Population pharmacokinetic analysis of fexofenadine in Japanese pediatric patients

A population pharmacokinetic analysis was conducted to characterize the pharmacokinetics of fexofenadine in Japanese pediatric patients (6 months through 16 years) with perennial allergic rhinitis or atopic dermatitis. The dataset was composed of 515 patients (including 109 adults), for a total of 1,080 concentration–time points. The analysis was performed with NONMEM using the SAEM method. Several structural models and residual error models were evaluated. The relationship between the individual estimates and the potential covariates was then investigated: demographic and pathophysiologic characteristics were tested as potential model covariates (forward selection method). The qualification of the model was performed using visual predictive check and bootstrap. A two-compartment disposition model with first-order absorption best fitted the data. The inter-individual variability was modeled through an exponential error model for all parameters (except for ka for which no inter-individual term could be estimated), while a proportional error model was used to model the residual variability. The final model included two covariates on elimination clearance and one on the intercompartmental clearance. CL/F was related to BSA and patient’s age (expressed in months) Q/F was also related to BSA. Once the model was correctly qualified, exposure parameters such as C_max and AUC_τ were computed and compared between each age sub-group and between Japanese and Caucasians patients. These comparisons did not reveal any major difference (less than 50 %) between subgroups.     

Relationship between hemoglobin level and quality of life in anemic patients with chronic kidney disease receiving epoetin alfa

ABSTRACT

Objectives: To evaluate the relationship between hemoglobin (Hb) level and quality of life (QOL) in anemic patients with non-dialysis chronic kidney disease receiving epoetin alfa.

Patients and methods: A post-hoc analysis using data from a multicenter, open-label, prospective study of epoetin alfa for anemia in patients with chronic kidney disease not on dialysis was conducted. The relationship between Hb and QOL was analyzed using correlation and longitudinal analyses, the latter adjusting for sample selection bias. The Linear Analog Scale Assessment (LASA) and the Kidney Disease Questionnaire (KDQ) subscales were used to measure QOL. The impact of an incremental 1?g/dL increase in Hb level on LASA and KDQ scores was determined using an incremental analysis.

Results: A total of 1183 and 1044 patients formed the study populations for the LASA and KDQ analyses, respectively. There was a positive and significant relationship between Hb levels and QOL (?p < 0.05). Using non-linear regression analysis, we characterized the sigmoid-shape of the relationship between Hb levels and QOL scores. Hemoglobin change was a statistically significant determinant of QOL improvement for both LASA and KDQ scales (?p < 0.05). The model predicted that, based on a 2?unit change in Hb, the greatest incremental QOL improvement per unit of Hb increase occurred when Hb was in the range of 11 to 12?g/dL.

Conclusions: This study demonstrates that, beyond the well-known relationship between Hb increases and QOL improvements, the maximal incremental gain in QOL occurred when Hb reached 11 to 12?g/dL. This suggests that treating anemic patients with non-dialysis chronic kidney disease until their Hb level reaches 12?g/dL will result in the greatest QOL improvement per Hb unit increase. The analyses were conducted based on an open-label study of epoetin alfa and could be further validated using a randomized, controlled trial, comparing incremental gains in QOL associated with treatment initiation at varying levels of Hb across arms.     

The relative dosing of epoetin alfa and darbepoetin alfa in chronic kidney disease

ABSTRACT

Objective: The purpose of this study was to review and analyze current research to evaluate the dose ratio of epoetin alfa and darbepoetin alfa for the treatment of anemia in chronic kidney disease (CKD) and to identify determinants of the variation in epoetin alfa: darbepoetin alfa dose ratios across studies.

Methods: A systematic review of the literature for comparative switch and non-switch studies of epoetin alfa and darbepoetin alfa treatments in CKD for the period 2000–2005 was performed. Two reviewers independently assessed the quality of the information. Data on the study design and outcomes were collected for each selected study. The dose ratio from epoetin alfa to darbepoetin alfa was calculated for each study, and the results were reported stratified by study characteristics. To control for differences in study design and characteristics that could explain the variability in the relative dosages of the two agents across studies, multivariate regression analysis was conducted. Based on these results, a dose conversion ratio for Canada was estimated.

Results: A total of 21 studies involving 16?378 patients exposed to epoetin alfa or darbepoetin alfa in CKD were identified. Univariate analysis of the dose ratios indicated a mean dose ratio of 217:1 (IU of epoetin alfa:µg of darbepoetin alfa). Results from the multivariate analysis demonstrated that the study design (i.e., switch study versus straight comparison studies) and geographical coverage (i.e., United States) affected the results. Based on the multivariate analysis, the dose conversion ratio between epoetin alfa and darbepoetin alfa for Canada was 169:1.

Conclusions: Despite limitations associated with switching studies and the limited total number of studies available, this systematic review based on aggregated results provides further evidence to the clinical community that the dose conversion ratio for epoetin alfa:darbepoetin alfa in CKD patients in Canada is approximately 169:1. At that ratio, treatment with epoetin alfa is 11–18% cheaper than treatment with darbepoetin alfa in Canada.     

Population pharmacokinetic modeling of flurbiprofen

The paper is to report the establishment of a population pharmacokinetic model for flurbiprofen (FP), an active metabolite of flurbiprofen axetil (FA). 246 FP serum concentration and clinical data were perspectively collected from 23 general anaesthesia patients receiving FA intravenously before operation in Dentofacial Surgery and Otorhinolaryngology Department of the First Affiliated Hospital of Fujian Medical University. Population pharmacokinetic data analysis was performed using NONMEM software. The measure of Bootstrap was applied for internal validation, while Visual Predictive check was adopted for external validation. The data of FP correspond with two-compartment model. The body weight (WT) had conspicuous effect on clearance and volume of central compartment, while sex, age and daily dose of administration had no marked effect on pharmacokinetic parameter of FP. The basic model was described as follows: CL (L x h(-1)) = 1.28x EXP(ETA(1)), V1 (L) = 5.03x EXP(ETA(2)), Q (L x h(-1)) = 8.5 x EXP(ETA(3)), V2 (L) = 4.39 x EXP(ETA(4)). The final model was described as follows: CL (L x h(-1)) = 1.32 x (WT/60) x EXP(ETA(1)), V1 (L) = 5.23 x (WT/60) x EXP(ETA(2)), Q (L x h(-1)) = 8.45 x EXP(ETA(3)), V2 (L) = 4.37 x EXP(ETA(4)). The population typical value of CL, V1, Q and V2 were: 1.32 L x h(-1), 5.23 L, 8.45 L x h(-1) and 4.37 L, respectively. Bootstrap and visual predictive check show that the final model of FP is stable, effective and predictable. A novel population pharmacokinetic model is developed to estimate the individual pharmacokinetic parameter for patients intravenous injecting FA in terms of patients' characteristics and dosing history, and to design a prior dosage regimen.     

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 pharmacokinetic and exposure-response analyses of guanfacine in Japanese pediatric ADHD patients

Guanfacine hydrochloride extended-release tablet (GXR) is approved for child and adolescent patients with attention-deficit/hyperactivity disorder (ADHD). The aims of this study were to develop a population pharmacokinetic model of guanfacine after administration of GXR and to evaluate factors influencing the pharmacokinetics of guanfacine in pediatric ADHD patients. A population pharmacokinetic analysis was performed using 3231 plasma concentration data items of guanfacine for pediatric ADHD patients aged 6–17 years obtained from clinical studies in Japan and the US. In addition, the relationship of the ADHD Rating Scale IV (ADHD RS-IV, efficacy endpoint) total score with exposure to guanfacine was assessed for Japanese pediatric ADHD patients. A one-compartment model with first-order absorption and lag time well described the plasma concentration data of guanfacine in pediatric ADHD patients. Body weight was selected as a covariate of apparent total body clearance and apparent volume of distribution. There was no pharmacokinetic difference between Japanese and non-Japanese pediatric ADHD patients. The results suggested a tendency of exposure-dependent reduction in the ADHD RS-IV total score, whereas the reduction was observed even at low plasma exposure levels compared with the placebo group.     

Population pharmacokinetic and pharmacodynamic analysis of ribavirin in patients with chronic hepatitis C

The population pharmacokinetics of ribavirin were assessed in patients with chronic hepatitis C virus (HCV) infection treated with interferon alpha-2b and ribavirin in four clinical efficacy studies. The authors collected 3450 ribavirin serum concentrations from 1105 patients at different treatment weeks for inclusion in the analysis. Population factors included gender, age, body weight, serum creatinine, creatinine clearance, and previous interferon treatment history. Ribavirin apparent clearance (CL/F) was calculated from individual patients' daily doses divided by concentration values, and the influence of these factors was assessed by multiple regression. Body weight, gender, age, and serum creatinine affected CL/F. Population mean CL/F estimates were 17.9 L/h (female) and 21.5 L/h (male) assuming an age of 40 years and body weight of 70 kg. Ribavirin apparent clearance increased as a function of body weight and decreased at ages greater than 40 years. Serum creatinine had little influence on CL/F, which may reflect the relatively normal renal function of these patients. Total CL/F variability was approximately 28%. The four covariates in the model explained 27% of this variability, and were thus of limited clinical significance because of the substantial residual variability not accounted for by the model. In assessing the relationship between pharmacokinetics and pharmacodynamics, the week 4 hemoglobin nadir value was negatively associated with week 4 ribavirin concentrations. The percentage of reduction from baseline was positively associated with ribavirin concentrations, although these data were highly variable. Loss of HCV-RNA at 24 weeks after completion of treatment was considered a response to interferon and ribavirin treatment in a logistic regression analysis of clinical and pharmacokinetic variables and treatment response in the interferon-naive patients. Hepatitis C virus genotype, pretreatment HCV-RNA titer, duration of treatment period, week 4 ribavirin concentration, and patient age affected the likelihood of response. Higher ribavirin concentrations at treatment week 4 were associated with a higher response rate. Variables that have predictive value for treatment outcome in patients treated with interferon and ribavirin are similar to those previously reported for interferon monotherapy.     

慢性肾脏病对患者氧化应激程度的影响及可能意义

目的 探讨慢性肾脏病患者氧化应激的变化以及可能意义.方法 选择我院肾内科住院的慢性肾脏病患者73例,以同期我院体检中心47例体检健康者为对照组.收集受试者血和尿标本,分别用硫代巴比妥酸法和黄嘌呤氧化酶法测定脂质过氧化产物丙二醛和超氧化物歧化酶(SOD)的水平;同时收集患者临床资料,分析慢性肾脏病患者氧化应激程度的变化,同时探讨慢性肾脏病不同分期对氧化应激程度的影响.结果 慢性肾脏病组血丙二醛明显高于对照组[(16.7±20.3)μmol/L比(5.9±1.2)μmol/L,P＜0.05],尿丙二醛和对照组差异无统计学意义[(3.7±3.2)μmol/L比(5.2±4.5)μmol/L,P＞0.05].慢性肾脏病组血SOD和尿SOD活性分别为(37 300±18 200)U/L、(16 200±5600)U/L明显低于对照组[分别为(44 000±9400)U/L、(24 600±7200)U/L,均P＜0.05].结论 慢性肾脏病患者氧化应激程度明显增高,氧化应激随着肾功能的恶化而进一步加重.

Abstract：

Objective To study the oxidative stress in patients with chronic kidney disease (CKD) and its potential significance. Methods Seventy-three in-patients with CKD at the division of nephrology and 47 health controls were enrolled in this study between 2007 and 2010. The blood and urine samples were collected to detect malonaldehyde (MDA) and the activity of superoxide dismutase (SOD). Meanwhile the clinical datum was analyzed to evaluate the impact of CKD on oxidative stress. Results Serum MDA dramatically increased in patients with CKD than that in controls [( 16.7 ± 20.3 ) μmol/L vs ( 5.9 ± 1.2 ) μmol/L,P ＜ 0.05], while SOD of serum and urine in CKD group decreased significantly compared with controls [(37 300 ± 18 200) U/L vs (44 000 ±9 400) U/L, ( 16200 ± 5 600) U/L vs ( 24 600 ± 7 200) U/L, P ＜ 0.05].. Conclusion Oxidative stress is enhanced in patients CKD and it aggravates with the deterioration of kidney function.     

Population pharmacogenetic pharmacokinetic modeling for flip-flop phenomenon of enteric-coated mycophenolate sodium in kidney transplant recipients

Purpose

Enteric-coated mycophenolate sodium (EC-MPS) is effective and safe in preventing rejection after transplantation and is mainly transported by ABCs and OATPs and metabolized by UGTs. The genetic polymorphisms affect the inter-individual variation in drug disposition and elimination. The aims of this study were to develop a population pharmacokinetic (PK) model and to evaluate the influence of genetic and clinical factors on the PK of mycophenolic acid (MPA) in Korean renal transplant recipients.

Methods

Population analysis of EC-MPS was performed using non-linear mixed effects modeling (NONMEM). After clinical and genetic factors were evaluated using a stepwise covariate method, we selected clinically relevant covariates considering covariate effects. The final model was validated by bootstrap and visual predictive check. At last, we performed the model-based simulations in order to explore an optimal dose to achieve target area under the curve (AUC) in hypothetical scenarios.

Results

From 166 plasma concentrations (n=34), a time-lagged two-compartment with a flip-flop model best describes the PK of MPA. The covariate analysis identified lower creatinine clearance (CLcr) and SLCO1B1 variant genotype were correlated with lower MPA clearance, on the contrary, UGT1A9 variant had decreased distribution of MPA, contributing to lower absorption. When considering to UGT1A9, SLCO1B1 genotypes, and renal function, the new recommended dose of 540 mg twice daily resulted in a higher success of achieving the target AUC_0-12h in the 30-60 mg.h/L.

Conclusions

CLcr, UGT1A9 and SLCO1B1 genotypes seem to be promising parameters to predict the pharmacokinetics with flip-flop phenomenon of EC-MPS in transplant recipient having stable renal function. This model on clinical practice may help prevent overexposure and achieve a proper AUC in the Korean population.     

丙戊酸清除率的群体药动学模型的建立

目的:建立中国癫痫病患者丙戊酸清除率的群体药动学模型.方法:前瞻性收集上海、北京两地4所医院服用丙戊酸的350名患者的稳态血药浓度(n=435).数据分析采用非线性混合效应模型.结果:最终模型为:CL(L·h-1)=0.0422·Dose·BSA0.269·1.41(如果合用卡马西平,否则为1)·1.37(如果合用苯妥因,否则为1)·(0.00735·PBS 0.807)(如果合用苯巴比妥,否则为1)·(Dose/950)(如果Dose大于950 mg·m-2·d-1,否则为1)·1.21(如果BSA大于1.7 m2,否则为1)·1.24(如果年龄小于6,否则为1).上式中Dose为日剂量(mg·m-2·d-1);BSA为体表面积(m2);PBS为苯巴比妥的日剂量(mg·m-2·d-1).结论:根据患者的生理用药资料,结合上述模型,可估算其清除率,为制定给药方案提供依据.     

A randomised,cross-over study comparing injection site pain with subcutaneous epoetin beta and subcutaneous darbepoetin alfa in patients with chronic kidney disease*

ABSTRACT

Objective: To compare injection site pain of subcutaneous (sc) epoetin beta and darbepoetin alfa in adult patients with chronic kidney disease.

Research design and methods: This was a multi-centre, randomised, two-arm, single-blind, cross-over study. Patients were randomised to receive weekly sc darbepoetin alfa 30?μg or weekly sc epoetin beta 6000?IU for 2 weeks and were then crossed over to the alternative treatment for 2 weeks. Injection site pain was assessed using a 10?cm ungraduated visual analogue scale (0?=?no pain, 10?=?worst pain) and a six-point verbal rating scale. Patient preference for treatment was also assessed.

Trial registration: http://clinicaltrials.gov/(NCT00377481).

Results: All randomised patients (N?=?48) completed the study. The sample comprised 29 chronic kidney disease patients (Stage 3 or Stage 4), 11 peritoneal dialysis patients and 8 renal transplant patients. Patients perceived significantly less pain with epoetin beta than darbepoetin alfa, using the visual analogue scale (relative pain score?=?2.75, darbepoetin alfa:epoetin beta, 95% CI: 1.85, 4.07; p?<?0.0001) and the verbal rating scale (median: 0.5, 95% CI: 0.5, 1.0 vs. median: 1.5, 95% CI: 1.0, 2.0; p?<?0.0001). Epoetin beta was preferred by significantly more patients (65%) than darbepoetin alfa (10%) (p?<?0.001); 25% of patients reported no preference.

Conclusions: Limitations included lack of an epoetin alfa comparator and limited blinding (patients were blinded to treatment, however, an unblinded nurse administered treatment). We show that sc injection of epoetin beta is significantly less painful than darbepoetin alfa and patient preference for epoetin beta confirms that the difference is clinically meaningful.     

Population pharmacokinetic modeling of pyrazinamide in children and adults with tuberculosis

STUDY OBJECTIVE: To determine population pharmacokinetic parameters of pyrazinamide after multiple oral doses given to children and adults with tuberculosis. DESIGN: Prospective, multiple-dose population pharmacokinetic study. SETTING: Five hospitals in the United States. PATIENTS: Sixty-seven adults and 23 children with active tuberculosis. INTERVENTION: The 90 patients received multiple oral doses of pyrazinamide as part of their treatment, based on the best clinical judgment of the attending physicians and in keeping with standard clinical practices at each institution. The patients also received other antituberculosis drugs empirically or based on in vitro susceptibility data. MEASUREMENTS AND MAIN RESULTS: Serum samples were collected over 12 hours after dosing and were assayed with a validated gas chromatography assay with mass selective detection. Concentration-time data were analyzed by using population methods. Pyrazinamide concentrations increased linearly with increasing oral doses (185-3550 mg). Median maximum serum concentration values were 41.0 microg/ml with daily dosing and 66.1 microg/ml with larger, twice-weekly dosing. Incomplete (18%) or delayed (30%) absorption was more common in children than in adults (1% for each). Pharmacokinetic parameters of pyrazinamide were independent of human immunodeficiency virus status and patient demographics, except for body weight. Population elimination half-life values in pediatric and adult patients were 3.5 and 6.0 hours, respectively. Median volume of distribution (L/kg) was 32% larger in children, and median clearance (L/hr/kg) was 106% larger in children, with a resultant median half-life 43% shorter in children. CONCLUSION: Pyrazinamide concentrations and most pharmacokinetic parameters were comparable to those previously published. Apparent half-life was somewhat shorter than that in previous reports. Compared with adults, absorption of pyrazinamide in children appeared more likely to be incomplete or delayed.