinate (reference formulation) in healthy male volunteers. A total of 36 subjects were enrolled in this randomized, open-label, single-dose, two-way crossover study. During each treatment period, subjects received the test formulation or reference formulation. Plasma samples were collected at pre-dose and at 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48 and 72 hours post-dose. Safety was assessed by adverse events, physical examinations, laboratory assessments, 12-lead electrocardiograms, and vital signs. Thirty-three subjects completed the study and were included in the pharmacokinetic analysis. The mean (standard deviation) values of AUC(last) for the test and reference formulations were 486.98 (138.47) and 469.07 (128.29) h·ng/mL, respectively. The mean (standard deviation) values of C(max) for the test and reference formulations were 14.66 (3.85) and 14.10 (3.37) ng/mL, respectively. The 90% confidence intervals for AUC(last) and C(max) were 0.9702 to 1.1097 and 0.9779 to 1.0993, respectively. All adverse events were mild or moderate, and there were no serious adverse events. The pharmacokinetic properties of solifenacin tartrate were similar to those of solifenacin succinate and met the acceptance criteria for bioequivalence. Both formulations were safe, and no significant difference was observed in the safety assessments of the formulations.

Effect of plasma membrane monoamine transporter genetic variants on pharmacokinetics of metformin in humans

Metformin, an oral hypoglycemic agent belonging to biguanide class, is widely used to treat type 2 diabetes mellitus, and several drug transporters such as organic cation transporters (OCTs), multidrug and toxin extrusion transporter (MATE), and plasma membrane monoamine transporter (PMAT) are thought to affect its disposition. We evaluated the role of PMAT genetic variations on the pharmacokinetic characteristics of metformin in a Korean population. In this retrospective study, 91 healthy subjects from four different metformin pharmacokinetic studies were analyzed; in each study, the subjects were administered two oral doses of metformin at intervals of 12 hours and dose-normalized pharmacokinetic parameters were compared between the subjects' genotypes. Subjects who had more than one allele of c.883-144A>G single nucleotide polymorphism (SNP) in PMAT gene (rs3889348) showed increased renal clearance of metformin compared to wild-type subjects (814.79 ± 391.73 vs. 619.90 ± 195.43 mL/min, p=0.003), whereas no differences in metformin exposure were observed between the PMAT variant subjects and wild-type subjects. Similarly, subjects with variant rs316019 SNP in OCT2 showed decreased renal clearance of metformin compared to wild-type subjects (586.01 ± 160.54 vs. 699.13 ± 291.40 mL/min, p=0.048). Other SNPs in PMAT and MATE1/2-K genes did not significantly affect metformin pharmacokinetics. In conclusion, the genetic variation of c.883-144A>G SNP in PMAT significantly affects the renal clearance of metformin in healthy Korean male subjects.

The first step to the powers for clinical trials: a survey on the current and future Clinical Trial Management System

A clinical trial management system (CTMS) is a comprehensive program that supports an efficient clinical trial. To improve the environment of clinical trials and to be competitive in the global clinical trials market, an advanced and integrated CTMS is necessary. However, there is little information about the status of CTMSs in Korea. To understand the utilization of current CTMSs and requirements for a future CTMS, we conducted a survey on the subjects related to clinical trials. The survey was conducted from July 27 to August 16, 2017. The total number of respondents was 596, and 531 of these responses were used. Almost half of the respondents were from hospitals (46%). The proportion of respondents who are currently using a CTMS was the highest for contract research organizations at 59%, whereas the proportion used by investigators was 39%. The main reason for not using a CTMS was that it is unnecessary and expensive, but it showed a difference between workplaces. Many respondents frequently used CTMSs to check the clinical trial schedule and progress status, which was needed regardless of workplace. While two-thirds of users tended to be satisfied with their current CTMS, there were many users who felt their CTMS was inconvenient. The most requested function for a future CTMS was one that could be used to manage the project schedule and subject enrollment status. Additionally, a systematic linkage to electronic medical records, including prescription and laboratory test results, and a function to confirm the participation history of subjects in other hospitals were requested.

Comparative pharmacokinetic and tolerability evaluation of two simvastatin 20 mg formulations in healthy Korean male volunteers

Simvastatin is used to reduce plasma cholesterol by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and is primarily used to treat hypercholesterolemia. This study was conducted to assess the bioequivalence between the generic formulation of simvastatin 20 mg and the branded formulation of simvastatin 20 mg. A generic formulation of simvastatin 20 mg tablet was developed and the pharmacokinetics of the generic formulation were compared with those of the branded formulation of simvastatin 20 mg tablet in 33 healthy male volunteers after a single oral dose in a randomized, open-label, two-period, two-sequence, crossover study. The reference (Zocor®, MSD Korea LTD.) and test (Simvarotin®, Korea Arlico Pharm Co., Ltd.) formulations, two 20 mg tablets each, were administered to all subjects in fasting status. The serial blood samples for pharmacokinetic analysis were collected before dosing and up to 24 hours post-dose, and plasma concentrations of simvastatin were determined by liquid chromatography-tandem mass spectrometry. The pharmacokinetic parameters including T(max), C(max), AUC(last), AUC(inf) and t½ were calculated for both formulations by non-compartmental method, and the log-transformed C(max) and AUC(last) were compared statistically. Geometric mean ratios (90% confidence intervals) of the test to the reference formulation in C(max) and AUC(last) were 0.9652 (0.8302–1.1223) and 0.9891 (0.8541–1.1455), respectively. No significant differences in tolerability profiles were noted between the two formulations. The two formulations of simvastatin 20 mg tablets exhibited comparable pharmacokinetic profiles and 90% confidence intervals were within the acceptable range of bioequivalence criteria.

Comparison of R(+)-α-lipoic acid exposure after R(+)-α-lipoic acid 200 mg and 300 mg and thioctic acid 600 mg in healthy Korean male subjects

Alpha-lipoic acid, a physiological form of thioctic acid, is a strong antioxidant that relieves diabetic neuropathic symptoms. R(+)-α-lipoic acid shows superior antioxidative effects to its racemate. We compared the pharmacokinetics (PKs) and tolerability of R(+)- and S(-)-α-lipoic acid after a single oral dose of R(+)-α-lipoic acid, Dexid®, and its racemate, thioctic acid in healthy male subjects. We used an open-label, randomized, single-dose, three-treatment, parallel study design to compare the PK exposure of the active form, R(+)-α-lipoic acid. Thirty subjects completed the study with no clinically relevant safety issues. The peak concentrations (C(max), mean±SD) of R(+)-α-lipoic acid after doses of R(+)-α-lipoic acid 200 mg, 300 mg and thioctic acid 600 mg were 4186.8±1956.7, 6985.6±3775.8 and 6498.4±3575.6 µg/L, respectively, and the areas under the plasma concentration-time curve from 0 to the last measurable concentration (AUC(last)) were 1893.6±759.4, 3575.2±1149.2 and 3790.0±1623.0 µg·h⁻¹·L⁻¹, respectively. The geometric mean ratio and 90% confidence intervals of R(+)-α-lipoic acid 200 mg to thioctic acid 600 mg for the C(max) and AUC(last) were 0.71 (0.43–1.15) and 0.51 (0.37–0.70), respectively. The corresponding R(+)-α-lipoic acid 300 mg to thioctic acid 600 mg values were 1.11 (0.68-1.80) and 0.97 (0.71-1.34), respectively. In conclusion, R(+)-α-lipoic acid 300 mg showed PK characteristics similar to those of thioctic acid 600 mg and both formulations were well tolerated.