Biomedical subjects

Dongwoo Kang

Publications and source records attributed to Dongwoo Kang.

7 recordsLinked to original sources

PubMed2007

Reversible jump Markov chain Monte Carlo for deconvolution.

To solve the problem of estimating an unknown input function to a linear time invariant system we propose an adaptive non-parametric method based on reversible jump Markov chain Monte Carlo (RJMCMC). We use piecewise polynomial functions (splines) to represent the input function. The RJMCMC algorithm allows the exploration of a large space of competing models, in our case the collection of splines corresponding to alternative positions of breakpoints, and it is based on the specification of transition probabilities between the models. RJMCMC determines: the number and the position of the breakpoints, and the coefficients determining the shape of the spline, as well as the corresponding posterior distribution of breakpoints, number of breakpoints, coefficients and arbitrary statistics of interest associated with the estimation problem. Simulation studies show that the RJMCMC method can obtain accurate reconstructions of complex input functions, and obtains better results compared with standard non-parametric deconvolution methods. Applications to real data are also reported.

Algorithms↗

PubMed2006

Population analyses of amlodipine in patients living in the community and patients living in nursing homes.

OBJECTIVE: Our objective was to determine the effects of age, sex, and morbidity on the apparent oral clearance (CL/F) of amlodipine. METHODS: Population pharmacokinetic analyses were performed on data from 211 patients receiving oral racemic amlodipine (dose of 7.2 +/- 3.6 mg/d [mean +/- SD]) on a long-term basis. Of the patients, 105 were men, with a mean age of 72 +/- 13 years and lean body weight (LBW) of 60.7 +/- 7.6 kg, and 106 were women, with a mean age of 79 +/- 11 years and LBW of 44.2 +/- 6.0 kg; 119 lived in the community, 20 in assisted living facilities, and 72 in nursing homes. Amlodipine was measured by liquid chromatography-tandem mass spectrometry. Population analyses were performed by use of NONMEM with sex, age, race, living site, alcohol intake, and concomitant medications considered as covariates. The significance of covariates was determined by likelihood ratio tests. RESULTS: Female sex and living in a nursing home were associated with a faster CL/F compared with men and community-dwelling patients, respectively. The mean CL/F was 7.83 +/- 0.50 mL.min(-1).kg(-1) (LBW) in women compared with 6.31 +/- 1.01 in men and 8.68 +/- 1.00 mL.min(-1).kg(-1) in nursing home residents compared with 6.32 +/- 1.17 in community-dwelling patients. Increasing age was associated with decreasing CL/F only in community-dwelling patients and residents of assisted living facilities. CONCLUSIONS: In middle-aged and very old (>80 years) patients, amlodipine CL/F was faster in women compared with men and was faster in nursing home residents compared with community-dwelling patients, with increasing age decreasing CL/F only in community-dwelling patients and residents of assisted-living facilities.

Aged↗

PubMed2006

Impact of oral contraceptives on sex hormone-binding globulin and androgen levels: a retrospective study in women with sexual dysfunction.

INTRODUCTION: Oral contraceptives (OCs) have been the preferred method of birth control because of their high rate of effectiveness. OC use, however, has been associated with women's sexual health complaints and androgen insufficiency. OC use is associated with a decrease of androgen ovarian synthesis and an increase in the production of sex hormone-binding globulin (SHBG). There have been limited studies assessing SHBG values after discontinuation of OC use. AIM: To retrospectively investigate SHBG levels before and after discontinuation of OC use. MAIN OUTCOME MEASURE: Sex hormone-binding globulin values were compared at baseline, while on the OC, and well beyond the 7-day half-life of SHBG at 49-120 (mean 80) days and >120 (mean 196) days after discontinuation of OCs. METHODS: A total of 124 premenopausal women with sexual health complaints for >6 months met inclusion/exclusion criteria. Three groups of women were defined: (i) "Continued-Users" (N = 62; mean age 32 years) had been on OCs for >6 months and continued taking them; (ii) "Discontinued-Users" (N = 39; mean age 33 years) had been on OCs for >6 months and discontinued them; and (iii) "Never-Users" (N = 23; mean age 36 years) had never taken OCs. RESULTS: Sex hormone-binding globulin values in the "Continued-Users" were four times higher than those in the "Never-User" group (mean 157 +/- 13 nmol/L vs. 41 +/- 4 nmol/L; P < 0.0001). Despite a decrease in SHBG values after discontinuation of OC use, SHBG levels in "Discontinued-Users" remained elevated in comparison with "Never-Users" (N = 26; P < 0.0001 for >120 days). CONCLUSION: In women with sexual dysfunction, SHBG changes in "Discontinued-Users" did not decrease to values consistent with "Never-Users." Long-term sexual, metabolic, and mental health consequences might result as a consequence of chronic SHBG elevation. Does prolonged exposure to the synthetic estrogens of OCs induce gene imprinting and increased gene expression of SHBG in the liver in some women? Prospective research is needed.

Adult↗

PubMed2006

Pharmacokinetics of dapoxetine, a new treatment for premature ejaculation: Impact of age and effects of a high-fat meal.

Dapoxetine is being developed as a treatment for premature ejaculation and has demonstrated rapid absorption and elimination in previous pharmacokinetic studies. Two open-label studies were conducted in healthy men: a parallel-group pharmacokinetic and safety study in young and elderly men and a randomized crossover food-effect study. Maximal plasma dapoxetine concentrations (C(max)) were similar in young and elderly men (338 and 310 ng/mL, respectively), as were the corresponding area under the plasma concentration versus time curve (AUC) values (2040 and 2280 ng x h/mL, respectively). When coadministered with food, C(max) was reduced by 11% (398 vs 443 ng/mL in the fed and fasted states, respectively), and the peak was delayed by approximately 30 minutes, indicating that food slowed the rate of absorption; however, systemic exposure to dapoxetine (ie, AUC) was not affected by food consumption. Thus, age or consumption of a high-fat meal has only a modest impact on dapoxetine pharmacokinetics in healthy men.

Adolescent↗

PubMed2005

Sample size computations for PK/PD population models.

We describe an accurate, yet simple and fast sample size computation method for hypothesis testing in population PK/PD studies. We use a first order approximation to the nonlinear mixed effects model and chi-square distributed Wald statistic to compute the minimum sample size to achieve given degree of power in rejecting a null hypothesis in population PK/PD studies. The method is an extension of Rochon's sample size computation method for repeated measurement experiments. We compute sample sizes for PK and PK/PD models with different conditions, and use Monte Carlo simulation to show that the computed sample size retrieves the required power. We also show the effect of different sampling strategies, such as minimal, i.e., as many observations per individual as parameters in the model, and intensive on sample size. The proposed sample size computation method can produce estimates of minimum sample size to achieve the desired power in hypothesis testing in a greatly reduced time than currently available simulation-based methods. The method is rapid and efficient for sample size computation in population PK/PD study using nonlinear mixed effect models. The method is general and can accommodate any type of hierarchical models. Simulation results suggest that intensive sampling allows the reduction of the number of patients enrolled in a clinical study.

Algorithms↗

PubMed2004

A sample size computation method for non-linear mixed effects models with applications to pharmacokinetics models.

We propose a simple method to compute sample size for an arbitrary test hypothesis in population pharmacokinetics (PK) studies analysed with non-linear mixed effects models. Sample size procedures exist for linear mixed effects model, and have been recently extended by Rochon using the generalized estimating equation of Liang and Zeger. Thus, full model based inference in sample size computation has been possible. The method we propose extends the approach using a first-order linearization of the non-linear mixed effects model and use of the Wald chi(2) test statistic. The proposed method is general. It allows an arbitrary non-linear model as well as arbitrary distribution of random effects characterizing both inter- and intra-individual variability of the mixed effects model. To illustrate possible uses of the method we present tables of minimum sample sizes, in particular, with an illustration of the effect of sampling design on sample size. We demonstrate how (D-)optimal or frequent sampling requires fewer subjects in comparison to a sparse sampling design. We also present results from Monte Carlo simulations showing that the computed sample size can produce the desired power. The proposed method greatly reduces computing times compared with simulation-based methods of estimating sample sizes for population PK studies.

Black People↗

PubMed2003

Population analyses of sustained-release verapamil in patients: effects of sex, race, and smoking.

OBJECTIVE: Our objective was to determine the effects of age, sex, and sustained-release formulation on apparent oral clearance of sustained-release racemic verapamil in patient populations. METHODS: Population pharmacokinetic analyses were performed on data from 186 patients with hypertension, coronary artery disease, or supraventricular arrhythmias who were receiving long-term sustained-release oral racemic verapamil (Covera SR in 105 patients, Calan SR in 67 patients, and other formulations in 14 patients; mean +/- SD dose, 280 +/- 139 mg) for clinical care or as a part of phase III efficacy studies. Of those 186 patients, 135 were men (age, 63 +/- 12 years; ideal body weight, 70.7 +/- 6.6 kg) and 51 were women (age, 60 +/- 17 years; ideal body weight, 53.7 +/- 7.2 kg). Verapamil was measured by HPLC, and population analyses were performed by use of NONMEM software. Sex, age, and formulation were the covariates considered in the population model building. Subgroup analyses of race, smoking, and alcohol consumption were also performed. Significance of covariates was determined by likelihood ratio tests. RESULTS: Sex significantly affected steady-state clearance of oral sustained-release racemic verapamil. Apparent oral clearance of sustained-release verapamil was 23.8 +/- 2.3 mL/min per kilogram in women compared with 18.6 +/- 3.4 mL/min per kilogram in men. Clearance estimates were faster in black subjects compared with white subjects, as well as in smokers compared with nonsmokers. Effects of age, formulation, and alcohol consumption were not detected. CONCLUSIONS: In middle-aged and older patients, apparent oral clearance of sustained-release racemic verapamil was affected by sex (faster in women compared with men), race (faster in black subjects compared with white subjects), and smoking (faster in smokers compared with nonsmokers) but not by age, alcohol, or formulation.

Administration, Oral↗