A randomized, open-label, single-dose, two-way crossover study to assess the pharmacokinetics between two tablets of fixed-dose combination formulation with raloxifene and cholecalciferol and concomitant administration of each agents in healthy male volunteers

A new fixed-dose combination (FDC) formulation of raloxifene 60 mg and cholecalciferol 800 IU was developed to improve the medication compliance and overall efficacy of raloxifene treatment in postmenopausal osteoporosis patients. The aim of this study was to compare the pharmacokinetics between two tablets of FDC formulation of raloxifene/cholecalciferol and the two products administered concomitantly at respective doses. This randomized, open-label, single-dose, two-treatment, two-way crossover study included 46 volunteers. During each treatment period, subjects received the test formulation (FDC formulation containing raloxifene and cholecalciferol) or the reference formulation (co-administration of raloxifene and cholecalciferol), with a 14-d washout period. Serial blood samples were collected periodically over 96 hours after drug intake. In total, 46 subjects completed the study. The geometric mean ratios and its 90% confidence intervals of the FDC to the single agents for the area under the concentration-time curve from zero to the last quantifiable time point and the maximum plasma concentration met the regulatory criteria for bioequivalence: 1.1364 (1.0584–1.2201) and 1.1010 (0.9945–1.2188) for raloxifene and 1.0266 (0.9591–1.0989) and 1.0354 (0.9816–1.0921) for baseline-corrected cholecalciferol, respectively. Both formulations were well tolerated. No significant differences was observed in the incidence of adverse events between the two treatments. It was concluded that two tablets of the newly developed FDC formulation of raloxifene and cholecalciferol and the corresponding two agents administered concomitantly at respective doses were bioequivalent.

The possibility of low isomerization of β-lapachone in the human body

β-Lapachone has been reported to have anticancer and various other therapeutic effects, but is limited in clinical applications by its low bioavailability. pH-Dependent isomerization can be suggested as one plausible factor influencing its low bioavailability. Since it is known that β-lapachone is converted to its isomer, α-lapachone in hydrochloric acid (HCl) solution, isomerization in the human body may be driven by HCl in the gastric fluid. The purpose of this study was to evaluate the possibility of isomerization of β-lapachone in the human body. Chemical reactions were conducted using simulated gastric fluid (SGF, pH 1.2) and simulated intestinal fluid (SIF, pH 7.5) at 37°C. β-Lapachone was observed in SGF at 37°C for 1 hour and SIF for 3 hours. In addition, biofluid analysis was performed on plasma samples 1 hour and 4 hours, and on urine sample 12 hours after oral administration of 100 mg MB12066, a synthetic β-lapachone, in healthy adult male. All samples were analyzed using liquid chromatography-tandem mass spectrometry. Only β-lapachone peaks existed in the spectra obtained from SGF and SIF. No isomerization of β-lapachone was observed in the analysis of any of the human samples. In the current study, the possibility of pH-dependent isomerization of β-lapachone in the human body was not confirmed.

Pharmacokinetics and bioequivalence of fixed-dose combination of candesartan cilexetil/amlodipine besylate (16/10 mg) versus coadministration of individual formulations in healthy subjects

This study compared the pharmacokinetics of a fixed-dose combination (FDC) of candesartan (16 mg) and amlodipine (10 mg) versus coadministration of individual formulations to clarify the bioequivalence of the FDC. In this randomized, open-label, single-dose, 2-treatment, 2-way crossover study, healthy Korean volunteers received a single dose of candesartan (16 mg) with amlodipine (10 mg) as either an FDC or single agents concomitantly administered, with a 2-week washout period. Serial blood samples were collected up to 72 hours after dosing for each treatment period, and plasma concentrations of candesartan and amlodipine were measured using a validated liquid chromatography-tandem mass spectrometry method. A total of 39 subjects completed the study. The geometric mean ratios (GMRs) and 90% confidence intervals (CIs) for the area under the plasma concentration-time curve from time 0 to the last measurement (AUC0-t) and the peak plasma concentration (Cmax) for candesartan were 1.0182 (0.9562–1.0841) and 0.9492 (0.8726–1.0324), respectively. The GMR and 90% CI for the AUC0-t and Cmax for amlodipine were 1.0552 (1.0255–1.0857) and 1.0668 (1.0259–1.1094), respectively. In conclusion, the new FDC formulation of candesartan (16 mg) and amlodipine (10 mg) was bioequivalent to the concomitant administration of single agents. A single dose of candesartan/amlodipine as the FDC or as single agents was well tolerated.

Metabolic Profiling of Plasma from Pancreatic Cancer Patients in Korea / 대한췌담도학회지

BACKGROUND/AIMS: Pancreatic cancer (PC) patients have poor prognoses because this cancer is typically diagnosed at an advanced stage and the therapeutic options are limited. We examined the potential of metabolic profiling for early diagnosis and identification of potential therapeutic targets. METHODS: Ten patients and 10 healthy volunteer controls older than 20 years of age were enrolled between May and December 2015. The patients were confirmed to have pancreatic ductal adenocarcinoma cytologically or histologically. Blood plasma samples were derivatized and analyzed by gas chromatography mass spectrometry (GC-MS). Untargeted GC-MS data were analyzed using statistical methods, including Wilcoxon rank-sum test and principal component analyses. RESULTS: L-lysine was 1.36-fold higher in patients than in healthy controls (p<0.05). L-leucine was 0.63-fold lower (p<0.01) and palmitic acid was 0.93-fold lower (p<0.5) in patients than in controls. Orthogonal partial least squared-discriminant analysis revealed significant differences between the patients and controls. CONCLUSIONS: This study suggests that the metabolic profiles of patients with PC are distinct from those of the healthy population. Further studies are required to develop methods for early diagnosis and identify therapeutic targets.

Metabolomic analysis of healthy human urine following administration of glimepiride using a liquid chromatography-tandem mass spectrometry

Glimepiride, a third generation sulfonylurea, is an antihyperglycemic agent widely used to treat type 2 diabetes mellitus. In this study, an untargeted urinary metabolomic analysis was performed to identify endogenous metabolites affected by glimepiride administration. Urine samples of twelve healthy male volunteers were collected before and after administration of 2 mg glimepiride. These samples were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and then subjected to multivariate data analysis including principal component analysis and orthogonal partial least squares discriminant analysis. Through this metabolomic profiling, we identified several endogenous metabolites such as adenosine 3′, 5′-cyclic monophosphate (cAMP), quercetin, tyramine, and urocanic acid, which exhibit significant metabolomic changes between pre- and posturine samples. Among these, cAMP, which is known to be related to insulin secretion, was the most significantly altered metabolite following glimepiride administration. In addition, the pathway analysis showed that purine, tyrosine, and histidine metabolism was affected by pharmacological responses to glimepiride. Together, the results suggest that the pharmacometabolomic approach, based on LC-MS/MS, is useful in understanding the alterations in biochemical pathways associated with glimepiride action.

Determination of sumatriptan in human plasma using liquid chromatography-mass spectrometry for pharmacokinetic study in healthy Korean volunteers

This study describes the development of an analytical method to determine sumatriptan levels in human plasma using high performance liquid chromatography (HPLC) coupled with triple quadrupole tandem mass spectrometry (MS/MS) and its application to a pharmacokinetic study in healthy Korean volunteers. A single 50 mg dose of sumatriptan was orally administered to twelve healthy volunteers (nine women and three men). The HPLC-MS/MS analytical method was validated with respect to its specificity, linearity, sensitivity, accuracy, precision, recovery, and stability. The calibration curve was linear over a concentration range of 0.3–100 ng/mL (r > 0.999). The lower limit of quantitation for sumatriptan in plasma was 0.3 ng/mL. The accuracy and precision of the analytical method were acceptable within 15% at all quality control levels. We compared plasma concentration-time curves as well as pharmacokinetic parameters such as the area under the curve (AUC) and maximum plasma concentration (C(max)). Both the mean AUC and C(max) of sumatriptan were 1.56 times higher in women than in men. These differences could be largely explained by the difference in body weight (44%) between women and men. The outcomes may provide insights into developing appropriate individualized treatment strategies.

Development and validation of a UPLC-MS/MS method for the quantification of acetaminophen in human plasma and its application to pharmacokinetic studies

We developed an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the determination of acetaminophen concentration in human plasma. Following protein precipitated extraction, the analytes were separated and analyzed using an UPLC-MS/MS in the multiple reaction monitoring (MRM) mode with the respective [M+H]+ ions, m/z 152.06 → 110.16 for acetaminophen and m/z 180.18 → 138.12 for phenacetin (internal standard, IS). The method showed a linear response from 1 to 100 µg/mL (r > 0.9982). The limit of quantitation for acetaminophen in plasma was 1 µg/mL. The intra- and inter-day accuracy ranged in the ranges of 94.40–99.56% and 90.00–99.20%, respectively. The intra- and inter-day precision ranged in the ranges of 2.64–10.76% and 6.84–15.83%, respectively. This method was simple, reliable, precise and accurate and can be used to determine the concentration of acetaminophen in human plasma. Finally, this fully validated method was successfully applied to a pharmacokinetic study of acetaminophen in healthy volunteers following oral administration.

Population pharmacokinetic analysis of the multiple peaks phenomenon in sumatriptan

The objective of this study was to develop a population pharmacokinetic (PK) model for sumatriptan, which frequently shows an atypical absorption profile with multiple peaks. Sumatriptan, a selective agonist for the vascular serotonin (5-HT1) receptor that causes vasoconstriction of the cerebral arteries, is used for the acute treatment of migraine attack with or without aura. Despite its relatively high between-subject variability, few reports have addressed PK modeling of sumatriptan. Plasma data obtained after a single 50-mg oral dose of sumatriptan in 26 healthy Korean male subjects were used. Blood samples were collected 0 (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, and 12 h after dosing. Plasma sumatriptan concentrations were analyzed using UPLC/MS/MS. Population PK analysis was performed using plasma concentration data for sumatriptan with NONMEM (ver. 7.2). A total of 364 concentrations of sumatriptan were captured by a one-compartment model with first-order elimination, and a combined transit compartment model and first-order absorption with lag time was successful in describing the PK with multiple peaks in the absorption phase of sumatriptan. The creatinine clearance as a covariate significantly (P < 0.01) influenced the absorption fraction (f ). The final model was validated through a visual predictive check and bootstrapping with no serious model misspecification.

Steady-State Pharmacokinetic Properties of Tamsulosin in Healthy Male Volunteers

BACKGROUND: To evaluate the pharmacokinetic properties of daily oral doses of tamsulosin administered to fasted healthy Korean male volunteers for 5 days. METHODS: In a randomized, open-label, multiple-dose, two-period, crossover study, all 44 subjects were randomly assigned in a 1:1 ratio to receive a newly developed generic capsule formulation (test) or a branded capsule formulation (reference) of tamsulosin 0.2 mg, followed by a 10-day washout period and administration of the other formulation. Plasma concentrations of tamsulosin were assessed after administration of five-day multiple doses, using HPLC-MS/MS. Clinical and laboratory adverse events (AE) were assessed. RESULTS: The mean (SD) pharmacokinetic properties with the test and reference formulations were as follows: Css,max, 9.0 (2.9) and 8.4 (2.6) ng/mL, respectively; median (range) tmax, 4 (2-6) and 5 (2-7) hours; AUCtau, 93.7 (31.5) and 88.2 (29.3) ng x h/mL; and t(1/2), 9.5 (2.6) and 10.0 (2.7) hours. The volume of distribution and clearance after oral administration of tamsulosin were 0.5 L/kg, and 0.04 L/h/kg, respectively. The accumulation ratios for 0.2 mg once-daily dosing regimen were 1.2. The 90% CIs of the geometric mean ratios for the log-transformed AUCtau (1.005-1.131) and Css,max (1.000-1.136) values were within the acceptable range for bioequivalence. No serious AE was reported during the study. Both formulations were well tolerated. CONCLUSION: The results demonstrate that the Css,max and AUCtau values in the fasted subjects were higher than those in the fed from other study, with a shorter tmax values.