Prediction and visualization of CYP2D6 genotype-based phenotype using clustering algorithms.

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.

Pharmacodynamics, pharmacokinetics, and tolerability of intravenous or subcutaneous GC1113, a novel erythropoiesis-stimulating agent.

BACKGROUND AND OBJECTIVES: GC1113, a hybrid Fc-fused erythropoietin, is a novel erythropoiesis-stimulating agent that is expected to have an extended duration of action. The preclinical data showed that the hemoglobin increase lasted longer following GC1113 administration than it did following the administration of darbepoetin alfa (NESP®). This study aimed to investigate the pharmacodynamic and pharmacokinetic characteristics and tolerability profiles of GC1113 in humans after single intravenous or subcutaneous administration and to compare the results with those for darbepoetin alfa. METHODS: A dose-block randomized, placebo- and active-controlled, dose-escalation phase I clinical trial was conducted in 96 healthy volunteers. Blood samples were collected before and up to 672 h after drug administration and the serum erythropoietin concentration following the GC1113 or darbepoetin alfa administration was measured by an ELISA. The reticulocyte counts were measured for pharmacodynamic assessments. Pharmacokinetic and pharmacodynamic parameters were determined using non-compartmental methods. RESULTS: The reticulocyte count-time profiles in the intravenous GC1113 3-5 µg/kg groups were comparable with those of the darbepoetin alfa 30 µg group. After subcutaneous administration of GC1113, reticulocyte count peaked later and decreased more slowly than it did following darbepoetin alfa administration. GC1113 (0.3-5 µg/kg intravenous, 1-8 µg/kg subcutaneous) was well-tolerated in the volunteers, and no immunogenicity was observed. CONCLUSION: GC1113 was tolerated and effective in the studied dose range; these findings could be applied to further clinical studies with patients.

Effects of HM30181, a P-glycoprotein inhibitor, on the pharmacokinetics and pharmacodynamics of loperamide in healthy volunteers.

AIMS: HM30181 is a third generation P-glycoprotein (P-gp) inhibitor currently under development. The objectives of this study were to evaluate the effects of a single dose of HM30181 on the pharmacodynamics and pharmacokinetics of loperamide, a P-gp substrate, and to compare them with those of quinidine. METHODS: Eighteen healthy male subjects were administered loperamide alone (period 1) or with loperamide plus quinidine or HM30181 in period 2 or 3, respectively. In period 3, subjects randomly received one of three HM30181 doses: 15, 60 or 180 mg. Changes in pupil size, alertness, oxygen saturation and the oral bioavailability of loperamide were assessed in each period. In addition, the pharmacokinetics of HM30181 were determined. RESULTS: Pupil size, alertness and oxygen saturation did not change over time when loperamide alone or loperamide plus HM30181 was administered while HM30181 significantly increased the systemic exposure to loperamide, i.e. the geometric mean ratio (90% confidence interval) of AUC(0,tlast ) for loperamide with and without HM30181 was 1.48 (1.08, 2.02). Co-administered quinidine significantly increased the systemic exposure to loperamide 2.2-fold (1.53, 3.18), which also markedly reduced pupil size, resulting in a decrease of 24.7 mm h in the area under the effect curve of pupil size change from baseline compared with loperamide alone. CONCLUSIONS: HM30181 inhibits P-gp mainly in the intestinal endothelium, which can be beneficial because pan-inhibition of P-gp, particularly in the brain, could lead to detrimental adverse events. Further studies are warranted to investigate adequately the dose-exposure relationship of HM30181, along with its duration of effect.

Pharmacokinetic properties and effects of PT302 after repeated oral glucose loading tests in a dose-escalating study.

BACKGROUND: PT302 is a sustained-release exenatide under clinical development for the treatment of type 2 diabetes mellitus. OBJECTIVE: The aim of this study was to evaluate the pharmacokinetic properties, pharmacodynamic properties, and tolerability of PT302 after a single subcutaneous injection in healthy individuals. METHODS: A dose-block randomized, double-blind, placebo-controlled, dose-escalating study (0.5, 1, 2, and 4 mg) was performed in 34 healthy individuals. The plasma concentrations of exenatide in serial blood samples were quantified for 56 days after dosing with an exendin-4 fluorescent immunoassay kit. Noncompartmental analysis was performed to assess the pharmacokinetic characteristics of PT302. Oral glucose tolerance tests were repeated weekly until day 42; the concentrations of serum glucose, serum C-peptide, plasma insulin, and plasma glucagon were measured for 2 hours to evaluate the pharmacodynamic characteristics of PT302. Clinical laboratory tests, vital signs, physical examinations, 12-lead ECGs, and adverse events were monitored to evaluate the safety profile and tolerability. RESULTS: PT302 exhibits a biphasic pharmacokinetic profile, with the initial peak occurring 2 hours after administration. PT302 was quantifiable in the plasma until days 23, 30, 32, and 55 (median) in the 0.5-mg, 1-mg, 2-mg, and 4-mg dosage groups of PT302, respectively. Systemic exposure increased proportionally to the dose during the entire dose range investigated. The pharmacodynamic effect of PT302 on the postprandial response of insulin and C-peptide was significant on days 21 to 28 at the 4-mg dose and was positively correlated with plasma exenatide concentrations, whereas the correlations with glucose and glucagon were not significant. The fasting levels of these pharmacodynamic biomarkers were not altered by PT302. The most common adverse events were injection site induration and pruritus related to inflammatory foreign body reaction, which were mild and spontaneously resolved within several weeks. CONCLUSION: The pharmacokinetic characteristics of PT302 were biphasic and dose proportional. A single 4-mg dose of PT302 significantly increased the insulin and C-peptide response to oral glucose loading and was well tolerated in healthy individuals.

Relationship between absolute neutrophil count profiles and pharmacokinetics of DA-3031, a pegylated granulocyte colony-stimulating factor (pegylated-G-CSF): a dose block-randomized, double-blind, dose-escalation study in healthy subjects.

BACKGROUND: DA-3031 is a newly developed pegylated filgrastim, a recombinant human granulocyte colony-stimulating factor, that is expected to have an extended duration of action compared with non-modified filgrastim. OBJECTIVE: This study evaluated the tolerability, pharmacokinetics, and pharmacodynamics of DA-3031 in humans, and compared them with filgrastim. METHODS: The study was conducted in 48 healthy male Korean subjects. Forty subjects received subcutaneous single doses of 1.8, 3.6, 6, or 18 mg of DA-3031 or placebo in a dose block-randomized, double-blind, dose-escalation design. The remaining eight subjects were given subcutaneous doses of 100 µg/m² of filgrastim daily for 5 days. Serial blood samples were collected for pharmacokinetic and pharmacodynamic analyses up to 312 h after the administration of DA-3031 and up to 264 h following the first administration of filgrastim. RESULTS: DA-3031 reached its peak plasma concentration at 6.0-48.0 h and was eliminated mono-exponentially. The pharmacokinetic parameters of DA-3031 increased with dose in a non-linear fashion. Absolute neutrophil count (ANC) levels increased with the dose of DA-3031, although the extent of the increase in ANC decreased at higher dose levels. DA-3031 resulted in similar ANC changes in the 3.6 to 6 mg dose range as 100 µg/m² of filgrastim. The most frequent adverse event was back pain, which was observed after both DA-3031 and filgrastim administration. CONCLUSIONS: DA-3031 showed non-linear pharmacodynamic and pharmacokinetic profiles and an extended duration of action compared with non-modified filgrastim, without unexpected toxicities in healthy subjects.

Sustained Increase in the Oral Bioavailability of Loperamide after a Single Oral Dose of HM30181, a P-glycoprotein Inhibitor, in Healthy Male Participants.

HM30181 is a new P-glycoprotein (P-gp) inhibitor. This study was conducted to investigate the effect of HM30181 and its duration of action on P-gp inhibition using loperamide as a probe drug. An open-label, five-period, fixed-sequence, cross-over study was conducted in 25 healthy Korean participants, who received a single oral dose of loperamide at 16 mg in five periods lasting for 17 days. In period II, participants also randomly received a single oral dose of HM30181 at 1, 5, 10, 15 mg simultaneously with loperamide. Serial pharmacokinetic blood samples were obtained up to 72 and 336 hr after loperamide and HM30181 administration, respectively. A mixed-effects analysis was performed to compare the area under the plasma concentration versus time curve from time 0 to 72 hr (AUC0-72 hr ) between periods and HM30181 dose groups. Tolerability was also assessed. The AUC0-72 hr of repeatedly administered loperamide was significantly increased 1.18-1.62 times for up to 14 days after a single oral administration of HM30181, particularly at doses ≥10 mg although the between-group difference failed to reach statistical significance. Plasma HM30181 was not detected in many participants including none at any sampling points beyond 48 hr after administration. Most adverse events (AEs) were mild to moderate and resolved spontaneously. The oral bioavailability of loperamide was significantly enhanced by a single oral administration of HM30181, which was sustained for up to 14 days. HM30181 was well tolerated in this selected population.

The effect of udenafil on the hemodynamics of healthy male volunteers administered tamsulosin.

OBJECTIVE: The purpose of this study is to evaluate the hemodynamic interactions between udenafil and tamsulosin. METHODS: After a placebo lead-in period, 27 healthy volunteers received 200 mg udenafil + tamsulosin placebo, udenafil placebo +0.4 mg tamsulosin, or 200 mg udenafil +0.4 mg tamsulosin. Blood pressure and pulse rate (PR) were measured at 15 time points from 0 to 24 hours. RESULTS: A single dose of udenafil, when administered with multiple tamsulosin doses, produced statistically significant increases in PR (mean: 10.7; 95% confidence interval: 5.3, 16.2 bpm; p < 0.001) compared with tamsulosin administered with an udenafil placebo. Systolic and diastolic blood pressure measurements remained unchanged. Two subjects who took udenafil with tamsulosin had a decrease in standing systolic blood pressure (SBP) greater than 30 mmHg in comparison to their baseline SBP; however, compared with the frequency of a decrease in standing SBP greater than 30 mmHg in comparison to the baseline, there was no significant difference in frequency among the four treatments (p = 0.243). There was no difference in the Cmax, AUClast, or AUCinf of udenafil and its active metabolite DA-8164 between the administration of udenafil and udenafil with tamsulosin. CONCLUSION: The coadministration of udenafil and tamsulosin was not associated with clinically significant hemodynamic changes in healthy volunteers. Although this study was conducted on a small number of healthy young subjects, the use of udenafil for the treatment of erectile dysfunction in patients taking tamsulosin for the treatment of benign prostatic hyperplasia is not expected to cause significant safety problems.

Pharmacokinetic-pharmacodynamic modelling of biomarker response to sitagliptin in healthy volunteers.

Pharmacokinetic/pharmacodynamic (PK/PD) models can be useful tools in new drug development and also optimal drug therapy in patients. This study was designed to develop a PK/PD model of sitagliptin based on the physiology of incretin. The PK/PD data included information derived from two different studies. Study 1 was conducted as a one-sequence, three-period, repeated-dose, dose escalation (sitagliptin 25, 50 and 100 mg q.d.) design in twelve healthy volunteers. Study 2 was a first-in-man study for the newly developed dipeptidyl peptidase-4 (DPP-4) inhibitor in healthy volunteers. In study 1, blood samples were collected to measure sitagliptin concentrations, DPP-4 activity and active glucagon-like peptide-1 (GLP-1) concentrations. In study 2, only data from the 'placebo group' were used, and blood samples were collected to measure DPP-4 activity, active GLP-1 concentrations and glucose concentrations. A PK/PD analysis was conducted using a non-linear mixed effects modelling approach. Sitagliptin pharmacokinetics was modelled using a two-compartment model with first-order absorption. Changes in DPP-4 inhibition were linked to the PK model using a sigmoid Emax model, whereas the active GLP-1 changes were explained using an indirect response model; this model incorporated the glucose and DPP-4 inhibition models. The PK/PD model developed adequately described the changes in sitagliptin concentration, DPP-4 inhibition and active GLP-1 concentration in healthy volunteers.

Increased systemic exposure of fimasartan, an angiotensin II receptor antagonist, by ketoconazole and rifampicin.

The authors studied the effects of ketoconazole and rifampicin on the pharmacokinetics of a single dose of fimasartan (BR-A-657), a newly developed angiotensin II receptor antagonist for the treatment of hypertension, in 22 healthy participants. Ketoconazole increased the maximumplasma concentration (Cmax) and area under the plasma concentration vs time curve to infinity (AUC∞ of fimasartan by 2.47-fold (90% confidence interval [CI], 1.61-3.79) and 2.03-fold (1.56-2.64), respectively. Concomitant administration of rifampicin increased the C(max) and AUC∞ of fimasartan by 10.33-fold (90% CI, 6.74-15.81) and 4.60-fold (3.54-5.97). In vitro studies indicated that ketoconazole inhibited the uptake of fimasartan into cells expressing OATP1B1 with a K(i) of 107.7 µM, and rifampicin inhibited OAT1- and OATP1B1-mediated fimasartan transport with a K(i) of 212 µM and 12.2 µM, respectively. The systemic exposure of fimasartan was significantly increased by coadministration of ketoconazole or rifampicin in healthy volunteers. This is consistent with the in vitro results, in which fimasartan is a substrate of CYP3A and OATP1B1.

Pharmacokinetic and pharmacodynamic properties of a new long-acting granulocyte colony-stimulating factor (HM10460A) in healthy volunteers.

BACKGROUND: HM10460A is a newly developed recombinant human granulocyte colony-stimulating factor with long-lasting characteristics. This factor is expected to be used for chemotherapy-related neutropenic conditions. OBJECTIVE: The aim of the present study was to evaluate the pharmacokinetics and pharmacodynamics of HM10460A following subcutaneous administration to healthy Korean subjects. METHODS: A randomized, double-blind, placebo-controlled, escalating single-dose study was conducted in 40 healthy Korean subjects. The subjects were allocated to single-dose groups of 5, 15, 45, 135 or 350 µg/kg, or placebo. Serial blood samples for pharmacokinetic/pharmacodynamic analyses were collected up to 22 days, and urine samples for pharmacokinetic analysis were collected up to 3 days after subcutaneous administration of HM10460A. The serum and urine concentrations were analyzed by enzyme-linked immunosorbent assay. RESULTS: Most of the serum concentrations in the 5 and 15 µg/kg dosing groups were below the lower limit of quantification (LLOQ). The median times to the peak concentration (T(max)) of HM10460A in the 45, 135, and 350 µg/kg dosing groups were 8.0, 14.0, and 24.0 h, respectively. The mean ± standard deviation values of the dose-normalized maximum concentration (C(max)) and dose-normalized area under the concentration-time curve (AUC(last)) for the 45, 135, and 350 µg/kg dosing groups were 14.13 ± 6.37, 66.19 ± 38.71, and 34.65 ± 19.69 µg/L/mg, respectively, and 265.0 ± 124.1, 2144 ± 1232, and 1386 ± 701.2 µg h/L/mg, respectively. The concentrations of HM10460A in the urine were below the LLOQ in all of the subjects. In all of the dosing groups, the area under the effect-time curve (AUEC(last)) of both the absolute neutrophil count (ANC) and the CD34(+) cell count increased as the dose increased. CONCLUSION: HM10460A showed dose-dependent pharmacokinetic characteristics, and the systemic exposure of HM10460A was positively correlated with the ANC and CD34(+) cell counts.

Apple juice greatly reduces systemic exposure to atenolol.

AIM: Fruit juice reduces the plasma concentrations of several ß-adrenoceptor blockers, likely by inhibiting OATP2B1-mediated intestinal absorption. The aim of this study was to investigate the effects of apple juice on the pharmacokinetics of atenolol. METHODS: Twelve healthy Korean volunteers with genotypes of SLCO2B1 c.1457C> T (*1/*1 (n = 6) and *3/*3 (n = 6)) were enrolled in this study. In a three-phase, one-sequence crossover study, the pharmacokinetics (PK) of atenolol was evaluated after administration of 50 mg atenolol. Subjects received atenolol with either 300 ml water, 1200 ml apple juice or 600 ml apple juice. RESULTS: Apple juice markedly reduced the systemic exposure to atenolol. The geometric mean ratios (95% confidence intervals) of apple juice : water were 0.18 (0.13, 0.25, 1200 ml) and 0.42 (0.30, 0.59, 600 ml) for the AUC(0,t(last)). In this study, the PK parameters of atenolol responded in a dose-dependent manner to apple juice. CONCLUSIONS: Apple juice markedly reduced systemic exposure to atenolol. The genetic variation of SLCO2B1 c.1457C>T had a minimal effect on the pharmacokinetics of atenolol when the drug was administered with water or apple juice.

Pharmacokinetic study of single and multiple oral administrations of 2 mg dienogest in healthy Korean women.

BACKGROUND: The progestin dienogest was developed for oral contraception, endometriosis treatment and menopause management. Dienogest's pharmacokinetics have been primarily studied in Caucasian women. This study evaluated the single- and multiple-dose pharmacokinetics of dienogest in Korean women. STUDY DESIGN: Sixteen healthy Korean adult women received a single administration of 2 mg dienogest, followed by multiple once-daily administrations for 14 days. The single-dose administration and the final dose of the multiple administrations were each followed by blood sampling over 60 h. RESULTS: The mean (SD) maximum serum concentration after multiple doses of dienogest was slightly increased compared with that after a single dose [from 51.6 (9.6) to 56.6 (11.9) ng/mL], as was the area under the concentration-time curves (AUC)0-24h [from 503 (56.3) to 613 (90.7) ng ∙ h/mL]. The linearity factor calculated by AUCs of single and multiple doses is 1.00 ± 0.14, and the terminal half-life remained unchanged when single dosing and multiple dosing were compared. CONCLUSIONS: The present study described the single- and multiple-dose pharmacokinetic profiles of dienogest in Korean women and showed linear pharmacokinetics of dienogest at steady state.

The relationship between antipsychotic D2 occupancy and change in frontal metabolism and working memory : A dual [(11)C]raclopride and [(18) F]FDG imaging study with aripiprazole.

RATIONALE: The effects of aripiprazole on cognitive function are obscure, possibly due to the difficulty in disentangling the specific effects on cognitive function from effects secondary to the improvement of other schizophrenic symptoms. This prompts the necessity of using an intermediate biomarker relating the drug effect on the brain to change in cognitive function. OBJECTIVES: To explore the effect of aripiprazole on cognitive function, we measured changes in frontal metabolism as an intermediate biomarker and sought to determine its relationship with D2 receptor occupancy and changes in working memory. METHODS: Fifteen healthy male volunteers participated in the study. Serial positron emission tomography (PET) scans with [(11)C]raclopride and [(18) F]FDG were conducted 1 day before and 2 days after the administration of aripiprazole. The subjects performed the N-back task just after finishing the [(18) F]FDG scan. RESULTS: The mean (±SD) D2 receptor occupancies were 22.2 ± 16.0 % in the 2 mg group, 35.5 ± 3.6 % in the 5 mg group, 63.2 ± 9.9 % in the 10 mg group and 72.8 ± 2.1 % in the 30 mg group. The frontal metabolism was significantly decreased after the administration of aripiprazole (t = 2.705, df = 14, p = 0.017). Greater striatal D2 receptor occupancy was related to greater decrease in frontal metabolism (r = -0.659, p = 0.010), and greater reduction in frontal metabolism was associated with longer reaction times (r = -0.597, p = 0.019) under the greatest task load. CONCLUSIONS: Aripiprazole can affect cognitive function and alter frontal metabolic function. The changes in these functions are linked to greater D2 receptor occupancy. This suggests that it may be important to find the lowest effective dose of aripiprazole in order to prevent adverse cognitive effects.

Comparative pharmacokinetics/pharmacodynamics of clopidogrel besylate and clopidogrel bisulfate in healthy Korean subjects.

BACKGROUND: Clopidogrel selectively inhibits platelet aggregation. Clopidogrel bisulfate (Plavix(®)) was first developed for atherothrombosis prevention and is commonly prescribed for this indication. A new clopidogrel formulation, clopidogrel besylate (KOVIX(®)), has recently been developed. OBJECTIVE: This study was designed to compare the multiple-dose pharmacokinetics/pharmacodynamics and tolerability of clopidogrel besylate with those of clopidogrel bisulfate in 40 healthy male subjects. METHODS: This was an open-label, randomized-sequence, multiple-dose, two-period, two-treatment crossover study. The subjects were randomly assigned to a sequence group that received two treatments: clopidogrel besylate 75 mg followed by clopidogrel bisulfate 75 mg, or vice versa. The subjects received a 300-mg loading dose on day 1 followed by 75 mg daily for the next 4 days. Serial blood samples were collected to determine the concentrations of clopidogrel and its carboxylic acid metabolite, SR26334. Platelet aggregation and bleeding times were measured. Tolerability was evaluated throughout the study. RESULTS: The clopidogrel plasma concentration-time profiles of the formulations were similar. The measured pharmacokinetic parameters did not differ significantly between the clopidogrel besylate and clopidogrel bisulfate groups. The geometric mean ratios of the clopidogrel besylate group to the clopidogrel bisulfate group with respect to the maximum plasma concentration (C(max)) and the area under the concentration-time curve (AUC) from time zero to the time of last measurable concentration (AUC(last)) were 0.96 (90 % confidence interval [CI] 0.82, 1.12) and 0.95 (0.81, 1.11), respectively. Moreover, the pharmacokinetic parameters of SR26334 did not differ significantly between the two treatment groups. Furthermore, the areas under the platelet aggregation inhibition-time curves (AUIC) and the maximum inhibitory effects (I(max)) did not differ significantly between the two groups. The geometric mean ratios (clopidogrel besylate to clopidogrel bisulfate) were 1.01 (90 % CI 0.95, 1.08) for the I(max) and 0.98 (0.89, 1.07) for the AUIC. Both formulations were well tolerated and exhibited comparable safety profiles. CONCLUSION: This study demonstrated that the pharmacokinetic/pharmacodynamic profiles of clopidogrel besylate were not significantly different from those of clopidogrel bisulfate. Both formulations were well tolerated in healthy subjects.

Evaluation of the pharmacokinetics, food effect, pharmacodynamics, and tolerability of DA-1229, a dipeptidyl peptidase IV inhibitor, in healthy volunteers: first-in-human study.

BACKGROUND: Inhibitors of dipeptidyl peptidase (DPP) IV are a class of oral hypoglycemic agents that increase glucagon-like peptide-1 (GLP-1) levels by inhibiting its degradation. OBJECTIVE: This study evaluated the pharmacokinetics, pharmacodynamics, and tolerability of DA-1229, which is a newly developed DPP IV inhibitor. This study was planned as part of a product development project at the request of the Korean regulatory agency. METHODS: A 7 parallel arm dose-escalation study was conducted in healthy Korean male volunteers. A single oral dose of DA-1229 or placebo was given to 10 subjects (8 active + 2 placebo) in each dose group of 1.25, 2.5, 5, 10, 20, 40, or 60 mg. To assess the effects of food, the subjects in the 10-mg dose group received a single dose of DA-1229 10 mg after a high-fat meal, crossing over from the administration of DA-1229 under a fasting state, after a 7-day washout period. Serial blood samples were collected up to 120 hours after drug administration for pharmacokinetic analysis and the assessment of DPP IV activity, and blood samples were collected up to 2 hours after each meal until the next morning of drug administration to evaluate active GLP-1, glucose, and insulin levels. RESULTS: Seventy-two subjects, aged 20 to 39 years and weighing 52.1 to 79.8 kg, participated in this study. Twenty-one adverse events were reported; all were mild, and all subjects recovered spontaneously. DA-1229 reached a peak at 3.0 to 5.5 hours after a single oral dose and the concentrations declined, with a terminal t(½) from 32.5 to 39.8 hours. The %CV of C(max) and AUC(0-last) ranged from 11.1% to 54.6%. Dose-proportional pharmacokinetics were confirmed within the dose range by using a linear regression analysis, and the 95% CIs of the slope of the log-transformed C(max) and AUC(0-last) included 1.0. The pharmacokinetics of DA-1229 were unchanged by food. The degree of DPP IV inhibition was dependent on the dose, and groups receiving ≥10 mg exhibited >80% DPP IV inhibition for >24 hours. The %CV of the time of the last quantifiable concentration ranged from 4.6% to 15.2%. C(max) of active GLP-1 was achieved at 30 minutes after meal intake. The active GLP-1 levels were enhanced in groups receiving ≥5 mg. There were no changes in the glucose and insulin levels after DA-1229 administration. CONCLUSIONS: DA-1229 was well tolerated within the dose range of 1.25 to 60 mg. DA-1229 pharmacokinetics suggested dose proportionality, and dose-dependent DPP IV inhibition was exhibited. ClinicalTrials.gov identifier: NCT00961025.

Reduced valproic acid serum concentrations due to drug interactions with carbapenem antibiotics: overview of 6 cases.

BACKGROUND: The plasma concentrations of valproic acid (VPA) are known to decrease during the concomitant administration of carbapenem antibiotics, such as meropenem, imipenem, and ertapenem. This study summarizes 6 cases of drug-drug interactions between VPA and carbapenem antibiotics. METHODS: To investigate the onset and severity of the reductions in the concentration of VPA in patients with or without the coadministration of carbapenem antibiotics, the authors performed a retrospective evaluation of therapeutic drug monitoring (TDM) reports that described a decrease in the serum concentrations of VPA during the concomitant use of carbapenem antibiotics from January 2008 to December 2010 in the Seoul National University Hospital. The evaluated TDM reports included 6 cases. The decrement ratio of the VPA serum concentration was calculated from the TDM reports, and the change in the half-life of the VPA was also estimated. RESULTS: Six cases presented with changes in the VPA serum concentration before and after the administration of carbapenem antibiotics. (Three cases were treated with meropenem, 2 were treated with ertapenem, and 1 was treated with imipenem.) The VPA concentrations reduced by (mean ± SD) 88.7 ± 5.3% (3 cases of meropenem), 74.0 ± 9.8% (2 cases of ertapenem), and 73.3% (1 case of imipenem), respectively, and the half-life of VPA reduced by 80.1 ± 9.0%, 64.4 ± 24.2%, and 50.6%, respectively. CONCLUSION: The interaction between VPA and carbapenem antibiotics caused decreases in the VPA serum concentrations; the extent of this decrease was greater in the meropenem-treated patients than in the imipenem-treated or ertapenem-treated cases. Because the therapeutic effect of VPA depends on its serum concentration, it should be recognized that there may be a loss of seizure control in patients using VPA with carbapenem antibiotics.

Assessment of the effect of mirodenafil on the hemodynamics of healthy male Korean volunteers administered tamsulosin: a randomized, double-blind, placebo-controlled, 2-period crossover study.

BACKGROUND: Both mirodenafil, a phosphodiesterase type 5 inhibitor for the treatment of erectile dysfunction, and tamsulosin, a selective α(1A)-adrenergic receptor antagonist for the treatment of benign prostatic hyperplasia, have mild vasodilational effects. OBJECTIVE: The aim of this study was to investigate the effect of mirodenafil on the hemodynamics of healthy volunteers who were administered tamsulosin. METHODS: Healthy, Korean normotensive male volunteers were enrolled in a randomized, placebo-controlled, double-blind, 2-sequence, 2-period crossover study. Mirodenafil 100 mg or placebo was administered orally after pretreatment with tamsulosin 0.2 mg once daily for 7 days in each period, with a 1-week washout period. Blood pressure (BP) and pulse rate (PR) in supine and standing positions were measured repeatedly before and until 24 hours after the administration of mirodenafil or placebo. The mean differences from the baseline values of the maximum changes of BP and PR, which were measured at 4 and 24 hours, were analyzed by using a mixed-effects model. RESULTS: Eighteen subjects (mean [SD] age, 26.8 [3.9] years; weight, 65.5 [7.0] kg) were administered any trial medication, and 16 of them completed the study. For 4 hours/24 hours after mirodenafil administration, the mean maximal changes from baseline versus placebo in supine systolic BP, diastolic BP, and PR were -1.0 mm Hg (95% CI, -4.2 to 2.2) (P = 0.53)/-1.2 mm Hg (95% CI, -5.3 to 2.9) (P = 0.56), -2.1 mm Hg (95% CI, -4.6 to 0.4) (P = 0.10)/-1.1 mm Hg (95% CI, -3.9 to 1.6) (P = 0.39), and 7.2 beats/min (95% CI, 4.7 to 9.6) (P < 0.05)/4.8 beats/min (95% CI, 1.4 to 8.1) (P < 0.05), respectively. Those changes in a standing position were -4.0 mm Hg (95% CI, -8.9 to 0.9) (P = 0.10)/-4.3 mm Hg (95% CI, -10.0 to 1.5) (P = 0.13), -1.1 mm Hg (95% CI, -4.9 to 2.7) (P = 0.54)/-1.9 mm Hg (95% CI, -5.5 to 1.7) (P = 0.27), and 10.7 beats/min (95% CI, 4.4 to 16.9) (P < 0.05)/6.0 beats/min (95% CI, 0.7 to 11.3) (P < 0.05), respectively. A total of 33 adverse events (AEs) were reported in 9 of 18 subjects. The number of subjects with AEs (P = 0.13) and the number of AEs (P = 0.26) were not significantly different between the 2 groups. The most common AEs were vasodilational symptoms, such as nasal congestion, headache, and flushing. CONCLUSIONS: The coadministration of mirodenafil 100 mg did not induce a significant decrease in BP when associated with an increase in PR in these healthy male Korean volunteers administered tamsulosin 0.2 mg compared with placebo. (Clinical Trial Registry, http://cris.cdc.go.kr/cris/en/: KCT0000117).

Multiple-dose pharmacokinetics of fesoterodine sustained-release in healthy Korean volunteers.

OBJECTIVE: Fesoterodine is a pro-drug of the active metabolite 5-hydroxymethyl tolterodine (5-HMT), a muscarinic receptor antagonist. This study aimed to evaluate the safety profile and pharmacokinetic characteristics of multiple oral doses of sustained-release fesoterodine (fesoterodine SR) in healthy Korean males. METHODS: A randomized, double-blind, placebo-controlled, multiple-dose study with two oral doses (4 mg and 8 mg) was conducted in healthy Korean male participants. The study drug was administered once daily for 5 days. The plasma concentration of 5-HMT was measured up to 72 hours after the last drug administration. The CYP2D6 genotype was analyzed using polymerase chain reaction (PCR) methods to assess the effect of genetic polymorphisms on the pharmacokinetic parameters. RESULTS: 20 participants completed the study. The mean (SD) areas under the plasma concentration-time curves during the dosing interval (AUCτ) of the 4 mg and 8 mg dose groups were 26.1 (8.0) and 64.2 (30.5) µg·h/ml and the mean peak concentrations (Cmax) were 2.6 (0.7) and 6.0 (2.0) µg/ml, respectively, at steady-state. The mean AUCτ and Cmax of 5-HMT increased in approximately the same proportion as the dose increased. Fesoterodine SR was well tolerated without any serious adverse events or abnormal clinical laboratory findings. CONCLUSION: Systemic 5-HMT exposure showed dose-proportional characteristics in the 4 mg to 8 mg dose range in healthy Korean males. Thus, 4 mg or 8 mg doses of fesoterodine SR taken once-daily were tolerable in healthy Korean males.

The effect of fimasartan, an angiotensin receptor type 1 blocker, on the pharmacokinetics and pharmacodynamics of warfarin in healthy Korean male volunteers: a one-sequence, two-period crossover clinical trial.

BACKGROUND: Fimasartan is an angiotensin II receptor antagonist used to treat hypertension. OBJECTIVE: The aim of this study was to evaluate the effects of fimasartan on the pharmacodynamics and pharmacokinetics of warfarin in healthy volunteers to meet regulatory requirements for drug marketing and labeling in Korea. METHODS: An open-label, 1-sequence, 2-treatment, 2-period crossover study was conducted in healthy male volunteers. The subjects were administered a single-dose of warfarin 25 mg on day 1. After a 7-day washout period, once-daily fimasartan 240 mg was administered every morning from day 8 to day 16. On day 11, warfarin 25 mg was administered concomitantly with fimasartan. Serial blood samples were collected for 144 hours after each warfarin dose. The plasma concentrations of R- and S-warfarin were analyzed by using HPLC-MS/MS, and the pharmacokinetic parameters were estimated by using noncompartmental analysis. The maximal international normalized ratio (INR) and the AUC-INR curve were evaluated to assess warfarin pharmacodynamics. Tolerability was assessed via vital sign measurements, physical examinations, ECGs, clinical laboratory tests, and adverse events. RESULTS: A total of 15 healthy Korean men aged 20 to 39 years (mean [SD], 26.7 [5.1] years) and weighing 60.2 to 85.7 kg (mean, 71.4 [8.3] kg) participated in the study; 12 completed the study. The geometric mean ratios (GMRs [90% CIs]) of C(max) and AUC(0-last) for R-warfarin were 1.06 (0.97-1.16) and 1.07 (1.03-1.12), respectively. For S-warfarin, the GMRs (90% CIs) of C(max) and AUC(0-last) were 1.02 (0.94-1.11) and 0.99 (0.94-1.04). The INR values reached 1.93 (0.31) and 1.96 (0.37) at 36 hours and decreased to <1.2 at 144 hours after warfarin treatment alone and coadministered with fimasartan, respectively. The GMRs (90% CIs) of the maximal INR and AUC-INR curve were 1.01 (0.97-1.05) and 0.98 (0.96-1.01). One (7.7%) of the 13 subjects reported epistaxis during treatment with warfarin alone, and 2 (16.7%) of 12 subjects receiving the combination treatment experienced headache, skin erosion, and an increase in blood creatine phosphokinase. No subjects had an elevated INR >4 or reported any symptoms related to hypotension, including fainting or dizziness. CONCLUSION: Multiple doses of fimasartan did not seem to alter the pharmacodynamics or pharmacokinetics of warfarin in this small, select population of healthy male volunteers.