Ju-Seop Kang

Overview of Therapeutic Drug Monitoring

Therapeutic drug monitoring (TDM) is the clinical practice of measuring specific drugs at designated intervals to maintain a constant concentration in a patients bloodstream, thereby optimizing individual dosage regimens. It is unnecessary to employ TDM for the majority of medications, and it is used mainly for monitoring drugs with narrow therapeutic ranges, drugs with marked pharmacokinetic variability, medications for which target concentrations are difficult to monitor, and drugs known to cause therapeutic and adverse effects. The process of TDM is predicated on the assumption that there is a definable relationship between dose and plasma or blood drug concentration, and between concentration and therapeutic effects. TDM begins when the drug is first prescribed, and involves determining an initial dosage regimen appropriate for the clinical condition and such patient characteristics as age, weight, organ function, and concomitant drug therapy. When interpreting concentration measurements, factors that need to be considered include the sampling time in relation to drug dose, dosage history, patient response, and the desired medicinal targets. The goal of TDM is to use appropriate concentrations of difficult-to-manage medications to optimize clinical outcomes in patients in various clinical situations.

Chromium picolinate supplementation improves insulin sensitivity in Goto-Kakizaki diabetic rats

Chromium picolinate (CrP) supplementation has been studied as a potential therapy of insulin resistance and lipid abnormalities. There have been some reports involving chromium supplementation in patients with diabetes, but the results are varied. The present study was conducted to assess the effects of CrP on insulin sensitivity and body weight in Goto-Kakizaki (GK) diabetic rats. We supplemented normal Sprague-Dawley (SD) rats and GK diabetic rats with supplemental CrP, 100 mg/kg/day once a day for 4 weeks. In the normal SD rats, the mean body weight of the control group increased by 50.5%, whereas that of the CrP-treated group increased by 65.9% (P < 0.05 vs control). Similarly, in the diabetic GK rats, CrP supplementation showed increased weight gain compared to the control group (133.4% vs 119.6% of the baseline weight, P < 0.01). Glucose tolerance tests (GTT) [ip injection of glucose; 2 g/kg] and insulin sensitivity tests [SQ injection of insulin (5 U/kg) plus ip injection of glucose (30 min after insulin injection)] were conducted. During insulin sensitivity tests at the end of treatment, the glucose levels were significantly lower in CrP-treated rats compared with the control rats (AUC0-->120; 113.1 +/- 32.0 vs 170.5 +/- 49.0 mg-min/mL, P < 0.05). During GTTs, the glucose levels and insulin concentrations in the CrP-treated rats were not different from those in the control rats. The results of these studies suggest that CrP supplementation in GK diabetic rats leads to increase of weight gain and improvement of insulin sensitivity. This raises the possibility that CrP supplementation can be considered to improve carbohydrate metabolism in patients with type 2 diabetes mellitus.

Determination of plasma topiramate concentration using LC‐MS/MS for pharmacokinetic and bioequivalence studies in healthy Korean volunteers

A rapid, simple and validated liquid chromatography coupled to tandem mass spectrometric method (LC-MS/MS) for topiramate analysis in human plasma has been applied to pharmacokinetic and bioequivalence studies in 24 healthy male Korean volunteers. The procedure involves a simple liquid extraction of topiramate and prednisone (internal standard) with acetonitrile and separation by HPLC equipped with a Capcell Pak C18 column using acetonitrile-0.1% triethylamine (80:20, v/v) as a mobile phase. Detection was carried out on an API 2000 MS system by multiple reactions monitoring mode. The ionization was optimized using ESI(-) and selectivity was achieved by MS/MS analysis, m/z 338.0 --> 77.5 and m/z 357.1 --> 327.2 for topiramate and prednisone, respectively. The method had a total run time of 2.5 min and showed good linearity over a working range of 20-5000 ng/mL in human plasma with a lower limit of quantification of 20 ng/mL. No metabolic compounds were found to interfere with the analysis. The inter-day and intra-day accuracy were in the ranges of 99.24-116.63 and 93.45-108.68%, respectively, and inter-day and intra-day precisions were below 6.24 and 5.25%, respectively. This method was successfully applied for pharmacokinetic and bioequivalence studies by analysis of blood samples taken up to 96 h after an oral administration of 100 mg of topiramate in 24 healthy Korean volunteers.

Modern Methods for Analysis of Antiepileptic Drugs in the Biological Fluids for Pharmacokinetics, Bioequivalence and Therapeutic Drug Monitoring

Epilepsy is a chronic disease occurring in approximately 1.0% of the worlds population. About 30% of the epileptic patients treated with availably antiepileptic drugs (AEDs) continue to have seizures and are considered therapy-resistant or refractory patients. The ultimate goal for the use of AEDs is complete cessation of seizures without side effects. Because of a narrow therapeutic index of AEDs, a complete understanding of its clinical pharmacokinetics is essential for understanding of the pharmacodynamics of these drugs. These drug concentrations in biological fluids serve as surrogate markers and can be used to guide or target drug dosing. Because early studies demonstrated clinical and/or electroencephalographic correlations with serum concentrations of several AEDs, It has been almost 50 years since clinicians started using plasma concentrations of AEDs to optimize pharmacotherapy in patients with epilepsy. Therefore, validated analytical method for concentrations of AEDs in biological fluids is a necessity in order to explore pharmacokinetics, bioequivalence and TDM in various clinical situations. There are hundreds of published articles on the analysis of specific AEDs by a wide variety of analytical methods in biological samples have appears over the past decade. This review intends to provide an updated, concise overview on the modern method development for monitoring AEDs for pharmacokinetic studies, bioequivalence and therapeutic drug monitoring.

Bioavailability and Bioequivalence of Two Oral Formulations of Alendronate Sodium 70 mg: An Open-Label, Randomized, Two-Period Crossover Comparison in Healthy Korean Adult Male Volunteers

BACKGROUND Alendronate sodium is a Bisphosphonate drug used to treat and prevent osteoporosis and several other bone diseases. A new formulation has been developed and is currently awaiting regulatory approval, pending findings on bioequivalence. OBJECTIVES The aims of the present study were to compare the bioavailability and pharmacokinetic (PK) properties, and to determine the bioequivalence, of a test and reference formulation of alendronate sodium 70 mg in a healthy Korean adult male population. METHODS This open-label, randomized, 2-sequence, 2-period crossover study was carried out at Hanyang University Medical Center (Seoul, Republic of Korea). Healthy Korean adult male volunteers were randomly assigned to receive a single 70-mg dose of the test or reference formulation of alendronate sodium, administered with 240 mL of water, followed by a 7-day washout period and administration of the alternate formulation. The study drugs were administered after a 12-hour overnight fast. Serial blood samples were collected and adverse events were monitored by a clinical investigator via observation, personal interview, and vital signs (blood pressure, heart rate, and body temperature) over a 7-hour period (at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, and 7 hours) after drug administration. Plasma alendronate sodium concentrations were determined using a validated high-performance liquid chromatographic-postcolumn fluorescence derivatization method, with visible detection in the range of 2 to 100 ng/mL and lower limit of quantification set at 2 ng/mL. PK properties, including AUC(0-t), AUC(0-infinity), C(max), T(max), t(1/2), and the elimination constant (k(e)), were determined using non-compartmental analysis. The formulations were considered bioequivalent if the 90% CI ratios for C(max) and AUC were within the predetermined interval of 80% to 125%, the regulatory definition set by the US Food and Drug Administration (FDA). RESULTS Twenty-three healthy male volunteers (mean [SD] age, 23.5 [2.0] years [range, 19-28 years]; height, 175.9 [5.4] cm [range, 162.0-185.0 cm]; and weight, 71.2 [9.5] kg [range, 61-96 kg]) were included in the study. No period or sequence effects were detected. The 90% CIs for the corresponding ratios of AUC(0-t), AUC(0-infinity) and C(max) were 84.97 to 114.47, 86.09 to 115.59, and 82.37 to 110.71, respectively. Additionally, the mean (range) of T(max) was 1.09 hours (0.5-2.0 hours), and the mean (SD) of t(1/2) and k(e) were 2.04 (0.97) hours and 0.34 (0.71) hour, respectively. The values for the test and reference formulations were within the FDA bioequivalence definition interval of 80% to 125%. No adverse events were reported in this study. CONCLUSIONS Single doses of these formulations of alendronate sodium 70 mg met the criteria for bio-equivalence. No statistically significant differences in AUC(0-t), AUC(0-infinity), and C(max) were found in this healthy Korean adult male population.

Quantification of isradipine in human plasma using LC–MS/MS for pharmacokinetic and bioequivalence study

A highly sensitive and rapid method for the analysis of isradipine in human plasma using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) was developed. The procedure involves a simple liquid-liquid extraction of isradipine and amlodipine (IS, internal standard) with methyl-t-butyl ether after alkaline treatment and separation by RP-HPLC. Detection was performed by positive ion electrospray ionization (ESI) in multiple reaction monitoring (MRM) mode, monitoring the transitions m/z 372.1-->m/z 312.2 and m/z 408.8-->m/z 237.9, for quantification of isradipine and IS, respectively. The standard calibration curves showed good linearity within the range of 10 to 5000 pg/mL (r(2)>or=0.9998). The lower limit of quantitation (LLOQ) was 10 pg/mL. The retention times of isradipine (0.81 min) and IS (0.65 min) suggested the potential for high throughput of the proposed method. In addition, no significant metabolic compounds were found to interfere with the analysis. This method offered good precision and accuracy and was successfully applied for the pharmacokinetic and bioequivalence studies of 5 mg of sustained-release isradipine in 24 healthy Korean volunteers.

Rapid quantification of levosulpiride in human plasma using RP-HPLC-MS/MS for pharmacokinetic and bioequivalence study

A rapid and validated method for analysis of levosulpiride in human plasma using liquid chromatography coupled to tandem mass spectrometry was developed. Levosulpiride and tiapride (IS, internal standard) were extracted from alkalized plasma samples with ethylacetate and separation by RP-HPLC. Detection was performed by positive ion electrospray ionization in multiple-reaction monitoring mode, monitoring the transitions m/z 342.1 --> m/z 112.2 and m/z 329.1 --> m/z 213.2, for quantification of levosulpiride and IS, respectively. The standard calibration curves showed good linearity within the range of 2-200 ng/mL (r(2) > or = 0.9990). The lower limit of quantitation was 2 ng/mL. The retention times of levosulpiride (0.63 min) and IS (0.66 min) presented a significant time saving benefit of the proposed method. No significant metabolic compounds were found to interfere with the analysis. This method offered good precision and accuracy and was successfully applied for the pharmacokinetic and bioequivalence study of a 25 mg of levosulpiride tablet in 24 healthy Korean volunteers.

Quantification of Galantamine in Human Plasma by Validated Liquid Chromatography–Tandem Mass Spectrometry using Glimepride as an Internal Standard: Application to Bioavailability Studies in 32 Healthy Korean Subjects

A simple, rapid and selective liquid chromatography method coupled with tandem mass spectrometry is developed and validated for the quantification of galantamine in human plasma using a commercially available compound, glimepride, as an internal standard (IS). Following simple one-step liquid-liquid extraction by ethyl acetate, the analytes are separated using an isocratic mobile phase consisting of acetonitrile and 0.01M ammonium acetate (95/5, v/v) on a reverse-phase C18 column and analyzed by tandem mass spectrometry in the multiple reaction monitoring mode using the transitions of respective (M + H)(+) ions, m/z 288.22 → 213.20 and m/z 491.17 → 352.30 for the quantification of galantamine and IS, respectively. The standard calibration curves show good linearity within the range of 4 to 240 ng/mL (r(2) = 0.9996, 1/x(2) weighting). The lower limit of quantification is 4 ng/mL. The retention times of galantamine and IS are 1.1 and 0.71 min, which showsthe high throughput potential of the proposed method. In addition, no significant metabolic compounds are found to interfere with the analysis. Acceptable precision and accuracy are obtained for the concentrations over the standard curve range. The validated method is successfully applied for pharmacokinetic and bioequivalence studies of 24 mg of a galantamine hydrobromide capsule in 32 healthy Korean subjects.

A simple and rapid LC-MS/MS method for the determination of Enalapril in human plasma for pharmacokinetic and bioequivalence studies in korean healthy volunteers under fasting conditions

A simple and rapid liquid chromatography-tandem mass spectrometry method for Enalapril in human plasma was developed and applied to pharmacokinetic and bioequivalence test for 2 formulations of Enalapril (10 mg) capsules in healthy korean volunteers under fasting state. The analytes were extracted from plasma by simple protein precipitation by acetonitrile, separated on YMC C8 column using methanol-10 mM ammonium formate (80: 20, v/v) as the mobile phase, and detected by tandem mass spectrometry with Turbo IonSpray interface operating in the positive ion mode for Enalapril and Glibenclamide (IS) in MRM mode. The ionization was optimized using electro-spray ionization (ESI) (+) and selectivity was achieved by MS/MS analysis, m/z 376.447 → 234.1 for Enalapril and m/z 494.1 → 369.1 for IS. The assay exhibited good linearity in the concentration ranges of 1.0 ∼ 300 ng/mL for Enalapril in human plasma with lower limit of quantification (LLOQ) of 1.0 ng/mL. The chromatographic run time was approximately 2.0 min. No endogenous compounds were found to interfere with the analysis. The accuracy and precision were acceptable for concentrations over the standard ranges. The method was successfully applied to pharmacokinetic (PK) and bioequivalence (BE) studies by determination of Enalapril in the blood sample taken up to 12 h after oral administration of two Enalapril (10 mg) formulations and results from PK analysis suggested that the 2 types of 10 mg Enalapril tablets should be considered to be bioequivalent for both the extent and rate of absorption in normal volunteers.

Abnormal Gas Diffusing Capacity and Portosystemic Shunt in Patients With Chronic Liver Disease

Background Pulmonary dysfunctions including the hepatopulmonary syndrome and portosystemic shunt are important complications of hepatic cirrhosis. To investigate the severity and nature of abnormal gas diffusing capacity and its correlation to portosystemic shunt in patients with chronic liver disease. Methods Forty-four patients with chronic liver disease (15 chronic active hepatitis (CAH), 16 Child-Pugh class A, and 13 Child-Pugh class B) without other diseases history were enrolled in the study. Evaluation of liver function tests, arterial blood gases analysis, ultrasonography, pulmonary function test including lung diffusing capacity of carbon monoxide (DLco), forced vital capacity(FVC), forced expiratory volume 1 seconds(FEV1), total lung capacity(TLC), DLco/AV(alveolar volume) and thallium-201 per rectum scintigraphy were performed. We were analyzed correlations between pulmonary function abnormalities and heart/liver (H/L) ratio in patients with chronic liver diseases. Results In CAH, percentage of patients with DLco and DLco/VA (< 80%) was 22.2 % but it was significantly increased to 47.2-54.5% in Child-Pugh class A and B patients. The means of DLco and DLco/VA were significantly (P < 0.05) decreased in Child-Pugh class. The mean H/L ratio in Child-Pugh class B increased markedly (P < 0.01) than those with CAH and Child-Pugh class A. The frequency of specific pulmonary function abnormality in patients with Child-Pugh class B was significantly (P < 0.01) greater than those with Child-Pugh class A and CAH. There was a inverse linear correlation between H/L ratio and DLco (r = -0.339, P < 0.05) and DLco/VA (r = -0.480, P < 0.01). Conclusion A total of 62% of patients with advanced liver disease have abnormal pulmonary diffusion capacity with a reduced DLco or DLco/VA and abnormal portosystemic shunt (increased H/L ratio) is common hemodynamic abnormality. Therefore, inverse linear correlation between DLco or DLco/VA and H/L ratio may be an important factor in predicting pulmonary complication and meaningful diagnostic and prognostic parameters in patients with advanced chronic liver disease.