UI14SDF100CW is a chewable tablet of sildenafil citrate, which was developed to improve compliance through convenience of administration. The purpose of this study was to compare the pharmacokinetic (PK) properties of sildenafil citrate chewable tablets (UI14SDF100CW) and conventional sildenafil citrate film-coated tablets (Viagra®, Pfizer). A randomized, open-label, single dose, two-treatment, two-period, two-way crossover study was conducted in 60 healthy male volunteers. In each period, the subjects received a single oral dose of UI14SDF100CW or Viagra® (both tablets contain 140.45 mg of sildenafil citrate, which is equivalent to 100 mg of sildenafil). Serial blood samples were collected up to 24 h post-dose for PK analysis. The plasma concentration of sildenafil was determined using a validated HPLC-MS/MS assay. PK parameters of sildenafil were calculated using non-compartmental methods. The plasma concentration-time profiles of sildenafil in both formulations were similar. For UI14SDF100CW, the C(max) and AUC(last) of sildenafil were 1068.69 ± 458.25 (mean ± standard deviation) mg/L and 3580.59 ± 1680.29 h·mg/L, and the corresponding values for Viagra® were 1146.84 ± 501.70 mg/L and 3406.35 ± 1452.31 h·/L, respectively. The geometric mean ratios (90% confidence intervals) of UI14SDF100CW to Viagra® for C(max) and AUC(last) were 0.933 (0.853–1.021) and 1.034 (0.969–1.108), respectively, which met the bioequivalence criteria of Korean regulatory agency. In conclusion, UI14SDF100CW and Viagra® showed similar PK properties. Therefore, UI14SDF100CW can be an alternative to sildenafil for the treatment of erectile dysfunction, providing better compliance.
Compliance ; Cross-Over Studies ; Erectile Dysfunction ; Humans ; Male* ; Pharmacokinetics ; Plasma ; Sildenafil Citrate* ; Tablets* ; Therapeutic Equivalency ; Volunteers

This study focused on the role of cytochrome P450 2D6 (CYP2D6) genotypes to predict phenotypes in the metabolism of dextromethorphan. CYP2D6 genotypes and metabolic ratios (MRs) of dextromethorphan were determined in 201 Koreans. Unsupervised clustering algorithms, hierarchical and k-means clustering analysis, and color visualizations of CYP2D6 activity were performed on a subset of 130 subjects. A total of 23 different genotypes were identified, five of which were observed in one subject. Phenotype classifications were based on the means, medians, and standard deviations of the log MR values for each genotype. Color visualization was used to display the mean and median of each genotype as different color intensities. Cutoff values were determined using receiver operating characteristic curves from the k-means analysis, and the data were validated in the remaining subset of 71 subjects. Using the two highest silhouette values, the selected numbers of clusters were three (the best) and four. The findings from the two clustering algorithms were similar to those of other studies, classifying *5/*5 as a lowest activity group and genotypes containing duplicated alleles (i.e., CYP2D6*1/*2N) as a highest activity group. The validation of the k-means clustering results with data from the 71 subjects revealed relatively high concordance rates: 92.8% and 73.9% in three and four clusters, respectively. Additionally, color visualization allowed for rapid interpretation of results. Although the clustering approach to predict CYP2D6 phenotype from CYP2D6 genotype is not fully complete, it provides general information about the genotype to phenotype relationship, including rare genotypes with only one subject.
Alleles ; Classification ; Cluster Analysis* ; Cytochrome P-450 CYP2D6* ; Dextromethorphan ; Genotype ; Metabolism ; Phenotype* ; ROC Curve

Caffeine is a naturally-occurring central nervous system stimulant found in plant constituents including coffee, cocoa beans, and tea leaves. Consumption of caffeine through imbibing caffeinated drinks is rapidly growing among children, adolescents, and young adults, who tend to be more caffeine-sensitive than the rest of the general public; consequently, caffeine-related toxicities among these groups are also growing in number. However, a quantitative and interactive tool for predicting the plasma caffeine concentration that may lead to caffeine intoxication has yet to be developed. Using the previously established population-pharmacokinetic model, we developed “caffsim” R package and its web-based applications using Shiny and EDISON (EDucation-research Integration through Simulation On the Net). The primary aim of the software is to easily predict and calculate plasma caffeine concentration and pharmacokinetic parameters and visualize their changes after single or multiple ingestions of caffeine. The caffsim R package helps understand how plasma caffeine concentration changes over time and how long toxic concentration of caffeine can last in caffeine-sensitive groups. It may also help clinical evaluation of relationship between caffeine intake and toxicities when suspicious acute symptoms occur.
Adolescent ; Cacao ; Caffeine* ; Central Nervous System ; Child ; Coffee ; Humans ; Pharmacokinetics ; Plants ; Plasma* ; Tea ; Young Adult

Rivaroxaban is a new oral anticoagulant used for the prevention of stroke in patients with atrial fibrillation. Hemorrhagic pericarditis is known to occur with rivaroxaban; however, only a few case reports in the literature describe such events. Recently, we experienced hemorrhagic pericarditis that treated with rivaroxaban for anticoagulation of newly diagnosed, non valvular AF patients with pacemaker. An 83 year old male with permanent pacemaker receiving rivaroxaban 20 mg daily once for 3 months presented at our emergency department complaining of exertional dyspnea. ECG showed intermittent atrial pacing failure and echocardiography showed large amount of pericardial effusion. After urgent pericardiocentesis, which resulted in removal of 500cc bloody fluid, there was an immediate and dramatic improvement in the patient's clinical state. He was discharged without anticoagulation therapy due to concern for further bleeding. This case highlight the potential for bleeding complications associated with novel anticoagulants. Rivaroxaban is being used with increasing frequently in outpatient care. However, no available laboratory test specifically measures the anticoagulant effect of rivaroxaban. Also, in the events of serious bleeding, no specific antidotes, reversal agents were available. Clinicians should be aware of the possibility of hemopericardium in patients treated with anticoagulants, including rivaroxaban who presented with cardiomegaly.
Ambulatory Care ; Anticoagulants ; Antidotes ; Atrial Fibrillation* ; Cardiomegaly ; Dyspnea ; Echocardiography ; Electrocardiography ; Emergency Service, Hospital ; Hemorrhage ; Humans ; Male ; Pericardial Effusion ; Pericardiocentesis ; Pericarditis* ; Rivaroxaban* ; Stroke

We report a case of Waldenström's macroglobulinemia (WM) treated using clarithromycin (CAM) and prednisolone (PSL). An 84-year-old woman was admitted to our hospital for bleeding after a tooth extraction and hematuria. Computed tomography showed multiple ill-defined nodules in the omentum (omental cake). Although the cause of the omental cake remained unclear, the patient was diagnosed with WM, based on the detection of M-protein of immunoglobulin (Ig) M in serum and lymphoplasmacytes in bone marrow. The bleeding tendency in the patient may have been due to acquired hemophilia and/or hyper IgM-induced platelet dysfunction. The patient was treated using CAM (800 mg/day) and PSL (10 mg/day). As a result, IgM levels gradually decreased. Because the omental cake contracted along with improvement in IgM, it was thought to be lymphoplasmacytic lymphoma-like lymphoma. This case shows that treatment using CAM and PSL may be effective in some cases of WM.
Aged, 80 and over ; Blood Platelets ; Bone Marrow ; Clarithromycin* ; Female ; Hematuria ; Hemophilia A ; Hemorrhage ; Humans ; Immunoglobulin M ; Immunoglobulins ; Lymphoma ; Omentum ; Prednisolone* ; Tooth Extraction ; Waldenstrom Macroglobulinemia*

In this tutorial, we introduce a differential equation simulation model for use in pharmacometrics involving NONMEM, Berkeley Madonna, and R. We report components of the simulation code and similarities/differences between software, rather than how to use each software. Depending on the purpose of the simulation, an appropriate tool can be selected for effective communication.
Computer Simulation ; Software

In the published version of this article, an error in the sponsor's identity was discovered in the acknowledgment section.

This study was to clarify population pharmacokinetics (PK) of sildenafil and its metabolite, N-desmethyl sildenafil (NDS) in Korean healthy male population using a pooled data from multiple clinical trials in consideration of inter-institution and inter-laboratory difference. A population PK analysis was performed with data of 243 healthy volunteers from five single-center (4 centers) comparative PK trials. The dataset included 7,376 sildenafil and NDS concentration (3,688 for each analyte) observed during 24 hours after the single dose of original sildenafil (either 50 mg or 100 mg of Viagra®). The plasma concentration was assayed in two laboratories. Various model structure was tested and the final model was evaluated using visual predictive checks. Demographic and clinical variables were assessed as potential covariates for PK parameters. A one-compartment first-order elimination model with proportional error was selected for the dispositional characteristics of sildenafil, and two-compartment model was chosen for NDS. Three transit compartments with Erlang-type absorption for fast absorption pathway and one compartment for slow absorption pathway constructed overall absorption model. The first-pass effect was rejected since it does not improve the model. The difference of NDS level by the bioanalysis laboratory was selected as the only covariate. Even though a direct comparison was difficult, the general trend in PK of sildenafil and NDS for Korean healthy male was considered similar to that of the other populations reported previously. It is recommended that the laboratory effect should be explored and evaluated when dataset is built using results from several laboratories.
Absorption ; Administration, Oral* ; Asian Continental Ancestry Group ; Dataset ; Healthy Volunteers ; Humans ; Male* ; Pharmacokinetics* ; Plasma ; Sildenafil Citrate* ; Volunteers*

Imatinib (Gleevec™; Novartis Pharmaceuticals) is an orally administered protein-tyrosine kinase inhibitor. The goal of this study was to investigate the population pharmacokinetics (PK) of imatinib (as imatinib mesylate) in healthy male Koreans. A total of 1,773 plasma samples from 112 healthy male volunteers enrolled in three phase I clinical studies were used. Among the subjects, 76 received 400 mg and 36 received 100 mg as single oral doses. Peripheral blood sampling for PK analysis was done at 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 48, 60 and 72 (at 400 mg group) h after dosing. The firstorder conditional estimation with interaction method of NONMEM® (ver. 7.3) was used to build the population PK model. A two-compartment model with Weibull absorption and elimination gave the best fit to the data. The estimates of clearance (CL/F), volume of central compartment (Vc/F), intercompartmental clearance (Q/F), peripheral volume (Vp/F) and their interindividual variabily (%CV) were 13.6 L/h (23.4%), 153 L (29.2%), 8.64 L/h (35.9%) and 64 L (67%), respectively.
Absorption ; Humans ; Imatinib Mesylate* ; Male ; Methods ; Pharmacokinetics* ; Plasma ; Protein-Tyrosine Kinases ; Volunteers

While phosphodiesterase type 5 inhibitors have been used for erectile dysfunction with acceptable safety profile, they can induce orthostatic hypotension in patients taking antihypertensive drugs with blood pressure lowering effect. This study evaluated the hemodynamic effects of 100 mg mirodenafil in hypertensive patients taking an amlodipine. Thirteen hypertensive patients who were taking 5 or 10 mg of amlodipine once daily participated in a randomized, double-blind, placebo-controlled, crossover study. A single oral dose of mirodenafil 100 mg or placebo was administered at 4.5 hour after administration of amlodipine. The maximal change in systolic and diastolic blood pressure (ΔmaxSBP and ΔmaxDBP) and pulse rate (ΔmaxPR) were compared between mirodenafil and placebo periods. Twelve patients completed this study and were included analysis. The values of ΔmaxPR in standing and supine position were significantly greater in the mirodenafil period (13.25±7.12 and 11.17±4.86 beats/minute) when compared to the placebo (8.50±4.72 and 6.58±3.90 beats/minute). The ΔmaxSBP and ΔmaxDBP in standing position appeared to be lower in the mirodenafil period, but they were not statistically different from those in the placebo period (ΔmaxSBP = -7.42±5.6 vs -4.42±5.37 mmHg and ΔmaxDBP = -7.17±5.72 vs -3.50±3.37 mmHg). Both ΔmaxSBP and ΔmaxDBP in standing and supine position were not significantly different between mirodenafil and placebo. This study demonstrated that mirodenafil exerted minimal hemodynamic effects in the patients taking amlodipine, that is unlikely associated with a clinically significant hypotensive event.
Amlodipine* ; Antihypertensive Agents ; Blood Pressure ; Cross-Over Studies ; Erectile Dysfunction ; Heart Rate ; Hemodynamics* ; Humans ; Hypotension, Orthostatic ; Male ; Phosphodiesterase 5 Inhibitors ; Posture ; Supine Position