Modeling the effect of sevoflurane on corrected QT prolongation: a pharmacodynamic analysis

BACKGROUND: Sevoflurane may prolong the corrected QT (QTc) interval in healthy humans when administered for induction and maintenance of anesthesia. Little information is available about the dose-response relationship of sevoflurane on the QTc interval. We performed a pharmacodynamic analysis of the relationship between end-tidal sevoflurane concentration (CET) and the QTc. METHODS: Twenty-one patients aged 20-50 yr were enrolled in this study. Sevoflurane concentrations were progressively increased and then decreased over 15 min at the start of anesthesia; CET and automated QT interval were recorded continuously. Pharmacodynamic analysis using a sigmoid Emax model was performed to assess the concentration-effect relationship. RESULTS: Maximal CET was 4.30 ± 0.33%. Measured baseline and maximally prolonged QTc interval values were 351.7 ± 15.4 ms and 397.8 ± 17.5 ms, respectively. During sevoflurane anesthesia, increased concentrations were correlated with prolonged QTc interval. Hysteresis between the CET and QTc interval were observed and accounted for in the model. Ce50 and ke0 were 2.5 ± 1.4 and 2.0 ± 1.0, respectively. The median prediction error, median absolute prediction error, and the coefficient of determination (R) were 0.02%, 0.75%, and 0.95, respectively. The effect-site concentration (Ce50) and QTc interval data fit to a sigmoid Emax model. CONCLUSIONS: Among patients receiving sevoflurane for anesthesia, QTc interval changes correlate to anesthetic level. The Ce50 for significant QTc change is at clinically relevant levels of sevoflurane anesthesia.ope

The Safety and the Pharmacokinetics and Pharmacodynamics of a Pegylated Interferon Alpha-2a Formulation, Dong-A's DA-3021

Background: Interferons (IFNs) are proteins made and released by lymphocytes in response to the presence of pathogens and used in the treatment of hepatitis B or C virus. The purpose of this study is to investigate the safety, pharmacokinetics and pharmacodynamics of a pegylated interferon alpha-2a formulation. Methods: This study was a randomized, open-label, 2-period, crossover design. Each group had 17 subjects who took $180\;{\mu}g$ of PEGASYS^® as a reference formulation and DA-3021 as a test formulation with a washout period of 21 days. Blood samples were obtained over 336 hours after the dose in each treatment period. Blood concentrations of interferon were analyzed using the enzyme-linked immunosorbent assay (ELISA). The primary pharmacokinetic parameters were Cmax and $AUC_{last}$. The pharmacodynamics were assessed by 2',5'-OAS (oligoadenylate synthetase) using a radioimmunoassay (RIA). The primary pharmacodynamic parameters were $E_{max}$ and $AUE_{last}$. Results: Thirty four healthy male volunteers participated in the study and completed both treatment periods. The 90% confidence intervals for the geometric mean ratios of the pharmacodynamic parameters (test : reference drug) were 0.95-1.09 for $AUE_{last}$ and 0.92-1.05 for $E_{max}$, lying within the bioequivalence range of 0.8-1.25, while the pharmacokinetics parameters were not included within the equivalence range. Most common adverse events were flu-like symptoms, with no serious adverse event reported. Conclusion: The results assessed by the bioequivalence criterion indicated that the pharmacodynamics of DA-3021 was equivalent to that of PEGASYS®.ope

건강한 한국인에 있어서 심바스타틴의 약동력학적 특성과 그에 영향을 미치는 인자

Dept. of Medical Science/박사Simvastatin is a widely used 3-hydroxy-3-methyglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, and has beneficial effects on coronary diseases and on decreasing mortality rates in patients with hypercholesterolemia. Large inter-individual variability in the concentrations and pharmacokinetic parameters of simvastatin makes it difficult to achieve effective treatment and to avoid toxicity. This suggests that therapeutic drug monitoring of simvastatin is required, and individual optimal dosage regimen should be proposed and initiated as early as possible.This study was aimed to develop the population pharmacokinetic and pharmacodynamic models of simvastatin, as well as to assess the effect of demographic and clinical covariates which might influence on the pharmacokinetics and the pharmacodynamics of simvastatin in Korean population.This study was composed of four parts. Part I was a 40 mg single-dose study in twelve healthy subjects, and Part II and III were a 40 mg multiple-dose studies during 8 and 9 days in fourteen and forty one healthy subjects, respectively. These three Parts were performed to determine the pharmacokinetics of simvastatin. Blood samples were obtained before and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 13, 17, 24, 36, and 48 hours after the dose in Part I, or after the first (day 1) and the last dose (day 8) in Part II, or after the last dose (day 9) in Part III to determine the simvastatin and the simvastatin acid concentrations. The compartment model for simvastatin and simvastatin acid was used to describe their pharmacokinetics. Part IV was a 20(n=9), 40(n=9) or 60(n=7) mg multiple-dose study during 28 days in twenty five healthy subjects. In Part IV, blood samples of 8 mL each were prepared in heparinized tubes before and at 1, 3, 6, 10, 14, 21, 28 days after the first dosing to determine the LDL level and to describe the pharmacodynamic of simvastatin.Simvastatin pharmacokinetics was best described by two-compartment model with first-order absorption, and simvastatin acid pharmacokinetics was linked directly to the central compartment of simvastatin using the metabolic rate constant, k24. In the final model, the estimate of Ka was 3.15 1/h in Part III, and 0.60 1/h in Part I and II. The estimate of V2 was 1660 L in Part III, and 2760 L in Part I and II. The estimate of K24 was 0.29 1/h in Part III, and 0.46 1/h in Part I and II. Other parameter did not differ much between Parts. Intra-individual variabilities were 44% and 39% for simvastatin and simvastatin acid, respectively. None of the covariates tested (age, weight, sex, smoke, alcohol, and C1236T, C3456T, G2677T/A genotypes of MDR1) was found significant in the pharmacokinetics of simvastatin and simvastatin acid.Simvastatin pharmacodynamics was described by the inhibitory kin type of indirect response model. In the final model, the estimates of R0 for 20 mg, 40 mg and 60 mg groups were 78.2, 111 and 132 mg/dL, respectively. The percent change of predicted LDL did not differ significantly among the three dose group at 28 days (p=0.1695). No covariate was found significant for any pharmacodynamic parameter.These preliminary results show that simvastatin pharmacokinetics in Korean adults might be described without considering covariate influences and its steady-state pharmacodynamics can be predicted similarly for a range of therapeutic doses. Further studies will be needed to validate the proposed results.restrictio

Effect of CYP2B6 genotype on the pharmacokinetics of sibutramine and active metabolites in healthy subjects

Sibutramine is a pharmacologic intervention for the treatment of obesity. The effect of CYP2B6 genotypes on the pharmacokinetics of sibutramine and its active metabolites (desmethylsibutramine [M1] and didesmethylsibutramine [M2]) was evaluated in 57 healthy subjects. Each subject received a single oral dose of 10 or 15 mg sibutramine, and blood samples were collected up to 72 hours after dosing. The relationship between the genotypes and the pharmacokinetics of sibutramine, M1, and M2 was examined. A statistically significant difference in the elimination half-life (t(1/2)) of sibutramine M1 was found among the 3 genotype groups (P = .0006), between the *1/*1 and *1/*6 groups (P = .0001), and between the *1/*4 and *1/*6 groups (P = .012). The mean value of M1 t(1/2) in *1/*6 (33.3 ± 10.5 hours) was about 58% and 61% greater than that of the *1/*1 group (21.0 ± 7.4 hours) and the *1/*4 group (20.7 ± 9.8 hours), respectively. No significant differences in area under the concentration-time curve or maximum plasma drug concentration were observed between the groups. The CYP2B6*6 allele may be associated with a lower metabolic clearance of the M1 metabolite of sibutramine in human subjects.ope

Effects of SLCO1B1 and ABCB1 genotypes on the pharmacokinetics of atorvastatin and 2-hydroxyatorvastatin in healthy Korean subjects

OBJECTIVE: This study aimed to evaluate the effect of genetic polymorphisms of SLCO1B1 and ABCB1 on the pharmacokinetics of atorvastatin and its metabolites. METHODS: 290 Koreans were genotyped for SLCO1B1, ABCB1 and CYP3A5, and 28 subjects were selected for the pharmacokinetic study. Each subject received a single oral dose of 20 mg atorvastatin and blood samples were collected up to 48 hr after dosing. The relationship between the genotypes and atorvastatin pharmacokinetics was examined. RESULTS: For SLCO1B1 genotypes, the mean area under the concentration-time curve from time 0 to infinity (AUC0-infinity) of atorvastatin was 148.2 ng x hr/ml for *15/*15 subjects (n = 3), which was significantly larger than for 1a/*15 and *1b/*15 (n = 8) (80.7 ng x hr/ml, p = 0.0121) and also larger than for *1a/*1a, *1a/*1b and *1b/*1b (n = 17) (66.3 ng x hr/ml, p = 0.0018). The mean AUC0-infinity of 2-hydroxyatorvastatin for *15/*15 was also larger than in *1a/*1a, *1a/*1b and *1b/*1b (p = 0.012). In lactone forms, no significant pharmacokinetic difference was found among the genotypes. For ABCB1 genotypes, the half-lives of atorvastatin, atorvastatin lactone, 2-hydroxyatorvastatin and 2-hydroxyatorvastatin lactone were significantly longer in c.2677TT-c.3435TT (n = 3) vs. c.2677GG-c.3435CC and c.2677GT-c.3435CT (n = 10), yielding p = 0.049, 0.007, 0.007 and 0.007, respectively. CONCLUSION: This study shows that the SLCO1B1*15 allele may be associated with the individual difference in the AUC0-infinity of atorvastatin whereas the ABCB1 TT-TT diplotype may affect the elimination half-life of the drug in the Korean population.ope

Pharmacokinetic comparison of controlled-release and immediate-release oral formulations of simvastatin in healthy Korean subjects: a randomized, open-label, parallel-group, single- and multiple-dose study

BACKGROUND: A controlled-release (CR) formulation of simvastatin was recently developed in Korea. The formulation is expected to yield a lower C(max) and similar AUC values compared with the immediate-release (IR) formulation. OBJECTIVE: The goal of this study was to compare the pharmacokinetics of the new CR formulation and an IR formulation of simvastatin after single- and multiple-dose administration in healthy Korean subjects. This study was developed as part of a product development project at the request of the Korean regulatory agency. METHODS: This was a randomized, open-label, parallelgroup, 2-part study. Eligible subjects were healthy male or female volunteers between the ages of 19 and 55 years and within 20% of their ideal weight. In part I, each subject received a single dose of the CR or IR formulation of simvastatin 40 mg orally (20 mg x 2 tablets) after fasting. In part II, each subject received the same dose of the CR or IR formulation for 8 consecutive days. Blood samples were obtained for 48 hours after the dose in part I and after the first and the last dose in part II. Pharmacokinetic parameters were determined for both simvastatin (the inactive prodrug) and simvastatin acid (the active moiety). An adverse event (AE) was defined as any unfavorable sign (including an abnormal laboratory finding) or symptom, regardless of whether it had a causal relationship with the study medication. Serious AEs were defined as any events that are considered life threatening, require hospitalization or prolongation of existing hospitalization, cause persistent or significant disability or incapacity, or result in congenital abnormality, birth defect, or death. AEs were determined based on patient interviews and physical examinations. RESULTS: Twenty-four healthy subjects (17 men, 7 women; mean [SD] age, 29 [7] years; age range, 22-50 years) were enrolled in part I, and 29 subjects (17 men, 12 women; mean age, 33 [9] years; age range, 19-55 years) were enrolled in part II. For simvastatin acid, C(max) was significantly smaller (1.68 vs 3.62 ng/mL; P < 0.013) and T(max) and apparent t((1/2)) significantly longer (10.33 vs 4.04 hours [P < 0.001] and 11.41 vs 4.16 hours [P < 0.011]) for the CR formulation compared with the IR formulation, respectively, after the single-dose administration. After the multiple-dose administration, for simvastatin acid, the C(max) for the CR formulation was significantly smaller (3.40 vs 5.16 ng/mL; P < 0.037), while the values for T(max) and apparent t((1/2)) were significantly longer (8.40 vs 4.57 hours and 13.09 vs 4.52 hours; both, P < 0.001) compared with the IR formulation. There was no significant difference between the CR and the IR formulations for AUC(0-last) and AUC(0-infinity)) during either the single- or multiple-dose testing. Both CR and IR formulations were well tolerated in all subjects, and no serious AEs or adverse drug reactions were found. No subjects reported any AEs during part I of the study. During part II, 6 subjects (3 from each formulation group) reported headache, 1 reported lumbago before the dose, and 1 subject had a hordeolum while receiving the CR formulation. CONCLUSIONS: The C(max) of the simvastatin CR formulation was found to be significantly smaller while the AUC of the active moiety did not differ significantly from that of the IR formulation in these healthy Korean subjects. The simvastatin CR and IR formulations were well tolerated, with no serious AEs observed. To evaluate the characteristics of the CR formulation, its clinical efficacy must be examined in patient populationsope

CYP3A5*3 genotype associated with intrasubject pharmacokinetic variation toward tacrolimus in bioequivalence study

Tacrolimus is metabolized by CYP3A and has highly variable pharmacokinetics. To study the factors contributing to this high variability in pharmacokinetics and to investigate the possibility of genotype-specific clinical applications, the effect of differing CYP3A5 genotypes on the intrasubject coefficients of variation for tacrolimus was investigated. Genotyping for CYP3A5*3 was performed in healthy volunteers who had previously participated in the pharmacokinetic study of 2 tacrolimus formulations with a 2 x 2 cross-over design. Intrasubject coefficients of variation calculated from analysis of variation in CYP3A5*1/*1+*1/*3 (n = 16) and CYP3A5*3/*3 (n = 13) groups were compared. The intrasubject CVs of AUClast and Cmax in the CYP3A5*3/*3 group were about 41.1% and 52.4% greater than those in the CYP3A5*1*1+*1/*3 group. The estimated total sample size for the bioequivalence study of tacrolimus with a 2 x 2 cross-over design was increased by 93.3% for AUClast (n = 30 versus 58) and 121.4% for Cmax (n = 28 versus 62) in the CYP3A5*3/*3 group compared with the CYP3A5*1/*1+*1/*3 group. The intraindividual variability of tacrolimus PK parameters may be associated with the CYP3A5 genotype. We propose that genotyping for CYP3A5 will provide a more efficient approach for bioequivalence designs and therapeutic drug monitoringope

Pharmacokinetic properties and tissue storage of FITC conjugated SA-MnMEIO nanoparticles in mice

Nowadays, attempts to use nanoparticles for medical applications are on the rise. However, the effect of nanoparticles in the body has not been clarified. In this study, we aimed to examine the pharmacokinetics of magnetized nanoparticles. FITC conjugated SA-MnMEIO nanoparticles were prepared for the purpose of tracing. Nanoparticles (15 nm diameter) were injected into the tail vein of BALB/c mice at a dose of 20 mg (Mn+Fe)/kg. A mouse was housed in a metabolic cage and sacrificed serially up to 14 days for the sampling of blood and tissues from various organs (i.e., heart, kidney, liver, and spleen). The concentration of nanoparticles was measured by detecting FITC using spectrofluorophotometer. Nanoparticles showed a half-life of 8.20 h. The fluorescence intensities of nanoparticles in tissues showed different time-dependent patterns among different organs. In the heart and the liver, the fluorescence intensities increased up to 2 weeks of observation, while those in the kidney and the spleen decreased. The results indicate that nanoparticles have unique pharmacokinetic characteristics and suggest that pharmacokinetic study is essential for the development of new nanoparticles for medical useope