西罗莫司治疗肾移植后排斥反应的疗效、不良反应与其血药浓度的相关性分析

目的:观察西罗莫司治疗肾移植后排斥反应时,其疗效、不良反应与血药浓度的相关性。方法:选择52名肾移植术后应用西罗莫司进行免疫抑制治疗的患者为研究对象,其中男性43人,女性9人。采用高效液相色谱(HPLC)法测定西罗莫司血药浓度,同时测定患者的肌酐清除率、肝功能指标、血常规等。结果:共收集西罗莫司血药浓度数据112份。西罗莫司的血药浓度与给药剂量/体重比呈正相关,与体重呈负相关,女性患者血药浓度明显高于男性患者(P<0.05),未发现西罗莫司血药浓度与年龄有明显相关性;西罗莫司的主要不良反应表现为肝功能损伤,将血药浓度分为<8ng·mL-1和>8ng·mL-1组,不同血药浓度组的肝功能差异有统计学意义(P<0.05);西罗莫司的临床疗效确切,将西罗莫司稳态谷浓度分成<4ng·mL-1、4～8ng·mL-1和>8ng·mL-1组,不同血药浓度组其肌酐清除率和肾功能恢复情况差异有统计学意义(P<0.05)。结论:西罗莫司副作用主要表现为肝功能异常,其血药浓度与临床疗效和不良反应均有相关性,西罗莫司稳态谷浓度宜控制在4～8ng·mL-1范围内。     

丙戊酸钠在癫痫患者中的群体药动学

目的建立丙戊酸钠在癫痫患者治疗中的群体药动学模型,为临床个体化给药提供参考。方法收集我院门诊60名癫痫患者丙戊酸钠稳态血药浓度监测数据和相应的人口学数据,应用非线性混合效应模型(non linearm ixed-effectmodel,NONMEM)程序对收集的数据进行分析,建立群体药动学模型。结果建立了癫痫患者口服丙戊酸钠群体药代动力学模型:CL/F=0.959×1.04x,(x=0,1),V/F=1.35,ka=2.38 h-1,说明丙戊酸的清除率与患者性别相关,即男性患者的清除率大于女性。结论初步建立癫痫患者口服丙戊酸钠群体药动学模型,为丙戊酸钠个体化用药提供理论基础。     

苯巴比妥在癫(癎)儿童中的群体药动学研究

目的 通过临床数据研究儿童苯巴比妥的群体药动学。方法采集298例儿童癫痫患者服用苯巴比妥常规治疗的监测资料数据,利用CPKDP程序分析药动学参数，结合Ｂayesian反馈法及二步迭代估算儿童个体药动学参数。结果癫痫儿童苯巴比妥群体药动学主要参数Ke、Vd、CL在单用苯巴比妥组分别为0.351 h-1、0.452 L·kg-1和5.135 L·h-1·kg-1；其中性别、身高以及辅助用药、用药持续时间未见明显影响；儿童年龄、体重、合并丙戊酸（vaproic， VPA）、氯硝西泮（clonazepam ， CNP）、托吡酯（topiramate ，TPM）、苯妥因（phenytion ，PHT）、卡马西平（carbamazepine， CBZ）为影响苯巴比妥清除率的重要因素，其中VPA、CBZ和PHT均增加PB的清除率，而CNP、TPM则会降低其清除率。结论 根据癫痫儿童的群体药动学模型，结合患儿的年龄、体重、服药剂量以及合并药等资料，可估算其清除率，预测患儿体内的药物浓度，制定个体化给药方案。     

银屑病患者甲氨蝶呤的群体药动学研究

目的:研究银屑病患者甲氨蝶呤(MTX)的群体药动学特征,为临床调整个体化用药提供新途径。方法:收集皮肤科50例银屑病患者单剂量静脉滴注MTX后稀疏血药浓度数据137个,采用荧光偏振免疫法(FPIA)测定,应用非线性混合效应模型(NONMEM)程序一步法估算MTX的群体药动学参数,并定量分析患者年龄、性别、体质量、肌酐清除率、尿素氮等因素对MTX药动学参数的影响。结果:按静脉滴注二房室线性开放模型估算的群体药动学参数中央室清除率(CL)、中央室表观分布容积(Vc)、外周室表观分布容积(Vp)及外周室清除率(Q)分别为10.4L·h-1、11.7L、6.61L及2.8L·h-1,其个体间变异ωCL、ωVc、ωVp、ωQ分别为16.8%、2.8%、11.7%及287.9%。且最终回归模型的MTX浓度估算值与实测值具有一致性。效应中尿素氮对Vp的影响具有显著意义(P>0.05),其协变量参数为(尿素氮/4)-0.845。结论:NONMEM法以二室模型群体参数估算的血药浓度值与实测值有良好相关性,此研究结果有助于MTX的临床合理应用。     

肾移植患者术后口服环孢素A的群体药动学研究

目的考察肾移植患者术后口服环孢素A的群体药动学(population pharmacokinetics,PPK)模型,为临床个体化用药提供参考。方法回顾性收集空军总医院62名肾移植术后口服环孢素A患者常规血药浓度监测数据160个。用NONMEM法建立PPK模型,并考察性别、年龄、体重、术后时间、肝肾功能及联合用药等固定效应对药动学参数的影响。结果患者体重(WT)、红细胞压积(HCT)、总胆红素水平(TBIL)对环孢素A体内清除率有影响。最终模型公式为:CL/F=30.5×[1+0.0105×(WT-61.36)]×[1-1.15×(HCT-0.289)]×[1-0.0125×(TBIL-9.26)](L.h-1);Vd/F=3.85×WT(L);Ka=1.28(h-1)。CL/F的个体间变异为10.9%。用Bootstrap法对模型进行内部验证,结果显示模型稳定可靠。结论用NONMEM软件拟合可获得肾移植患者术后口服环孢素A的PPK最终模型,该模型可为临床合理使用环孢素A提供参考依据。     

非线性混合效应模型法估算肾移植患者环孢素A的相对清除率

目的:用非线性混合效应模型(NONMEM)法定量考察年龄、性别、体重、合并用药、肝功能、合并症和服药持续时间对清除率的影响.方法:收集中山大学附属第一医院由1999～2001年临床221例肾移植患者323人次肾移植后服用环孢素A(CsA)3 d以上谷值浓度,应用SAS程序估算其药动学参数(参考NONMEM程序一步法).结果:按口服吸收一室开放模型的群体药动学参数:清除率CL、表观分布容积Vd分别等于13.46 L·h-1,228.2 L,浓度观察值与模型预测值的残差变异σE(%)等于0.006 5.其个体间变异σCL(%)为5.94.CL(L·h-1)的最终回归方程为:CL=13.46-0.063 A 0.082 W.其中A为患者年龄;W为患者体重(kg).结论:年龄越大,CL越小;体重越大,CL越大.     

中国肾移植患者西罗莫司群体药动学模型研究

回顾性收集60例中国肾移植患者常规监测的西罗莫司(1)稳态谷浓度(c0)及病理生理数据,检测患者CYP3A5*3基因型,采用非线性混合模型(NONMEM)软件建立中国肾移植患者服用1后的群体药动学(PPK)模型,并定量研究包括年龄、性别、体重、肝肾功能、CYP3A5*3基因型等因素对于PPK参数的影响.最终模型采用Bootstrap法验证.共回顾性收集患者移植后不同阶段的1血药浓度数据486个,平均c0浓度为(7.1±3.4) ng/ml.60位患者中包括3、22、35位CYP3A5* 1/*1、*1/*3及*3/*3基因型.结果表明中国肾移植患者中1药动学符合一室模型,清除率(CL/F)为(13.1±0.78) L/h;分布容积(Vd/F)为(755±38.2)L;吸收速率常数(Ka)为2.20 h-1.体重、总胆红素(TBIL)和CYP3A5基因型对1的清除率均影响显著(P＜0.01).     

中国成年患者万古霉素群体药动学研究

目的:利用万古霉素治疗药物监测(TDM)数据建立群体药动学(PPK)模型,用于估算个体化药动学参数。方法:选择使用万古霉素成年患者,详细记录用药、TDM数据以及病理生理资料。采用非线性混合效应模型(NONMEM)法建立万古霉素群体药动学模型。结果:169例患者数据来源于血液科及重症监护(ICU)病房等9个科室,共获得385个血药浓度数据,其中峰浓度39个,谷浓度346个。根据文献资料及TDM数据建立二室PPK模型,万古霉素清除率(CL)、中央室(V1)及外周室(V2)分布容积、室间清除率分别为4.08 L·h-1、21.7 L、65.3 L、5.95 L·h-1,患者肌酐清除率及体重分别对CL及V2具有显著影响。根据模型预测169位患者AUC0-24h为(450.1±231.8)mg·L-1·h。结论:本研究建立的万古霉素PPK模型可以用于中国成年患者个体化药动学参数估算。     

拉氧头孢对映异构体在儿童群体中的药动学研究和剂量优化

目的:建立拉氧头孢对映异构体在儿童患者中的群体药动学模型,研究拉氧头孢在儿童患者体内的药动学特点,为拉氧头孢在儿童患者中的个体化用药提供依据。方法:检测145例静脉滴注拉氧头孢患儿的血药浓度,收集患儿临床资料。采用非线性混合效应模型法建立拉氧头孢对映异构体在儿童患者群体中药动学模型,并用自举法、拟合优度图和正态化预测分布误差进行验证。采用蒙特卡洛模拟评价不同给药方案的合理性。结果:四房室模型可以较好描述拉氧头孢对映异构体在儿童患者体内的药动学特征。最终模型稳定,预测结果可靠。拉氧头孢R和S对映异构体的表观分布容积(V_d)分别为5.57 L和4.15 L,清除率(CL)分别为0.78 L·h^-1和1.32 L·h^-1。体质量对拉氧头孢异构体药动学参数有显著影响。结论:该研究成功建立了拉氧头孢对映异构体在儿童患者群体中的药动学模型,可为拉氧头孢的个体化用药提供参考。     

肾移植术后西罗莫司的应用方案选择

本综述总结西罗莫司用于预防肾移植术后排斥反应的各种用药方案,从急性排斥发生率、肾功能、人/肾存活率4个方面综合比较各种用药方案同其他传统免疫抑制方案的优劣。综合比较显示,肾移植术后转换使用西罗莫司是最值得推荐的用药方案。在环孢素与西罗莫司联用（CsA＋SRL）过程中减、停环孢素也是可以考虑的方案,但要注意控制西罗莫司浓度。西罗莫司可以替换麦考酚酸酯,此时钙调神经蛋白抑制剂（CNI）应适当减量。起始低剂量西罗莫司与CNI联用（CNI＋SRL）,以及起始足量CNI＋SRL并维持、起始不含CNI以及术后移植肾功能延迟恢复（DGF）过渡期使用西罗莫司均应当避免。西罗莫司支持术后撤停激素,此种情况下推荐西罗莫司与他克莫司联用。需定期监测西罗莫司谷浓度,并多数情形下推荐使用首剂负荷剂量。     

一例体外膜肺氧合及肾脏替代治疗并行患者的美罗培南药动学/药效学

目的：测定一例体外膜肺氧合（extracorporeal membrane oxygenation,ECMO）及肾脏替代治疗（renal replacement therapy,RRT）并行患者不同时间点的美罗培南血药浓度,得出药动学参数,将浓度值与最低抑菌浓度（MIC）作比较,探讨ECMO及RRT同时进行治疗对美罗培南药动学/药效学（PK/PD）的影响。方法：选自重症监护室（ICU）的一位进行体外膜肺氧合及肾脏替代治疗的急性循环衰竭患者,按美罗培南1 g q8h,静脉滴注30 min。采用HPLC法测定美罗培南给药前和给药后0.25、0.5、0.75、1、2、4、8h的血药浓度。将测得的血药浓度代入药代动力学软件Winnonlin5.2,求出该患者的药代动力学参数。计算不同MIC值时PK/PD靶目标100%T>MIC的达标情况。结果：该患者美罗培南给药后30 min的峰浓度（Cmax）为44.94μg·mL-1,经8 h谷浓度（Cmin）为9.79μg·mL-1,0~8 h药-时曲线下面积（AUC0-8）为133.69 h·μg-1·mL-1,半衰期（t1/2）为2.68 h,表观分布容积（Vd）为33.12 L,清除率（CL）为4.38 L·h-1。当MIC为敏感值2μg·mL-1或中介值8μg·mL-1时,PK/PD靶目标100%T>MIC均达标。结论：进行体外膜肺氧合及肾脏替代治疗的急性循环衰竭患者使用美罗培南时,药动学参数发生了一定变化,但常规剂量1 g q8h/30 min延长静脉滴注能够满足抗感染的PK/PD靶目标,提示该类患者治疗初期可经验性给予常规剂量的美罗培南进行抗感染的治疗,之后根据血药浓度监测进行剂量的调整。     

Pharmacokinetics of mycophenolate mofetil in hematopoietic stem cell transplant recipients

Mycophenolate mofetil (MMF), a prodrug of mycophenolic acid (MPA), is increasingly used in the prophylaxis of graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation (HCT). Few pharmacokinetic data are available about the use of MMF for this indication. This case series aimed at analyzing the pharmacokinetics of MMF in a population of HCT recipients representative for everyday practice. From 15 HCT recipients, serial plasma samples were taken after twice-daily oral intake of MMF. Plasma concentrations of total MPA and its glucuronide metabolites, as well as free MPA, were quantified. Median apparent oral MPA clearance (CL/F), apparent half-life, and total MPA area under the curve for hours 0 to 12 (AUC0-12, normalized to 1000 mg MMF) were, respectively, 56 L/h (range: 29-98 L/h), 2.3 hours (range: 0.8-5.7 hours), and 18.0 mg*h/L (range: 10-35 mg*h/L). Total MPA concentrations were below 2 mg/L 8 hours after MMF administration, indicating reduced enterohepatic recirculation. Median free MPA AUC0-12 (normalized to 1000 mg MMF) was 224 microg*h/L (range: 56-411 microg*h/L). Because of high CL/F, total MPA exposure in HCT recipients is low and apparent half-life is short in comparison with reference values from renal transplantation. Exposure may be improved in HCT recipients by higher or more frequent MMF dosing.     

健康志愿者二甲双胍缓释片群体药动学模型的初步研究

目的 建立中国健康志愿者服用二甲双胍缓释片的群体药动学(PPK)模型,并研究不同生理因素对二甲双胍药动学参数的影响。方法 20名中国健康受试者(男性11名、女性9名),单剂量给予二甲双胍缓释片 1 000 mg,收集受试者服药后0~24 h血样标本,建立液相色谱-质谱/质谱(LC-MS/MS)方法测定人血浆二甲双胍浓度,采用非线性混合效应模型(NONMEM)建立二甲双胍的群体药动学(PPK)模型,并探讨生理因素对二甲双胍药动学的影响。结果 二甲双胍药动学符合一房室模型,清除率(CL/F)、分布容积(Vd/F)和吸收速率常数K_a分别为(95.8±7.46) L/h、(553±45.9) L及(0.596±0.070)/h。引入体重作为CL/F及Vd/F的协变量,使模型显著改善(P<0.05)。结论 NONMEM法可以用于二甲双胍药动学研究,且体重对二甲双胍清除率存在显著影响。     

Population pharmacokinetics of duloxetine in Japanese pediatric patients with major depressive disorder

The objectives of this analysis were to characterize the pharmacokinetics of duloxetine in Japanese pediatric patients aged 9–17 years with major depressive disorder (MDD) and to explore potential intrinsic factors affecting its pharmacokinetics. A population pharmacokinetic (PK) model was developed with plasma steady-state duloxetine concentrations from Japanese pediatric patients with MDD in an open-label long-term extension trial in Japan (ClinicalTrials.gov Identifier: NCT03395353). Duloxetine pharmacokinetics in Japanese pediatric patients was well described by a one-compartment model with first-order absorption. The population mean estimates of CL/F and V/F of duloxetine were 81.4 L/h and 1170 L, respectively. Patient intrinsic factors were assessed for their potential influence on duloxetine apparent clearance (CL/F). Only sex was identified as a statistically significant covariate of duloxetine CL/F. Duloxetine pharmacokinetic parameters and model-predicted duloxetine concentrations at steady state in the Japanese pediatric population were compared with those in Japanese adults. The mean duloxetine CL/F in pediatrics is slightly higher than adults, it is, however, expected that comparable steady-state duloxetine exposure in pediatric patients can be achieved with the approved dose regimen for adults. The population PK model provides useful information to understand the pharmacokinetic characteristics of duloxetine for Japanese pediatric patients with MDD.ClinicalTrials.gov identifierNCT03395353     

左旋多巴中国人群药动学模型的建立

目的:建立中国人群左旋多巴/苄丝肼复合制剂中左旋多巴的群体药动学模型。方法:前瞻性收集服用多巴丝肼片的帕金森病(PD)门诊患者稳态谷浓度97例102个血样和健康志愿者13例153个密集血样,高效液相色谱-电化学(HPLC-ECD)法测定左旋多巴(LD)血药浓度。应用NONMEM软件进行群体药动学数据分析,Bootstrap重复抽样用于模型的内部验证。另收集20例PD患者22个血样点作为验证组进行模型外部验证,计算最简模型和最终模型对验证组的平均预测误差(MPE)和平均绝对误差(MAE)对模型进行外部验证。结果:数据采用一房室模型拟合,年龄(AGE)对LD清除率有显著影响,性别(SEX)、体质量(WT)、给药剂量(TAMT)、合并用药不影响LD的药动学参数。LD的基础模型为:CL(CL/F)(L.h-1)=18.2×EXP[ETA(1)],V(V/F)(L)=48.4,ka(h-1)=2.13×EXP[ETA(2)];最终模型为:CL(CL/F)(L.h-1)=17.9×(55/AGE)0.59×(EXP[ETA(1)],V(V/F)(L)=47.5,ka(h-1)=2.14×EXP[ETA(2)]。CL、V、ka的群体典型值分别为17.9 L.h-1、47.5 L、2.14 h-1。Bootstrap重复抽样显示所建立的最终模型稳定、可靠,最终模型对验证组的MPE和MAE较最简模型有显著改善,显示模型有效,且有一定代表性。结论:根据患者的生理用药资料,结合上述模型,可估算个体药动学参数,为临床个体化给药提供参考。     

Population pharmacokinetics of oxycodone in children 6 months to 7 years old

Young children are often undertreated for pain. One barrier to effective pain treatment is understanding the pharmacokinetic behavior of analgesics in this age group. Oxycodone is a commonly prescribed opioid for severe pain, yet little is known about its pharmacokinetics in young children. This article used population pharmacokinetic modeling to synthesize pharmacokinetic data from several studies into a model. A single population model that described the observed pharmacokinetics was developed. The combined data were best described with a 2-compartment linear model with different first-order absorption rates depending on route of administration. Weight was found to significantly influence both clearance (CL) and volume of distribution (Vd). The following model adequately describes the population pharmacokinetic profile of oxycodone where absolute bioavailability (F) is estimated for each administration route: CL/F=55x(body weight/70)0.87; V/F=86x(body weight/70)1.16. The interindividual coefficients of variation in CL and Vd were 20.2 and 19.7%, respectively. This finding confirms that the allometric scaling using the above model explained most of the variability in exposure observed among children. This model confirms using a weight-based dose for oxycodone without adjustment for age between 6 months and 7 years and is valuable for evaluating dosing schedules and dosing routes.     

Population pharmacokinetics of rhTNFR-Fc in healthy Chinese volunteers and in Chinese patients with Ankylosing spondylitis

Aim:

To investigate the population pharmacokinetics of recombinant human tumor necrosis factor receptor-Fc fusion protein (rhTNFR-Fc) administered via subcutaneous (SC) injection in healthy Chinese volunteers and in Chinese patients with ankylosing spondylitis (AS).

Methods:

Thirty-two healthy volunteers were randomly assigned to receive a single SC injection of 12.5, 25, 37.5, or 50 mg of rhTNFR-Fc. Twenty male patients with moderate AS were randomly assigned to receive seven consecutive SC injections of rhTNFR-Fc at either 25 mg twice a week (BIW) or 50 mg once a week (QW). Population pharmacokinetic (PK) analysis was applied to obtain PK parameters of rhTNFR-Fc by the NONMEM method.

Results:

The data were best described by a one-compartment model with lag time. We found that gender had a significant effect on the apparent clearance (CL/F), with the male CL/F ratio being only 0.665 times the female ratio; the absorption coefficient (F) of multiple dosages of rhTNFR-Fc was only 0.674 times that of a single dosage. The outcome parameters were CL/F (female: 0.168 L/h, male: 0.110 L/h), the apparent volume of distribution (Vd/F: 15.5 L), the absorption rate constant (Ka) (single dosage: 0.0605 h⁻¹, multiple dosage: 0.0408 h⁻¹), and the lag time (T_lag: 1.03 h). The inter-individual variability in the CL/F, Vd/F, Ka, and T_lag were 33.3%, 42.7%, 55.6%, and 81.8%, respectively.

Conclusion:

Chinese females have a higher CL/F than Chinese males, and multiple dosings can significantly decrease the absorption of rhTNFR-Fc (SC). The population PK parameters of rhTNFR-Fc in healthy Chinese volunteers and patients with AS were similar to those reported for subjects in published American studies.     

癌光啉在兔体内的药代动力学及生物利用度

目的研究癌光啉在兔体内的药代动力学及生物利用度特点,为药物进一步研究提供依据。方法兔腹腔注射或静脉注射10 mg.kg-1癌光啉,于给药后的10 min、30 min、1h、2 h、4 h、8 h、24 h、48 h、72 h耳缘静脉采血,以全波长酶标仪荧光法测定兔血浆中癌光啉浓度,用3P97处理血药浓度-时间数据,分析房室模型,得到最佳房室模型和药代动力学参数。结果家兔腹腔注射癌光啉10 mg.kg-1的时量曲线符合一室开放模型,静脉注射时的时量曲线符合三室模型,但其消除快于ip。主要药代动力学参数:ip给药组,T12Ke=11.6 h,Cmax=2.312 mg.L-1,AUC=43.177 mg.L-1.h,CL=0.232 L.kg-1.h-1,V/F(c)=3.888 L.kg-1;iv给药组,Vc=0.75 L.kg-1,T12α=2.824 h,T 12β=40.632 h,AUC=65.161 mg.L-1.h,CL(s)=0.153 L.kg-1.h-1。腹腔给药后绝对生物利用度是66.2%。结论癌光啉在兔体内吸收快、起效快、消除快,无蓄积现象,给药方式不同,药代动力学特点不同。     

Population pharmacokinetics of nevirapine in an unselected cohort of HIV-1-infected individuals

AIMS: To study the population pharmacokinetics of nevirapine and to identify relationships between patient characteristics and pharmacokinetics in an unselected population of patients attending our outpatient clinic. METHODS: Ambulatory HIV-1-infected patients from the outpatient clinic of the Slotervaart Hospital who were being treated with a nevirapine-containing regimen were included. During each visit, blood samples were collected for the determination of nevirapine plasma concentrations and clinical chemistry parameters. Variables that were collected at baseline were serology for hepatitis B (HBV) and C (HCV) viruses, liver enzymes, and total bilirubin (TBR). In addition, information about concomitant use of St John's wort and patient demographics were included. The pharmacokinetics of nevirapine were described by first-order absorption and elimination using nonlinear mixed effect modelling (NONMEM V1.1). Population pharmacokinetic parameters (apparent clearance (CL/F), volume of distribution (V/F), absorption rate constant (k a)) were estimated, as were interindividual, interoccasion, and residual variability in the pharmacokinetics. The influence of patient characteristics on the pharmacokinetics of nevirapine was determined. RESULTS: From 173 outpatients a total number of 757 nevirapine plasma concentrations at a single random time point and full pharmacokinetic curves for 13 patients were available resulting in a database of 1329 nevirapine plasma concentrations. Mean CL/F, V/F, and k a were 3.27 l h-1, 106 l, and 01.66 h-1, respectively. CL/F of nevirapine was correlated with weight, chronic HCV infection, and baseline aspartate aminotransferase (ASAT). Chronic HCV and baseline ASAT> 1.5 x upper limit of normal (ULN) decreased CL/F by 27.4% and 13.2%, respectively, whereas an increase in body weight of 10 kg increased CL/F by 0.14 l h-1. A trend towards a lower CL/F in patients of the Negroid race was observed. No significant covariates were found for V/F. CONCLUSIONS: The pharmacokinetics of nevirapine were adequately described by our population pharmacokinetic model. Weight, chronic HCV infection, and baseline ASAT were found to be significant covariates for CL/F of nevirapine. The model incorporating these significant covariates may be an important aid in further optimizing nevirapine-containing therapy.     

他克莫司在中国肾移植患者中的群体药物动力学研究

本研究旨在考察口服他克莫司(tacrolimus)在中国肾移植患者中的群体药物动力学特征并探讨群体药物动力学参数和相关因素间的关系。研究中回顾性搜集了58例肾移植患者的802份他克莫司稳态全血样本资料。患者随机分为模型建立组(41例)和模型验证组(17例)。用非线性混合效应模型(NONMEM)程序中的一级评估法(first-order estimation，FO)对模型建立组的数据进行分析。计算清除率(CL/F)、表观分布容积(V/F)的群体典型值，定量评价人口统计学指标、生化指标和合并用药等固定效应因素对药物动力学参数的影响。单室一级吸收和消除模型能够较好地拟合数据。最终模型包含了移植术后时间(POD)、红细胞压积(HCT)、谷草转氨酶(AST)、合并使用佩尔地平(NICA)和地尔硫(DIL)等对CL/F的影响。用模型验证组数据进行验证的结果表明观测值和模型预测值之间没有明显的偏倚，模型的稳定性和准确度较好。CL/F和V/F的群体典型值分别为21.7 L·h^-1和241 L；相应的个体间变异分别为41.6%和49.7%。观测值与预测值之间的残差SD为2.19 μg·L^-1。本文建立的模型可以为临床他克莫司剂量选择提供一定参考。