Simvastatin is a lipid-lowering drug that is metabolized to its active metabolite simvastatin acid (SA). We developed and validated a sensitive liquid chromatography-tandem mass spectrometry (LC/MS/MS) method to quantitate SA in human plasma using a liquid-liquid extraction method with methanol. The protonated analytes generated in negative ion mode were monitored by multiple reaction monitoring. Using 500-mL plasma aliquots, SA was quantified in the range of 0.1-100 ng/mL. Calibration was performed by internal standardization with lovastatin acid, and regression curves were generated using a weighting factor of 1/χ2. The linearity, precision, and accuracy of this assay for each compound were validated using quality control samples consisting of mixtures of SA (0.1, 0.5, 5, and 50 ng/mL) and plasma. The intra-batch accuracy was 95.3-107.8%, precision was -2.2% to -3.7%, and linearity (r2) was over 0.998 in the standard calibration range. The chromatographic running time was 3.0 min. This method sensitively and reliably measured SA concentrations in human plasma and was successfully used in clinical pharmacokinetic studies of simvastatin in healthy Korean adult male volunteers.
Adult ; Calibration ; Humans* ; Liquid-Liquid Extraction ; Lovastatin ; Male ; Mass Spectrometry* ; Methanol ; Plasma* ; Protons ; Quality Control ; Running ; Simvastatin* ; Volunteers

There is increasing interest in the application of personalized therapy to healthcare to increase the effectiveness of and reduce the adverse reactions to treatment. Pharmacogenomics is a core element in personalized therapy and pharmacogenomic research is a growing field. Understanding pharmacogenomic research tools enables better design, conduct, and analysis of pharmacogenomic studies, as well as interpretation of pharmacogenomic results. This review provides a general and brief introduction to pharmacogenomics research tools, including genotyping technology, web-based genome browsers, and software for haplotype analysis.
Delivery of Health Care ; Genome ; Haplotypes ; Humans ; Pharmacogenetics*

During the past two years, three immune checkpoint inhibitors, ipilimumab, nivolumab and pembrolizumab, have been approved and revolutionized cancer immunotherapy. Translational and clinical pharmacology of these agents have contributed in identifying patients who will receive benefit, dose effect relationship and surrogate endpoints of clinical benefit. In addition, population pharmacokinetics/pharmacodynamics have facilitated scientific clinical development, which has led to accelerated approval of these agents. This paradigm may show how early phase studies may allow identification of subgroup of patients who can benefit and subsequent approval of drugs based on smaller patient population. This may speed the access of effective treatment for patients with life-threatening diseases.
Biomarkers ; Humans ; Immunotherapy ; Pharmacokinetics ; Pharmacology, Clinical

Pharmacology is the study of the actions of synthetic or semisynthetic chemicals or naturally occurring substances on molecules, cells, tissues, and living organisms, as seen in physiological and pathological systems, seeking to establish order, pattern, and sequence among them, aiming ultimately to determine the rules by which pathophysiological information can be coded into molecules, allowing prediction of both beneficial and harmful consequences. Clinical pharmacology is the application, informed by an understanding of pharmacology, of all aspects of the study and use of medicines in humans, whose practitioners, normally medically qualified, teach, do research, frame policy, and give information and advice about the actions and proper uses of medicines in humans and implement that knowledge in clinical practice. Clinical pharmacology expanded in the UK during the 1960s and 1970s and maintained a steady state during the 1980s, but thereafter started to decline. Since 2006 this decline has been halted and partly reversed through the efforts of the British Pharmacological Society, by demonstrating the need for clinical pharmacology in clinical practice, teaching, research, and policy making, and bringing that need to the attention of medical colleagues, regulators, government, and the public. Efforts continue to maintain and enhance this recovery, using the VOICE paradigm, which involves improving and maintaining the Visibility of the specialty, Outreach to advertise its attractiveness to potential trainees and creating a public image for the specialty, Integration with other disciplines, encouraging Coverage of neglected areas, and the use of Emissaries, particularly younger members of the discipline, to promote it, both within medicine and in the wider world. Fortuitously, translation of the five elements of this paradigm into Korean, and back-translation into English, with the addition of a sixth element, provides a RECIPE for the future of clinical pharmacology and therapeutics.
Humans ; Pharmacology ; Pharmacology, Clinical* ; Policy Making ; Voice*

Levofloxacin is a bactericidal broad spectrum antibiotic against Gram-positive and Gram-negative pathogens. A randomized, two-treatment, two-period, two-way crossover study was conducted to evaluate the bioequivalence of Lectacin 250 mg tablet, a generic levofloxacin, to its reference drug, Cravit 250 mg tablet. Each period was separated by a 7-day washout. Serial blood samples were collected until 24 h after dosing and plasma levofloxacin concentrations were determined using a high performance liquid chromatography. Pharmacokinetic parameters were analyzed using K-BE Test 2007 and BA calc 2007 (Ministry of Food and Drug Safety, Cheongju-si, South Korea). The peak concentration (Cmax) and the area under the plasma concentration versus time curve from 0 to the last measurable concentration (AUC(0-t)) for the generic and reference levofloxacin were 4.48+/-0.89 mg/L and 4.46+/- 0.95 mg/L, and 25.33+/-4.12 mg*h/L and 25.77+/-4.01 mg*h/L, respectively, leading to a geometric mean ratio (90% confidence interval) of the generic to the reference levofloxacin of 1.0060 (0.9339-1.0842) and 0.9810 (0.9476-1.0159), respectively, for Cmax and AUC(0-t). Lectacin 250 mg tablet is bioequivalent to Cravit 250 mg tablet.
Chromatography, Liquid ; Chungcheongbuk-do ; Cross-Over Studies ; Humans ; Levofloxacin* ; Male ; Pharmacokinetics ; Plasma ; Tablets* ; Therapeutic Equivalency*

Cigarette smoking may be associated with the augmentation of pro-inflammatory cytokines including Tumor Necrosis Factor-alpha (TNF-alpha), which may affect the outcomes of pharmacological agents such as TNF-alpha inhibitors. The purpose of this study was to investigate the impact of smoking on the effectiveness of TNF-alpha inhibitors in patients with rheumatoid arthritis (RA) or Crohn's disease (CD). We used systematic literature review methods. A total of 1,147 articles were selected after exclusion of duplicates through a database search. Among them, 28 articles were finally selected through a review of titles and abstracts and a subsequent review of full articles. The effectiveness of TNF-alpha inhibitors in patients with RA or CD among the selected articles was summarized by their smoking status. Meta-analysis was performed with random effect model. When current smokers were compared with non-smokers for response after adjustments through meta-analysis among patients with RA, current smokers had 59% less response than non-smokers with statistical significance (Pooled adjusted OR=0.41, 95% CI=0.17-0.95). In patients with CD, current smokers tended to have lower clinical response than non-smokers, but statistical significance was not shown. In subgroup analyses for luminar CD or fistulizing CD, current smokers tended to have a lower response in luminar CD (Pooled OR=0.62, 95% CI=0.34-1.14), but smoking status was not associated with drug response in fistulizing CD. This study raises awareness of the adverse effects of smoking in terms of clinical response in patients treated with TNF-alpha inhibitors.
Arthritis, Rheumatoid* ; Crohn Disease* ; Cytokines ; Humans ; Smoke* ; Smoking* ; Tumor Necrosis Factor-alpha*

SKL10406, triple monoamine reuptake inhibitor, is a novel antidepressant candidate. A PET study was performed to investigate the occupancies of serotonin and dopamine transporters (SERT and DAT) in human brain, and the relationship between SKL10406 concentration and SERT occupancy was assessed using pharmacokinetic-pharmacodynamic (PK-PD) modeling methods. Fifteen healthy volunteers were given SKL10406 100 mg/day for 6 days or 150 mg/day for 6 days after 100 mg/day for 4 days. Each subject underwent full PK sampling for SKL10406 and PET scans at predose, 4 h and 16 h after dosing at a steady state to investigate the occupancies of SERT and DAT using 11C-DASB and 11C-PE2I, respectively. Naive pooled method (NPM) and nonlinear mixed-effect methods (ME) including a direct ME (DME) and an effect compartmental ME (EME) were used (NONMEM Ver. 7.2). Six and five subjects completed the studies for SERT and DAT, respectively. The final estimates of Emax (53.4%) and EC50 (11.8 ng/mL) from DME were relatively lower than those from NPM (Emax, 74.1%; EC50, 36.8 ng/mL) and EME (Emax, 68.6%; EC50, 40.2 ng/mL). DAT occupancy results were not modeled because of lower occupancies. The results showed that the dosage regimens may be applied in patient studies. However, difference between estimation methods alerts that ME may not be a recommendable analysis tool for sparsely sampled PET scan data.
Brain ; Dopamine ; Healthy Volunteers ; Humans ; Positron-Emission Tomography ; Serotonin ; Serotonin Plasma Membrane Transport Proteins*

The structural complexity of crossover studies for bioequivalence test confuses analysts and leaves them a hard choice among various programs. Our study reviews PROC GLM and PROC MIXED in SAS and compares widely used SAS codes for crossover studies. PROC MIXED based on REML is more recommended since it provides best linear unbiased estimator of the random between-subject effects and its variance. Our study also considers the covariance structure within subject over period which most PK/PD studies and crossover studies ignore. The QT interval data after the administration of moxifloxacin for a fixed time point are analyzed for the comparison of representative SAS codes for crossover studies.
Cross-Over Studies* ; Therapeutic Equivalency

The Vietnamese-Koreans, especially offspring between a Vietnamese mother and a Korean father constituted the highest proportion (64.2%) of total Kosian population according to a census in 2014. To evaluate genetic characteristics in the Vietnamese-Koreans, a total of 25 alleles from CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 were genotyped using SNaPshot method with DNA samples of 127 Vietnamese-Koreans. The previous reports on the CYPs of Korean and Vietnamese populations were also analyzed for the comparative studies for the frequencies of CYP alleles. The statistical significances in allele and genotype frequencies among the ethnics were analyzed by Chi-square or Fisher's exact probability test. Although most of variants analyzed in 5 CYPs did not reach the statistically significant difference between the Vietnamese-Koreans and Vietnamese, some alleles were only found in Vietnamese-Koreans. Compared with Korean population, frequencies of CYP2D6*1 and CYP2D6*10B were statistically different from Vietnamese-Koreans (p<0.05). This is the first report to describe the CYP genotype profiles of Vietnamese-Koreans, which may provide important insight for the genotype based prediction of CYP activities of this admixture of Korean and Vietnamese.
Alleles ; Asian Continental Ancestry Group ; Censuses ; Cytochrome P-450 CYP2D6* ; Cytochrome P-450 Enzyme System ; DNA ; Fathers ; Genotype ; Humans ; Mothers ; Polymorphism, Genetic*

The aging process is linked to changes in the physiological function of organs and changes in body composition that alter the pharmacokinetics of drugs and pharmacodynamic responses. Comorbidity and polypharmacy in the elderly decreases tolerability of drugs, leading to greater vulnerability to adverse drug reactions than that observed in younger adults. In geriatric pharmacotherapy, the general recommendation is dose reduction and slow titration, which is based on pharmacokinetic considerations and concern for adverse drug reactions, rather than clinical trial data. Older patients are under-represented in clinical trials. In the absence of evidence, extrapolation of risk-benefit ratios from younger adults to geriatric populations is not necessarily valid. Sound evidence through prospective clinical trials is essential, and geriatric societies, governments, and patient advocacy groups should collaborate to promote the inclusion of older people in clinical trials. It is believed that all involved in clinical trials have both an obligation and an opportunity to eliminate age discrimination in clinical trial practice.
Adult ; Aged* ; Ageism ; Aging ; Body Composition ; Comorbidity ; Drug Therapy ; Drug-Related Side Effects and Adverse Reactions ; Geriatrics ; Humans ; Patient Advocacy ; Pharmacokinetics ; Pharmacology, Clinical* ; Polypharmacy