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Cilostazol is a selective inhibitor of phosphodiesterase III (PDE III), which is prescribed for patients with peripheral arterial disease, especially intermittent claudication. The purpose of the study was to investigate the pharmacokinetic (PK) of cilostazol and its metabolites on the immediate (IR) formulation of cilostazol in healthy Korean male volunteers by population PK modeling analysis implemented using NONMEM software. A 2 × 2 crossover study comparing multiple oral doses of IR and SR formulations of cilostazol were conducted. Serial plasma concentrations of cilostazol and its active metabolites were used in this analysis. The PK was best depicted by one-compartment model, with absorption kinetics of cilostazol having mixed first- and zero-order kinetics with a time delay at the beginning of absorption. The introduction of interoccasion variabilities into zero-order (D1), first-order (Ka), and relative bioavailability (F1) significantly improved the model fit, and total body water (TBW) was identified as a significant covariate positively affecting the clearance of cilostazol. The model validation suggested that the model constructed in this study predicted the plasma concentration of cilostazol and its two active metabolites reasonably well. The PK model we developed explored the PK characteristics of cilostazol in Korean male subjects, and may be useful for identifying optimal individual dosing regimens of cilostazol. [ABSTRACT FROM AUTHOR]

Penile glans ischemia or necrosis developing after internal pudendal arterial embolization is very rare; no relevantreport has yet appeared. A 53-year-old male who visited our emergency room because of massive urethral bleedingwas diagnosed with an internal pudendal artery-urethral fistula; he underwent selective embolization of the internalpudendal artery. However, unexpected penile glans ischemic necrosis developed after embolization. We successfullytreated the patients with intravenous infusion of alprostadil, oral pentoxifylline and tadalafil.

The purpose of this simulation study is to explore the limitation of the population PK/PD analysis using data from a clinical study and to help to construct an appropriate PK/PD design that enable precise and unbiased estimation of both fixed and random PD parameters in PK/PD analysis under different doses and Hill coefficients. Seven escalating doses of virtual drugs with equal potency and efficacy but with five different Hill coefficients were used in simulations of single and multiple dose scenarios with dense sampling design. A total of 70 scenarios with 100 subjects were simulated and estimated 100 times applying 1-compartment PK model and sigmoid E max model. The bias and precision of the parameter estimates in each scenario were assessed using relative bias and relative root mean square error. For the single dose scenarios, most PD parameters of sigmoid E max model were accurately and precisely estimated when the C max was more than 85% of EC 50 , except for typical value and inter-individual variability of EC 50 which were poorly estimated at low Hill coefficients. For the multiple dose studies, the parameter estimation performance was not good. This simulation study demonstrated the effect of the relative range of sampled concentrations to EC 50 and sigmoidicity on the parameter estimation performance using dense sampling design., Competing Interests: Conflict of interest: The authors have nothing to declare., (Copyright © 2017 Translational and Clinical Pharmacology.)

Background: A new extended-release form of cilostazol has recently been developed. This study was conducted to compare the pharmacokinetic characteristics of sustained-release (SR) and immediate-release (IR) formulations of cilostazol after multiple oral doses in healthy male Korean volunteers., Methods: This was an open-label, randomized, multiple-dose, crossover study conducted in 30 healthy Korean subjects. In each treatment period, subjects received oral doses of 200 mg SR formulation every 24 hours or 100 mg IR formulation every 12 hours for 5 consecutive days in a fed state, with a washout period of 9 days. The plasma concentrations of cilostazol and its metabolites were determined using a validated liquid chromatography-tandem mass spectrometry method. The area under the plasma concentration-time curve within a dosing interval (AUC T ), the measured peak plasma concentration at steady state (C max,ss), and the time to reach C max,ss (t max,ss) were analyzed using a noncompartmental method., Results: A total of 24 healthy male subjects completed the study. The mean (standard deviation [SD]) AUC T (96-120 hours) values for SR and IR were 27,378.0 (10,301.6) ng·h/mL and 27,860.3 (7,152.3) ng·h/mL, respectively. The mean (SD) C max,ss values were 2,741.4 (836.0) ng/mL and 2,051.0 (433.2) ng/mL, respectively. The median t max,ss values were 8.0 hours and 4.0 hours, respectively. The geometric mean ratios (90% confidence intervals) of the SR to IR formulations were 0.937 (0.863-1.017), 0.960 (0.883-1.043), and 0.935 (0.859-1.017) for AUC T and 0.644 (0.590-0.703), 0.586 (0.536-0.642), and 0.636 (0.577-0.702) for dose-normalized C max,ss of cilostazol, OPC-13015 (3,4-dehydro-cilostazol), and OPC-13213 (4'-trans-hydroxyl-cilostazol), respectively. All formulations were well tolerated., Conclusion: At steady state, the AUC T of cilostazol SR 200 mg is comparable to that of cilostazol IR 100 mg twice a day in healthy male Korean subjects. Both formulations are well tolerated.

Purpose: To characterize the pharmacokinetics (PK) of letrozole by noncompartmental and mixed effect modeling analysis with the exploration of effect of body compositions on the PK., Methods: The PK data of 52 normal healthy male subjects with intensive PK sampling from two separate studies were included in this analysis. Subjects were given a single oral administration of 2.5 mg letrozole (Femara®), an antiestrogenic aromatase inhibitor used to treat breast cancer. Letrozole concentrations were measured using validated high-performance liquid chromatography with tandem mass spectrometry. PK analysis was performed using NONMEM® 7.2 with first-order conditional estimation with interaction method. The association of body composition (body mass index, soft lean mass, fat free mass, body fat mass), CYP2A6 genotype (*1/*1, *1/*4), and CYP3A5 genotype (*1/*1, *1/*3, *3/*3) with the PK of letrozole were tested., Results: A two-compartment model with mixed first and zero order absorption and first order elimination best described the letrozole concentration-time profile. Body weight and body fat mass were significant covariates for central volume of distribution and peripheral volume of distribution (Vp), respectively. In another model built using more readily available body composition measures, body mass index was also a significant covariate of Vp. However, no significant association was shown between CYP2A6 and CYP3A5 genetic polymorphism and the PK of letrozole in this study., Conclusion: Our results indicate that body weight, body fat mass, body mass index are associated with the volume of distribution of letrozole. This study provides an initial step toward the development of individualized letrozole therapy based on body composition.