Schwartz公式计算所得的儿童肾小球滤过率和万古霉素理想剂量之间的相关性研究

摘 要 目的：了解Schwartz公式计算所得到的儿童肾小球滤过率（GFR）和万古霉素理想剂量之间的关联性。评估是否可以通过GFR估算出万古霉素的理想剂量。方法: 通过治疗药物监测,计算出患儿万古霉素的清除率和理想日剂量。依据患儿血肌酐值,以Schwartz公式计算所得GFR值,观察不同GFR值范围内相对应的万古霉素日剂量分布,并采用线性回归分析法,评价GFR和上述药动学参数的相关性。结果: GFR值超过200 ml·min-1·(1.73m2)-1时,72.22%的患者理想剂量＞60 mg·kg-1·d-1;线性回归分析结果, GFR对于清除率和理想日剂量之间存在统计学意义上的线性关系,但其回归系数R2分别仅为0.307和0.361,GFR和理想日剂量之间的回归方程为Y=0.169X+29.577。结论: 由Schwartz公式所得的GFR值和万古霉素理想日剂量之间存在着统计学意义上的的线性关系,但是其相关性强度不高,无法用来准确估算万古霉素剂量。     

HPLC法测定血浆中卡铂的AUC

目的建立高效液相色谱法(HPLC)测定血浆中总铂浓度-时间曲线下面积(AUC)的方法.方法22例患者,接受卡铂的治疗,剂量按AUC为6mg.ml-1min估算.采用柱外衍生化的高效液相色谱法测定血浆中不同时间卡铂的浓度.在NH3.H2O-NH4Cl(pH=9.0)缓冲体系中,卡铂与NaDDTC形成络合物,YWG-C18(4.6×250mm,5μm)色谱柱,甲醇水=7030(流速0.8mlmin-1)混合液洗脱,在波长λ=254nm下检测,用梯形法计算卡铂的AUC.结果本HPLC法简便、准确、重线性好.平均回收率73.1%,RSD＜10%.22例患者中有6例AUC在(6±10%)mgml-1min之内,6例AUC＞(6+10%)mgml-1min,10例AUC＜(6-10%)mgml1min.结论建立的HPLC法可用于测定血浆中卡铂AUC,从而调整卡铂的剂量达到个体化给药.     

根据曲线下面积计算奈达铂剂量联合紫杉醇治疗晚期食管癌

目的本研究基于Ishibashi公式调整剂量的奈达铂化疗剂量,探讨其对食管癌患者疗效及不良反应的影响。方法 36例晚期食管癌依据体表面积(BSA)计算剂量的经典方案组:紫杉醇135mg/m2,奈达铂80mg/m2;34例晚期食管癌为Ishibashi公式方案组:紫杉醇135mg/m2,奈达铂剂量参照Ishibashi公式。Ishibashi公式为:清除率(CL)=0.073 8×内生肌酐清除率(Ccr)+4.47,曲线下面积(AUC)设为10,剂量奈达铂=AUC×CL。结果 BSA的经典方案组和Ishibashi公式方案组有效率和临床获益率差异无统计学意义。Ishibashi公式方案组白细胞减少发生率为68%,较BSA的经典方案组发生率(89%)明显降低。结论根据Ishibashi公式确立奈达铂剂量在中国晚期食管癌人群是有效和安全的,可为临床治疗提供一定的参考。     

血清胱抑素-C和肾小球滤过方程在慢性肾脏病患者临床应用的实用性探讨

目的探讨血清胱抑素-C（Cys-C）和各种肾小球滤过方程在诊断慢性肾脏病（CKD）患者中的临床意义。方法双血浆法^99mTc-DTPA清除率测定肾小球滤过率（rGFR）作为标准,MDRD方程7、简化MDRD方程、简化改良MDRD方程、Cockcroft-Gault公式计算的GFR及Cys-C与^99mTc-DTPA清除率测定肾小球滤过率做比较,观察它们的相关性。结果在CKD1、2期,简化的MDRD方程和Cockcroft-Gault公式明显低估了GFR,简化的MDRD方程低估GFR的程度高于Cockcroft-Gault公式;改良简化MDRD方程,其相关系数为0.812、0.867,显示了改良简化MDRD方程评估CKD患者早期肾功能的变化具有优势;在CKD3期,改良简化MDRD方程与rGFR比较,其相关性最强。在CKD4、5期,各种方程均能很好地评估GFR。结论肾功能轻中度损害时,使用改良简化MDRD方程和Cystatin-C预测肾小球滤过率,肾功能重度损害时,可以根据当地医院的条件选用目前的各种方程评估GFR。     

儿童肾功能评估公式和更昔洛韦清除率的相关性确证与剂量优化

目的:采用群体药动学分析方法考察不同肾小球滤过率(GFR)公式估计更昔洛韦清除率的适用性,并用于更昔洛韦给药剂量优化。方法:收集100例患者的血药浓度数据和临床资料,采用基于不同生物标志物的公式计算GFR。建立儿童患者静脉滴注更昔洛韦的群体药动学模型,考察体质量和肾功能对药动学参数的影响,并对最终模型进行内部验证。在建模过程中探索不同公式获取的GFR和更昔洛韦清除率之间的相关性。确定最适用的GFR公式后,根据体质量和肾功能对给药剂量进行个体化设计。结果:具有一级消除的一房室模型能够很好地描述更昔洛韦在儿童群体中的药动学特征。验证结果显示最终模型稳定可靠,预测性能较好。综合可视化检验和协变量分析结果,可确定Flanders Metadata公式计算获得的GFR与更昔洛韦清除率相关性较高,临床适用性较好。在此基础上提出了基于GFR和患者体质量的个体化给药方案。结论:本研究确证了最适用于预测儿童群体更昔洛韦清除率的GFR公式,为该药物治疗提供了一种基于建模手段的个体化给药策略。     

卡铂-乳酸/羟基乙酸共聚物微囊在家兔体内的药动学

目的 :考察卡铂 乳酸 /羟基乙酸共聚物微囊在家兔体内的药动学过程。方法 :健康家兔 8只 ,随机交叉试验 ,单剂量注射卡铂微囊混悬液和卡铂原料药溶液后 ,采用等离子体原子发射光谱法测定血药浓度 ,药 时数据经PKS计算机程序拟合 ,自动判别最佳模型及计算药动学参数。结果 :两种剂型的的药 时曲线符合三室模型 ,二者的药动学参数Cmax、t1/ 2 β、MRT、AUC、CL差异存在显著性 (P <0 .0 5 )。结论 :卡铂制成微囊后 ,在家兔体内具有明显的缓释作用 ,有效作用时间延长 ,有利于其抗肿瘤作用     

运用Excel表格程序设计静脉滴注的给药方案

目的建立一种简化的静脉滴注的给药方法。方法采用Excel软件编写基于药动学参数的给药方案设计程序。结果输入药动学参数、给药间隔（T）、输注时间（T）、给药剂量初值或维持量（d）和药后时间t后，Excel表格显示任一次给药后的t时刻血药浓度、AUC值和负荷剂量；通过对Excel表格的操作，显示第n周期（或稳态）任一次给药后的t时刻血药浓度、AUC值和负荷剂量，Excel规划求解法获得最大给药剂量（dmax）、最低给药剂量（dmin）、有效血药浓度时间（tec）。结论方法设计简单，使用直观简便，既能为临床用药提供安全有效的剂量，又能对某一用药方案作出评价。     

中国非小细胞肺癌患者培美曲塞联合卡铂化疗剂量的影响因素

目的:通过分析临床非小细胞肺癌化疗剂量的分布情况,寻找影响临床化疗剂量的相关因素,为临床药师化疗医嘱审核及临床用药分析提供参考依据。方法:调取2015年中国医学科学院北京协和医学院肿瘤医院肿瘤内科收治的所有非小细胞肺癌患者病历,以培美曲塞联合卡铂化疗的肺腺癌患者为研究对象,通过分析患者基本信息、功能状态评分、合并症、化疗疗效与毒性反应、化疗方案和化疗药物剂量,分析临床选择化疗剂量的影响因素。结果:采用培美曲塞联合卡铂化疗方案的221例患者共接受了704周期的化疗,培美曲塞的给药剂量平均值为(507.70±37.38)mg·m^(-2),最大剂量为629 mg·m^(-2),最小剂量为349 mg·m^(-2);卡铂给药的曲线下的面积(area under curve,AUC)平均值为3.93±0.62,最大值为5.54,最小值为2.16;化疗剂量的选择与患者年龄、基础疾病(糖尿病)、不同医生有关(P<0.05)。结论:培美曲塞化疗剂量与指南推荐基本一致,而卡铂则低于指南的推荐剂量;临床药师在审核化疗医嘱化疗剂量时应考虑国内外患者的差异以及个体差异。     

HPLC法研究唑尼沙胺分散片在中国健康志愿者的药动学简

目的：建立人血浆唑尼沙胺浓度的测定方法,研究唑尼沙胺分散片在健康受试者体内的单、多剂量药动学.方法：30 名健康志愿者（男女各半）分3 组,分别单剂量（200、300、400 mg）口服唑尼沙胺分散片,300 mg 剂量组单剂量结束后继续进入多剂量研究,每日1 次,连续14 d.采用HPLC法测定血浆中唑尼沙胺的浓度,用DAS 2.1.1 软件计算药动学参数.结果：在200 ～400 mg 剂量范围内,唑尼沙胺的AUC0-t、AUC0-∞、Cmax 均与剂量呈线性关系,中剂量组多次给药后的药动学参数如下：Cmax 为（27.305 ± 5.201） μg·mL-1;tmax 为（2.556 ± 0.726） h;t1/2 为（59.286 ± 8.882） h;AUC0-t 为（2 435.713 ± 668.845）μg·h·mL-1;AUC0-∞ 为（2 522.230 ± 720.554） μg·h·mL-1.结论：男、女受试者单次给药后的Cmax存在显著性差异.唑尼沙胺在连续多次给药后,可达稳态血药浓度.     

简化的Excel表格程序设计静脉推注给药方案

目的 建立一种简便的静脉推注给药方案. 方法 采用Excel软件编写简化的Excel表格程序. 结果 输入药动学参数、给药间隔τ、给药剂量初值或维持量（d）和药后时间(t)后,Excel表格显示任一次给药后的t时刻血药浓度、AUC值;通过对Excel表格的操作,显示第n周期（或稳态）任一次给药后的t时刻血药浓度、AUC值和负荷剂量. Excel规划求解法获得最大给药剂量（dmax）、最低给药剂量（dmin）、有效血药浓度时间（tec）. 结论 该方法 设计简单,使用直观简便,既能为临床用药提供安全有效的剂量,又能对某一用药方案作出评价.     

Carboplatin dosage formulae can generate inaccurate predictions of Carboplatin exposure in carboplatin/paclitaxel combination regimens

Carboplatin is a frequently used antitumour agent recommended to be administered according to the Calvert formula: dose = AUC x (GFR+25), where GFR is the glomerular filtration rate as measured by (51)Cr-EDTA clearance and AUC is the targeted area under the carboplatin concentration versus time curve. In several modified Calvert formulae, the GFR is estimated on the basis of serum creatinine levels. We compared AUCs of carboplatin that were predicted by modified Calvert formulae with actual measured AUCs in 75 courses in patients with non-small cell lung cancer or ovarian cancer who were treated with the combination of carboplatin-paclitaxel. Predictions were made using two modified Calvert formulae, in which the GFR was calculated by serum creatinine level-based equations, according to Jelliffe (Eq. 1) and Cockroft-Gault (Eq. 2). We also studied the performance of a formula for the clearance of carboplatin, as proposed by Chatelut (Eq. 3). The actual measured mean AUC was 4.6 mg/ml.min (range 1.9 to 10.4 mg/ml.min, SD 1.7). Equation 1 overestimated the AUC by 32.9% with an imprecision of 43.0%, and equation 2 overestimated the AUC by 27.6% with an imprecision of 33.4%. For equation 3, an AUC overestimation of only 10.2%, but with an imprecision of 25.3%, was observed. In conclusion, all three equations overestimated the carboplatin AUCs and had poor precisions. We concluded that the real carboplatin AUCs were lower than calculated, using the three tested formulae. This may have important consequences for ongoing and future phase II and III studies with carboplatin-paclitaxel combinations, utilising these formulae to calculate the carboplatin dose. Thus far, the original Calvert dosage formula remains the 'golden standard'.     

Pharmacokinetically guided administration of chemotherapeutic agents

The current practice for the dose calculation of most anticancer agents is based on body surface area in m2, although lower interpatient variation in pharmacokinetic parameters has been reported with pharmacokinetically guided administration. As chemotherapeutic agents have a narrow therapeutic window, pharmacokinetically guided administration may lead to less toxicity and higher efficacy than administration on the basis of body surface area. Pharmacokinetically guided administration, using parameters such as area under the plasma concentration-time curve (AUC), steady-state plasma drug concentration and drug exposure time above a certain plasma concentration, has been studied for many antineoplastic agents. Assessment of pharmacokinetic profiles allows the characterisation of relationships between pharmacokinetic parameters and efficacy and toxicity. AUC appears to be more closely correlated with pharmacodynamics than does the dose per unit of body surface area. In particular, the AUC-guided administration of carboplatin has been extensively studied, based on the close relationship between the renal clearance of the drug and glomerular filtration rate. Several formulae and limited sampling models have been derived to predict the AUC of carboplatin. The relationship between AUC and pharmacodynamics has also been studied for other anticancer agents, for example fluorouracil, topotecan, etoposide, cisplatin and busulfan, but all less extensively than for carboplatin. The pharmacokinetically guided administration of these agents needs to be investigated further before the use of alternative administration formulae can become standard clinical practice. Prospective studies of pharmacokinetically guided versus surface area-based administration should be performed to validate pharmacokinetic-pharmacodynamic relationships and to facilitate optimal dosage of anticancer agents in the clinic.     

Melphalan pharmacokinetics in children with malignant disease: influence of body weight, renal function, carboplatin therapy and total body irradiation

AIM: To analyse the pharmacokinetics of melphalan in 52 children (0.3-18 years) and determine whether any clinical factors affect the pharmacokinetic parameters Additionally, to examine whether a test melphalan dose can predict the pharmacokinetics of a full dose, when there are 5 intervening days of carboplatin therapy. METHODS: Melphalan concentrations were measured in 14 blood samples collected from each child following doses ranging from 30 to 180 mg m(-2). The pharmacokinetics were analysed with Kinetica 4.0. RESULTS: Children who did not have carboplatin (n = 27) had median melphalan clearance (CL) of 15.5 l h(-1) m(-2) (interquartile range: 12.4-19.9 l h(-1) m(-2)) and steady state volume of distribution (Vss) of 14.9 l m(-2) (interquartile range: 12.7-18.3 l m(-2)). Children who had carboplatin (n = 25) had 34% lower median CL (10.2 l h(-1) m(-2)) and 18% lower median Vss (12.2 l m(-2)) (P < 0.001). Melphalan elimination was impaired in a separate group of three children given concomitant carboplatin and etoposide. Stepwise multiple linear regression indicated that weight, carboplatin, glomerular filtration rate (GFR) and total body irradiation (TBI) significantly affected CL, while weight and carboplatin influenced Vss. A test dose (10 mg m(-2)) tended to underpredict the area-under-the-concentration-vs.-time-curve for a full (180 mg m(-2)) dose in 19 individuals given carboplatin. CONCLUSIONS: In children, melphalan CL is influenced by weight, carboplatin, TBI and GFR. Vss is influenced by weight and carboplatin.     

Effect of age on systemic exposure and haematological toxicity of carboplatin in advanced non-small cell lung cancer patients

The aim of this study was to evaluate systemic exposure to carboplatin and its haematological toxicity in patients with advanced non-small cell lung cancer both older and younger than 70 years when the target area under the curve (AUC) in elderly patients was reduced by 20%. For this purpose, a population pharmacokinetic model was developed and the haematological toxicity of the drug was assessed. A total of 33 patients received carboplatin on day 1 and gemcitabine (1250 mg/m(2) ) on days 1 and 8. This schedule was repeated every 21 days. The Calvert-Crokcoft-Gault formula was employed to calculate a dose of carboplatin with a target AUC of 5 mg/min./mL in patients under 70 years and 4 mg/min./mL in patients aged 70 or older. The data of 24 patients were treated for population modelling performed with the nonmem (University of California, San Francisco, CA, USA) approach. Haematological toxicity was evaluated for all 33 patients enrolled in the study. The carboplatin systemic exposure measured by the AUC (mg/min./mL) was 5.98 (5.45; 6.51) and 5.36 (5.02; 5.69) for the younger patients and older groups, respectively. No significant differences were observed between the two groups with respect to rates of grade 3+ anaemia, neutropenia or thrombocytopenia. In clinical practice, a target AUC of 4 mg/min./mL carboplatin is applied to patients aged 70 and over, but the actual systemic exposure to the drug is higher. This supports a target AUC of 4 mg/min./mL carboplatin for patients older than 70 years when the dose is calculated by means of the Calvert-Crokcoft-Gault formula.     

Cystatin C as a new covariate to predict renal elimination of drugs: application to carboplatin

BACKGROUND AND OBJECTIVE: The individual dosing of drugs that are mainly eliminated unchanged in the urine is made possible by assessing renal function. Most of the methods used are based on serum creatinine (SCr) levels. Cystatin C (CysC) has been proposed as an alternative endogenous marker of the glomerular filtration rate (GFR). Carboplatin is one of the drugs for which elimination is most dependent on the GFR. A prospective clinical trial including 45 patients was conducted to assess the value of serum CysC as a predictor of carboplatin clearance (CL). METHODS: The patients were receiving carboplatin as part of established protocols. Carboplatin was administered as a daily 60-minute infusion at doses ranging from 290 to 1700mg. A population pharmacokinetic analysis was performed using the nonlinear mixed effect modelling NONMEM program according to a two-compartment pharmacokinetic model. RESULTS: Data from 30 patients were used to test the relationships between carboplatin CL and morphological, biological and demographic covariates previously proposed for prediction of the GFR. The interindividual variability of carboplatin CL decreased from 31% (no covariate) to 14% by taking into account five covariates (SCr, CysC, bodyweight [BW], age and sex). Prospective evaluation of these relationships using the data from the other 15 patients confirmed that the best equation to predict carboplatin CL was based on these five covariates, with a mean absolute percentage error of 13% as an assessment of precision. NONMEM analysis of the whole dataset (n = 45 patients) was performed. The best covariate equation corresponding to the overall analysis was: CL (mL/min) = 110 x (SCr/75)-0.512 x (CysC/1.0)-0.327 x (BW/65)0.474 x (age/56)-0.387 x 0.854sex, with SCr in micromol/L, CysC in mg/L, BW in kilograms, age in years and sex = 0 if male and 1 if female. To put the value of CysC as an endogenous marker of the GFR into perspective, covariate equations without SCr were also evaluated; a better prediction was obtained by considering CysC together with age and BW (interindividual variability of 16.6% vs 23.3% for CysC alone). CONCLUSION: CysC is a marker of drug elimination that is at least as good as SCr for predicting carboplatin CL. The model based on five covariates was superior to those based on only four covariates (with BW, age and sex combined with either SCr or CysC), indicating that CysC and SCr are not completely redundant to each other. Further pharmacokinetic evaluation is needed to determine whether SCr or CysC is the better marker of renal elimination of other drugs.     

Dose-banding of carboplatin: rationale and proposed banding scheme.

BACKGROUND: In dose-banding (DB) prescribed doses of cancer chemotherapy are fitted to doseranges or 'bands' and standard doses for each band are provided using a selection of pre-filled infusions or syringes, either singly or in combination. DB is used for several drugs where dose is based on body surface area. No DB-scheme has been reported for carboplatin, which, in clinical practice, is routinely dosed according to renal function. STUDY OBJECTIVE: To assess the rationale for DB of carboplatin with regards to factors that influence dosing accuracy, develop a DB scheme, and discuss its potential use and limitations. METHODS: Prospective evaluations of carboplatin area under the plasma concentration -- time curve (AUC) following application of the Calvert-formula were identified by a literature search. A relevant carboplatin dose range for construction of a DB-scheme with Calvert-formula based doses was obtained from published glomerular filtration rate distributions for patients receiving carboplatin. RESULTS: A DB-scheme was developed for individually calculated carboplatin doses of 358-1232 mg, with 35 mg increments between each standard dose and a maximum deviation of 4.7% from prescribed dose. The proposed DB-scheme covers the GFR-ranges 47-221 mL/min and 26-151 mL/min for patients receiving doses based on the target AUCs of 5 and 7 mg/mL/min, respectively. CONCLUSION: There is a strong scientific rationale to support DB of carboplatin. The proposed banding scheme could introduce benefits to patients and healthcare staff but, as with other DB schemes, should be validated with prospective clinical and pharmacokinetic studies to confirm safety and efficacy.     

Comparison of nonlinear mixed-effect and non-parametric expectation maximisation modelling for Bayesian estimation of carboplatin clearance in children

OBJECTIVE: The pharmacodynamic-pharmacokinetic relationships for carboplatin involve the area under the curve of ultrafiltrable plasma concentrations versus time (AUC). The objective of the study was to compare two specific population pharmacokinetic methodologies, nonlinear mixed-effect model (NONMEM) and non-parametric expectation maximisation (NPEM), when they are applied to sparse carboplatin pharmacokinetic data in order to obtain an individual value for carboplatin clearance by Bayesian estimation. METHODS: The data from 117 patients (from 1 month to 18 years old) were available. For 20 patients randomly selected, the carboplatin clearance obtained by Bayesian estimation using two plasma ultrafiltrable concentrations was compared with that obtained by individual analysis using all concentrations. RESULTS: Both methodologies were unbiased with mean relative percentage errors (95%CI) of -1.9% ( 7.8; +4.1%) and +6.4% (-2.1; +14.9%) for NONMEM and NPEM, respectively. A comparison of precision between the two methods showed that they were not significantly different (12.5% for NONMEM, and 18.9% for NPEM), but the percentage error ranged between -21% and + 19% for NONMEM, and -35% and + 42% for NPEM. A NONMEM analysis was also performed with all the data available (117 children) in order to update an equation describing the relationship between carboplatin clearance and the patients' covariates. The best relationship corresponded to the equation: clearance (ml/min) = [4.47 x body weight x (1 -0.22 x Np)/(l + 0.0156 x Scr)] +6.4, with body weight in kilograms and where Scr is serum creatinine in micromoles per litre and Np= 1 or 0 for unilateral nephrectomy or not, respectively. CONCLUSION: These methodologies may be useful for dose individualisation and drug monitoring of carboplatin in paediatric patients. Since the mode of administration of carboplatin in paediatric practice in some protocols is daily 1-h i.v. infusion repeated up to five times, dose individualisation may be performed from the clearance observed after the first administration, given an overall target AUC.     

贝伐单抗联合培美曲塞加卡铂二线治疗晚期非小细胞肺癌的临床观察

目的:观察贝伐单抗联合培美曲塞加卡铂二线治疗晚期非小细胞肺癌(NSCLC)的疗效及不良反应。方法:30例晚期NSCLC患者采用随机数字表法分为试验组(10例,贝伐单抗15mg·kg-1+培美曲塞500mg·m-2+卡铂AUC6)与对照组(20例,培美曲塞500mg·m-2+卡铂AUC6),21d为1个周期。完成2个周期以上评价疗效和不良反应。结果:试验组与对照组的疾病控制率分别为80.0%、40.0%(P<0.05),中位无进展生存期分别为4.7、3.2个月(P<0.05),有效率分别为20.0%、5.0%(P>0.05),中位生存期分别为9.2、7.9个月(P>0.05)。2组主要不良反应比较,差异无统计学意义(P>0.05)。结论:贝伐单抗联合培美曲塞加卡铂二线治疗晚期NSCLC在疾病控制率和中位无进展生存期方面优于培美曲塞加卡铂方案,且未加重不良反应,患者能够耐受。     

Sparse sampling design for therapeutic drug monitoring of sequentially administered cyclophosphamide, thiotepa, and carboplatin (CTC)

The alkylating agents cyclophosphamide, thiotepa, and carboplatin (CTC) are administered simultaneously in high-dose chemotherapy regimens. This regimen is sometimes complicated by severe organ toxicities, which may be caused by interindividual variability in the pharmacokinetics of the agents. Monitoring plasma levels and adapting doses may reduce variability in exposure to the compounds and their metabolites. The aim of this study was to develop and validate a sparse sampling design for routine dose individualization of cyclophosphamide, thiotepa, and carboplatin both during and between courses in the CTC regimen. Models describing the population pharmacokinetics of the prodrug cyclophosphamide (4000 or 6000 mg/m) and its activated metabolite 4-hydroxycylophosphamide, thiotepa (320 or 480 mg/m), and its equipotent metabolite tepa, and carboplatin (1067 or 1600 mg/m) in the 4-day CTC regimen have been developed previously using the program NONMEM. Based on these models, plasma concentrations were calculated in 20 groups of 50 simulated patients in each group during multiple courses of therapy, and the exposure, expressed as area under the plasma concentration-versus-time curve (AUC), was calculated. Subsequently, individual model-predicted AUCs were calculated for all courses, based on selected simulated plasma concentrations during the first course of therapy. Strategies were compared by assessment of their predictive performance of the AUC and their applicability in clinical practice. Withdrawal of 3 samples on the first day of the course at 190, 290, and 400 minutes after start of cyclophosphamide infusion resulted in unbiased and precise first course AUC predictions of 4-hydroxycylophosphamide, thiotepa and tepa, and carboplatin (precision [root mean squared relative prediction error, %RMSE] 20%, 16%, 8.8%, respectively). Applying this same strategy at day 3 (or 4) of the course, with an additional sample at 600 minutes on both days, resulted in unbiased and precise predictions of the AUC of a following course (%RMSE 21%, 18%, 17%, respectively). Prospective validation of the strategies in 23 additional patients yielded comparable results. It can be concluded that a good and useful sparse sampling design was developed for precise and accurate estimation of the AUCs of 4-hydroxycyclophosphamide, thiotepa and tepa, and carboplatin in the CTC regimen. This method is valuable in pharmacokinetically guided dose adaptation both during and between CTC courses.     

Phase I study of paclitaxel on a 3-hour schedule followed by carboplatin in untreated patients with stage IV non-small cell lung cancer

This study sought to determine the principal toxicities and feasibility of administering paclitaxel as a 3-hour infusion followed by carboplatin without and with granulocyte colony-stimulating factor (G-CSF) in chemotherapy-naive patients with stage IV non-small cell lung carcinoma (NSCLC), and to recommend doses for subsequent clinical trials. Twenty-three patients were treated with paclitaxel at doses ranging from 175 to 225 mg/m² followed by carboplatin targeting area under the concentration-time curve (AUC) 7 or 9 mg/mL.min every 3 weeks. AUCs were targeted using the Calvert formula with estimated creatinine clearance as a surrogate for the glomerular filtration rate. A high rate of intolerable, mutually exclusive toxicities, consisting primarily of thrombocytopenia, as well as neutropenia, nausea and vomiting, and mucositis, precluded escalation of carboplatin above a targeted AUC of 7 mg/mL.min with paclitaxel 225 mg/m², which approaches the maximum tolerated dose (MTD) of paclitaxel given as a single agent on a 3-hour schedule. Moderate to severe peripheral neurotoxicity occurred in several patients after multiple courses. Due to the heterogeneous nature of the principal toxicities and the ability to administer clinically-relevant doses of both agents in combination without G-CSF, further dose escalation using G-CSF was not performed. Nine of 23 (39%) total patients and 43% of 21 assessable patients had partial responses (PR). The recommended doses for subsequent clinical trials are paclitaxel 225 mg/m² as a 3-hour infusion followed by carboplatin at a targeted AUC of 7 mg/mL.min. The ability to administer clinically-relevant single agent doses of paclitaxel and carboplatin in combination, as well as the significant antitumor activity noted in this phase I trial, indicate that further evaluations of this regimen in both advanced and early stage NSCLC are warranted.