Population pharmacokinetics of mycophenolic acid and its glucuronide metabolite in lung transplant recipients with and without cystic fibrosis

1.?Cystic fibrosis (CF) is a disease affecting multiple organs that may reduce the systemic exposure of some drugs. The objective of this work was to characterize and compare the population pharmacokinetics (PK) of the immunosuppressant mycophenolic acid (MPA), and its glucuronide metabolite (MPAG) in adult lung transplant recipients with and without CF (NCF) following repeated oral administration of the prodrug mycophenolate mofetil (MMF).

2.?A population PK model was developed, with simultaneous modeling of MPA and MPAG, using nonlinear mixed effects modeling. MPA and MPAG serum concentration-time data were adequately described by a compartmental model including enterohepatic recirculation (EHR). Both MPA and MPAG apparent clearance values were significantly elevated (>65%) in patients with CF (24.1 and 1.95?L/h, respectively) compared to the values in the NCF patients (14.5 and 1.12?L/h, respectively), suggesting a notable influence of CF on MPA absorption and disposition.

3.?The population PK model developed from our study successfully characterized the absorption, distribution, elimination and EHR of MPA and the metabolite MPAG in lung transplant recipients with or without CF. This model may help to further understand the impact of CF to the overall clinical effects of MPA therapy including immunosuppression and gastrointestinal side effects.     

Column-switching chromatographic determination of itraconazole and its metabolite hydroxy-itraconazole in human serum

A column-switching HPLC assay is described for the determination of the antifungal agent itraconazole and its main metabolite hydroxy-itraconazole in serum samples. Three precolumns packed with alkyl-diol silica sorbents differing in alkyl chain length are compared in the sample clean-up step. Chromatographic separation is achieved with a Symmetry C8 column. The assay presented shows a robust and selective analytical procedure with low requirements for sample quantity, no manual sample treatment and high sample throughput.     

Population pharmacokinetics of melphalan in paediatric blood or marrow transplant recipients

AIM: To develop a population pharmacokinetic model for melphalan in children with malignant diseases and to evaluate limited sampling strategies for melphalan. METHODS: Melphalan concentration data following a single intravenous dose were collected from 59 children with malignant diseases aged between 0.3 and 18 years. The data were split into two sets: the model development dataset (39 children, 571 concentration observations) and the model validation dataset (20 children, 277 concentration observations). Population pharmacokinetic modelling was performed with the NONMEM software. Stepwise multiple linear regression was used to develop a limited sampling model for melphalan. RESULTS: A two-compartment model was fitted to the concentration-vs.-time data. The following covariate population pharmacokinetic models were obtained: (i) Clearance (l h(-1)) = 0.34.WT - 3.17.CPT + 0.0377.GFR, where WT = weight (kg), CPT = prior carboplatin therapy (0 = no, 1 = yes), and GFR = glomerular filtration rate (ml min(-1) 1.73 m(-2)); (ii) Volume of distribution (l) = 1.12 + 0.178.WT. Interpatient variability (coefficient of variation) was 27.3% for clearance and 33.8% for volume of distribution. There was insignificant bias and imprecision between observed and model-predicted melphalan concentrations in the validation dataset. A three-sample limited sampling model was developed which adequately predicted the area under the concentration-time curve (AUC) in the development and validation datasets. CONCLUSIONS: A population pharmacokinetic model for melphalan has been developed and validated and may now be used in conjunction with pharmacodynamic data to develop safe and effective dosing guidelines in children with malignant diseases.     

Population pharmacokinetics of tacrolimus in Asian paediatric liver transplant patients

AIMS: The purpose of this study was to describe the population pharmacokinetics of intravenous and oral tacrolimus (FK506) in 20 Asian paediatric patients, aged 1-14 years, following liver transplantation and to identify possible relationships between clinical covariates and population parameter estimates. METHODS: Details of drug dosage histories, sampling times and concentrations were collected retrospectively from routine therapeutic drug monitoring data accumulated for at least 4 days after surgery. Before analysis, patients were randomly allocated to either the population data set (n = 16) or a validation data set (n = 4). The population data set was comprised of 771 concentration measurements of patients admitted over the last 3 years. Population modelling using the nonlinear mixed-effects model (NONMEM) program was performed on the population data set, using a one-compartment model with first-order absorption and elimination. Population average parameter estimates of clearance (CL), volume of distribution (V) and oral bioavailability (F) were sought; a number of clinical and demographic variables were tested for their influence on these parameters. RESULTS: The final optimal population models related clearance to age, volume of distribution to body surface area and bioavailability to body weight and total bilirubin concentration. Predictive performance of this model evaluated using the validation data set, which comprised 86 concentrations, showed insignificant bias between observed and model-predicted blood tacrolimus concentrations. A final analysis performed in all 20 patients identified the following relationships: CL (l h-1) = 1.46 *[1 + 0. 339 * (AGE (years) -2.25)]; V (l) = 39.1 *[1 + 4.57 * (BSA (m2)-0. 49)]; F = 0.197 *[1 + 0.0887 * (WT (kg) -11.4)] and F = 0.197 *[1 + 0.0887 * (WT (kg) -11.4)] * [1.61], if the total bilirubin > or = 200 micromol l-1. The interpatient variabilities (CV%) in CL, V and F were 33.5%, 33.0% and 24.1%, respectively. The intrapatient variability (s.d.) among observed and model-predicted blood concentrations was 5.79 ng ml-1. CONCLUSIONS: In this study, the estimates of the pharmacokinetic parameters of tacrolimus agreed with those obtained from conventional pharmacokinetic studies. It also identified significant relationships in Asian paediatric liver transplant patients between the pharmacokinetics of tacrolimus and developmental characteristics of the patients.     

环孢素A对兔体内伊曲康唑及其代谢物羟基伊曲康唑的药动学影响

目的:探讨环孢素A(CsA)与伊曲康唑在兔体内合用后,环孢素A对伊曲康唑ITZ和羟基伊曲康唑(OH-ITZ)的药动学影响。方法:24只新西兰兔随机分成3组进行平行对照实验。第1组为健康对照组,单侧耳缘静脉注射(ITZ);第2组为免疫力低下组,单侧耳缘静脉注射ITZ;第3组为免疫力低下组,于免疫抑制兔中单侧耳缘静脉分别注射CsA和ITZ。用高效液相色谱-荧光法测定血浆中ITZ和OH-ITZ的浓度,采用Winnolin非房室模型计算药动学参数。结果:免疫力低下兔组中,第3组与第2组比较,ITZ的药动学参数差异无显著性(P>0.05),而OH-ITZ的AUC0-48 h明显增加,即(4 753.1±1 241.7)h.μg.L-1 vs(7 134.1±3 111.1)h.μg.L-1,P<0.05;峰浓度Cmax也明显变大,即(299.4±60.5)μg.L-1 vs(472.9±267.8)μg.L-1,P<0.05,但达峰时间tmax和半衰期t1/2则无统计学意义。第1组与第2,3组比较,ITZ t1/2明显增大,即分别(12.3±5.5)h vs(7.0±1.6)h vs(8.0±3.8)h,P<0.05。...     

Population pharmacokinetics of aminoglycoside antibiotics in patients with cystic fibrosis.

The population pharmacokinetics of gentamicin and tobramycin were investigated in a group of 51 young adults with cystic fibrosis. Their ages ranged from 14-35 years, weights from 38-82 kg, and 27 of the patients were female. None of the patients had renal impairment, but 3 patients were treated in the intensive therapy unit (ITU) during one of their courses of therapy. Data comprised 219 courses of therapy and 544 concentrations (mean: 11 per patient). Concentration-time data were analyzed using a nonlinear mixed-effects model package (NONMEM) and were best described by a one-compartment model. Factors identified as potentially influencing aminoglycoside pharmacokinetics were added in a stepwise fashion and the best model found that drug clearance and volume of distribution were related to body surface area and admission to ITU. The mean population estimates were a clearance of 2.89 L/hr/m2 and a volume of distribution of 9.21 L/m2 with a 60% increase in patients who were admitted to ITU. Interpatient variability in clearance and volume were 14% and 8%, respectively. The results suggested that a dose of 120 mg/m2 should achieve an average 1 hour postdose peak of 10 mg/L and trough of <1 mg/L and that higher doses might be required in ITU patients.     

Cyclosporin pharmacokinetics in heart-lung transplant recipients with cystic fibrosis

Cyclosporin (CsA) is currently the main immunosuppressive agent used in organ transplantation with considerable improvement in graft survival. Oral CsA solution is highly lipophilic, and its bioavailability may be reduced in cystic fibrosis (CF) heart-lung transplant recipients with pancreatic, gastrointestinal, and hepatic insufficiency. The bioavailability of oral CsA solution in 7 CF transplant recipients (5 male and 2 female with a mean age of 27 years and a mean weight of 49 kg) and 3 non-CF heart-lung recipients (1 male and 2 female with a mean age of 41 years and a mean weight of 60 kg) was studied.Following intravenous CsA administration, the kinetic curves were similar with no significant difference in the volume of distribution and clearance of CsA demonstrated between the CF and non-CF groups. The mean daily dose of oral CsA in 7 CF subjects (23.3 mg·kg^–1) was significantly higher than the 3 non-CF heart-lung recipients (4.8 mg·kg^–1). The mean maximum blood concentration of CsA for the oral dose was 776 ng·ml^–1 for the 7 CF subjects, which was comparable with the mean peak values of 789 ng·ml^–1 for the 3 non-CF control subjects. Poor enteral absorption of CsA probably accounts for the significantly lower mean bioavailability in the 7 CF subjects (14.9%) compared with the 3 non-CF control subjects (39.4%).The effects on the bioavailability of oral CsA solution by pancreatic enzymes (Creon) and histamine-2 antagonist (ranitidine) were also evaluated in the 7 CF subjects. No significant difference was demonstrated.     

中国成年癫痫患者奥卡西平活性代谢产物的群体药动学

目的：建立中国癫痫患者奥卡西平活性代谢产物10-羟基卡马西平的群体药动学模型,进而取得对癫痫患者有效的数据参数,为癫痫患者给出有针对性的给药治疗依据。方法：通过实地收集参与研究使用奥卡西平片患者血液药物含量监测数据,利用NLME软件来实现近似群体药动学数学逻辑模型,建立基础模型和统计学模型后,考察年龄、体质量、合并用药等潜在影响10-羟基卡马西平药动学的相关变量参数,将Bootstrap估得的和原始数据估得的参数值进行对比分析,确保模型对实验有效以及测验结果稳定,对建立的模型通过自举法进行验证。结果：共收集了119个患者的180个浓度点,所建立的10-羟基卡马西平的群体药动学模型符合一级吸收、一级消除的一室模型,CL/F及V_d/F群体值分别为1.22 L·h^-1和43.21 L;K_a固定为0.5 h^-1。体表面积对10-羟基卡马西平的清除率有显著影响。结论：初步建立了中国癫痫患者奥卡西平活性代谢产物10-羟基卡马西平的群体药动学模型,为癫痫患者给出了有针对性的给药治疗依据。     

Altered pharmacokinetics of cyclosporin in heart-lung transplant recipients with cystic fibrosis

The cyclosporin dose versus blood concentration relationship for 11 heart-lung transplant recipients with cystic fibrosis was studied retrospectively. Eleven patients, closely matched for age and gender, who received heart-lung transplantation for other diseases were selected as controls. Cystic fibrosis patients received 16.7 (SD 7.2) mg/kg/day of oral cyclosporin compared with 8.2 (SD 1.9) mg/kg/day given to the control patients (p less than 0.01). Nine of the cystic fibrosis patients received higher mean daily doses of cyclosporin. Mean blood cyclosporin concentrations were, however, not significantly different (p = 0.58), and there were no apparent differences in clinical outcome in terms of rejection, infection, and nephrotoxicity in the two groups. The apparent oral clearance of cyclosporin was significantly higher (p less than 0.01) in cystic fibrosis patients. Cyclosporin dosage individualization with the aid of cyclosporin blood concentration measurements is critically important in this subpopulation of heart-lung transplant recipients.     

Population pharmacokinetics of valganciclovir prophylaxis in paediatric and adult solid organ transplant recipients

Aim

Our aims were to quantify ganciclovir pharmacokinetics in paediatric and adult kidney, liver and lung transplant patients taking a range of valganciclovir doses to prevent herpes virus infections, including a 450 mg regimen, and to identify sources of pharmacokinetic variability.

Method

Plasma samples were collected at 2, 4, 8 and 12 weeks post-transplant and at 4, 6, 8 and 12 months post-transplant in subjects prescribed longer courses. Ganciclovir was measured by liquid chromatography/ultraviolet detection. Non-linear mixed effects modelling was used to analyze the concentration–time data and evaluate demographic and transplant-related covariates.

Results

A two compartment model with first order absorption best described the data. Given the range of body sizes, clearance and volume of distribution terms were scaled using standard weight-based allometric exponents. Creatinine clearance was included on apparent oral clearance. Final estimates in a standard 70 kg individual for apparent oral clearance, central volume of distribution, intercompartmental clearance and peripheral volume of distribution were 14.5 l h⁻¹, 87.5 l, 4.80 l h⁻¹ and 42.6 l, respectively. The median terminal half-life for kidney, liver and lung transplant recipients was 9.4, 9.5 and 8.2 h, respectively. Median exposure (i.e. AUC(0,∞) in subjects taking valganciclovir 900 mg or 450 mg once daily was 57.4 and 34.3 μg ml⁻¹ h, respectively.

Conclusion

Allometric scaling allowed simultaneous analysis of data from children and adults. Ganciclovir pharmacokinetics were similar among kidney, liver and lung transplant recipients. Ganciclovir exposure after valganciclovir 450 mg once daily may be suboptimal in some individuals and requires evaluation along with virologic outcomes data.     

Management of graft-versus-host disease in paediatric bone marrow transplant recipients

We discuss clinical strategies for the prophylaxis and treatment of both acute and chronic graft-versus-host disease (GVHD) with particular attention to children. Grades II to IV acute GVHD occur in 10 to 50% of patients given an allogeneic transplantation of haemopoietic stem cells (HSCT) from a genotypically HLA-identical donor. A significantly higher incidence and severity of the disease is reported in patients receiving transplants from partially matched family donors or unrelated volunteers. Younger individuals or patients receiving HSCT from younger donors develop GVHD less frequently than do older recipients. Severe acute GVHD is characterised by a significant decrease in survival probability, even though the graft-versus-leukaemia activity associated with both acute and chronic GVHD may reduce the risk of leukaemia relapse. Prophylaxis of acute GVHD usually consists of in vivo post-grafting immunosuppression with cyclosporin alone or in combination with methotrexate; methotrexate alone can be considered in leukaemia patients with a high risk of relapse. In recent years, tacrolimus is increasingly being used instead of cyclosporin, alone or in combination with methotrexate. In vitro T cell depletion in paediatric patients is usually reserved for those with transplants from partially matched family donors or unrelated volunteers. The treatment of patients with grades II to IV acute GVHD should be immediate and aggressive, as the quality and duration of the response directly correlates with survival. The overall response rate to treatment is often unsatisfactory, ranging from 40 to 50% of cases. First-line treatment usually consists of corticosteroids. In patients not responding to corticosteroids, antilymphocyte globulin and monoclonal antibodies directed towards lymphocytes and/or cytokines produced during GVHD are employed, but with variable success. Patients experiencing acute GVHD are also prone to develop chronic GVHD. whose classical treatment is based on the use of cyclosporin and corticosteroids. More recently, encouraging results in the treatment of patients with chronic GVHD have been reported with the use of extracorporeal photochemotherapy. Other drugs, such as ursodeoxycholic acid, etretinate and clofazimine, are under evaluation.     

Population pharmacokinetics and Bayesian estimation of tacrolimus exposure in paediatric liver transplant recipients

Aims

The objectives of this study were to develop a population pharmacokinetic (PopPK) model for tacrolimus in paediatric liver transplant patients and determine optimal sampling strategies to estimate tacrolimus exposure accurately.

Methods

Twelve hour intensive pharmacokinetic profiles from 30 patients (age 0.4–18.4 years) receiving tacrolimus orally were analysed. The PopPK model explored the following covariates: weight, age, sex, type of transplant, age of liver donor, liver function tests, albumin, haematocrit, drug interactions, drug formulation and time post-transplantation. Optimal sampling strategies were developed and validated with jackknife.

Results

A two-compartment model with first-order absorption and elimination and lag time described the data. Weight was included on all pharmacokinetic parameters. Typical apparent clearance and central volume of distribution were 12.1 l h⁻¹ and 31.3 l, respectively. The PopPK approach led to the development of optimal sampling strategies, which allowed estimation of tacrolimus pharmacokinetics and area under the concentration–time curve (AUC) on the basis of practical sampling schedules (three or four sampling times within 4 h) with clinically acceptable prediction error limit. The mean bias and precision of the Bayesian vs. reference (trapezoidal) AUCs ranged from −2.8 to −1.9% and from 7.4 to 12.5%, respectively.

Conclusions

The PopPK of tacrolimus and empirical Bayesian estimates represent an accurate and convenient method to predict tacrolimus AUC_(0–12) in paediatric liver transplant recipients, despite high between-subject variability in pharmacokinetics and patient demographics. The developed optimal sampling strategies will allow the undertaking of prospective trials to define the tacrolimus AUC-based therapeutic window and dosing guidelines in this population.     

肝移植患者术后口服他克莫司群体药动学研究

目的:考察肝移植患者术后口服他克莫司的群体药动学模型,为临床个体化用药提供参考。方法:回顾性收集天津市第一中心医院18例肝移植患者术后口服他克莫司12 h全血药浓度监测数据145个。运用非线性混合效应模型(nonlinear mixed effect model,NONMEM)建立他克莫司群体药动学模型,并考察了年龄、性别、移植术后天数、血清肌酐等固定效应对药动学参数的影响,得到最终模型方程,最后利用Bayesian反馈得到的个体药动学参数值进行个体化给药方案设计。结果:本次研究建立起了口服他克莫司一级吸收和消除的二房室群体药动学模型,并通过NONMEM模拟程序为1例患者进行了个体化给药设计。结论:NONMEM法建立的模型能较好地估算他克莫司的个体及群体药动学参数,为临床合理使用他克莫司提供参考依据。     

Population pharmacokinetics of clozapine and its primary metabolite norclozapine in Chinese patients with schizophrenia

Aim:

To develop a combined population pharmacokinetic model (PPK) to assess the magnitude and variability of exposure to both clozapine and its primary metabolite norclozapine in Chinese patients with refractory schizophrenia via sparse sampling with a focus on the effects of covariates on the pharmacokinetic parameters.

Methods:

Relevant patient concentration data (eg, demographic data, medication history, dosage regimen, time of last dose, sampling time, concentrations of clozapine and norclozapine, etc) were collected using a standardized data collection form. The demographic characteristics of the patients, including sex, age, weight, body surface area, smoking status, and information on concomitant medications as well as biochemical and hematological test results were recorded. Persons who had smoked 5 or more cigarettes per day within the last week were defined as smokers. The concentrations of clozapine and norclozapine were measured using a HPLC system equipped with a UV detector. PPK analysis was performed using NONMEM. Age, weight, sex, and smoking status were evaluated as main covariates. The model was internally validated using normalized prediction distribution errors.

Results:

A total of 809 clozapine concentration data sets and 808 norclozapine concentration data sets from 162 inpatients (74 males, 88 females) at multiple mental health sites in China were included. The one-compartment pharmacokinetic model with mixture error could best describe the concentration-time profiles of clozapine and norclozapine. The population-predicted clearance of clozapine and norclozapine in female nonsmokers were 21.9 and 32.7 L/h, respectively. The population-predicted volumes of distribution for clozapine and norclozapine were 526 and 624 L, respectively. Smoking was significantly associated with increases in the clearance (clozapine by 45%; norclozapine by 54.3%). The clearance was significantly greater in males than in females (clozapine by 20.8%; norclozapine by 24.2%). The clearance of clozapine and norclozapine did not differ significantly between Chinese patients and American patients.

Conclusion:

Smoking and male were significantly associated with a lower exposure to clozapine and norclozapine due to higher clearance. This model can be used in individualized drug dosing and therapeutic drug monitoring.     

伏立康唑在肾移植患者中的群体药动学研究

目的：建立肾移植患者服用伏立康唑的群体药动学（PopPK）特征,探究影响伏立康唑药动学参数的因素,为临床个体化给药提供依据。方法：回顾性收集84例肾移植患者进行治疗药物监测的谷浓度和生理病理资料,利用Phoenix NLME软件建模,并用VPC法和Bootstrap法进行内部验证。结果：肾移植患者的伏立康唑的药动学特征符合一级消除一室模型,最终PopPK模型为：表观分布容积V（L）=183.69×[1+（HGB-98）×0.016]×exp（η_V）,清除率CL（L·h^-1）=7.24×[1+（ALB-36）×0.037]×exp（η_CL）。结论：血红蛋白（HGB）对V有显著影响,白蛋白（ALB）对CL有显著影响,所建PopPK模型较稳定,可以较好地描述肾移植患者伏立康唑的药动学特征。     

The pharmacokinetics of colistin in patients with cystic fibrosis

The safety and pharmacokinetics of colistin were determined after first dose (n = 30) and again under steady-state conditions (n = 27) in 31 patients with cystic fibrosis receiving the drug as a component of their treatment for an acute pulmonary exacerbation of their disease. Patients ranged in age from 14 to 53 years and received colistin for 6 to 35 days. Each patient was started on colistin 5 to 7 mg/kg/day administered intravenously in three equally divided doses. Elimination half-life (t1/2), mean residence time (MRT), steady-state volume of distribution (Vdss), total body clearance (Cl), and renal clearance (Clr) after first-dose administration averaged 3.4 hours, 4.4 hours, 0.09 l/kg, and 0.35 and 0.24 ml/min/kg, respectively. No differences in colistin disposition characteristics between first-dose and steady-state evaluations were observed. Sputum sampling was incomplete and confounded by previous aerosol administration but revealed colistin concentrations that markedly exceeded observed plasma concentrations. Twenty-one patients experienced one or more side effects attributed to colistin administration. The most common reactions involved reversible neurologic manifestations, including oral and perioral paresthesias (n = 16), headache (n = 5), and lower limb weakness (n = 5). All of these apparent colistin-induced neurologic adverse effects, though bothersome, were benign and reversible. Intermittent proteinuria was observed on urinalysis in 14 patients, and 1 patient developed reversible, colistin-induced nephrotoxicity. No relationship between the occurrence of any colistin-associated adverse effect and plasma colistin concentration or colistin pharmacokinetic parameter estimate was observed. These data provide no basis for routine monitoring of colistin plasma concentrations to guide dosing for patient safety and suggest slow upward dose titration to minimize the incidence and severity of associated side effects.     

Population pharmacokinetics and bioavailability of tacrolimus in kidney transplant patients

What is already known about this subject

• In spite of its success in ensuring graft survival, therapeutic use of tacrolimus is complicated by its narrow therapeutic index and wide intra- and interpatient variability.
• Some studies of population pharmacokinetics have already been conducted in liver transplant recipients and in paediatric patients.

What this study adds

• Our work determined population pharmacokinetic parameters, in particular bioavailability, in kidney transplant recipients and the relative importance of factors influencing the disposition of tacrolimus.
• Clearance was modelled and days postoperation and corticosteroids dose were significant covariates.

Aims

The use of tacrolimus is complicated by its narrow therapeutic index and wide intra- and interpatient variability. Tacrolimus population pharmacokinetics, including bioavailability, were investigated in an adult kidney transplant cohort to identify patient characteristics that influence pharmacokinetics.

Methods

The database (drug monitoring data) included 83 adult kidney transplant recipients and analysis was performed by a population approach with NONMEM. Data were collected during the first months after transplantation. Patients were administered oral or intravenous tacrolimus as part of a triple immunosuppressive regimen that also included mycophenolate mofetil and corticosteroids. Subsequent doses were adjusted on the basis of clinical evidence of efficacy and toxicity as in routine therapeutic drug monitoring.

Results

A one compartment open model with linear absorption and elimination adequately described the data. The typical value of minimal clearance was 1.8 ± 0.2 l h⁻¹. Clearance increased with time post transplantation to reach 50% of maximal value after 3.8 ± 0.5 days, with a maximal value of 5.6 l h⁻¹. Moreover clearance increased by approximately 1.6 fold (range 0.5–1.6) if the dose of prednisone was >25 mg. The typical value for volume of distribution, V, (98 ± 13 l kg⁻¹) was similar to reported values in kidney transplant patients. The oral bioavailability of tacrolimus was poor and ranged from 11.2 to 19.1%. No covariates significantly influenced V or F.

Conclusions

The number of days postoperation and corticosteroid dose were significant covariates influencing tacrolimus clearance.