[Show abstract][Hide abstract] ABSTRACT: Background:
This report focuses on the adaptive phase I trial design aimed to find the clinically applicable dose for decitabine maintenance treatment after allogeneic hematopoietic stem cell transplantation in patients with higher-risk myelodysplastic syndrome and secondary acute myeloid leukemia.
The first cohort (three patients) was given the same initial daily dose of decitabine (5 mg/m(2)/day, five consecutive days with 4-week intervals). In all cohorts, the doses for Cycles 2 to 4 were individualized using pharmacokinetic-pharmacodynamic modeling and simulations. The goal of dose individualization was to determine the maximum dose for each patient at which the occurrence of grade 4 (CTC-AE) toxicities for both platelet and neutrophil counts could be avoided. The initial doses for the following cohorts were also estimated with the data from the previous cohorts in the same manner.
In all but one patient (14 out of 15), neutrophil count was the dose-limiting factor throughout the cycles. In cycles where doses were individualized, the median neutrophil nadir observed was 1100/mm(3) (grade 2) and grade 4 toxicity occurred in 5.1 % of all cycles (while it occurred in 36.8 % where doses were not individualized). The initial doses estimated for cohorts 2 to 5 were 4, 5, 5.5, and 5 mg/m(2)/day, respectively. The median maintenance dose was 7 mg/m(2)/day.
We determined the acceptable starting dose and individualized the maintenance dose for each patient, while minimizing the toxicity using the adaptive approach. Currently, 5 mg/m(2)/day is considered to be the most appropriate starting dose for the regimen studied.
Full-text · Article · Oct 2015 · Journal of Hematology & Oncology
[Show abstract][Hide abstract] ABSTRACT: No wholly successful weight-control drugs have been developed to date, despite the tremendous demand. We present an exposure-response model of sibutramine mesylate that can be applied during clinical development of other weight-control drugs. Additionally, we provide a model-based evaluation of sibutramine efficacy. Data from a double-blind, randomized, placebo-controlled, multicenter study were used (N=120). Subjects in the treatment arm were initially given 8.37 mg sibutramine base daily, and those who lost <2 kg after 4 weeks' treatment were escalated to 12.55 mg. The duration of treatment was 24 weeks. Drug concentration and body weight were measured predose and at 4 weeks, 8 weeks, and 24 weeks after treatment initiation. Exposure and response to sibutramine, including the placebo effect, were modeled using NONMEM 7.2. An asymptotic model approaching the final body weight was chosen to describe the time course of weight loss. Extent of weight loss was described successfully using a sigmoidal exposure-response relationship of the drug with a constant placebo effect in each individual. The placebo effect was influenced by subjects' sex and baseline body mass index. Maximal weight loss was predicted to occur around 1 year after treatment initiation. The difference in mean weight loss between the sibutramine (daily 12.55 mg) and placebo groups was predicted to be 4.5% in a simulation of 1 year of treatment, with considerable overlap of prediction intervals. Our exposure-response model, which included the placebo effect, is the first example of a quantitative model that can be used to predict the efficacy of weight-control drugs. Similar approaches can help decision-making during clinical development of novel weight-loss drugs.
Full-text · Article · Sep 2015 · Drug Design, Development and Therapy
[Show abstract][Hide abstract] ABSTRACT: Purpose:
This study aimed to determine the effect of PET scan timings on the reliability of occupancy parameter estimates and to identify the scan timing design that gives the most reliable occupancy parameter estimates.
We compared the performance of designs with various sets of sampling time points using the stochastic simulation and estimation method in Perl-speaks-NONMEM. Biases, relative standard errors, relative estimation errors, and root mean square errors were used to compare the performance of designs.
Unlike the results of a previous report, we found that rather complicated designs where each subject or group of subjects are allocated to different scan timings were not superior to the simple, conventional fixed-time designs regardless of whether effect compartment or receptor binding models were used.
We conclude that the conventional fixed-time designs that have been used so far may give robust PD parameter estimates for occupancy data obtained from human PET studies of CNS drugs.
No preview · Article · Sep 2015 · European Journal of Clinical Pharmacology
[Show abstract][Hide abstract] ABSTRACT: BR-TD-1001 was developed as a booster for the immunity maintenance of diphtheria and tetanus. The aim of this study was to evaluate the safety and immunogenicity of BR-TD-1001 (test vaccine) in comparison with placebo and an active comparator in healthy Korean adults. A randomized, double-blind, placebo-controlled, active comparator, phase I clinical trial was conducted. Fifty subjects were randomly assigned to one of three treatment groups in a ratio of 2:2:1, and were administered a single intramuscular dose of test vaccine, active comparator, or placebo, respectively. All subjects were monitored for four weeks after injection. The antibody titers of the patients two and four weeks after vaccination were compared with the baseline. The frequencies of all adverse events including adverse drug reactions in the test group were not statistically different from those of the other treatment groups (P = 0.4974, 0.3061). No serious adverse event occurred, and no subject was withdrawn from the study for safety. The seroprotection rates against both tetanus and diphtheria at four weeks after vaccination were over 0.95. For anti-tetanus antibody, the geometric mean titer in the test group was significantly higher than those of the other groups (P = 0.0364, 0.0033). The geometric mean titer of anti-diphtheria antibody in the test group was significantly higher than the value of the placebo (P = 0.0347) while it was not for the value of the active comparator (P = 0.8484). In conclusion, BR-TD-1001 was safe, well-tolerated, and showed sufficient immunogenicity as a booster for diphtheria and tetanus.
Full-text · Article · Jun 2015 · Human Vaccines & Immunotherapeutics
[Show abstract][Hide abstract] ABSTRACT: A single 400 mg dose of moxifloxacin has been the standard positive control for thorough QT (TQT) studies. However, it is not clearly known whether a 400 mg dose is also applicable to TQT studies in Asian subjects, including Koreans. Thus, we aimed to develop a pharmacokinetic (PK)-pharmacodynamic (PD) model for moxifloxacin, to evaluate the time course of its effect on QT intervals in Koreans. Data from three TQT studies of 33 healthy male Korean subjects who received 400 and 800 mg of moxifloxacin and placebo (water) were used. Twelve-lead electrocardiograms were taken for 2 consecutive days: 1 day to record diurnal changes and the next day to record moxifloxacin or placebo effects. Peripheral blood samples were also obtained for PK analysis. The PK-PD data obtained were analyzed using a nonlinear mixed-effects method (NONMEM ver. 7.2). A two-compartment linear model with first-order absorption provided the best description of moxifloxacin PK. Individualized QT interval correction, by heart rate, was performed by a power model, and the circadian variation of QT intervals was described by two mixed-effect cosine functions. The effect of moxifloxacin on QT interval prolongation was well explained by the nonlinear dose-response (Emax) model, and the effect by 800 mg was only slightly greater than that of 400 mg. Although Koreans appeared to be more sensitive to moxifloxacin-induced QT prolongation than were Caucasians, the PK-PD model developed suggests that a 400 mg dose of moxifloxacin is also applicable to QT studies in Korean subjects.
Full-text · Article · Feb 2015 · Drug Design, Development and Therapy
[Show abstract][Hide abstract] ABSTRACT: The maximum likelihood estimator is the point estimator of the top priority in statistical data analysis because of its optimum properties for large sample size. While the maximum likelihood estimator is widely used, it has been an abstruse subject for pharmacometricians without statitics bagkround because of high dimensional calculus and asymptotic theories. This tutorial provides a general and brief introduction to the maximum likelihood estimator and its related caluculus for non-statisticians.
[Show abstract][Hide abstract] ABSTRACT: This study aimed to evaluate the change in the pharmacokinetics (PK) of cyclosporine in the non-steady-state period in the first week after renal transplantation; the factors influencing this change, including genetic variability; and the time point concentration that correlated best with drug exposure. Data were obtained from 69 patients, and PK studies were conducted on postoperative days (PODs) 2, 3, and 7. Samples were taken pre-dose and at 1, 2, 3, 4, 6, 8, and 12 hours after drug administration. MDR1, CYP3A4, and CYP3A5 were genotyped. A population PK analysis and correlational analysis between the concentration at each time point and the area under the time-concentration curve were performed. A two-compartment model with first-order absorption was chosen. The rate and extent of drug absorption showed a significant increase on POD3, followed by a slight decrease on POD7. Until POD3, 8 hours post-dose was the single time point concentration that correlated best with drug exposure and 3 hours was the best time point on POD7. In both analyses, the MDR1 genotype showed potential as a factor influencing PK change. We conclude that oral administration of cyclosporine and dose adjustment based on a single concentration measurement might result in unexpected drug exposure during this early posttransplantation period.
Full-text · Article · Nov 2014 · Drug Design, Development and Therapy
[Show abstract][Hide abstract] ABSTRACT: Plasma ionized calcium (Ca(2+)) concentrations are tightly regulated in the body and maintained within a narrow range; thus it is challenging to quantify calcium absorption under normal physiologic conditions. This study aimed to develop a mechanistic model for the parathyroid hormone (PTH) response after calcium intake and indirectly compare the difference in oral calcium absorption from PTH responses. PTH and Ca(2+) concentrations were collected from 24 subjects from a clinical trial performed to evaluate the safety and calcium absorption of Geumjin Thermal Water in comparison with calcium carbonate tablets in healthy subjects. Indirect response models (NONMEM Ver. 7.2.0) were fitted to observed Ca(2+) and PTH data, respectively, in a manner that absorbed but unobserved Ca(2+) inhibits the secretion of PTH. Without notable changes in Ca(2+) levels, PTH responses were modeled and used as a marker for the extent of calcium absorption.
Full-text · Article · Jun 2014 · Korean Journal of Physiology and Pharmacology
[Show abstract][Hide abstract] ABSTRACT: Moxifloxacin 400 mg is a widely used positive control in thorough QT (TQT) studies, but its QT-prolonging effects in Korean subjects have not been studied. The present study was conducted to collect pilot data in Korean subjects after moxifloxacin administration to evaluate the adequacy of moxifloxacin as a positive control.
Thirty-eight, healthy, Korean, male subjects were recruited for pharmacokinetic (PK) blood sampling and electrocardiography (ECG) recordings at three different study sites. On day 1, a baseline 12-lead ECG was recorded, and on day 2, ECG recordings were conducted after placebo, or moxifloxacin 400- or 800-mg administration. Baseline-corrected, placebo-adjusted, corrected QT (ΔΔQTc) values were calculated. Blood samples were collected after moxifloxacin administration and PK parameters were assessed.
A total of 33 subjects completed the study. The largest time-matched ΔΔQTc occurred approximately 4 h after dosing, with ΔΔQTcI (QT interval corrected by individual QT-RR regression model) values of 11.66 ms (moxifloxacin 400 mg) and 20.96 ms (800 mg). The mean and 90 % confidence intervals of ΔΔQTcI did not include zero at any of the measurement time points. There was a positive correlation between plasma moxifloxacin concentration and ΔΔQTcI (r = 0.422). Dose-proportional PK profiles were observed.
Moxifloxacin 400 mg is an adequate positive control in Korean TQT studies. Our results indicate that moxifloxacin 400 mg can be used to evaluate the cardiac safety of a drug in Korean subjects.
[Show abstract][Hide abstract] ABSTRACT: 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. Naïve 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.
[Show abstract][Hide abstract] ABSTRACT: In this study, we developed a pharmacokinetic (PK)- pharmacodynamic (PD) model of a new sustained release formulation of interferon-alpha-2a (SR-IFN-alpha) using the blood concentration of IFN-alpha and neopterin in order to quantify the magnitude and saturation of neopterin production over time in healthy volunteers. The SR-IFN-alpha in this study is a solid microparticular formulation manufactured by spray drying of a feeding solution containing IFN-alpha, a biocompatible polymer (polyethylene glycol) and sodium hyaluronate.
The full PK and PD (neopterin concentration) datasets from 24 healthy subjects obtained after single doses of 9, 18, 27 and 36 MIU of subcutaneous SR-IFN-alpha were used to build the mixed-effect model using NONMEM (version 7.2) with the GFORTRAN compiler.
A one-compartment model with first-order elimination and a mixture of zero- and first-order absorption was chosen to describe the PK of SR-IFN-alpha. The time-concentration profile of neopterin, the PD marker, was described by a turnover model combined with a single transit compartment. The saturable pattern of the neopterin response blurring the dose--response relationship of SR-IFN-alpha was addressed by introducing the concept of the EC50 increasing over time.
The PK-PD model of SR-IFN-alpha developed in this study has presented a quantitative tool to assess the time-course of a saturable neopterin response in humans.
Full-text · Article · Oct 2013 · Journal of Translational Medicine
[Show abstract][Hide abstract] ABSTRACT: Background:
The aim of this study was to assess the efficacy and safety of combination regimen of capecitabine plus everolimus in patients with refractory gastric cancer who have failed to at least two cytotoxic regimens.
Patients received capecitabine 650 mg/m(2) twice daily (D1-14) and everolimus 5 mg twice daily (D1-21) every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint of the study was overall response (partial or complete response) and the secondary endpoints were progression-free survival (time between registration and disease progression or death) and overall survival. Pharmacokinetic analysis was also performed. Patients who have failed to at least two cytotoxic regimens were enrolled.
Between March 2010 and June 2012, 47 patients were enrolled. 33 patients (70.2%) had received more than three previous regimens prior to enrolment. Among 43 evaluable patients for treatment response, 5 patients achieved confirmed partial response and 18 patients showed stable disease, resulting in an overall response rate (ORR) of 10.6% (95% C.I.: 1.8-19.4%) and disease control rate of 48.9% (95% C.I.:34.6-63.2%). At a median follow-up of 106 weeks (range, 21-141 weeks), the median progression-free survival and overall survival were 11.0 weeks (95% C.I.: 5.7-16.3 weeks) and 21.0 weeks (95% C.I.: 14.3-27.7 weeks), respectively. Grade 3 nausea, diarrhea and stomatitis occurred in two, three and three patients, respectively. Elevated liver enzyme was observed in 21 patients and no patient had pulmonary fibrosis.
The combination of capecitabine 650 mg/m(2) twice daily and everolimus 5 mg twice daily was found to be effective in a small subset of GC patients who were heavily pre-treated.
No preview · Article · Sep 2013 · Investigational New Drugs
[Show abstract][Hide abstract] ABSTRACT: Background:
We performed a phase I study to determine the dose and safety of everolimus as a combination chemotherapy in peripheral T-cell lymphoma (PTCL).
Four dose levels (2.5 to 10 mg) of everolimus from days 1 to 14 with CHOP (750 mg/m(2) cyclophosphamide, 50 mg/m(2) doxorubicin, and 1.4 mg/m(2) (maximum 2 mg) vincristine on day 1, and 100 mg/day prednisone on days 1 to 5) every 21 days were planned.
Fifteen patients newly diagnosed with stage III/IV PTCL were enrolled. One of 6 patients at dose level 2 (5 mg everolimus) had grade 3 hepatotoxicity and 3 of 6 patients at level 3 (7.5 mg everolimus) had grade 4 hematologic toxicities (two grade 4 thrombocytopenia and one grade 4 neutropenia with fever lasting more than 3 days). The recommended dose of everolimus for combination was 5 mg. There were no differences in steady state trough concentrations of everolimus between cycles 1 and 2 for all three dose levels. All evaluable patients achieved response (8 complete and 6 partial).
Everolimus (5 mg) can be safely combined with CHOP leading to a feasible and effective regimen for PTCL. The subsequent phase II is now in progress.
No preview · Article · Aug 2013 · Investigational New Drugs
[Show abstract][Hide abstract] ABSTRACT: Colistin is increasingly used as a salvage therapy of nosocomial infections caused by multidrug-resistant gram-negative bacteria such as Pseudomonas aeruginosa and Acinetobacter baumannii. However, the available pharmacokinetic (PK) data of colistin are limited to guide dosing. The aim of this study was to develop a population PK model of colistin and to identify the optimal dosage regimens for burn patients.Fifty patients with burns ranging from 4% to 85% of total body surface area treated with colistimethate sodium (CMS) were studied. CMS which is hydrolyzed in vivo to an active metabolite was intravenously administered every 12 h. Blood samples were collected at 0, 1, 2, 4, 6, and 8 h after more than five infusions to measure the colistin concentration using a LC/MS/MS system. The population PK model was developed using nonlinear mixed effect modeling (NONMEM, ver. 6.2).A one-compartment linear PK model for colistin best described the data. The covariates included in the final model were creatinine clearance on the relative fraction of CMS converted into colistin and the presence of edema on the turnover rate constant of CMS converted into colistin. Steady-state 24 h the area under the concentration-time curve was simulated from 1,000 virtual patients receiving 150 mg colistin base activity every 12 h using the final model. Unlike previous reports in critically ill patients, the elimination half-life of colistin (6.6 h) was much shorter and continuous renal replacement therapy was not a significant covariate for any PK parameters.
Full-text · Article · Feb 2013 · Antimicrobial Agents and Chemotherapy
[Show abstract][Hide abstract] ABSTRACT: Levodropropizine is non-opioid agent whose peripheral antitussive action may result from its modulation of sensory neuropeptide levels. Currently, levodropropizine 60 mg is taken three-times daily. A controlled release formulation of levodropropizine (levodropropizine CR) 90 mg was developed, which can be taken twice daily. The aim of this study was to evaluate the safety and pharmacokinetic characteristics after multiple oral administrations of levodropropizine CR 90 mg tablets in healthy male volunteers.
Full-text · Article · Jan 2013 · Journal of Korean Society for Clinical Pharmacology and Therapeutics
[Show abstract][Hide abstract] ABSTRACT: Background: The objective of this study was to compare the pharmacokinetics and safety between newly developed sildenafil (Please Orally Soluble Film) and sildenafil citrate (VIAGRA®) after single oral administration in healthy Korean male subjects. Methods:A randomized, open-label, single dose, 2-way crossover study was conducted in 50 healthy male subjects. Each sequence group consisted of 25 subjects, received a single oral 50 mg dose of Please Orally Soluble Film (test formulation) or VIAGRA® (reference formulation) by study period. Blood samples were obtained during a 24-hour period after dosing. Sildenafil and its metabolite concentrations were determined using validated LC-MS/MS. A non-compartmental pharmacokinetic analysis was performed. Safety was assessed through monitoring of adverse events, vital sign check-up, physical examination, laboratory tests and electrocardiography. Results: All enrolled participants completed the study. The point estimates and 90 % confidence intervals of log transformed Cmax and AUClast of the test formulation in comparison to those of reference formulation were 0.9294(0.8353 - 1.0341) and 0.9415 (0.8869 - 0.9994) respectively. The analysis of variance showed no significant influences of formulation, sequence and period on the pharmacokinetic parameters. The frequencies of adverse events were not statistically different between the formulations. No serious adverse event was observed or reported. Conclusion:Please Orally Soluble Film could be considered bioequivalent to VIAGRA® and had similar safety properties in healthy Korean male subjects.
Full-text · Article · Jan 2013 · Journal of Korean Society for Clinical Pharmacology and Therapeutics