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1.
Purpose. To evaluate the MDR1 genotype frequency in the Japanese population and to study the relationship between the MDR1 genotype and the pharmacokinetics of digoxin after single oral administration in healthy subjects. Methods. The MDR1 genotype at exon 26 was determined in 114 healthy volunteers by polymerase chain reaction-restriction fragment length polymorphism. The serum concentration-time profile of digoxin was examined after single oral administration at a dose of 0.25 mg. Results. It was found that 35.1 % (40/114) of subjects were homozygous for the wild-type allele (C/C), 52.6 % (60/114) were compound heterozygotes with a mutant T-allele (C3435T) (C/T), and 12.3 % (14/114) were homozygous for the mutant allele (T/T). There was no effect of gender or age on the distribution. The serum concentration of digoxin after a single oral administration increased rapidly, attaining a steady state in all subjects; however, it was lower in the subjects harboring the T-allele. AUC0-4 h values (±SD) were 4.11 ± 0.57, 3.20 ± 0.49, and 3.27± 0.58 ng h/ml, respectively, with a significant difference between C/C and C/T or T/T. Conclusions. The serum concentration of digoxin after single oral administration was lower in the subjects harboring a mutant allele (C3435T) at exon 26 of the MDR1 gene.  相似文献   

2.
Cefixime (CL 284,635; FK 027) is a new third-generation oral cephalosporin. To study dose-dependent pharmacokinetics of cefixime in dogs, two balanced four-way crossover studies were conducted. In the first study, oral doses of 50, 100, and 200 mg/kg and an intravenous dose of 50 mg/kg cefixime were administered. In the second study, oral doses of 6.25, 12.5, and 25 mg/kg and an intravenous dose of 12.5 mg/kg cefixime were administered to the same dogs. A period of 1 month separated the two studies. When the two intravenous doses were compared (i.e., 12.5 and 50 mg/kg), a twofold increase in clearance and volume of distribution was observed after the higher dose. The oral systemic bioavailability in the dose range 6.25–50 mg/kg was 55%. It decreased to 44% at 100 mg/kg and 27% at 200 mg/kg. The average peak serum concentrations ranged from 15.8 µg/ml at 6.25 mg/kg to 119 µg/ml at 200 mg/kg. Within this concentration range, the fraction of free drug in serum (unbound to proteins) increased from 7 to 25%. This concentration-dependent protein binding was primarily responsible for changes in total clearance, volume of distribution, and bioavailability of the drug in dogs.  相似文献   

3.
种族差异对药代动力学影响的研究进展   总被引:7,自引:3,他引:7  
ICHE5指导原则是为评价药物在不同种族人群的差异,并帮助将一个地区的临床资料合理外推至新的地区,而药代动力学是评价药物种族差异的主要因素之一。本文探讨种族差异对药物吸收、分布、代谢和排泄的影响。  相似文献   

4.
AIMS: The pharmacokinetics of unbound platinum after administration of an anticancer drug nedaplatin, cis-diammineglycolateplatinum were examined using population analysis. The relevant covariates and the extent of inter- and intra-individual variability were evaluated. METHODS: In order to clarify the pharmacokinetic profile of nedaplatin, unbound platinum concentrations (789 points) in plasma after intravenous infusion of nedaplatin were obtained from 183 courses for 141 patients. Plasma concentration data were analysed by nonlinear mixed effect modelling using NONMEM to evaluate the population mean parameters and variances for inter- and intra-individual random effects. The final population model was validated by parameter sensitivity analysis using objective function mapping, the bootstrap resampling and a data-splitting technique, i.e. the Jackknife method, and the predictive performance of the final model was evaluated. RESULTS: A two-compartment pharmacokinetic model with zero-order input and first order elimination described the current data well. The significant covariates were creatinine clearance (CLcr) for clearance of platinum (CL) [population mean [95% confidence interval (CI)] CL (l h(-1)) = 4.47 (3.27, 5.67) + 0.0738 (0.0581, 0.0896) x CLcr (CLcr: ml min(-1))] and body weight (BW: kg) for volume of distribution of platinum (Vc) [Vc (l) = 12.0 (7.5, 16.5) + 0.163 (0.081, 0.246) x BW]. Inter-individual variations (CV%, 95% CI) for CL and Vc were 25.5% (20.7, 29.6) and 21.4% (17.0, 24.1), respectively, and intra-individual variation (CV%, 95% CI) was 12.6% (10.5, 14.4). The effects of pretreatment with nedaplatin or other platinum agents on clearance and volume of distribution were also tested, but no significant effect was found. The relationship between the observed and predicted unbound platinum concentration by empirical Bayesian prediction showed good correlation with no bias, suggesting that the final model explains well the observed data in the patients. The mean prediction error and root mean square prediction error (95% CI) were - 0.0164 micro g ml(-1) (- 0.4379, 0.4051) and 0.2155 micro g ml(-1) (not calculable, 0.6523), respectively. The values of mean, standard error and 95% CI for objective function mapping, the bootstrap resampling, the Jackknife estimates and the final model coincided well. CONCLUSIONS: A population pharmacokinetic model was developed for unbound platinum after intravenous infusion of nedaplatin. Only creatinine clearance was found to be a significant covariate of clearance, and BW was found to be a significant covariate of volume of distribution. These population pharmacokinetic estimates are useful for setting initial dosing of nedaplatin using its population mean and can also be used for setting appropriate dosage regimens using empirical Bayesian forecasting.  相似文献   

5.
Purpose The aim of this study is to define and illustrate metrics for the external evaluation of a population model.Materials and Methods In this paper, several types of metrics are defined: based on observations (standardized prediction error with or without simulation and normalized prediction distribution error); based on hyperparameters (with or without simulation); based on the likelihood of the model. All the metrics described above are applied to evaluate a model built from two phase II studies of gliclazide. A real phase I dataset and two datasets simulated with the real dataset design are used as external validation datasets to show and compare how metrics are able to detect and explain potential adequacies or inadequacies of the model.Results Normalized prediction errors calculated without any approximation, and metrics based on hyperparameters or on objective function have good theoretical properties to be used for external model evaluation and showed satisfactory behaviour in the simulation study.Conclusions For external model evaluation, prediction distribution errors are recommended when the aim is to use the model to simulate data. Metrics through hyperparameters should be preferred when the aim is to compare two populations and metrics based on the objective function are useful during the model building process.  相似文献   

6.

Aim:

S-1 is an oral anticancer fluoropyrimidine formulation consisting of tegafur, 5-chloro-2,4-dihydroxypyridine and potassium oxonate. The aim of this study was to evaluate the pharmacokinetics and bioequivalence of a newly developed generic formulation of S-1 in Chinese cancer patients in comparison with the branded reference formulation of S-1.

Methods:

A single-dose, randomized-sequence, open-label, two-way self-crossover study was conducted in 30 Chinese cancer patients. The subjects alternatively received the two formulations (40 mg/m2, po) with a 7-d interval. Plasma concentrations of FT, CDHP, Oxo, and 5-Fu were determined using LC-MS/MS. Pharmacokinetic parameters, including Cmax, Tmax, t1/2, AUC0–t, and AUC0–∞ were determined using non-compartmental models with DAS2.0 software. Bioequivalence of the two formulations were to be evaluated according to 90% CIs for the log-transformed ratios of AUC and Cmax of S-1. Adverse events were evaluated through monitoring the symptom, physical and laboratory examinations, ECGs and subject interviews.

Results:

The mean values of Cmax, AUC0–t, and AUC0–∞ of FT, 5-Fu, CDHP, and Oxo for the two formulations had no significant differences. The 90% CIs for natural log-transformed ratios of Cmax, AUC0–t, and AUC0–∞ were within the predetermined bioequivalence acceptance limits. A total of 11 mild adverse events, including fatigue, nausea and vomiting, anorexia, diarrhea and myelosuppression, were observed, and no serious and special adverse events were found.

Conclusion:

The newly developed generic formulation and reference formulation of S-1 have similar pharmacokinetics with one dose (40 mg/m2) in Chinese cancer patients. Both the formulations of S-1 are well tolerated.  相似文献   

7.
Pharmacokinetics and Oral Bioavailability of Scopolamine in Normal Subjects   总被引:1,自引:0,他引:1  
The pharmacokinetics and bioavailability of scopolamine were evaluated in six healthy male subjects receiving 0.4 mg of the drug by either oral or intravenous administration. Plasma and urine samples were analyzed using a radioreceptor binding assay. After iv administration, scopolamine concentrations in the plasma declined in a biexponential fashion, with a rapid distribution phase and a comparatively slow elimination phase. Mean and SE values for volume of distribution, systemic clearance, and renal clearance were 1.4 ± 0.3 liters/kg, 65.3 ± 5.2 liters/hr, and 4.2 ± 1.4 liters/hr, respectively. Mean peak plasma concentrations were 2909.8 ± 240.9 pg/ml following iv administration and 528.6 ± 109.4 pg/ml following oral administration. Elimination half-life of the drug was 4.5 ± 1.7 hr. Bioavailability of the oral dose was variable among subjects, ranging between 10.7 and 48.2%. The variability in absorption and poor bioavailability of oral scopolamine indicate that this route of administration may not be reliable and effective.  相似文献   

8.
Deriving a population pharmacokinetic model from real data is always associated with numerous assumptions. Violations of these assumptions, especially if undetected, may lead to inappropriate conclusions being made from the analysis. Routinely, only a few of the assumptions are explicitly stated and justified in the reporting of a population model. Here, we attempt to be exhaustive in the presentation of the assumptions made in the course of an analysis of moxonidine pharmacokinetics. The different ways that assumptions were justified, through experience, graphical examination, or additional modeling, are outlined. Models for relaxing assumptions regarding the covariate and statistical submodels, not previously reported in the area of population pharmacokinetic modeling, are also described.  相似文献   

9.
Baloxavir marboxil is a prodrug of baloxavir acid, an inhibitor of cap-dependent endonuclease, and suppresses the replication of influenza virus. The aim of this study was to investigate its pharmacokinetic characteristics in Japanese pediatrics. Population pharmacokinetic analysis was conducted for baloxavir acid with 328 plasma concentration data points in a clinical study of 107 Japanese pediatric influenza patients. The plasma baloxavir acid concentration profiles were well captured by a 2-compartment model including first-order absorption and lag time. Body weight was considered to be the most crucial covariate, which affects clearance and volume of distribution. The body weight–based dose regimen (10 mg for 10 kg to less than 20 kg pediatrics, 20 mg for 20 kg to less than 40 kg pediatrics, and 40 mg for at least 40 kg pediatrics) for Japanese pediatrics can provide comparable exposure to baloxavir acid to that for adults. In conclusion, the population pharmacokinetic model would be useful to comprehend the characteristics of baloxavir acid pharmacokinetics in pediatric patients.  相似文献   

10.
目的:分析免疫比浊法(My5-FUTM法)和LC-MS/MS法测定胃癌患者服用替吉奥(S-1)后血浆中5-FU浓度,构建My5-FUTM法测定服用替吉奥后5-FU的血药浓度。方法:30例初治胃癌患者首次服用替吉奥50 mg,分别采用My5-FUTM法和LC-MS/MS法测定口服替吉奥0、2、4、6、8、12 h血浆中5-FU的浓度,获得患者的AUC0-12、AUC0-∞、Tmax、Cmax、T1/2。结果:My5-FUTM法获得AUC0-12、AUC0-∞、Tmax、Cmax、T1/2分别为:(1109±488) ng·mL-1·h,(1240±589) ng·mL-1· h,(3.64±1.34) h,(196±69) ng·mL-1和(2.52±1.34) h;LC-MS/MS法为:(614±280) ng·mL-1·h,(656±318) ng·mL-1·h,(3.58±1.27) h,(119±43) ng·mL-1,(2.28±1.03) h。两种方法所获得药代动力学参数具有显著的相关性,血浆中5-FU的均值浓度变化差异显著(P=0.0045)。结论:My5-FUTM法可以用于检测胃癌患者口服替吉奥后5-FU的血浆浓度,具有操作简便、快速、稳定性高等优点,也可用于服药替吉奥后5-FU药代动力学研究。  相似文献   

11.
刘荷英  丁黎  于勇  储妍  朱贺 《药学学报》2012,(10):1363-1369
研究单次及多次给药后替吉奥胶囊在晚期胃癌患者体内的药代动力学特征。12名晚期胃癌患者,单次给药时口服60 mg;多次给药时100 mg.d 1或120 mg.d 1,连续服药28天。单次给药后替加氟、5-氟尿嘧啶、吉美嘧啶、奥替拉西钾和尿嘧啶的Cmax分别为(2207±545)、(220.0±68.2)、(374.9±103.0)、(110.5±100.8)和(831.1±199.9)ng.mL 1;t1/2分别为(11.8±3.8)、(4.4±3.3)、(7.8±5.1)、(3.1±0.9)和(8.8±4.1)h;多剂量连续给药6天后平均稳态血药浓度(Cav)分别为(2 425±1 172)、(73.88±18.88)、(162.6±70.8)、(36.89±29.35)和(435.3±141.0)ng.mL 1。48 h内替加氟、5-氟尿嘧啶、吉美嘧啶和奥替拉西钾的尿药累积排泄率分别为(4.2±2.8)%、(4.7±1.6)%、(18.5±6.0)%和(1.7±1.2)%。多次给药过程中替加氟有一定的蓄积现象,5-氟尿嘧啶、吉美嘧啶、奥替拉西钾和尿嘧啶均无蓄积现象。  相似文献   

12.
目的 应用非线性混合效应模型NONMEM考察成人肾病综合征患者他克莫司的群体药动学特征。方法 回顾性收集肾病综合征患者51例,246个血药浓度监测数据。以其年龄、性别、体质量、他克莫司日剂量、肝肾功能及合并用药等为协变量,采用具有一级吸收和消除的一室模型拟合数据,并通过自举法和正态化预测分布误差法对模型进行验证。结果 他克莫司的表观清除率(CL/F)为13.9 L·h-1,表观分布容积(V/F)为382 L,他克莫司日剂量(DD,mg·d-1)、红细胞压积(HCT)、合并使用五酯胶囊对CL/F有显著影响。模型评价显示该模型及参数估算值可靠稳定,CL/F的最终模型为CL/F=13.9×0.668WZ×(DD/2)0.354×(HCT/0.394)-0.522,其中合并使用五酯胶囊时WZ为1,反之为0。结论 建立的肾病综合征患者口服他克莫司的群体药动学模型能较好地估算患者的群体及个体药动学参数,可为该药的个体化给药方案设计提供参考。  相似文献   

13.
14.
Summary Administration of drugs by the sublingual route provides rapid systemic absorption and avoids first-pass metabolism. The purpose of the present study was to assess the pharmacokinetics, efficacy and adverse effects of standard salbutamol tablets given by this route to patients with asthma. Seven asthmatic patients were given either sublingual salbutamol tablet 2 mg (SL), swallowed tablet 2 mg (O), metered dose inhaler 200 µg (MDI) or placebo (PL), in a randomized single-blind cross-over design. Airways responses (FEV1, FVC, PEFR), finger tremor (Tr), heart rate (HR), plasma potassium (K) and plasma salbutamol were measured over a 6 h period following drug administration.There were highly significant changes in FEV1 with MDI, O and SL routes compared with PL, although the response to MDI was greater and more rapid than with O or SL. There were similar findings for FVC and PEFR responses. There were no adverse effects with MDI, whereas both 0 and SL produced significant tremor responses. There were no differences between O and SL for any of the pharmacodynamic parameters. In addition, pharmacokinetic profiles for O and SL were also similar apart from an initial delay in absorption with SL. There were however, no significant differences in any of the pharmacokinetic parameters, between O and SL.This suggests that buccal absorption of salbutamol was negligible, and that systemic absorption occurred after swallowing of the dissolved sublingual tablet. These results show that sublingual administration of salbutamol tablet has no clinical benefit over the oral route.  相似文献   

15.
Purpose. Population pharmacokinetics of a fast release diclofenac wereassessed with special focus on pharmacodynamic implications. Methods In a double blind four-way crossover study, 20 healthyvolunteers received orally 50 and 100 mg diclofenac-Na effervescent(fast-release NSAID), 50 mg diclofenac tablets (control), or placebo.Population pharmacokinetics of the fast release diclofenac wereassessed using a nonlinear mixed effects modeling approach(NON-MEM). Analgesic effects were investigated by means of anexperimental pain model based on both pain-ratings and cortical evoked potentialsafter specific stimulation of nasal nociceptors with short pulses ofgaseous CO2. Results. Pharmacokinetics of fast release diclofenac were bestdescribed by a two-compartment population model, with an estimatedterminal half-life of 1.2 hours. Pharmacokinetics of diclofenac tabletswere highly variable and a population pharmacokinetic model couldnot be obtained. As an indication of an early onset of analgesic effects,100 mg fast release diclofenac but not the tablets significantly reducedthe amplitudes of pain-related evoked potentials at 30 min afteradministration. Conclusions. Earlier drug absorption and lower pharmacokineticvariability of the fast-release formulation are likely to be preserved ina population.  相似文献   

16.
叶敏  朱珠  付强  孙强  茅枫 《中国药学》2006,15(3):131-138
目的描述卡培他滨在血浆、乳腺肿瘤组织和正常组织中向氟脲嘧啶转化的药物动力学过程。方法27名乳腺癌化疗患者口服卡培他滨1 255 mg·m-2,同步采集血浆、肿瘤组织和相邻正常组织样品,并用HPLC法测定卡培他滨和5-FU的浓度。使用自建的药物动力学模型拟合卡培他滨和5-FU的药时曲线,并利用拟合参数计算血浆和乳腺组织中卡培他滨和5-FU的组织分布因子,以及卡培他滨向5-FU的转化率。结果卡培他滨在肿瘤组织中的组织分布因子(AUCTumor/AUCplasma)为0.637 1,正常组织中的组织分布因子(AUCH-tissue/AUCplasma)为0·851 4;5-FU在乳腺肿瘤的组织分布因子AUCTumor/AUCplasma为3.992 6,正常组织的组织分布因子AUCH-tissue/AUCplasma为2.438 0。卡培他滨向5-FU的转化率在肿瘤、邻近正常组织和血浆中分别为1.026、0.489 5和0.163。结论血浆、乳腺肿瘤组织和相邻正常组织的药时曲线拟合对卡培他滨转化为5-FU及5-FU消除过程进行了较好的描述。卡培他滨在血浆、乳腺肿瘤组织和相邻正常组织中的分布较为接近,其活性代谢产物5-FU在肿瘤组织中分布为血浆的10·14倍,为正常组织的3·41倍。卡培他滨在肿瘤组织中向5-FU的转化率较高。  相似文献   

17.
AIM: To investigate the pharmacokinetics, pharmacodynamics and tolerability of the dual endothelin receptor antagonist tezosentan in caucasian and Japanese subjects. METHODS: Twelve subjects of each ethnic origin were treated in a double-blind, randomized design with sequential 3-h infusions of 2.5, 5.0, 12.5 and 25 mg h(-1), or placebo. Vital signs, ECG and adverse events were recorded and blood samples collected for determination of plasma concentrations of tezosentan and endothelin-1 (ET-1). RESULTS: Tezosentan was well tolerated in both ethnic groups with no clinically significant differences in laboratory measurements, ECG parameters and vital signs. The plasma concentration-time profiles of tezosentan were described by a three-compartment model with half-lives of approximately 5 min, 41 min and 3.6 h. Mean clearance and volume of distribution were approximately 35 l h(-1) and 20 l, respectively. Differences in the means (95% confidence intervals) between ethnic groups in these two parameters were 6.0 l h(-1) (-1.3, 13.3) and 4.3 l (-1.3, 9.9), respectively. Baseline ET-1 concentrations were similar but increases in response to tezosentan were greater in caucasian than in Japanese subjects. An indirect response model described the relationship between tezosentan and ET-1 plasma concentrations. The mean concentrations inhibiting 50% of ET-1 clearance (IC(50)) in caucasian and Japanese subjects were 243 and 227 ng ml(-1), respectively, with a difference in the means of 28.6 ng ml(-1) (-52.7, 110). CONCLUSIONS: The data in healthy subjects suggest that caucasian and Japanese patients can be treated with a similar dosing regimen of tezosentan.  相似文献   

18.
Purpose. The population PK/PD approach was prospectively used to determine the PK/PD of cisatracurium in various subgroups of healthy surgical patients. Methods. Plasma concentration (Cp) and neuromuscular block data from 241 patients in 8 prospectively-designed Phase I–III trials were pooled and analyzed using NONMEM. The analyses included limited Cp-time data randomly collected from 186 patients in efficacy/safety studies and full Cp-time data from 55 patients in pharmacokinetic studies. The effects of covariates on the PK/PD parameters of cisatracurium were evaluated. The time course of neuromuscular block was predicted for various patient subgroups. Results. The population PK/PD model for cisatracurium revealed that anesthesia type, gender, age, creatinine clearance, and presence of obesity were associated with statistically significant (p < 0.01) effects on the PK/PD parameters of cisatracurium. These covariates were not associated with any clinically significant changes in the predicted recovery profile of cisatracurium. Slight differences in onset were predicted in patients with renal impairment and patients receiving inhalation anesthesia. Based on the validation procedure, the model appears to be accurate and precise. Conclusions. The prospective incorporation of a population PK/PD strategy into the clinical development of cisatracurium generated information which influenced product labeling and reduced the number of studies needed during development.  相似文献   

19.
Purpose. To study the pharmacokinetics (PK) and pharmacodynamics (PD) of an investigational antipsychotic agent, CI-1007, in rats and monkeys. Methods. CI-1007 and a pharmacologically active metabolite, PD 147693 (Ml), were evaluated in animal antipsychotic tests (inhibition of dopamine neuron firing and spontaneous locomotor activity in rats, and inhibition of continuous avoidance in monkeys). Plasma concentrations of CI-1007 and Ml were determined using validated HPLC assays. Log-linear and link models were used for PK/PD analysis. Results. CI-1007 and Ml have shown similar effects on dopamine neuron firing (2.5 mg/kg i.p.), and produced dose-related effects on spontaneous locomotor activity in rats (0.3–30 mg/kg, p.o.) and on continuous avoidance in monkeys (0.6–1.2 mg/kg p.o.). After pharmacologically active CI-1007 doses, mean plasma CI-1007 Cmax increased from 19 to 200 ng/ml in Sprague-Dawley rats at doses of 3–30 mg/ kg, and from 8.1 to 34 ng/ml in squirrel monkeys at doses of 0.6–1.2 mg/kg, but corresponding plasma M1 Cmax values were near or below the limit of quantitation (5 ng/ml). CI-1007 EC50 was 31.1 ng/ml in rats, calculated from a log-linear regression. In monkeys, CI-1007 ECe50, , and Keo at 0.6 and 1.2 mg/kg were 4.8 and 4.5 ng/ml, 1.9 and 2.0, and 0.47 and 0.48 hr–1, respectively, calculated by the link model. Conclusions. CI-1007 has shown dose-related pharmacokinetics and pharmacodynamics in rats and monkeys. Although Ml produces anti-psychotic-like effects similar to CI-1007, the contribution of Ml to the activity of the parent drug may not be significant in rats and monkeys as based on plasma levels. CI-1007 plasma concentration correlates log-linearly with inhibition effect from the rat locomotor study. The counter-clockwise hysteresis relationship of CI-1007 plasma concentration and inhibition effect from the monkey avoidance test was described by a link model, and the resulting Ce (concentration in effect compartment) versus effect profile exhibits a sigmoidal curve.  相似文献   

20.
Aims: To derive useful pharmacokinetic (PK) and pharmacodynamic (PD) information for guiding the clinical use of sotalol in pediatric patients with supraventricular (SVT) or ventricular tachyarrhythmia (VT).Methods: Two studies were conducted in-patients with SVT or VT in the age range between birth and 12 years old. Both studies used an extemporaneously compounded formulation prepared from sotalol HCl tablets. In the PK study, following a single dose of 30 mg/m2 sotalol, extensive blood samples (n=10) were taken. The PK–PD study used a dose escalation design with doses of 10, 30, and 70 mg/m2, each administered three times at 8-hr intervals without a washout. Six ECG recordings for determination of QT and RR were obtained prior to the initial dose of sotalol. Four blood samples were collected six ECG's were determined during the third interval at each dose level. Plasma concentrations of sotalol (C) were assayed by LC/MS/MS. The data analysis used NONMEM to obtain the population PK and PD parameter estimates. The individual PK and PD parameters were estimated with empirical Bayes methodology.Results: A total of 611 C from 58 patients, 477 QTc and 499 RR measurements from 23 and 22 patients, respectively, were available for analysis. The PK of sotalol was best described by a linear two-compartment model. Oral clearance (CL/F) and volume of central compartment (Vc/F) were linearly correlated with body surface area (BSA), body weight or age. CL/F was also linearly correlated with creatinine clearance. The best predictor for both CL/F and Vc/F was BSA. The remaining intersubject coefficients of variation (CV's) in CL/F, and Vc/F were 21.6% and 20.3%, respectively. The relationship of QTc to C was adequately described by a linear model. The intersubject CV's in slope (SL) and intercept (E0) were 56.2 and 4.7%, respectively. The relationship of RR to C was also adequately described by a linear model in which the baseline RR and SL were related to age or BSA. The intersubject CV's for SL and E0 were 86.7 and 14.4%, respectively.Conclusions: BSA is the best predictor for the PK of sotalol. Both QTc and RR effects are linearly related to C. No covariates are found for the QTc–C relation, while the RR–C relation shows age or BSA dependency.  相似文献   

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