The kinetics of flurbiprofen in synovial fluid

Steady state plasma and synovial fluid flurbiprofen concentrations obtained from 26 rheumatoid arthritis patients receiving 100 mg of flurbiprofen b.i.d. were analyzed using the NONMEM program. Only one synovial fluid sample per patient was available. Population estimates for the plasma parameters, clearance, volume of distribution, and elimination half-life were 1.75 L hr⁻¹, 11.9 L, and 4.8 hr, respectively, and the corresponding interindividual variances in these parameters were 29, 19, and 23%, respectively. The apparent elimination half-life from synovial fluid was 7.1 hr. After accounting for interindividual variability there was a residual variability of approximately 40% in both the plasma and synovial fluid concentrations.     

Population pharmacokinetics of oral diclofenac for acute pain in children

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Diclofenac is an effective oral analgesic for acute postoperative pain. In adults 25 mg is half as effective as 50 mg, but 50 mg and 100 mg are similarly effective (ceiling effect). Diclofenac has linear pharmacokinetics in this range.
• Diclofenac is frequently used ‘off-label’ in children for acute pain but optimum dosing is unclear (dosing of diclofenac in clinical paediatric studies ranges from 0.5–2.5 mg kg⁻¹). There is currently no licensed oral paediatric formulation of diclofenac.

WHAT THIS STUDY ADDS

• Using a new diclofenac oral suspension, a dose of 1 mg kg⁻¹ in children aged 1 to 12 years gives a similar exposure to 50 mg in adults; paediatric patients are unlikely to benefit from higher doses.

AIMS

To develop a population pharmacokinetic model for a new diclofenac suspension (50 mg 5 ml⁻¹) in adult volunteers and paediatric patients, and recommend a dose for acute pain in children.

METHODS

Blood samples were drawn at the start and end of surgery, and on removal of the venous cannula from 70 children (aged 1 to 12 years, weight 9 to 37 kg) who received a preoperative oral 1 mg kg⁻¹ dose; these were pooled with rich (14 post-dose samples) data from 30 adult volunteers. Population pharmacokinetic modelling was undertaken with NONMEM. The optimum adult dose of diclofenac for acute pain is 50 mg. Simulation from the final model was performed to predict a paediatric dose to achieve a similar AUC to 50 mg in adults.

RESULTS

A total of 558 serum diclofenac concentrations from 100 subjects was used in the pooled analysis. A single disposition compartment model with first order elimination and dual absorption compartments was used. The estimates of CL/F and V_D/F were 53.98 l h⁻¹ 70 kg⁻¹ and 4.84 l 70 kg⁻¹ respectively. Allometric size models appeared to predict adequately changes in CL and V_D with age. Of the simulated doses investigated, 1 mg kg⁻¹ gave paediatric AUC_{(0, 12 h)} to adult 50 mg AUC_{(0, 12 h)} ratios of 1.00, 1.08 and 1.18 for ages 1–3, 4–6 and 7–12 years respectively.

CONCLUSIONS

This study has shown 1 mg kg⁻¹ diclofenac to produce similar exposure in children aged 1 to 12 years as 50 mg in adults, and is acceptable for clinical practice; patients are unlikely to obtain further benefit from higher doses.     

Plasma and cerebrospinal fluid concentrations of indomethacin in humans

Summary Plasma and cerebrospinal fluid (CSF) concentrations of indomethacin have been determined in 52 patients hospitalized for nerve-root compression pain. Samples of blood and CSF were collected at the same time in each subject, 0.5 to 12 h after a single intramuscular injection of 50 mg indomethacin. Analgesic effect was assessed by the absolute and percentage variation in Huskisson's visual analogue scale between dosing and sampling.According to its high lipid solubility, indomethacin rapidly crossed the blood-brain barrier, being detected in CSF 0.5 h after administration. After attainment of equilibrium within 2 h, the CSF level exceeded the free plasma level. Since the drug was extensively bound to serum albumin (99.7±0.1%), this phenomenon may represent a slight degree of binding of indomethacin in CSF.The analgesic activity was not related to either the plasma or CSF concentration of indomethacin.Supported by a grant from Merck-Sharp and Dohme Chibret France     

Population pharmacokinetics of lamotrigine in Chinese children with epilepsy

Aim:

To establish a population pharmacokinetics (PPK) model for lamotrigine (LTG) in Chinese children with epilepsy in order to formulate an individualized dosage guideline.

Methods:

LTG steady-state plasma concentration data from therapeutic drug monitoring (TDM) were collected retrospectively from 284 patients, with a total of 404 plasma drug concentrations. LTG concentrations were determined using a HPLC method. The patients were divided into 2 groups: PPK model group (n=116) and PPK valid group (n=168). A PPK model of LTG was established with NONMEM based on the data from PPK model group according to a one-compartment model with first order absorption and elimination. To validate the basic and final model, the plasma drug concentrations of the patients in PPK model group and PPK valid group were predicted by the two models.

Results:

The final regression model for LTG was as follows: CL (L/h)=1.01^*(TBW/27.87)^0.635*e^−0.753*VPA*e^0.868*CBZ*e^0.633*PB, Vd (L)= 16.7^*(TBW/27.87). The final PPK model was demonstrated to be stable and effective in the prediction of serum LTG concentrations by an internal and external approach validation.

Conclusion:

A PPK model of LTG in Chinese children with epilepsy was successfully established with NONMEM. LTG concentrations can be predicted accurately by this model. The model may be very useful for establishing initial LTG dosage guidelines.     

Population pharmacokinetics of oxycodone in plasma and cerebrospinal fluid after epidural and intravenous administration

Objectives: To establish the first plasma and cerebrospinal fluid (CSF) oxycodone population pharmacokinetic (PopPK) model after epidural (EPI) and intravenous (IV) oxycodone administration.

Methods: The study was conducted with 30 female subjects undergoing elective gynecological surgery with epidural analgesia. A parallel single dose of EPI oxycodone with IV placebo (EPI group; n = 18) or IV oxycodone with EPI placebo (IV group; n = 12) was administered. An epidural catheter for drug administration was placed at T12/L1 and a spinal catheter for CSF sampling at L3/4. Plasma and CSF for oxycodone analysis were frequently collected. A PopPK model was built using the NONMEM software package.

Results: Plasma and CSF oxycodone concentrations were evaluated using separate central plasma and CSF compartments and separate peripheral plasma and CSF compartments. Epidural space served as a depot compartment with transfer to both the plasma and CSF central compartments. The population parameters for plasma clearance and apparent distribution volumes for central and peripheral compartments for plasma and CSF were 37.4 L/h, 90.2 L, 68.9 L, 0.035 L (fixed based on literature), and 0.039 L, respectively.

Conclusion: A PopPK model was developed and found to precisely and accurately describe oxycodone time-concentration data in plasma and CSF.     

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.     

Diclofenac readily penetrates the cerebrospinal fluid in children

AIMS

The primary aim was to study the cerebrospinal fluid (CSF) penetration of intravenous diclofenac in children. The secondary aim was to evaluate the plasma diclofenac concentration at the onset of wound pain after inguinal surgery in children.

METHODS

A total of 31 children (24 boys) aged 3 months to 12 years received a single intravenous injection of diclofenac 1 mg kg⁻¹. Paired CSF and blood samples were obtained 5 min to 22 h (median 69 min) later. In children having inguinal surgery a second blood sample was obtained at the time that the children felt wound pain for the first time after surgery. Diclofenac concentrations in CSF, plasma and protein free plasma were measured by gas chromatography with mass spectrometric detection.

RESULTS

In the 28 CSF samples obtained at 5 min to 3 h 43 min after injection, diclofenac concentrations ranged between 0.5 and 4.7 μg l⁻¹. At 5.5 h the CSF concentration was 0.1 μg l⁻¹, and no diclofenac was detected in the two CSF samples obtained at 22 h. The median of plasma diclofenac concentration at the time when pain returned after inguinal surgery was 104 μg l⁻¹ (range 70–272 μg l⁻¹). No serious or unexpected adverse effects were reported.

CONCLUSIONS

Diclofenac penetrates the CSF rapidly, and a sufficient concentration to inhibit cyclooxygenase enzymes is sustained for up to 4 h.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Diclofenac, a nonselective nonsteroidal anti-inflammatory drug,, exerts analgesic action both in the peripheral tissues and in the central nervous system by inhibiting cyclooxygenase enzymes COX-1/2, but central nervous system penetration of diclofenac has not been evaluated in humans.

WHAT THIS STUDY ADDS

• Diclofenac penetrates the cerebrospinal fluid rapidly, and after a single intravenous dose of 1 mg kg⁻¹, sufficient concentrations to inhibit COX-1/2 are sustained for up to 4 h.

     

The diffusion of pirprofen into the cerebrospinal fluid in man

Summary We have measured the concentrations of pirprofen at various times in plasma and cerebrospinal fluid (CSF) samples, drawn during diagnostic myelography from 28 patients affected by sciatica.After intramuscular injection of 400 mg plasma concentrations of pirprofen reached a peak in 60 min then fell slowly. In contrast, the CSF concentration rose until 12 h and then fell. Pirprofen rapidly crossed the blood-brain barrier and was detectable in CSF at 15–30 min after injection.These results support the suggested hypothesis of a central analgesic action of pirprofen along with the known peripheral one. A new sensitive HPLC method was developed for measuring the concentration of pirprofen in the CSF.     

氟比洛芬口服混悬剂的兔药物动力学及其生物利用度

目的:研究氟比洛芬口服给药的药物动力学及生物利用度。方法:利用HPLC法测定氟比洛芬的血药浓度,以交叉给药方式分别给予家兔注射剂和口服混悬剂并且对其药物动力学和生物利用度进行研究。结果:氟比洛芬在家兔体内药动学静脉注射符合二室开放模型,口服符合一室开放模型,氟比洛芬口服混悬剂的绝对生物利用度为61.9%。结论:在进行氟比洛芬剂型研究时应注重提高其口服制剂的生物利用度。     

用NONMEM法建立中国癫痫儿童丙戊酸钠的群体药动学/药效学结合模型

目的:建立中国癫痫儿童应用丙戊酸钠(VPA)的群体药动学药效学(PPKPD)结合模型,为设计个体化用药方案奠定基础。方法:回顾性收集246例癫痫患儿应用VPA的临床数据。血药浓度是常规监测的稳态浓度。用246例患儿的数据,通过NONMEM法已经自行成功建立PPK模型。现将246例中单用VPA的69例的数据与已经建立的PPK模型结合,建立PPKPD模型。药效指标用癫痫发作次数减少百分比,分为5级。应用Logistic回归分析,拟合线性药效模型,用NONMEM法建立PPKPD模型,求算血药浓度获得某一级疗效的概率。结果:应用Logistic回归分析,拟合线性药效模型,求算出血药浓度获得某一级疗效的概率:血药浓度超过23μg·ml-1时,5级的概率小于50%,获得4、3、2级的最大概率及浓度为(30μg·ml-1,32.3%)、(50μg·ml-1,26.3%)、(65μg·ml-1,36.5%);血药浓度超过78μg·ml-1时,1级的概率大于50%;浓度为100μg·ml-1时,1级的概率约84.2%。结论:用NONMEM法成功地建立了中国癫痫儿童应用VPA的PPKPD模型,定量地求出某一血药浓度获得不同疗效等级的概率。     

Population pharmacokinetics of valproate in Mexican children with epilepsy

Background. The aim of this study was to determine the factors that influence valproate clearance (CL) in Mexican epileptic pediatric patients using a mixed‐effect model and sparse data of serum concentrations of valproic acid (VPA) collected during routine clinical care of patients. Methods. The number of patients included in the study was 110. The population CL was calculated by using the NONMEM program. The following covariates were tested by their influence on CL: total body weight (TBW), height, age, body surface area, daily dose (DD), sex of the patient and comedication with phenobarbital (PB) or carbamazepine. Results. The final regression model for valproic CL found best to describe the data was: CL/F=(0.0466+0.00363 TBW+0.000282 DD) ^* (1+0.236 PB). This model allows a reduction of 50% of the interindividual variability and of 31% of the residual variability described by the basic model that does not include covariables. Conclusions. Total body weight, daily dose of valproate and concomitant therapy with PB are factors that significantly influence VPA kinetic disposition and they should be considered in programming dosage regimens for this antiepileptic drug in the pediatric population. The validation of the model supports its acceptability for clinical purposes. Copyright © 2008 John Wiley & Sons, Ltd.     

Morphine and morphine-6-glucuronide in the plasma and cerebrospinal fluid of children

AIMS: To measure morphine and morphine-6-glucuronide in the plasma and cerebrospinal fluid of children following a single intravenous dose of morphine. METHODS: Twenty-nine paired samples of cerebrospinal fluid and plasma were collected from children with leukaemia undergoing therapeutic lumbar puncture. An intravenous dose of morphine was administered at selected intervals before the procedure. Concentrations of morphine and morphine-6-glucuronide (M6G) were measured in each sample. Morphine was measured using a specific radioimmunoassay (r.i.a.) and M6G was measured using a novel enzyme-linked immunosorbent assay (ELISA). RESULTS: The ELISA for measuring M6G was highly sensitive. The intra-and interassay variations were less than 15%. Using a two-compartment model for plasma morphine, the area under the curve to infinity (AUC, 7143 ng ml-1 min), volume of distribution (3.6 l kg-1 ) and elimination half-life (88 min) were comparable with those reported in adults. Clearance (35 ml min-1 ) was higher than that in adults. Morphine-6-glucuronide was readily synthesized by the children in this study. The elimination half-life (321 min) and AUC (35507 ng ml-1 min) of plasma M6G were much greater than those of morphine. CONCLUSIONS: Extensive metabolism of morphine to M6G in children with cancer has been demonstrated. These data provide further evidence to support the importance of M6G accumulation after multiple doses. There was no evidence that morphine passed more easily into the CSF of children than adults.     

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.     

Pharmacokinetics,cerebrospinal fluid concentration,and safety of intravenous rifampin in pediatric patients undergoing shunt placements

Summary The objectives of this study were to characterize the pharmacokinetics and determine the cerebrospinal fluid concentrations and safety of intravenous rifampin in pediatric patients undergoing shunt placement. Nine patients (mean age 5.6 y) received a single dose of rifampin, 20 mg · kg⁻¹, administered intravenously 1 h prior to surgery. The peak serum concentrations ranged from 13.5–26.7 μg · ml⁻¹; cerebrospinal fluid concentrations ranged from 0.12–3.0 (mean: 1.4) μg · ml⁻¹. The mean total clearance, apparent distribution volume, and elimination half-life were 0.291 · kg⁻¹ · h⁻¹, 1.11 · kg⁻¹, and 2.8 h. The concentrations of rifampin achieved in the cerebrospinal fluid exceeded the minimum inhibitory concentrations by 100-to 1000-fold against Staphylococcus epidermidis. However, 5 of 9 patients developed cutaneous reactions during intravenous rifampin prophylactic therapy. Because of the high frequency of adverse effects and more than adequate rifampin concentrations achieved in the cerebrospinal fluid, rifampin doses lower than that used in this study may be evaluated in future studies. Supported by grants from the Children's Hospital Research Foundation, and Ohio State University office of Health Services     

美罗培南在化脓性脑膜炎新生儿血浆和脑脊液中药动学和药效学的关联研究

目的 探讨美罗培南在化脓性脑膜炎的新生患儿血浆和脑脊液中的药动学和药效学的关联。方法 试验招募2016年5月—2021年5月在扬州大学附属医院诊断为化脓性脑膜炎的58例新生儿患者,均获得血浆样品,其中17人获得脑脊液样品。出生后2～4周的新生儿以及4～6周的婴幼儿使用8 h的剂量间隔,美罗培南使用剂量为40 mg·kg^-1,输注时间超过30 min。使用带有DIGITAL FORTRAN编译器的NONMEM软件包分析数据。超高效液相色谱联用串联质谱（UHPLC-MS/MS）测定血浆和脑脊液中的美罗培南浓度。使用最终模型估计值的蒙特卡罗模拟（n＝1 000）用于生成不同给药方案的游离血药浓度水平维持在目标菌群的最低抑菌浓度（MIC）之上的时间（fT＞MIC）占1个给药间隔的百分比（% fT＞MIC）和最小抑菌浓度（MIC）值：1、2、4、8 mg·L^-1。结果 美罗培南在血浆中的峰浓度（C_max）、曲线下面积（AUC）、清除率（CL）、表观分布容积（V_d）高于脑脊液中的各项数据,差异有统计学意义（P＜0.05）;血浆中的半衰期（t_1/2）低于脑脊液,差异有统计学意义（P＜0.05）。用蒙特卡罗模拟10 000例患者目标获得概率,随着MIC值增加,血浆目标获得概率降低;血浆中40%最低抑菌浓度（MIC）的时间百分比（40% TMIC）、60% TMIC、80% TMIC、100% TMIC目标获得概率逐渐降低。随着MIC值增加,脑脊液目标获得概率降低;脑脊液中40% TMIC、60% TMIC、80% TMIC、100% TMIC目标获得概率逐渐降低。结论 模拟试验表明,当MIC为2 μg·mL^-1时,美罗培南在血浆中的目标获得概率可以达标,其在脑脊液中的目标获得概率不能达标,治疗时需要增加美罗培南的剂量或缩短给药间隔,以达到治疗目标。     

Paracetamol plasma and cerebrospinal fluid pharmacokinetics in children

Aims Paracetamol has a central action for both antipyresis and analgesia. Maximum temperature decrease and peak analgesia are reported at 1–2  h after peak plasma paracetamol concentration. We wished to determine the relationship between plasma and cerebrospinal fluid (CSF) pharmacokinetics in children.
Methods Concentration-time profiles in plasma and CSF after nasogastric paracetamol 40  mg  kg⁻¹ were measured in nine children who had indwelling ventricular drains. Estimation of population pharmacokinetic parameters was made using both a standard two-stage population approach (MKMODEL) and a nonlinear mixed effect model (NONMEM). Results were standardized to a 70  kg person using an allometric power model.
Results Both approaches gave similar estimates. NONMEM parameter estimates were clearance 10.2  l  h⁻¹ (CV 47%), volume of distribution 67.1  l (CV 58%) and absorption rate constant 0.77  h⁻¹ (CV 49%). Cerebrospinal fluid concentrations lagged behind those of plasma. The equilibration half time was 0.72  h (CV 117%). The CSF/plasma partition coefficient was 1.18 (CV 8%).
Conclusions Higher concentrations in the CSF probably reflect the lower free water volume of plasma. The CSF equilibration half time suggests that CSF kinetics approximate more closely to the effect compartment than plasma, but further time is required for paracetamol to exert its effects. Effect site concentrations equilibrate slowly with plasma. Paracetamol should be given 1–2  h before anticipated pain or fever in children.     

Population pharmacokinetics of valproate in Chinese children with epilepsy

Aim： The aim of the present study is to establish a population pharmacokinetic （PPK） model of valproate （VPA） in Chinese epileptic children to promote the reasonable use of anti-epileptic drugs. Methods： Sparse data of VPA serum concentrations from 417 epileptic children were collected. These patients were divided into 2 groups： the PPK model group （n=317） and the PPK valid group （n=100）. The PPK parameter values of VPA were calculated by NONMEM software using the data of the PPK model group. A basic model and a final model were set up. To validate the 2 models, the concentrations of PPK valid group were predicted by each model, respectively. The mean prediction error （MPE）, mean squared prediction error （MSPE）, root mean squared prediction error （RMSPE）, weight residues （WRES）, and the 95% confidence intervals （95% CI） were also calculated. Then, the values between the 2 models were compared. Results： The PPK of VPA was determined by a 1-compartment model with a first-order absorption process. The basic model was： Ka=3.09 （h^-1）, V/F=20.4 （L）, CL/F=0.296 （L/h）. The final model was： Ka=0.251＋2.24-（1-HS） （h^-l）, V/F=2.8 8＋0.157-WT （L）, CL/F=0.106^0.98.CO＋ 0.0157·AGE （L/h）. For the basic model, the MPE, MSPE, RMSPE, WRES, and the 95% CI were -23.53 （-30.36,-16.70）, 3728.96 （2872.72, 4585.20）, 39.62 （34.34, 44.90）, and-0.06 （-0.14, 0.02）, respectively. For the final model, the MPE, MSPE, RMSPE, WRES, and the 95% CI were -1.16 （-4.85, 2.53）, 1002.83 （1050.64,1143.61）, 23.04 （21.12, 24.96）, and 0.08 （-0.04, 0.20）, respectively. The final model was more optimal than the basic model. Conclusion： The PPK model of VPA in Chinese epileptic children was successfully established. It will be valuable to facilitate individualized dosage regimens.     

Plasma and cerebrospinal fluid pharmacokinetics of naproxen in children

The aim of this study was to characterize pediatric pharmacokinetics and central nervous system exposure of naproxen after oral administration. The pharmacokinetics of naproxen was studied in 53 healthy children aged 3 months to 12 years undergoing surgery with spinal anesthesia. Children received preoperatively a single dose of 10 mg/kg oral naproxen suspension. A single cerebrospinal fluid (CSF) sample (n = 52) was collected at the induction of anesthesia, and plasma samples (n = 270) were collected before, during, and after the operation (up to 51 hours after administration). A population pharmacokinetic model was built using the NONMEM software. Naproxen concentrations in plasma were well described by a 2-compartment model. The estimated oral clearance (CL/F) was 0.62 L/h when linearly scaled by weight to 70 kg. The apparent volume of distribution at steady state (Vss/F) was 12.5 L /70 kg. The findings are consistent with previously reported pharmacokinetic parameters for children older than 5 years. Naproxen permeated into the CSF and reached CSF concentrations that were 4 times higher than unbound plasma concentrations. Based on these data, weight can be used as a basis for naproxen dosing in children older than 3 months of age.     

用NONMEM法建立西酞普兰群体药代动力学模型

目的建立中国人西酞普兰(抗抑郁药)的群体药代动力学(PPK)模型,为临床个体化给药提供参考。方法用群体药代动力学方法,对西酞普兰生物等效性研究中23例受试者的血药浓度和临床资料进行分析,用NON-MEM软件求算西酞普兰的PPK参数值,建立西酞普兰的PPK模型,并进行模型验证。结果经NONMEM法处理,所有因素中,年龄、体重以及CYP2C19基因型对中央隔室清除率有显著性的影响;体重对分布容积有显著性的影响。年龄和体重的增加对清除率影响分别为-0.39L·h-1.a-1和0.18L.h-1·kg-1。结论用NONMEM软件拟合获得的西酞普兰群体药代动力学最终模型,经验证稳定可靠。     

Pharmacokinetics,cerebrospinal fluid penetration,and metabolism of piroxantrone in the Rhesus monkey

Summary Piroxantrone is an anthrapyrazole derivative with broad anti-tumor activityin vitro and less cardiac toxicity than the anthracyclines. The metabolic pathways and central nervous system penetration of piroxantrone have not been determined. In this study we examined the pharmacokinetic behavior of piroxantrone in plasma and cerebrospinal fluid in a non-human primate model. In addition, a urinary metabolite of piroxantrone was isolated and its cytotoxicity evaluatedin vitro. The disappearance of piroxantrone from plasma after an intravenous dose of 150 mg/m² given over 60 minutes was biexponential with mean t_1/2 alpha of 1.0 minutes and a mean t_1/2 beta of 180 minutes. The mean area under the curve was 220 M·min and the clearance was 1420 ml/min/m². Piroxantrone was not detectable in the cerebrospinal fluid.Piroxantrone and three other compounds not present in pre-treatment samples were detected in urine. The major urinary metabolite was isolated. Its cytotoxicity against MOLT-4 cellsin vitro was at least one log less than that of piroxantrone. In addition, one of the other compounds detected in urine was determined to be a glucuronide conjugation product of the major metabolite.The results of this study may be useful in the interpretation of the activity and toxicity of piroxantrone in clinical trials.