Population pharmacokinetic analysis of diurnal and seasonal variations of plasma concentrations of cilostazol in healthy volunteers.

BACKGROUND: The background of this study was (1) to examine factors influencing cilostazol pharmacokinetics by developing a population model incorporating diurnal variation and other covariate effects and (2) to assess the feasibility of applying the developed model to determine the optimal dosing times. METHODS: Data obtained from a cilostazol pharmacokinetic study consisting of 2 clinical trials (a single twice-a-day (BID) dosing trial in winter and a multiple BID dosing trial in summer) conducted in healthy Korean subjects were used for model building. A basic model was built, followed by a diurnal variation model, and then a final model was built incorporating covariates, including a seasonal difference. The optimal morning and evening dosing times were determined from simulations. RESULTS: Diurnal variation in cilostazol pharmacokinetics was explained by the morning absorption rate constant being faster than in the evening, yielding values of 0.278 versus 0.234/h in summer, when 24- and 12-hour circadian rhythms were included in the model. The seasonal variation was explained by a 26.9% and a 31.8% decrease in the absorption rate constant and clearance, respectively, in winter compared with summer. Based on twice-a-day (BID) dosing, dosing times of 9 AM and 5 PM in summer and 10 AM and 7 PM in winter were expected to produce the smallest peak-to-peak fluctuations in cilostazol concentration, possibly minimizing unwanted effects of the drug. CONCLUSIONS: This study demonstrated the intraday and interseasonal time-varying nature of cilostazol pharmacokinetics using a population modeling approach and developed a strategy for optimizing dosing times. It is suggested that these methods can be similarly applied to analyses and controls of other drugs that exhibit characteristics of time-varying pharmacokinetics.ope

Development of a Pharmacokinetic Interaction Model for Co-administration of Simvastatin and Amlodipine

A model for drug interaction between amlodipine and simvastatin was developed using concentration data obtained from a multiple-dose study consisting of single- and co-administration of amlodipine and simvastatin conducted in healthy Koreans. Amlodipine concentrations were assumed to influence the clearance of simvastatin and simvastatin acid, which as well as the oral bioavailability was allowed to vary depending on genetic polymorphisms of metabolic enzymes. Covariate effects on drug concentrations were also considered. The developed model yielded a 46% increase in simvastatin bioavailability and a 13% decrease in simvastatin clearance when amlodipine 10 mg was co-administered. When CYP3A4/5 polymorphisms were assessed by a mixture model, extensive metabolizers yielded a decrease in simvastatin bioavailability of 81% and a decrease in simvastatin clearance by 4.6 times as compared to poor metabolizers. Sixty percent of the usual dose was the optimal simvastatin dose that can minimize the interaction with amlodipine 10 mg. Age and weight had significant effects on amlodipine concentrations. In conclusion, this study has quantitatively described the pharmacokinetic interaction between simvastatin and amlodipine using a modeling approach. Given that the two drugs are often prescribed together, the developed model is expected to contribute to more efficient and safer drug treatment when they are co-administered.ope

The Safety and the Pharmacokinetics and Pharmacodynamics of a Pegylated Interferon Alpha-2a Formulation, Dong-A's DA-3021

Background: Interferons (IFNs) are proteins made and released by lymphocytes in response to the presence of pathogens and used in the treatment of hepatitis B or C virus. The purpose of this study is to investigate the safety, pharmacokinetics and pharmacodynamics of a pegylated interferon alpha-2a formulation. Methods: This study was a randomized, open-label, 2-period, crossover design. Each group had 17 subjects who took $180\;{\mu}g$ of PEGASYS^® as a reference formulation and DA-3021 as a test formulation with a washout period of 21 days. Blood samples were obtained over 336 hours after the dose in each treatment period. Blood concentrations of interferon were analyzed using the enzyme-linked immunosorbent assay (ELISA). The primary pharmacokinetic parameters were Cmax and $AUC_{last}$. The pharmacodynamics were assessed by 2',5'-OAS (oligoadenylate synthetase) using a radioimmunoassay (RIA). The primary pharmacodynamic parameters were $E_{max}$ and $AUE_{last}$. Results: Thirty four healthy male volunteers participated in the study and completed both treatment periods. The 90% confidence intervals for the geometric mean ratios of the pharmacodynamic parameters (test : reference drug) were 0.95-1.09 for $AUE_{last}$ and 0.92-1.05 for $E_{max}$, lying within the bioequivalence range of 0.8-1.25, while the pharmacokinetics parameters were not included within the equivalence range. Most common adverse events were flu-like symptoms, with no serious adverse event reported. Conclusion: The results assessed by the bioequivalence criterion indicated that the pharmacodynamics of DA-3021 was equivalent to that of PEGASYS®.ope

Moxifloxacin 투약에 따른 QT 간격 변화를 평가하기 위한 경시적 모델의 개발

Dept. of Medical Science/박사ICH Guidance E14 on the evaluation of QT/QTc interval prolongation for non-antiarrhythmic drugs was endorsed in 2005. Standard statistical analysis of QT measurements from these studies usually compares time-matched baseline corrected QTc of placebo and active treatments. In thorough-QT studies, moxifloxacin is often used as a positive control to assess the relative risk of a test drug. Recent work has examined the time course of moxifloxacin and placebo effects. Characterizing the moxifloxacin effect over time, the influence of any covariate on this effect is important to interpret future TQT studies. With this background, this work analyzed QT interval data observed in placebo and moxifloxacin treatments obtained from a meta-analysis of subject-level data from 12 QT studies drawn from different drug programs and comprising 749 subjects of diverse demographic characteristics.The purpose of this work was to develop a longitudinal model to describe the time course of QT interval in healthy volunteers given placebo and moxifloxacin treatments and to examine the source of variability affecting QT interval with a focus on the variability in demographic factors and inter-study differences.Electrocardiograph data from placebo and 400 mg moxifloxacin treatments were analyzed using NONMEM software. A longitudinal QT interval model incorporating the variability in demographic factors and the inter-study difference was developed within a mixed effects model framework according to the following steps: individual correction, baseline correction, drug effect, inter-study difference, covariate effect, and model evaluation. The data from 12 studies were modeled together using a meta-analysis approach.- Individual correction: The exponent on RR in the QT correction factor was estimated for each individual rather than assuming fixed values as used in the Bazett and Fridericia corrections.- Baseline correction: Following an appropriate individual correction of the QT interval for heart rate, a mixed effect model was fit to the data obtained from the placebo treatment to explore the circadian effect on the baseline QT interval using cosine functions with up to three periods (24, 12, 6 or 8 hours). Interindividual variability was included in acrophase and amplitude for each period.- Drug effect: The data obtained from the moxifloxacin treatment were then analyzed by fixing the baseline structural model to the one obtained from the placebo treatment in the previous step. The drug effect on QT interval was described as a direct function of time and QT measurements was modeled and tested using diverse equations.- Inter-study difference: The variability among different studies was modeled using a fixed study-effect method on the assumption that the model parameters of the individuals follow the same distributions across studies. The method assumes that there are different unrelated model parameter values between different studies, and the study effect is introduced as a covariate for the model parameter.- Covariate effect: The covariate effect is analyzed by a stepwise covariate model building process. Categorical covariates such as sex, race and smoking and continuous covariates such as age, height, weight, BMI, or average amount of alcohol drinking were tested.- Model evaluation: Visual Predictive Checks were used to examine the model fit to the observed data.The estimated QTc interval yielded a heart-rate correction slope alpha of 0.35 with 16% (CV) inter-subject variation. A two-oscillator model with 24- and 12-hour period best described the circadian variation of baseline QT measurements. For the effect of moxifloxacin on QT interval, a Bateman function was selected to represent the elongating aspect of QT interval for the early phase followed by shortening for the later part of the observation. The difference among the 12 studies was best modeled using separate baseline mesor parameters for each study, ranging between 378 and 410. In the covariate effect, the baseline QTc interval and the magnitude of the drug effect were found to be significantly higher in women than in men. The acrophase for the 24-hour period circadian rhythm was estimated to be lower in Asians than in other ethnic groups. Age was also found to be an important covariate, showing that baseline value increased with age. When the final model was evaluated using VPC, the model was found to adequately described the observed data.The present analysis was carried out as a meta-analysis using observed data across a number of QT trials. The developed longitudinal mixed effects model well described the time course of the QT interval when the source of variability in the QT interval was appropriately included. The model provided useful information on potential covariates influencing the QT interval change such as sex, age, and race. The final model may influence future trial design and will assist in contextualizing information from future TQT studies.restrictio

Pharmacokinetic Interaction Between Rosuvastatin and Metformin in Healthy Korean Male Volunteers: A Randomized, Open-label, 3-period, Crossover, Multiple-dose Study

PURPOSE: Rosuvastatin is indicated for hypercholesterolemia or dyslipidemia and metformin mainly for type 2 diabetes. These 2 drugs are frequently prescribed in combination due to the high comorbidity of the 2 diseases. However the nature of pharmacokinetic interaction between the 2 drugs has not been previously investigated. The purpose of our study was to investigate the pharmacokinetic interaction between rosuvastatin and metformin in healthy Korean male volunteers. METHODS: This was a randomized, open-label, 6-sequence, 3-period, crossover, multiple-dose study. Eligible subjects, aged 20 to 50 years and within 20% of the ideal body weight, received 1 of the following 3 treatments for each period once daily for 5 consecutive days with a 10-day washout period between the treatments: monoadministration of rosuvastatin 10 mg tablet, monoadministration of metformin 750 mg tablet, and coadministration of rosuvastatin 10 mg tablet with metformin 750 mg tablet. Blood samples were collected up to 72 hours after the last dose and pharmacokinetic parameters for rosuvastatin and metformin were compared between combination and monotherapy. Adverse events were investigated and evaluated based on subject interviews and physical examinations. FINDINGS: Among the 36 enrolled subjects, 31 completed the study. The coadministration of rosuvastatin with metformin produced a significant pharmacokinetic interaction in rosuvastatin Css,max, with the 90% CI for the geometric mean ratio (coadministration:monoadministration) being 110.27% to 136.39% (P = 0.0029), whereas no significant interaction was observed in rosuvastatin AUCtau, yielding the 90% CI of 104.41% to 118.95%. When metformin was coadministered with rosuvastatin, no significant pharmacokinetic interaction was observed for Css,max and AUCtau of metformin, yielding the 90% CIs of the geometric mean ratio for coadministration to monoadministration as 87.38% to 102.54% and 86.70% to 99.08%, respectively. Overall, 19 mild and 1 moderate adverse events occurred in 12 subjects, with no significant differences in the incidence among the 3 treatments. IMPLICATIONS: Although the Css,max of rosuvastatin was significantly influenced by coadministration with metformin, the degree of interaction seen was considered clinically insignificant, with no significant interaction observed in the other pharmacokinetic measures between the 2 drugs. These results imply that drug effects of rosuvastatin and metformin will also not be significantly influenced by coadministration of the 2 drugs. All treatments were well tolerated and no serious adverse events occurred. ClinicalTrials.gov identifier: NCT01526317.ope

Pharmacokinetic Comparison of an Orally Disintegrating Film Formulation With a Film-Coated Tablet Formulation of Sildenafil in Healthy Korean Subjects: A Randomized, Open-Label, Single-Dose, 2-Period Crossover Study

BACKGROUND: An orally disintegrating film (ODF) formulation of sildenafil was recently developed in Korea. This formulation is expected to enhance dosing convenience and increase patient compliance while yielding pharmacokinetics comparable to those of the conventional film-coated tablet (FCT) formulation. OBJECTIVE: The goal of this study was to compare the pharmacokinetic profiles of a newly developed ODF formulation with those of a FCT formulation of sildenafil in healthy Korean male volunteers. METHODS: This was a randomized, open-label, single-dose, 2-period crossover study conducted in 2 parts. Eligible subjects were between the ages of 20 and 50 years and within 20% of their ideal weight; subjects were equally divided into parts 1 and 2. Each subject received a single dose of the ODF and FCT formulations of sildenafil orally in a fasted state (part 1, 50 mg; part 2, 100 mg), with a 7-day washout period between the formulations. Blood samples were collected up to 24 hours postdosing. Pharmacokinetic parameters were determined for sildenafil and its active metabolite (N-desmethyl sildenafil). Adverse events (AEs) were evaluated based on subject interviews and physical examinations. RESULTS: Among the 120 enrolled subjects (60 subjects for each part), 110 completed the study (part 1, n = 53; part 2, n = 57). In both parts, all the primary pharmacokinetic parameters were included in the range for assumed bioequivalence in sildenafil, yielding 90% CI ratios of 91.07% to 120.67% for AUC0-last and 86.68% to 122.93% for Cmax in part 1, and 101.68% to 114.78% for AUC0-last and 93.76% to 109.76% for Cmax in part 2. In part 1, headache was the most frequently noted AE, occurring in 3 subjects with both the test and the reference formulations. All other AEs occurred in <3 subjects. In part 2, nasal congestion was the most frequently observed AE (7 with the test formulation and 1 with the reference formulation), followed by abnormal vision (4 with the test formulation and 4 with the reference formulation), headache (4 with the test formulation and 4 with the reference formulation), and rhinorrhea (5 with the test formulation). All other AEs occurred in <3 subjects. CONCLUSIONS: The study findings suggest that the pharmacokinetics of the ODF formulation of sildenafil do not differ significantly from those of the conventional FCT formulation (50 and 100 mg) in these healthy Korean male subjects. The 2 formulations were well tolerated in both parts of the study, with no serious AEs observed. ClinicalTrials.gov identifier: NCT01769638.ope

Pharmacokinetics of Rosuvastatin/Olmesartan Fixed-Dose Combination: A Single-Dose, Randomized, Open-Label, 2-Period Crossover Study in Healthy Korean Subjects

BACKGROUND: Rosuvastatin, a lipid-lowering agent, has been widely used with olmesartan, a long-acting angiotensin II receptor blocker, indicated for the treatment of dyslipidemia accompanied by hypertension. A fixed-dose combination (FDC) tablet of these 2 drugs was recently developed to enhance the dosing convenience and to increase patient compliance while yielding pharmacokinetic profiles comparable to coadministration of each drug as individual tablets. OBJECTIVE: The goal of present study was to compare the pharmacokinetic profiles of single-dose administration of an FDC tablet containing rosuvastatin/olmesartan 20/40 mg (test formulation) with coadministration of a rosuvastatin 20-mg tablet and a olmesartan 40-mg tablet (reference formulation) in healthy Korean male volunteers, for the purpose of determining bioequivalence. METHODS: This single-dose, randomized, open-label, 2-period crossover study enrolled subjects aged 20 to 50 years and within 20% of ideal body weight. Each subject received a single dose of the test and reference formulations orally in a fasted state, with a 7-day washout period between the administrations. Blood samples were collected up to 72 hours after dosing, and pharmacokinetic parameters were determined for rosuvastatin, its active metabolite (N-desmethyl rosuvastatin), and olmesartan. Bioequivalence was concluded if the 90% CIs of the geometric mean ratios for the primary pharmacokinetic parameters were within the predetermined range of 80% to 125%. Adverse events (AEs) were evaluated based on subject interviews and physical examinations. RESULTS: Among the 58 enrolled subjects, 54 completed the study. The 90% CIs of the geometric mean ratios of the primary pharmacokinetic parameters were as follows: rosuvastatin: AUC(last), 85.60% to 97.40% and C(max), 83.16% to 98.21%; N-desmethyl rosuvastatin: AUC(last), 82.08% to 93.45% and C(max), 79.23% to 93.41%; and olmesartan: AUC(last), 97.69% to 105.69% and C(max), 100.35% to 109.42%. The most frequently noted AE was headache, occurring in 3 and 6 patients with the test and reference formulations, respectively. All of the AEs were expected, and there was no significant difference in the prevalences of AEs between the 2 formulations. CONCLUSIONS: The pharmacokinetic properties of the newly developed FDC tablet of rosuvastatin/olmesartan 20/40 mg suggest that it is bioequivalent to co-administration of each drug as individual tablets in these healthy Korean male subjects. The two formulations were well tolerated, with no serious AEs observed. ClinicalTrials.gov identifier: NCT01823900.ope

Pharmacokinetic Interaction Between Rosuvastatin and Olmesartan: A Randomized, Open-label, 3-period, Multiple-dose Crossover Study in Healthy Korean Male Subjects

PURPOSE: Rosuvastatin has been widely used in combination with olmesartan for the treatment of dyslipidemia accompanied by hypertension. With no information currently available on the interaction between the 2 drugs, a pharmacokinetic study was conducted to investigate the influence of rosuvastatin on olmesartan and vice versa when the 2 drugs were coadministered. The purpose of this study was to investigate the pharmacokinetic profile of coadministration of the rosuvastatin 20-mg tablet and the olmesartan 40-mg tablet and the associated drug-drug interaction in healthy Korean male volunteers. METHODS: This was a randomized, open-label, 3-period, multiple-dose crossover study. Eligible subjects were aged 20 to 50 years and within 20% of their ideal body weight. After being randomly assigned to 6 groups of equal number, subjects received each of the following 3 formulations once a day for 7 consecutive days with an 8-day washout period between the formulations: rosuvastatin 20-mg tablet, olmesartan 40-mg tablet, and coadministration of the rosuvastatin 20-mg tablet and the olmesartan 40-mg tablet. Blood samples were collected up to 72 hours after dosing, and pharmacokinetic parameters were determined for rosuvastatin, its active metabolite (N-desmethyl rosuvastatin), and olmesartan. Adverse events were evaluated based on subject interviews and physical examinations. FINDINGS: Among the 36 enrolled subjects, 34 completed the study (mean [range] age, 28.6 [23-49] y; mean [range] weight, 66.4 [52.2-78.7] kg). The 90% CIs of the geometric mean ratios for the primary pharmacokinetic parameters for the coadministration of the 2 drugs to the mono-administration of each drug were 85.14% to 96.08% for AUCτ and 81.41% to 97.48% for Css,max for rosuvastatin, and 77.55% to 89.48% for AUCτ and 75.62% to 90.12% for Css,max for N-desmethyl rosuvastatin; those values were 95.61% to 102.57% for AUCτ and 91.73% to 102.98% for Css,max for olmesartan. Dizziness was the most frequently noted adverse drug reaction, occurring in 1 subject receiving mono-administration of rosuvastatin, 1 subject receiving mono-administration of olmesartan, and 4 subjects receiving coadministration of rosuvastatin and olmesartan. All the adverse events were expected, and there was no significant difference in the incidence between the 2 formulations. IMPLICATIONS: This study suggests that rosuvastatin and olmesartan did not significantly influence each other's pharmacokinetics when coadministered. Although the pharmacokinetics of N-desmethyl rosuvastatin were influenced by olmesartan, such interactions were considered clinically insignificant. All 3 formulations were well tolerated, and no serious adverse events or drug reactions were noted.ope

Pharmacokinetic Interaction between Rosuvastatin and Telmisartan in Healthy Korean Male Volunteers: A Randomized, Open-label, Two-period, Crossover, Multiple-dose Study

PURPOSE: Rosuvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, and telmisartan, an angiotensin receptor blocker, are commonly prescribed in combination for the treatment of dyslipidemia accompanied by hypertension. However, the nature of the pharmacokinetic interaction between the 2 drugs is not clearly understood. The goal of the present study was to investigate the pharmacokinetic drug-drug interaction between rosuvastatin and telmisartan in a healthy Korean population. METHODS: This was a randomized, 2-part, open-label, 2-period, crossover, multiple-dose study, with each part composed of different subjects between the ages of 20 and 55 years. In part 1, each subject received rosuvastatin 20 mg with and without telmisartan 80 mg once daily for 6 consecutive days. In part 2, each subject received telmisartan 80 mg with and without rosuvastatin 20 mg once daily for 6 consecutive days. In both parts, there was a 16-day washout period between mono- and coadministration. Blood samples were collected up to 72 hours after the last dose. Adverse events (AEs) were evaluated through interviews and physical examinations. FINDINGS: In part 1, the 90% CIs of the geometric mean ratios for the primary pharmacokinetic parameters for coadministration of the 2 drugs to monoadministration of each drug were 1.0736-1.2932 for AUCτ and 1.7442-2.3229 for Cmax,ss for rosuvastatin and 0.9942-1.1594 for AUCτ and 1.3593-1.7169 for Cmax,ss for N-desmethyl rosuvastatin, whereas in part 2, the CIs were 1.0834-1.2672 for AUCτ and 1.1534-1.5803 for Cmax,ss for telmisartan. The most frequently noted AE was cough in part 1, which occurred in 2 subjects receiving the combination therapy, and oropharyngeal pain in part 2, which occurred in 3 subjects receiving the combination therapy. All reported AEs were mild or moderate, and there was no significant difference in incidence between the treatments. IMPLICATIONS: These findings demonstrated that rosuvastatin and telmisartan mutually affected each other's pharmacokinetics, suggesting a possibility of drug-drug interaction. However, based on dose-response characteristics of the 2 drugs and previous results from other interaction studies, the degree of drug interaction observed in this study was not regarded as clinically significant. All treatments were well tolerated, with no serious AEs observed. ClinicalTrials.gov identifier: NCT01992601.ope

Pharmacokinetic Comparison of 2 Fixed-Dose Combination Tablets of Amlodipine and Valsartan in Healthy Male Korean Volunteers: A Randomized, Open-Label, 2-Period, Single-Dose, Crossover Study

BACKGROUND: Amlodipine and valsartan have different mechanisms of action, and it is known that the combination therapy with the 2 drugs increases treatment effects compared with the monotherapy with each drug. A fixed-dose combination (FDC) drug is a formulation including fixed amounts of active drug ingredients combined in a single dosage form that is expected to improve medication compliance. OBJECTIVE: The goal of this study was to compare the pharmacokinetic profiles of single administration of a newly developed FDC tablet containing amlodipine orotate 10 mg and valsartan 160 mg (test formulation) with the conventional FDC tablet of amlodipine besylate 10 mg and valsartan 160 mg (reference formulation) in healthy male Korean volunteers. METHODS: This was a randomized, open-label, single-dose, 2-way crossover study. Eligible subjects were between the ages of 20 and 50 years and within 20% of their ideal weight. Each subject received a single dose of the reference and the test formulations, with a 14-day washout period between formulations. Blood samples were collected up to 144 hours after the dose, and pharmacokinetic parameters were determined for amlodipine and valsartan. Adverse events were evaluated based on subject interviews and physical examinations. RESULTS: Forty-eight of the 50 enrolled subjects completed the study. For both amlodipine and valsartan, the primary pharmacokinetic parameters were included in the range for assumed bioequivalence, yielding 90% CI ratios of 0.9277 to 0.9903 for AUC(0-last) and 0.9357 to 1.0068 for C(max) in amlodipine, and 0.9784 to 1.1817 for AUC(0-last) and 0.9738 to 1.2145 for C(max) in valsartan. Dizziness was the most frequently noted adverse event, occurring in 4 subjects with the test formulation, followed by oropharyngeal pain occurring in 1 subject with the test formulation and 3 subjects with the reference formulation. All other adverse events occurred in <3 subjects. CONCLUSIONS: These findings suggest that the pharmacokinetics of the newly developed FDC tablet of amlodipine and valsartan did not differ significantly from the conventional FDC tablet in these healthy Korean male subjects. Both formulations were well tolerated, with no serious adverse events observed. ClinicalTrials.gov identifier: NCT01823913.ope