Sangmin Choe

Effectiveness, safety, and pharmacokinetic and pharmacodynamic characteristics of microemulsion propofol in patients undergoing elective surgery under total intravenous anaesthesia

BACKGROUND The aims of this study were to investigate the effectiveness, safety, pharmacokinetics, and pharmacodynamics of microemulsion propofol, Aquafol (Daewon Pharmaceutical Co., Ltd, Seoul, Republic of Korea). METHODS In total, 288 patients were randomized to receive 1% Aquafol or 1% Diprivan (AstraZeneca, London, UK) (n=144, respectively). A 30 mg test dose of propofol was administered i.v. over 2 s for assessing injection pain. Subsequently, a bolus of propofol 2 mg kg(-1) (-30 mg) was administered. Anaesthesia was maintained with a variable rate infusion of propofol and a target-controlled infusion of remifentanil. Mean infusion rates of both formulations and times to loss of consciousness (LOC) and recovery of consciousness (ROC) were recorded. Adverse events and pharmacokinetic and pharmacodynamic characteristics were evaluated. RESULTS Mean infusion rate of Aquafol was not statistically different from that of Diprivan (median: 6.2 vs 6.3 mg kg(-1) h(-1)). Times to LOC and ROC were slightly prolonged in Aquafol (median: 21 vs 18 s, 12.3 vs 10.8 min). Aquafol showed similar incidence of adverse events to Diprivan. Aquafol (vs Diprivan caused more severe (median VAS: 72.0 vs 11.5 mm) and frequent (81.9 vs 29.2%) injection pain. The dose-normalized AUC(last) of Aquafol and Diprivan was 0.71 (0.19) and 0.74 (0.20) min litre(-1). The V(1) of both formulations were proportional to lean body mass. Sex was a significant covariate for k(12) and Ce(50) of Aquafol, and for k(e0) of Diprivan. CONCLUSIONS Aquafol was as effective and safe as Diprivan, but caused more severe and frequent injection pain. Aquafol demonstrated similar pharmacokinetics to Diprivan.

Impact of CYP2D6, CYP3A5, CYP2C19, CYP2A6, SLCO1B1, ABCB1, and ABCG2 gene polymorphisms on the pharmacokinetics of simvastatin and simvastatin acid.

Objective The effects of various polymorphisms in cytochrome P450 (CYP) enzyme and transporter genes on the pharmacokinetics (PK) of simvastatin were evaluated in healthy Korean men. Methods Plasma concentration data for simvastatin and simvastatin acid were pooled from four phase I studies comprising 133 participants. The polymorphisms CYP2D6*4, CYP2D6*5, CYP2D6*14, CYP2D6*41, CYP3A5*3, CYP2C19*2, CYP2C19*3, CYP2A6*7, and CYP2A6*9; SLCO1B1 rs4149056, rs2306283, and rs4149015; ABCB1 rs1128503, rs2032582, and rs1045642; and ABCG2 rs2231142 were evaluated in each participant. Noncompartmental PK results were compared by genotype. Results CYP2D6*5 and CYP2D6*14 were found to be associated with a higher area under the curve (AUC) for simvastatin, whereas the AUC of simvastatin acid was significantly increased in patients with the SLCO1B1 rs4149056, ABCG2 rs2231142, and CYP2D6*41 allele variants. Patients with the CYP2D6*41 variant showed a higher peak serum concentration (Cmax) of both simvastatin and simvastatin acid. The SLCO1B1 rs4149056 and rs4149015 polymorphisms were associated with an increased AUC ratio (i.e. ratio of simvastatin acid to simvastatin), whereas the SLCO1B1 rs4149056 and CYP2D6*5 variants were related to a higher Cmax ratio. Conclusion The CYP2D6*5, CYP2D6*14, CYP2D6*41, CYP3A5*3, SLCO1B1 rs4149056 and rs4149015, and ABCG2 rs2231142 genetic polymorphisms are associated with the PK of both simvastatin and simvastatin acid. This could potentially be used as a basis for individualized simvastatin therapy by predicting the clinical outcomes of this treatment.

A Simple Dosing Scheme for Intravenous Busulfan Based on Retrospective Population Pharmacokinetic Analysis in Korean Patients

Busulfan is an antineoplastic agent with a narrow therapeutic window. A post-hoc population pharmacokinetic analysis of a prospective randomized trial for comparison of four-times daily versus once-daily intravenous busulfan was carried out to search for predictive factors of intravenous busulfan (iBu) pharmacokinetics (PK). In this study the population PK of iBu was characterized to provide suitable dosing recommendations. Patients were randomized to receive iBu, either as 0.8 mg/kg every 6 h or 3.2 mg/kg daily over 4 days prior to hematopoietic stem cell transplantation. In total, 295 busulfan concentrations were analyzed with NONMEM. Actual body weight and sex were significant covariates affecting the PK of iBu. Sixty patients were included in the study (all Korean; 23 women, 37 men; mean [SD] age, 36.5 [10.9] years; weight, 66.5 [11.3] kg). Population estimates for a typical patient weighing 65 kg were: clearance (CL) 7.6 l/h and volume of distribution (Vd) 32.2 l for men and 29.1 L for women. Inter-individual random variabilities of CL and Vd were 16% and 9%. Based on a CL estimate from the final PK model, a simple dosage scheme to achieve the target AUC0-inf (defined as median AUC0-inf with a once-daily dosage) of 26.18 mg/l·hr, was proposed: 24.79·ABW0.5 mg q24h, where ABW represents the actual body weight in kilograms. The dosing scheme reduced the unexplained interindividual variabilities of CL and Vd of iBu with ABW being a significant covariate affecting clearance of iBU. We propose a new simple dosing scheme for iBu based only on ABW.

Evaluation of Pharmacokinetic and Pharmacodynamic Profiles and Tolerability After Single (2.5, 5, or 10 mg) and Repeated (2.5, 5, or 10 mg BID for 4.5 days) Oral Administration of Ivabradine in Healthy Male Korean Volunteers

BACKGROUND Ivabradine, a selective inhibitor of the pacemaker current in the sinoatrial node, has shown pure heart rate (HR)-reducing effects with anti-ischemic efficacy as well as improvement in heart failure outcomes. OBJECTIVE The purpose of this study was to explore pharmacokinetic (PK) and pharmacodynamic (PD) characteristics and tolerability in healthy male Korean volunteers, as well as to compare them with PK/PD profiles of white subjects. METHODS This was a randomized, double-blind, placebo-controlled Phase I study conducted in healthy male subjects. For each of the 3 dosing groups, 9 subjects were randomized to receive ivabradine and 3 to receive placebo. Subjects received a single oral dose of ivabradine 2.5, 5, or 10 mg and after a 3-day washout period, repeat doses of 2.5, 5, or 10 mg BID for 4.5 days. Blood and urine samples were collected over 72 hours during each period, and levels of ivabradine and its metabolite S18982 were determined by using validated LC-MS/MS, followed by noncompartmental PK analysis. For PD properties and tolerability, 24-hour Holter recordings were obtained: at baseline, after a single dose, after repeated doses, and after the last dose. Serial resting 12-lead ECG assessments were also performed throughout the study. RESULTS Forty-eight subjects were enrolled, and 45 completed the study. After single doses of 2.5, 5, and 10 mg, respective mean Cmax levels of ivabradine were 9, 15, and 39 ng/mL, and mean AUC0-last values were 30, 52, and 121 ng h/mL. At steady state, mean Cmax,ss levels were 11, 19, and 42 ng/mL, reached at a median Tmax of 0.67 hour for all 3 doses. The mean AUC0-τ levels were 43, 58, and 139 ng h/mL, respectively. The PK findings were linear with dose and time. Decreases in mean HR on both the Holter recordings and ECGs were observed in all of the ivabradine groups compared with placebo. After the repeated doses, mean decreases in HR were greater than those for the single doses for the same period. Statistically significant differences were observed between the 5- and 10-mg ivabradine groups and placebo. A total of 3 adverse events were reported in 2 subjects receiving ivabradine; both fully recovered without sequelae. CONCLUSIONS Single and repeated administration of ivabradine were generally well tolerated in these healthy male Korean volunteers. Ivabradine induced significant reductions in HR, especially at doses of 5 and 10 mg. PK/PD characteristics were similar to those found in white subjects, suggesting that the dose concentration-response relationship of ivabradine is similar between Korean and white subjects.

The pharmacokinetics of letrozole: association with key body mass metrics

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.

Pharmacokinetic Comparison of 2 Formulations of Anastrozole (1 mg) in Healthy Korean Male Volunteers: A Randomized, Single-Dose, 2-Period, 2-Sequence, Crossover Study

BACKGROUND Anastrozole is an aromatase inhibitor used to treat advanced breast cancer in postmenopausal women. A generic 1-mg tablet of anastrozole was recently developed. OBJECTIVE The study was designed to provide data to submit to Korean regulatory authorities to allow marketing of the test formulation. We evaluated the comparative bioavailability and tolerability of the test and reference formulations in healthy male adult volunteers. METHODS This single-dose, randomized, double-blind, 2-way crossover trial was conducted in the Clinical Trial Center at the Asan Medical Center (Seoul, Korea). A total of 24 healthy male Korean volunteers were enrolled. Subjects were randomized to receive 1 mg of the test or reference formulation, and pharmacokinetic (PK) parameters were measured. After a 3-week washout period, the other formulation was administered, and PK parameters were measured again. C(max) and AUC(last) were determined from blood samples obtained at 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 168, and 216 hours after drug administration. The formulations were considered bioequivalent if the 90% CIs of the geometric mean ratios of test-to-reference formulations for AUC(last) and C(max) were within the bioequivalence limits of 0.8 to 1.25. Nonlinear mixed-effect modeling and Monte Carlo simulations for both formulations were also conducted, and the results were used to characterize and compare the PK properties. Safety profile and tolerability were assessed using measurements of vital signs, clinical chemistry tests, and interviews. RESULTS All enrolled subjects completed the study. A total of 8 adverse events (AEs) were reported (2 on test formulation, 6 on reference formulation) in 7 of 24 participants. These AEs were headache (n = 1), hordeolum (n = 1), and abnormal laboratory test values (n = 6). Both formulations were well tolerated, and there were no serious AEs. Both formulations were best described by a 2-compartment disposition model with lag phase. The 90% CIs of the geometric mean ratios of test formulation to reference formulation were 0.96 to 1.08 for C(max) and 0.93 to 1.0 for AUC(last). CONCLUSION The test and reference formulations had similar PK parameters and similar plasma concentration-time profiles. The test formulation of anastrozole met the Korean regulatory criteria (AUC and C(max)) for assuming bioequivalence. ClinicalTrials.gov identifier: NCT01105299.

Pharmacokinetic comparison of sustained- and immediate-release formulations of cilostazol after multiple oral doses in fed healthy male Korean volunteers

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 (AUCT), the measured peak plasma concentration at steady state (Cmax,ss), and the time to reach Cmax,ss (tmax,ss) were analyzed using a noncompartmental method. Results A total of 24 healthy male subjects completed the study. The mean (standard deviation [SD]) AUCT (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) Cmax,ss values were 2,741.4 (836.0) ng/mL and 2,051.0 (433.2) ng/mL, respectively. The median tmax,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 AUCT and 0.644 (0.590–0.703), 0.586 (0.536–0.642), and 0.636 (0.577–0.702) for dose-normalized Cmax,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 AUCT 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.

Assessment of the influence of severe renal impairment on the pharmacokinetics of mirodenafil in Korean male volunteers.

OBJECTIVE To evaluate and compare the pharmacokinetics and tolerability of a single oral dose of mirodenafil in volunteer patients with severe renal impairment and healthy volunteers. METHODS AND MATERIALS This open-label, single-dose, parallel group clinical study enrolled a total 12 volunteers (6 healthy volunteers and 6 volunteer patients with severe renal impairment). Each volunteer was orally administered 50 mg mirodenafil and serial blood samples were obtained after drug administration to determine the plasma concentration of mirodenafil using LC-MS/MS. The measured individual plasma concentrations were used to calculate the pharmacokinetic parameters using noncompartmental methods. Tolerability was also assessed using measurements of vital signs, clinical chemistry tests, and interviews. RESULTS All of the volunteers completed the study with no serious adverse events (AEs). A total of 4 AEs were reported, but all were of mild or moderate intensity and not considered to be related to the study drug. The geometric mean (95% CI) of the terminal half-life (t1/2β) and the apparent clearance (CL/F) values of mirodenafil were 2.2 (1.4 - 3.4) h and 127.2 (95.1 - 170.2) l/h in the volunteer patients, and 3.0 (2.1 - 4.4) h and 136.1 (74.4 - 249.2) l/h in the healthy volunteers, respectively. The geometric mean of the AUC0-t of the volunteer patients was 8% higher and the geometric mean for clearance was 7% lower compared with the healthy volunteers. However, the geometric mean of the Cmax of the volunteer patients was 38% higher than that of the healthy volunteers. CONCLUSIONS A single oral 50-mg dose of mirodenafil was well tolerated. Exposure (AUC0-t) to mirodenafil was similar in both healthy volunteers and volunteer patients with severe renal impairment and healthy volunteers.

Effects of Renal Impairment on the Pharmacokinetics and Safety of Udenafil

Udenafil is a phosphodiesterase‐5 inhibitor used to treat erectile dysfunction. Although udenafil is not predominantly eliminated by the kidney, renal impairment can alter its secretion/transport pathways. Drug pharmacokinetics and safety must therefore be assessed in subjects with a renal impairment. We investigated the effects of impaired renal function on the pharmacokinetics and safety of a single 100‐mg oral dose of udenafil in a single‐dose, open‐label, parallel‐group study of 31 subjects. Cockcroft‐Gault creatinine clearance was used to stratify these subjects into healthy controls (>80 mL·min−1) and individuals with mild (50 to ≤80 mL·min−1), moderate (30 to ≤50 mL·min−1), and severe (<30 mL·min−1) renal impairment. Pharmacokinetic measurements and safety assessments indicated that the geometric mean of the area under the concentration‐time curve to the last measurement in mildly, moderately, and severely renally impaired subjects was 1.30‐ (90% CI 1.05‐1.60), 1.62‐ (90% CI 1.28‐2.06), and 1.60‐ (90% CI 1.28‐2.01) fold higher, respectively, than the healthy controls. The geometric mean of the maximum observed concentration was 1.41‐ (90% CI 1.05‐1.88), 2.02‐ (90% CI 1.47‐2.79), and 1.65‐ (90% CI: 1.21‐2.24) fold higher, respectively. Significant correlations were observed among the creatinine clearance, oral clearance, and maximum concentration of udenafil (P < .01). All adverse events were mild, and no subject discontinued the study. Udenafil administration was well tolerated in all groups. In view of the clinical relevance of drug exposure, our findings indicate that a dose adjustment of udenafil is warranted in subjects with moderate or severe renal impairment.

Response surface modelling of the pharmacodynamic interaction between propofol and remifentanil in patients undergoing anaesthesia.

This study describes the pharmacodynamic interaction between propofol and remifentanil. Sixty patients who were scheduled for elective surgery under general anaesthesia (30 males/30 females) were enrolled. Patients were randomly allocated to receive one of 15 combinations of drug levels. Baseline electroencephalograms (EEGs) were recorded for 5 minutes prior to administering the drugs. Patients received a target‐controlled infusion at one of four predefined doses of propofol (high, 3 μg/mL; medium, 1.5 μg/mL; low, 0.5 μg/mL; or no drug) and of remifentanil (high, 6 or 8 ng/mL; medium, 4 ng/mL; low, 2 ng/mL; or no drug). The occurrence of muscle rigidity, apnoea, and loss of consciousness (LOC) was monitored, and EEGs were recorded during the drug administration phase. Electroencephalographic approximate entropy (ApEn) and temporal linear mode complexity (TLMC) parameters at baseline and under steady state conditions were calculated off‐line. Response surfaces were developed to map the interaction between propofol and remifentanil to the probability of occurrence for quantal responses (muscle rigidity, apnoea, LOC) and ApEn and TLMC measurements. Model parameters were estimated using non‐linear mixed effects modelling. The response surface revealed infra‐additive and synergistic effects for muscle rigidity and apnoea, respectively. The effects of the combined drugs on LOC and EEG parameters (eg, ApEn and TLMC) were additive. The C50 estimates of remifentanil (ng/mL) and propofol (μg/mL) were 9.11 and 130 000 for muscle rigidity, 8.99 and 6.26 for apnoea, 13.9 and 3.04 for LOC, 23.4 and 10.4 for ApEn, and 14.8 and 6.51 for TLMC, respectively. The probability of occurrence for muscle rigidity declined when propofol was combined with remifentanil.