Seok-Joon Jin

The Population Pharmacokinetics of Fentanyl in Patients Undergoing Living-Donor Liver Transplantation

Fentanyl, an opioid analgesic with a high hepatic extraction ratio, is frequently used to supplement general anesthesia during liver transplantation and is also continuously infused to provide postoperative analgesia. However, because fentanyl is metabolized mainly in the liver, the pharmacokinetics of fentanyl may vary widely during the different phases of the surgery, potentially leading to adverse events. Using nonlinear mixed‐effects modeling, we characterized the pharmacokinetics of fentanyl in 15 patients (American Society of Anesthesiologists Physical Status Classification 2 or 3) undergoing living‐donor liver transplantation (LDLT). Fentanyl was continuously infused at the rate of 200‐400u2003µg/h throughout the operation. The time course of the fentanyl plasma concentration levels was best described in terms of a two‐compartment model. Estimates were made of the pharmacokinetic parameters during the preanhepatic, anhepatic, and neohepatic phases: central volume of distribution (V1) (l): 59.0 + hourly volume infused by rapid infusion system (RIS) × 42.5, 113.0, and 189.0, respectively, × (body weight/69)1.3; peripheral volume of distribution (V2) (l): 94.3, 412.0, and 427.0, respectively; intercompartmental clearance (Q) (l/h): 96.4 × (cardiac output (CO)/6.7)2.5, 22.6, and 28.2, respectively; metabolic clearance (Cl) (l/h): 21.7 during the preanhepatic and neohepatic phases, and 0 during the anhepatic phase. The preanhepatic central volume of distribution was found to be markedly influenced by the massive infusion of fluids and blood products. The more hyperdynamic the circulation was during the preanhepatic phase, the higher the distributional clearance.

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.

Pharmacokinetic Interaction Between Pitavastatin and Valsartan: A Randomized, Open-Labeled Crossover Study in Healthy Male Korean Volunteers

BACKGROUNDnPitavastatin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, and valsartan, an angiotensin receptor blocker, are used concurrently in some patients who are both hyperlipidemic and hypertensive. However, to date, no published studies have explored whether there is an interaction between pitavastatin and valsartan.nnnOBJECTIVEnThe aim of this study was to investigate the potential pharmacokinetic interaction between pitavastatin and valsartan in healthy male volunteers in Korea.nnnMETHODSnA randomized, open-label crossover study was conducted in healthy male Korean volunteers. In varying sequences, each subject received pitavastatin 2 × 2 mg, valsartan 2 × 160 mg, and both treatments, once daily for 7 consecutive days, with a 7-day washout period between each treatment period. Plasma samples were obtained at steady state for the pharmacokinetic evaluation of pitavastatin and valsartan. Pharmacodynamic assessment included lipid profiles and vital sign measurements (systolic and diastolic blood pressure [SBP and DBP, respectively] and pulse rate [PR]). A safety profile assessment, which included vital sign measurements, ECG, and clinical laboratory testing, was performed in each subject.nnnRESULTSnA total of 24 subjects were enrolled (mean age, 30.5 years [range, 23.0-45.0 years]; mean body weight, 71.2 kg [range, 56.1-86.0 kg]; and mean body mass index, 23.2 kg/m(2) [range, 19.2-25.8 kg/m(2)]). The 95% CIs of the geometric mean ratios of AUC(τ) and C(max,ss) of pitavastatin were 0.97 to 1.11 and 0.73 to 1.09, respectively. The 95% CIs of the geometric mean ratios of AUC(τ) and C(max,ss) of valsartan were 0.90 to 1.27 and 0.81 to 1.29. Pitavastatin administered as monotherapy and in combination with valsartan was associated with significantly lowered total cholesterol and LDL-C compared with valsartan monotherapy (both, P < 0.05). Differences in lipid-lowering effects were not statistically significant between pitavastatin monotherapy and pitavastatin combined with valsartan. Valsartan monotherapy and valsartan combined with pitavastatin were associated with significantly lower SBP and DBP compared with baseline (both, P < 0.05), although no significant changes in PR were observed. No significant differences in BP or PR changes were noted between concurrent administration of valsartan monotherapy compared with pitavastatin + valsartan. There were no serious AEs reported, and none of the subjects discontinued the study due to AEs.nnnCONCLUSIONSnThe pharmacokinetic profiles of pitavastatin and valsartan administered as monotherapy were comparable to combination treatment in these healthy male Korean volunteers, suggesting that individual pharmacokinetic properties are not significantly affected by concurrent administration. The concurrent administration of pitavastatin and valsartan was generally well tolerated. The findings from the present study provide a basis for a larger study in hypertensive patients with hyperlipidemia.

The pharmacokinetics of letrozole: association with key body mass metrics

PURPOSEnTo characterize the pharmacokinetics (PK) of letrozole by noncompartmental and mixed effect modeling analysis with the exploration of effect of body compositions on the PK.nnnMETHODSnThe 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.nnnRESULTSnA 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.nnnCONCLUSIONnOur 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.

Impact of aminophylline on the pharmacodynamics of propofol in beagle dogs

This study aimed to characterize pharmacodynamic interaction between propofol and aminophylline. Nine beagle dogs were randomly allocated at the propofol rates of 0.75 (group A), 1.00 (group B), and 1.25 (group C) mg/kg/min. During period 1, propofol only was infused, while during period 2, aminophylline only, at the rate of 0.69 (group A), 1.37 (group B), and 2.62 (group C) mg/kg/h. During periods 3–5, the two drugs were co-administered. The aminophylline infusion rate was 0.69 (period 3), 1.37 (period 4), and 2.62 (period 5) mg/kg/h. The aminophylline was infused from 0 to 30xa0h, and the propofol was infused at 24xa0h for 20xa0min. Blood samples and electroencephalograms were obtained at preset intervals. In the linear regression between log-transformed doses of aminophylline and AUCinf, the slope was 0.6976 (95xa0% CI 0.5242–0.8710). Pharmacokinetics of aminophylline was best described by a one-compartment, with enzyme auto-induction, model. Pharmacokinetics and pharmacodynamics of propofol were best described by a three-compartment model and a sigmoid Emax model, respectively. Pharmacodynamic parameter estimates of propofol were: ke0xa0=xa00.805/min, E0xa0=xa00.76, Emaxxa0=xa00.398, Ce50 naxa0=xa02.38xa0μg/mL (without aminophylline-exposure), Ce50 waxa0=xa04.49xa0μg/mL (with aminophylline-exposure), and γxa0=xa02.21. Propofol becomes less potent when exposed to aminophylline. Pharmacodynamic antagonistic interaction of aminophylline with propofol sedation, may occur, not in a dose-dependent manner, but in an all-or-none response.

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

OBJECTIVEnTo evaluate and compare the pharmacokinetics and tolerability of a single oral dose of mirodenafil in volunteer patients with severe renal impairment and healthy volunteers.nnnMETHODS AND MATERIALSnThis 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.nnnRESULTSnAll 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.nnnCONCLUSIONSnA 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.

Risk factors for intraoperative massive transfusion in pediatric liver transplantation: a multivariate analysis.

Background: Pediatric liver transplantation (LT) is strongly associated with increased intraoperative blood transfusion requirement and postoperative morbidity and mortality. In the present study, we aimed to assess the risk factors associated with massive transfusion in pediatric LT, and examined the effect of massive transfusion on the postoperative outcomes. Methods: We enrolled pediatric patients who underwent LT between December 1994 and June 2015. Massive transfusion was defined as the administration of red blood cells ≥100% of the total blood volume during LT. The cases of pediatric LT were assigned to the massive transfusion or no-massive transfusion (administration of red blood cells <100% of the total blood volume during LT) group. Univariate and multivariate logistic regression analyses were performed to evaluate the risk factors associated with massive transfusion in pediatric LT. Kaplan-Meier survival analysis, with the log rank test, was used to compare graft and patient survival within 6 months after pediatric LT between the 2 groups. Results: The total number of LT was 112 (45.0%) and 137 (55.0%) in the no-massive transfusion and massive transfusion groups, respectively. Multivariate logistic regression analysis indicated that high white blood cell (WBC) count, low platelet count, and cadaveric donors were significant predictive factors of massive transfusion during pediatric LT. The graft failure rate within 6 months in the massive transfusion group tended to be higher than that in the no-massive transfusion group (6.6% vs. 1.8%, P = 0.068). However, the patient mortality rate within 6 months did not differ significantly between the massive transfusion and no-massive transfusion groups (7.3% vs. 7.1%, P = 0.964). Conclusion: Massive transfusion during pediatric LT is significantly associated with a high WBC count, low platelet count, and cadaveric donor. This finding can provide a better understanding of perioperative blood transfusion management in pediatric LT recipients.

Comparison of the Efficacy and Safety of a Pharmacokinetic Model-based Dosing Scheme Versus a Conventional Fentanyl Dosing Regimen For Patient-controlled Analgesia Immediately Following Robot-assisted Laparoscopic Prostatectomy: A Randomized Clinical Trial.

AbstractConventional, intravenous, patient-controlled analgesia, which is only administered by demand bolus without basal continuous infusion, is closely associated with inappropriate analgesia. Pharmacokinetic model-based dosing schemes can quantitatively describe the time course of drug effects and achieve optimal drug therapy. We compared the efficacy and safety of a conventional dosing regimen for intravenous patient-controlled analgesia that was administered by demand bolus without basal continuous infusion (group A) versus a pharmacokinetic model-based dosing scheme performed by decreasing the dosage of basal continuous infusion according to the model-based simulation used to achieve a targeted concentration (group B) following robot-assisted laparoscopic prostatectomy.In total, 70 patients were analyzed: 34 patients in group A and 36 patients in group B. The postoperative opioid requirements, pain scores assessed by the visual analog scale, and adverse events (eg, nausea, vomiting, pruritis, respiratory depression, desaturation, sedation, confusion, and urinary retention) were compared on admission to the postanesthesia care unit and at 0.5, 1, 4, 24, and 48u200ah after surgery between the 2 groups. All patients were kept for close observation in the postanesthesia care unit for 1 h, and then transferred to the general ward.The fentanyl requirements in the postanesthesia care unit for groups A and B were 110.0u200a±u200a46.4u200a&mgr;g and 77.5u200a±u200a35.3u200a&mgr;g, respectively. The pain scores assessed by visual analog scale at 0.5, 1, 4, and 24u200ah after surgery in group B were significantly lower than in group A (all Pu200a<u200a0.05). There were no differences in the adverse events between the 2 groups.We found that the pharmacokinetic model-based dosing scheme resulted in lower opioid requirements, lower pain scores, and no significant adverse events in the postanesthesia care unit following robot-assisted laparoscopic prostatectomy in comparison with conventional dosing regimen.

A single-dose, crossover study comparing the pharmacokinetics and pharmacodynamics of 2 formulations of metformin in healthy volunteers.

OBJECTIVEnTo compare pharmacokinetics and pharmacodynamics of two formulations of metformin in healthy male volunteers under fasting conditions.nnnMETHODS AND MATERIALSnThis was a randomized, 3-treatment, 6-sequence, 3-period, crossover study in healthy Korean volunteers. Subjects received a placebo or a single oral dose of reference formulation (500-mg metformin hydrochloride) or a test formulation (571-mg metformin acetate). The pharmacodynamic profile was assessed according to the blood glucose level.nnnRESULTSnA total of 30 healthy male volunteers were included, although 2 of them withdrew consent before drug administration. For the test formulation, the mean (SD) pharmacokinetic parameters of Cmax and AUC(0-24) were 1,691 (476.7) μg/ ml and 11,081 (2,804.5) mg×h/ml, respectively. For the reference formulation, the mean (SD) pharmacokinetic parameters of C(max) and AUC(0-24) were 1,749 (494.4) mg/ml and 11,814 (3,344.2) mg×h/ml, respectively. The 90% CIs for the test:reference ratio were 86.6 - 103.5 for logarithm-transformed AUClast and 87.9 - 107.4 for logarithm-transformed C(max), respectively. In pharmacodynamic analysis, the average blood glucose levels were obtained in the first 4 hours and 5 - 8 hours after drug administration. The 90% CIs for the test:reference ratio of the average blood glucose level were 96.5 - 101.8 for the intervals up to 4 hours during continued fasting and 99.3 - 106.8 for 5 - 8 hours after drug administration, respectively.nnnCONCLUSIONnThe data suggests that the test and reference formulations meet the regulatory criteria for the pharmacokinetic equivalence in fasting healthy Korean male volunteers. The pharmacodynamic profile was similar between the test and reference formulations. Both metformin formulations appeared to be generally well-tolerated.

Comparison of postoperative pain between laparoscopic and robot-assisted partial nephrectomies for renal tumors: A propensity score matching analysis.

Abstract Robot-assisted partial nephrectomy (RAPN) has emerged as an alternative to laparoscopic partial nephrectomy (LPN) for removal of renal tumors. Several advantages of robotic surgery have been reported, but there is no comparative study on postoperative pain between the 2 techniques. Therefore, we compared the postoperative numerical rating scale (NRS) of pain intensity between patients who underwent LPN and those who underwent RAPN. We included 705 patients who underwent either LPN (nu200a=u200a200) or RAPN (nu200a=u200a505) for renal tumors between January 2000 and September 2016. After 1:1 propensity score matching, the final analysis included 142 patients each in the LPN and RAPN groups. The primary endpoint was postoperative NRS of pain intensity. The secondary endpoints were opioid requirement, opioid-related complications, and duration of hospital stay. Preoperative and intraoperative values of propensity score matched patients (nu200a=u200a284) were not significantly different between the LPN and RAPN groups. There was no significant difference in NRS of pain intensity between the 2 groups. Opioid requirement was different between the 2 groups on postoperative day (POD) 0 (12.4 vs 11.3u200amg of morphine-equivalent dose), but not from POD 1 to POD 4. The incidence of opioid-related complications and duration of hospital stay were not significantly different between the 2 groups. Postoperative pain was not significantly different between patients who underwent RAPN and those who underwent LPN. This result provides a potentially useful knowledge of postoperative pain characteristics in RAPN and LPN.