Population pharmacokinetics of mycophenolic acid in children and young people undergoing blood or marrow and solid organ transplantation

AIMS

To characterize the population pharmacokinetics of mycophenolic acid (MPA) and evaluate dose regimens using a simulation approach and accepted therapeutic drug monitoring targets in children and young people undergoing blood or marrow, kidney and liver transplantation.

METHODS

MPA concentration–time data were collected using an age specific sampling protocol over 12 h. Some patients provided randomly timed but accurately recorded blood samples. Total and unbound MPA were measured by HPLC. NONMEM was employed to analyze MPA pharmacokinetic data. Simulations (n = 1000) were conducted to assess the suitability of the MPA dose regimens to maintain total MPA AUC(0,12 h) within the range 30 and 60 mg l⁻¹ h associated with optimal outcome.

RESULTS

A two-compartment pharmacokinetic model with first-order elimination best described MPA concentration–time data. Population mean estimates of MPA clearance, inter-compartmental clearance, volumes of distribution in the central and peripheral compartments, absorption rate constant and bioavailability were 6.42 l h⁻¹, 3.74 l h⁻¹, 7.24 l, 16.8 l, 0.39 h⁻¹ and 0.48, respectively. Inclusion of bodyweight and concomitant ciclosporin reduced the inter-individual variability in CL from 54.3% to 31.6%. Children with a bodyweight of 10 kg receiving standard MPA dose regimens achieve an MPA AUC below the target range suggesting they may be at a greater risk of acute rejection.

CONCLUSIONS

The population pharmacokinetic model for MPA can be used to explore dosing guidelines for safe and effective immunotherapy in children and young people undergoing transplantation.     

Investigation on pharmacokinetics of mycophenolic acid in Chinese adult renal transplant patients

AIMS: To characterize the pharmacokinetics of mycophenolic acid (MPA) in Chinese renal transplant patients. METHODS: Thirty-one renal transplant patients (17 male, 14 female) receiving mycophenolate mofetil (MMF) 1.0 g twice daily were included in this study. A pharmacokinetic study was performed during an interval in dosing after steady state had been reached within 2 months after transplantation. The plasma MPA concentration were measured by high-performance liquid chromatography (HPLC) at 0.5, 1, 1.5, 2, 4, 6, 8, 10 and 12 h after the administration of a single dose. Pharmacokinetic parameters were calculated with 3P97 software. SAS software was used for statistical analysis. Multiple linear regression analysis was used to determine limited sampling approaches. RESULTS: The mean peak plasma concentration (C(max)) and area under the concentration-time curve (AUC(0-12)) were 19.67 +/- 8.21 microg ml(-1) and 52.16 +/- 12.50 microg h ml(-1), but there was large variability in these pharmacokinetic parameters. Regression analysis between each plasma concentration and AUC for the limited sampling strategy of MMF therapeutic drug monitoring demonstrated that each of the concentrations at 0.5, 1, 4 and 10 h was positively correlated with AUC (r = 0.60, P = 0.0004; r = 0.60, P = 0.0003; r = 0.61, P = 0.0003; r = 0.64, P = 0.0001, respectively). The combined use of these four samples explained over 90% of the variance in the total (nine-point) AUC(0-12). A formula was obtained for the assessment of MPA AUC based on four samples: MPA AUC = 12.61 + 0.37 x C(0.5) + 0.49 x C(1) + 3.22 x C(4) + 8.17 x C(10). CONCLUSIONS: Chinese renal transplant patients had higher median AUCs than caucasians and African-Americans. As in other studies, there was large interindividual variability. A limited four-point AUC was in good agreement with the 12-h AUC and provided the basis of a predictive formula.     

霉酚酸在肝移植受者的药代动力学与药效学相关性研究

目的研究肝移植受者早期口服霉酚酸(免疫抑制剂)药代动力学与药效学的相关性。方法20例肝移植受者口服霉酚酸酯前、后,用酶增强免疫法测定患者血浆霉酚酸浓度。服药前(0h)及服药后1,2h,用患者血清处理人急性淋巴细胞白血病T淋巴(CEM)细胞,检测CEM细胞的增殖情况。结果口服霉酚酸酯前,CEM细胞增殖率显著高于服药后1,2h(P<0.05);服药后1,2h霉酚酸浓度与相应的CEM细胞增殖率呈负相关(P<0.05)。结论肝移植受者口服霉酚酸酯后,血清对CEM细胞的增殖产生显著抑制作用,其作用和霉酚酸浓度呈显著负相关。     

霉酚酸在肝移植病人体内的药代动力学研究

目的研究免疫抑制剂霉酚酸酯(MMF)的活性代谢物霉酚酸(MPA)在肝移植病人体内的药代动力学。方法38例肝移植病人(男30例，女8例)术后早期按推荐剂量(每次1.0 g，每天两次)口服MMF达稳态，在给予一个早晨的剂量(1.0 g)后，在1个给药间隔内，于给药前及给药后不同时间点采血，用HPLC法测定MPA血药浓度，用3P97软件计算药代动力学参数。结果病人口服MMF后，血浆MPA浓度在给药后0.5～6.0 h内达峰值，部分病人在给药后4～12 h出现第2个小峰，血药峰浓度(C_max)和药-时曲线下面积(AUC_{0-12 h})均值分别为(12±7) μg·mL^-1和(44±16) μg·h·mL^-1，病人个体间存在较大差异。结论MPA在肝移植病人体内的药代动力学存在较大个体差异，提示在临床用药时需要监测MPA血药浓度，进行个体化给药。     

Population pharmacokinetics of mycophenolic acid and dose optimization with limited sampling strategy in liver transplant children

AIMS

The aims were to estimate the mycophenolic acid (MPA) population pharmacokinetic parameters in paediatric liver transplant recipients, to identify the factors affecting MPA pharmacokinetics and to develop a limited sampling strategy to estimate individual MPA AUC(0,12 h).

METHODS

Twenty-eight children, 1.1 to 18.0 years old, received oral mycophenolate mofetil (MMF) therapy combined with either tacrolimus (n= 23) or ciclosporin (n= 5). The population parameters were estimated from a model-building set of 16 intensive pharmacokinetic datasets obtained from 16 children. The data were analyzed by nonlinear mixed effect modelling, using a one compartment model with first order absorption and first order elimination and random effects on the absorption rate (k_a), the apparent volume of distribution (V/F) and apparent clearance (CL/F).

RESULTS

Two covariates, time since transplantation (≤ and >6 months) and age affected MPA pharmacokinetics. k_a, estimated at 1.7 h⁻¹ at age 8.7 years, exhibited large interindividual variability (308%). V/F, estimated at 64.7 l, increased about 2.3 times in children during the immediate post transplantation period. This increase was due to the increase in the unbound MPA fraction caused by the low albumin concentration. CL/F was estimated at 12.7 l h⁻¹. To estimate individual AUC(0,12 h), the pharmacokinetic parameters obtained with the final model, including covariates, were coded in Adapt II® software, using the Bayesian approach. The AUC(0,12 h) estimated from concentrations measured 0, 1 and 4 h after administration of MMF did not differ from reference values.

CONCLUSIONS

This study allowed the estimation of the population pharmacokinetic MPA parameters. A simple sampling procedure is suggested to help to optimize pediatric patient care.     

Population pharmacokinetics of ciclosporin in haematopoietic allogeneic stem cell transplantation with emphasis on limited sampling strategy

AIM

To develop a population pharmacokinetic model of ciclosporin (CsA) in haematopoietic allogeneic stem cell transplantation to facilitate a limited sampling strategy to determine systemic exposure (area under the curve [AUC]), in order to optimize CsA therapy in this patient population.

METHODS

The pharmacokinetics of CsA were investigated prospectively in 20 patients following allogeneic haematopoietic stem cell transplantation (HSCT). CsA was given twice daily, as a 3 h i.v. infusion starting at day 1 of the conditioning scheme, and orally later on, when oral intake was well tolerated. Fluconazole was given as antimycotic prophylaxis. Pharmacokinetic parameter estimation was performed using nonlinear mixed effect modelling as implemented in the NONMEM program. A first order absorption model with lag time was compared with Erlang frequency distribution and Weibull distribution models. The influence of demographic variables on the individual empirical Bayesian estimates of clearance and distribution volume was tested. Subsequently two limited sampling strategies (LSS) were evaluated: posterior Bayesian fitting and limited sampling equations.

RESULTS

Twenty patients were included and 435 samples were collected after i.v. and oral administration of CsA. A two compartment model with first order absorption best described the data. Clearance (CL) was 21.9 l h⁻¹ (relative standard deviation [RSD]± 5.2%) with an inter-individual variability of 21%. The central volume of distribution (V_c) was 18.3 l (RSD ± 8.7%) with an inter-individual variability of 29%. Bioavailability (F) was 0.71 (RSD ± 9.9%) with and inter-individual variability of 25% and lag time (t_lag) was 0.44 h (RSD 5.5%). Weight, body surface area, haematocrit, albumin, ALAT and ASAT had no significant influence on pharmacokinetic parameters. The best multiple point combination for posterior Bayesian fitting, in terms of estimating systemic CsA exposure, appeared to be C0 + C2 + C3.Two selected LSS two time point equations and all selected three and four time point equations predicted de all AUC(0,12 h) within 15% bias and prediction.

CONCLUSIONS

The i.v. and oralcurves were best described with a two compartment model with first-order absorption with lag time. With the Bayesian estimators from this model, the area under the concentration−time curve in HSCT patients taking fluconazole can be estimated with only three blood samples (0, 2, 3 h) with a bias of 1% and precision of 4%.     

Population pharmacokinetics of unbound mycophenolic Acid in pediatric and young adult patients undergoing allogeneic hematopoietic cell transplantation

Mycophenolate mofetil (MMF) is an immunosuppressant routinely used in allogeneic hematopoietic cell transplantation (alloHCT) to promote stem cell engraftment and prevent acute graft vs host disease. Administered as a prodrug, MMF is converted by esterases to the active moiety, mycophenolic acid (MPA). The impact of clinical covariates on unbound MPA exposure was investigated with a population pharmacokinetic approach. Pharmacokinetic data were obtained from routine area under the curve (AUC) monitoring of unbound MPA drug levels in 36 pediatric (n = 31) and young adult (n = 5) patients undergoing alloHCT for a variety of malignant and nonmalignant disorders. Unbound MPA pharmacokinetics were well described by a 2-compartment model with linear elimination and first-order absorption. The important clinical covariates affecting unbound MPA pharmacokinetics were weight, estimated creatinine clearance, and total bilirubin. Unbound MPA clearance was reduced, and exposure (AUC(0-8)) increased in individuals with decreased renal function. In individuals with severe hepatic dysfunction (total bilirubin >10 mg/dL) unbound MPA clearance was approximately 3-fold lower compared with patients with normal to mild hepatic impairment. In alloHCT recipients with renal dysfunction or severe hepatic injury, dose reductions may be necessary to prevent toxicity and ensure optimal immunosuppression.     

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.     

Associations of UDP-glucuronosyltransferases polymorphisms with mycophenolate mofetil pharmacokinetics in Chinese renal transplant patients

Aim:

To evaluate the effects of UDP-glucuronosyltransferases (UGTs) polymorphisms on the pharmacokinetics of the immunosuppressant mycophenolate mofetil (MMF) in Chinese renal transplant recipients.

Methods:

A total of 127 renal transplant patients receiving MMF were genotyped for polymorphisms in UGT1A9 −1818T>C, I399C>T, −118T9/10, −440C>T, −331T>C, UGT2B7 IVS1+985A>G, 211G>T, −900A>G, UGT1A8 518C>G and UGT1A7 622T>C. The plasma concentrations of the MMF active moiety mycophenolic acid (MPA) and main metabolite 7-O-MPA-glucuronide (MPAG) were analyzed using HPLC. Univariate and multivariate analyses were used to assess the effects of UGT-related gene polymorphisms on MPA pharmacokinetics.

Results:

The dose-adjusted MPA AUC_{0–12 h} of the patients with the UGT2B7 IVS1+985AG genotype was 48% higher than that of the patients with the IVS1+985AA genotype, which could explain 11.2% of the inter-individual variation in MPA pharmacokinetics. The dose-adjusted MPAG AUC_{0–12 h} of the patients with the UGT1A7 622CC and UGT1A9 −440CT/−331TC genotypes, respectively, was significantly higher than that of the patients with 622T homozygotes and −440C/−331T homozygotes. Furthermore, the genotypes UGT1A9 −1818T>C and UGT1A8 518C>G were associated with a low dose-adjusted MPAG AUC_{0–12 h}.

Conclusion:

The UGT2B7 11+985A>G genotype is associated with the pharmacokinetics of MPA in Chinese renal transplant patients, which demonstrates the usefulness of this SNP for individualizing MMF dosing.     

Population pharmacokinetics of oral high-dose busulfan in adult patients undergoing hematopoietic stem cell transplantation

Background and the purpose of the study

Many factors have been reported that contribute to the wide intra- and inter-patient variability of Busulfan (Bu) disposition. The purpose of this study was to develop a population pharmacokinetic model and to determine the covariates affecting the pharmacokinetics (PK) of Bu in Iranian adult patients who received oral high-dose as a conditioning regimen before Hematopoietic Stem Cell Transplantation (HSCT).

Methods

A population PK analysis was performed in 30 patients who received an oral Bu and cyclophosphamide regimen before HSCT. Bu was given orally according to the protocol of the institution. In order to prevent seizures caused by Bu, phenytoin was administered orally one hour before each dose of Bu.A total of 180 blood samples were analyzed by HPLC and PK parameters were estimated by the non-linear mixed effect model by MONOLIX 3.1 program. A one-compartment model with an additive error model was used to describe the concentration-time profile of Bu.

Results

Patients’ disease and weight was found to be the determinant factors for clearance (CL) and the volume of distribution (Vd) according to Monolix analysis. The covariate entered in final model followed by these equations:CL = 13.4[1 + (0.141 × Disease)],  Vd = 42.6[1 + 0.010 × (Weight - 63.9)] In this limited study, the age (15–43 years) had no significant effect. For a patient weighting 60 kg, the typical CL and Vd were estimated to be 13.4 l/hr and 42.6 L, respectively. The interindividual variability of CL and Vd were 13.6 and 6.3%, respectively. There was no significant metabolic induction in these four days as is evident by comparing the trough levels of Bu. However it should be mentioned that, one tailed t-test p-values of the days of two and three, two and four and three and four were 0.083, 0.069 and 0.388, respectively.

Major conclusions

Results of this study showed that the type of disease was a determinant of CL and the weight of patient was a determinant of Vd for Bu population PK parameters. A reliable PK parameters and Css, estimated from only one plasma concentrations (5 hrs after the first dose), were validated. Since these methods require few sampling and are easy to be used, the limited sampling methods might be advantageous in the routine clinical practice.     

异基因造血干细胞移植患者全血中环孢素A浓度的监测分析

目的对我院2000~2003年间所进行的异基因造血干细胞移植(allo-HSCT)患者全血中环孢素A(CsA)浓度的监测结果加以分析,以便探讨其临床有效性和安全性,为更好地开展CsA浓度监测和科研工作提供参考。方法采用反相高效液相色谱法(RP-HPLC)测定12例allo-HSCT患者全血中CsA浓度。结果全血中CsA线性范围为25~1600μg.L-1,最低检测浓度为10μg.L-1,回收率为90.14%,日内和日间变异均小于9.0%。监测allo-HSCT患者CsA血药浓度共107例次:达有效血药浓度(100~400μg.L-1)74例次(69.2%);低于100μg.L-1为19例次(17.7%);高于400μg.L-1为14例次(13.1%)。12例患者CsA平均血药浓度为218.61±110.04μg.L-1,每位患者的血药浓度波动较大,且个体差异也较大。结论CsA血药浓度受多种因素的影响,对allo-HSCT患者进行CsA浓度监测具有重要的临床意义。     

Population pharmacokinetics analysis of intravenous busulfan in Chinese patients undergoing hematopoietic stem cell transplantation

There are several reports describing population pharmacokinetic (popPK) models of busulfan (BU). However, limited information is available in Chinese hematopoietic stem cell transplantation (HSCT) patients. The present study aimed to establish a popPK model of intravenous BU in Chinese HSCT patients for individualized drug therapy. The popPK model of BU was developed from a total of 284 concentration–time points from 53 patients. The effects of demographic and biochemical covariates were investigated by nonlinear mixed effect model (NONMEM) software. Plots, visual predictive check (VPC), bootstrap and normalized prediction distribution error (NPDE) were performed to determine the stability and the reliability of the final model. A one‐compartment model with first‐order elimination process was confirmed as the final structural model for BU. For a typical patient whose body surface area (BSA) is 1.7 m², the population typical values of CL and Vd were 11.86 L/h, and 48.2 L, respectively. The result suggested BSA showed significant influence on CL and Vd (P<.001). Plots revealed the final model was performing a goodness fit. The steady rate verified by bootstrap was 100%, relative deviation was less than 4.00%, estimated value of final model was in the 95% confidence interval (CI). The VPC results showed the observed values were almost all positioned within the 5th and 95th CIs. The mean and variance of the NPDE were 0.0363 (Wilcoxon signed‐rank test, 0.298) and 0.877 (Fisher variance test, 0.134; SW test of normality, 0.108), respectively. The global adjusted P value was 0.305, which indicated that the prediction of the BU popPK model was adequate. A physician‐friendly Microsoft Excel‐base tool was implemented using the final popPK model for designing individualized dosing regimens.     

用HPLC-MS/MS法同时测定Caco-2细胞单层转运介质中吗替麦考酚酯和麦考酚酸的浓度

目的:建立HPLC-MS/MS法同时测定Caco-2细胞单层转运介质中吗替麦考酚酯(mycophenolate mofetil,MMF)和麦考酚酸(mycophenolic acid,MPA)的浓度,用于药物转运实验研究。方法:采用Zorbax Eclipse XDB-C18色谱柱(50mm×2.1mm,3.5μm);流动相A相:甲醇(含0.05%甲酸),B相:水(含0.05%甲酸);梯度洗脱:0～3.60min,40%A,流速:0.3ml/min,3.61～7.00min,65%A,流速:0.6ml/min,7.01～10.00min,40%A,流速:0.6ml/min;柱温:30℃,以吲哚美辛为内标。质谱检测方式:多种反应监测(MRM),选择监测的离子为:m/z433.8→194.8(MMF),m/z319.1→191.0(MPA)和m/z356.0→312.1(吲哚美辛)。结果:MMF和MPA检测的线性范围均为0.01～20μmol/L,线性回归方程分别为MMF:As/Ai=-0.035 2+0.394 5 c(r=0.999 1);MPA:As/Ai=0.005 5+0.050 8 c(r=0.999 5)。低、中、高浓度(0.1、1.5、15μmol/L)MMF的回收率分别为(103.2±7.5)%、(97.3±3.1)%和(96.0±3.4)%,日内、日间RSD<7.27%;低、中、高浓度(0.1、1.5、15μmol/L)MPA的回收率分别为(106.9±1.0)%、(106.0±5.7)%和(108.4±3.2)%,日内、日间RSD<9.25%(n=5)。结论:本研究建立的测定方法简便、准确、灵敏度高,适用于MMF和MPA体外转运实验研究。     

异基因造血干细胞移植术后患者静脉用环孢素A群体药动学研究

目的：研究并建立环孢素A（cyclosporine,CsA）静脉持续滴注方式在中国异基因造血干细胞移植术后患者中的群体药动学模型,为临床制定个体化给药方案提供依据。方法：回顾性统计了62例行异基因造血干细胞移植术的患者CsA静脉持续滴注期间的血药浓度监测结果共571例次,同时收集患者的人口学资料、临床指标及合并用药等,运用非线性混合效应模型程序建立群体药动学模型。结果：红细胞压积、术后时间以及唑类抗真菌药物的使用是影响清除率的主要协变量。最终模型为CL=θ₁·θ₂^（POD/15）·θ₃^{（HCT/0.26）}·θ₄^ⅠNHⅠ,V=θ₅。CsA清除率（CL）和分布容积（V）的群体典型值分别为28.4 L·h^-1,586.7 L,个体间变异分别为15.8%,52.3%,个体内变异系数为16.2%。Bootstrap法验证模型有效稳定,外部验证结果模型预测值与观察值有较好的相关性。贝叶斯反馈法计算患者CsA的AUC_0-24值为5.17±1.19（2.58~9.94）g·L^-1·h。结论：本研究建立的群体药动学模型可用于异基因造血干细胞移植术后患者CsA的血药浓度预测及个体参数的估算,为个体化治疗提供有效依据。     

Effect of hepatic drug transporter polymorphisms on the pharmacokinetics of mycophenolic acid in patients with severe renal dysfunction before renal transplantation

1.?The objective of this study was to examine the association of UGT1A9, SLCO, and ABCC polymorphisms with mycophenolic acid (MPA) pharmacokinetics in ABO blood type (ABO) incompatible patients with severe renal dysfunction pre-transplantation.

2.?In all patients, on day 14 after beginning mycophenolate mofetil (MMF) treatment (1 week before transplantation) and on day 28 after renal transplantation, samples were collected just prior to and 1, 2, 3, 4, 6, 9, and 12?h after oral MMF administration.

3.?The median dose-adjusted AUC_0–12 of MPA after renal transplantation was significantly lower than before transplantation (57.9 versus 76.5?μg h/mL, respectively, p?=?0.002).

4.?Although the enterohepatic circulation of MPA pre-transplantation was extremely high (57.6%), this level was significantly reduced after renal transplantation (34.6%).

5.?In the multivariate analysis, pre-transplantation, patients with the SLCO1B3 334T allele (p?=?0.003), higher alanine aminotransferase (p?=?0.002), and lower body weight were independently predictive for a higher dose-adjusted AUC_0–12 of MPA.

6.?In patients with severe renal dysfunction pre-transplantation, MPA is excreted mainly to bile from the liver, and as a consequence, the SLCO1B3 334T?>?G polymorphism was found to be significantly associated with MPA exposure.     

Population pharmacokinetics and maximum a posteriori probability Bayesian estimator of abacavir: application of individualized therapy in HIV-infected infants and toddlers

AIMS

To develop a population pharmacokinetic model for abacavir in HIV-infected infants and toddlers, which will be used to describe both once and twice daily pharmacokinetic profiles, identify covariates that explain variability and propose optimal time points to optimize the area under the concentration–time curve (AUC) targeted dosage and individualize therapy.

METHODS

The pharmacokinetics of abacavir was described with plasma concentrations from 23 patients using nonlinear mixed-effects modelling (NONMEM) software. A two-compartment model with first-order absorption and elimination was developed. The final model was validated using bootstrap, visual predictive check and normalized prediction distribution errors. The Bayesian estimator was validated using the cross-validation and simulation–estimation method.

RESULTS

The typical population pharmacokinetic parameters and relative standard errors (RSE) were apparent systemic clearance (CL) 13.4 l h⁻¹ (RSE 6.3%), apparent central volume of distribution 4.94 l (RSE 28.7%), apparent peripheral volume of distribution 8.12 l (RSE14.2%), apparent intercompartment clearance 1.25 l h⁻¹ (RSE 16.9%) and absorption rate constant 0.758 h⁻¹ (RSE 5.8%). The covariate analysis identified weight as the individual factor influencing the apparent oral clearance: CL = 13.4 × (weight/12)^1.14. The maximum a posteriori probability Bayesian estimator, based on three concentrations measured at 0, 1 or 2, and 3 h after drug intake allowed predicting individual AUC_0–t.

CONCLUSIONS

The population pharmacokinetic model developed for abacavir in HIV-infected infants and toddlers accurately described both once and twice daily pharmacokinetic profiles. The maximum a posteriori probability Bayesian estimator of AUC_0–t was developed from the final model and can be used routinely to optimize individual dosing.     

A phase I study on pharmacokinetics and pharmacodynamics of higenamine in healthy Chinese subjects

Aim:

To investigate the pharmacokinetics, pharmacodynamics, and safety of higenamine, an active ingredient of Aconite root, in healthy Chinese volunteers.

Methods:

Ten subjects received continuous, intravenous infusion of higenamine at gradually escalating doses from 0.5 to 4.0 μg·kg⁻¹·min⁻¹, each dose was given for 3 min. Blood and urine samples were collected at designated time points to measure the concentrations of higenamine. Pharmacodynamics was assessed by measuring the subject''s heart rate. A nonlinear mixed-effect modeling approach, using the software Phoenix NLME, was used to model the plasma concentration-time profiles and heart rate.

Results:

Peak concentrations (C_max) of higenamine ranged from 15.1 to 44.0 ng/mL. The half-life of higenamine was 0.133 h (range, 0.107–0.166 h), while the area under concentration-time curve (AUC), extrapolated to infinity, was 5.39 ng·h·mL⁻¹ (range, 3.2-6.8 ng·h·mL⁻¹). The volume of distribution (V) was 48 L (range, 30.8–80.6 L). The total clearance (CL) was 249 L/h (range, 199-336 L/h). Within 8 h, 9.3% (range, 4.6%–12.4%) of higenamine was recovered in the urine. The pharmacokinetics of higenamine was successfully described using a two-compartment model with nonlinear clearance. In the pharmacodynamic model, heart rates were related to the plasma drug concentrations using a simple direct effect model with baseline. The E₀, E_max, and EC₅₀ were 68 bpm, 73 bpm and 8.1 μg/L, respectively.

Conclusion:

Higenamine has desirable pharmacokinetic and pharmacodynamic characteristics. The results provide important information for future clinical studies on higenamine.     

The effect of Ginkgo biloba extracts on the pharmacokinetics and pharmacodynamics of cilostazol and its active metabolites in healthy Korean subjects

AIMS

The primary objective of this study was to evaluate the effects of Ginkgo biloba extracts (GBE) on the pharmacokinetics of cilostazol and its metabolites. The secondary objective was to assess the effect of GBE on the pharmacodynamics of cilostazol.

METHODS

A randomized, double-blind, two-way crossover study was conducted with 34 healthy Korean subjects. All subjects were given an oral dose of cilostazol (100 mg) plus GBE (80 mg) or cilostazol (100 mg) plus placebo twice daily for 7 days. Plasma concentrations of cilostazol and its active metabolites (3,4-dehydrocilostazol and 4′-trans-hydroxycilostazol) were measured using liquid chromatography–tandem mass spectroscopy on day 7 for pharmacokinetic assessment. The adenosine diphosphate-induced platelet aggregation and bleeding time were measured at baseline and on day 7 for pharmacodynamic assessment.

RESULTS

The geometric mean ratios of area under the concentration–time curve for dosing interval for cilostazol plus GBE vs. cilostazol plus placebo were 0.96 (90% confidence interval, 0.89–1.03; P = 0.20) for cilostazol, 0.96 (90% confidence interval, 0.90–1.02; P = 0.30) for 3,4-dehydrocilostazol and 0.98 (90% confidence interval, 0.93–1.03; P = 0.47) for 4′-trans-hydroxycilostazol. The change of aggregation after administration of cilostazol plus GBE seemed to be 1.31 times higher compared with cilostazol plus placebo, without statistical significance (P = 0.20). There were no significant changes in bleeding times and adverse drug reactions between the treatments.

CONCLUSIONS

Co-administration of GBE showed no statistically significant effects on the pharmacokinetics of cilostazol in healthy subjects. A large cohort study with long-term follow-up may be needed to evaluate the possible pharmacodynamic interaction between cilostazol and GBE, given that there was a remarkable, but not statistically significant, increase in inhibition of platelet aggregation.     

Risk of diarrhoea in a long-term cohort of renal transplant patients given mycophenolate mofetil: the significant role of the UGT1A8*2 variant allele

AIM

In renal transplant patients given mycophenolate mofetil (MMF), we investigated the relationship between the digestive adverse events and polymorphisms in the UGT genes involved in mycophenolic acid (MPA) intestinal metabolism and biliary excretion of its phase II metabolites.

METHODS

Clinical data and DNA from 256 patients transplanted between 1996 and 2006 and given MMF with cyclosporin (CsA, n = 185), tacrolimus (TAC, n = 49) or sirolimus (SIR, n = 22), were retrospectively analysed. The relationships between diarrhoea and polymorphisms in UGT1A8 (*2; 518C>G, *3; 830G>A), UGT1A7 (622C>T), UGT1A9 (−275T>A), UGT2B7 (−840G>A) and ABCC2 (−24C>T, 3972C>T) or the co-administered immunosuppressant were investigated using the Cox proportional hazard model.

RESULTS

Multivariate analysis showed that patients on TAC or SIR had a 2.8 higher risk of diarrhoea than patients on CsA (HR = 2.809; 95%CI (1.730, 4.545); P < 0.0001) and that non-carriers of the UGT1A8*2 allele (CC518 genotype) had a higher risk of diarrhoea than carriers (C518G and 518GG genotypes) (HR = 1.876; 95%CI (1.109, 3.175); P = 0.0192). When patients were divided according to the immunosuppressive co-treatment, a significant effect of UGT1A8*2 was found in those co-treated with CsA (HR = 2.414; 95%CI (1.089, 5.354); P = 0.0301) but not TAC or SIR (P = 0.4331).

CONCLUSION

These results suggest that a possible inhibition of biliary excretion of MPA metabolites by CsA and a decreased intestinal production of these metabolites in UGT1A8*2 carriers may be protective factors against MMF-induced diarrhoea.