Intravenous indometacin in preterm infants with symptomatic patent ductus arteriosus. A population pharmacokinetic study

AIMS: To characterize the population pharmacokinetics of indometacin in preterm infants with symptomatic patent ductus arteriosus and to investigate the influence of various factors on the response to treatment. METHODS: Data were collected from 35 infants (gestational age 25-34 weeks; postnatal age 1-77 days) in neonatal units in Belfast and Copenhagen. Infants received an initial course of up to three doses of intravenous indometacin (0.1-0.2 mg kg(-1)) as considered appropriate by the treating physician. For those infants who did not respond to therapy or in whom the ductus reopened, a second course was sometimes given. Population analysis of the 185 plasma concentrations obtained was conducted using NONMEM and pharmacokinetic and demographic differences between responders and nonresponders were compared. RESULTS: The concentration-time course of indometacin was best described by a one-compartment model. The final population parameter estimates of clearance (CL) and volume of distribution (V) (standardized to the median weight of 1.17 kg) were 0.00711 l h(-1) and 0.266 l, respectively. CL increased from birth by approximately 3.38% per day and V by approximately 1.47% per day. Concomitant digoxin therapy resulted in a 30% decrease in V. Interindividual variability in CL and V was 41% and 21%, respectively. Interoccasion variability for CL was 43%. Residual variability corresponded to a standard deviation of 0.148 mg l(-1). Closure occurred in 75% of infants with a plasma concentration > or = 0.4 mg l(-1) 24 h after the last dose. CONCLUSIONS: Dosing regimens for indometacin should take into account the weight and postnatal age of the infant and any concomitant digoxin therapy. The population estimates can be used to determine typical values of CL and V allowing the prediction of individualized doses of indometacin that should increase the probability of achieving a 24 h plasma concentration > or = 0.4 mg l(-1). Although the pharmacokinetic estimates will be affected by both interindividual and within-individual variation, it is anticipated that this approach will decrease the variability of exposure and optimize treatment outcome.     

Gentamicin pharmacokinetics in preterm infants with a patent and a closed ductus arteriosus

Background and aim: A patent ductus arteriosus (PDA) may influence renal and hepatic blood flow and hence pharmacokinetics of drugs in neonates compared to neonates with a closed ductus arteriosus (CDA). A 10percent difference of gentamicin pharmacokinetic parameters between PDA and CDA has been reported, but its implications are unclear. The relevance of this difference relative to the variability within the neonatal population was investigated. Methods: Twentyfour neonates (12 with a PDA and 12 with a CDA) treated with gentamicin were retrospectively included. Before closing treatment of the PDA, serum levels were drawn and analysed for regular therapeutic drug monitoring of gentamicin. Data were analysed using the standard twostage approach (STS) and an iterative 2stage Bayesian population analysis approach (It2B). Results: Both types of analysis showed no significant differences between both populations for gentamicin total body clearance per kg bodyweight (CL/kg). Volume of distribution per kg bodyweight (Vd/kg) tended to be larger and elimination rate (Kel) tended to be smaller in neonates with PDA. Multiple regression analysis showed for both populations highly significant correlations between total body clearance and body weight (p<0.0001) or gestational age (p<0.0001), and between volume of distribution and body weight (p<0.0001) or gestational age (p<0.0001). Conclusion: Although neonates with a PDA may have small differences in gentamicin pharmacokinetics compared to neonates with a CDA, this is not relevant for clinical practice taking the variability within that population into account.     

早产儿动脉导管未闭的治疗进展

摘要：动脉导管未闭（PDA）是严重影响新生儿尤其是早产儿存活及生存质量的一种疾病。目前针对PDA的治疗仍存在很大争议。本文介绍了近年来关于PDA的治疗时机选择、治疗方式（内科治疗、手术结扎及预防性治疗）及药物选择（吲哚美辛、布洛芬及对乙酰氨基酚）的研究进展,并对其利弊进行分析。     

预防性口服布洛芬对早产儿动脉导管未闭的临床价值

目的 评价预防性口服布洛芬治疗早产儿动脉导管未闭(PDA)的疗效与安全性。 方法 选取西安高新医院新生儿科2013年3月至2016年3月收治的153例胎龄小于30周的早产儿作为研究对象,采用随机数字表法分为预防性治疗组76例和常规治疗组77例。预防性治疗组,出生后24 h内给予口服首剂布洛芬10 mg·kg-1,每隔24 h后口服第二、三剂布洛芬5 mg·kg-1。常规治疗组在出生后第3天对超声证实存在PDA的患儿给予相同剂量的布洛芬口服。出生后第3天,第7天分别行心脏超声检查,抽外周血查肾功及血常规,并监测有无不良反应,两组进行观察比较。 结果 预防性治疗组在出生后第3天及出生后第7天PDA关闭率(73.7%、78.9%)均高于常规治疗组(55.8%、63.2%),差异有统计学意义(P<0.05);预防性治疗组在出生后第3天及出生后第7天的尿素氮及肌酐水平与常规治疗组相比,差异无统计学意义(P>0.05);在近期并发症如肾功损害、尿少、坏死性小肠结肠炎、重度脑室内出血发生率方面两组差异无统计学意义(P>0.05)。 结论 口服布洛芬能够有效关闭早产儿动脉导管,不增加近期不良反应发生率,安全性好。     

Effectiveness and pharmacokinetics of indomethacin in premature newborns with patent ductus arteriosus

Summary A review of the published data on pharmacological closure of PDA in premature newborns shows that doses of 0.2 mg/kg indomethacin are less successful when given enterally (18 to 85% closure) than when given intravenously (88 to 90% closure). The elimination half-life is markedly prolonged in premature newborns compared to adults but there are wide differences between the patients and some discrepancies between mean values reported by various authors. The present study compares clinical and pharmacological results obtained in two groups of low birth weight infants with symptomatic PDA and treated with 0.2 mg/kg indomethacin: 7 patients treated enterally (group A) and 11 patients treated intravenously (group B). Permanent closure of the ductus was observed in 4 cases in group A and in 9 cases in group B. Transient closure was observed twice in each group. Of a total of 18 infants, 15 were saved (83%). One baby treated with indomethacin in spite of preexisting oliguria died from persistent anuria. Indomethacin plasma levels were measured by gas chromatography. The mean elimination half-life of the drug in group A (40.3±12.2 h) did not differ from that in group B (33.9±11.7 h). The apparent plasma half-life appears to be inversely correlated with gestational age (r=0.66,p<0.05). No relationship between peak plasma levels and ductal closure was established, but a significant difference was found for area under the curve (0 to 24 h) between patients in whom a permanent closure was obtained and those in whom the closure was either transient or absent.Presented at the International Workshop on Perinatal and Pediatric Aspects of Clinical Pharmacology, Heidelberg, Federal Republic of Germany, 27–29 February 1980     

动脉导管未闭早产儿口服布洛芬治疗中超声心动图监测的价值

目的 探讨动脉导管未闭(PDA)早产儿口服布洛芬治疗中超声心动图监测的价值.方法 将生后7d内经超声心动图确诊的PDA早产儿(PDA直径小于5mm) 142例随机分为两组:观察组82例,口服布洛芬治疗;对照组60例,未服用布洛芬.超声心动图监测动脉导管关闭率.结果 观察组PDA直径＜3m者,闭合率90.3％,明显高于对照组的67.5％ (P＜0.05).观察组PDA直径为3-5 mm者,治疗后闭合率30.0％,明显高于对照组的15.0％ (P＜0.05).结论 超声心动图监测有助于评估PDA早产儿口服布洛芬疗效,并可根据PDA直径大小指导临床治疗.     

经导管封堵器介入治疗动脉导管未闭的临床研究

目的观察经导管封堵器治疗动脉导管未闭(PDA)的临床疗效.方法32例单纯PDA患者采用蘑菇伞动脉导管封堵器经皮经股静脉封堵治疗PDA,应用X线造影术观察即刻疗效,术后72 h、1个月、3个月分别行超声心动图评价治疗效果.结果X线主动脉造影测量PDA最窄处的直径平均6.8±1.1(3～12)mm,封堵器直径平均12.6±1.3(6～18)mm.全组技术成功率100%;术后10 min降主动脉造影显示29例无残余分流,3例存在极少量残余分流.术后肺动脉平均压较术前明显下降(P＜0.05).术中无任何严重并发症,3个月随访,未发现残余分流、封堵器移位、溶血、血栓或主、肺动脉狭窄.结论应用蘑菇伞动脉导管封堵器经导管介入治疗PDA安全有效,创伤小,成功率高,操作简单.     

布洛芬与对乙酰氨基酚治疗早产儿症状性动脉导管未闭对患儿血浆和尿前列腺素E_2水平的影响

目的分析布洛芬与对乙酰氨基酚治疗早产儿症状性动脉导管未闭(sPDA)对患儿血浆和尿前列腺素E_2(PGE_2)水平的影响。方法纳入2014年7月至2016年12月我院出生的患有sPDA的84例早产儿作为观察对象。随机纳入42例给予布洛芬进行治疗(A组),另外42例给予对乙酰氨基酚治疗(B组)。对比两组治疗疗效,治疗前后血浆和尿PGE_2水平以及不良反应。结果两组患儿在各时段的关闭率以及总关闭率的组间差异均无统计学意义(P>0.05)。经治疗,两组患儿血浆PGE_2和尿PGE_2水平均较治疗前下降,与治疗前比较差异有统计学意义(P<0.05);A组下降程度稍大于B组,但组间差异均无统计学意义(P>0.05)。经治疗,两组患儿肝肾功能指标血肌酐(SCr)和丙氨酸氨基转移酶(ALT)水平均较治疗前略有上升(P>0.05),血小板(PLT)较治疗前有所下降,但差异无统计学意义(P>0.05);两组SCr、ALT及PLT水平比较差异无统计学意义(P>0.05)。B组高胆红素血症比例低于A组,组间差异有统计学意义(P<0.05),其他不良反应上,组间差异均无统计学意义(P>0.05)。结论布洛芬与对乙酰氨基酚的疗效相当,其对血浆PGE_2和尿PGE_2水平的影响略强于对乙酰氨基酚,但对乙酰氨基酚高胆红素血症的比例低于布洛芬。     

Vancomycin dosing assessment in intensive care unit patients based on a population pharmacokinetic/pharmacodynamic simulation

AIM

To estimate the vancomycin pharmacokinetic profile in adult ICU patients and to assess vancomycin dosages for increasing the likelihood of optimal exposure.

METHODS

Five hundred and sixty-nine concentration–time data from 191 patients were analysed using a population pharmacokinetic approach (NONMEN™). External model evaluation was made in 46 additional patients. The 24 h area under the concentration–time curve (AUC(0,24 h)) was derived from the final model. Minimum inhibitory concentration (MIC) values for S. aureus were obtained from the EUCAST database. AUC(0,24 h) : MIC ≥ 400 was considered as PK/PD efficacy index. The probability of different dosages attaining the target considering different strains of S. aureus and patient subgroups was estimated with Monte Carlo simulation.

RESULTS

Vancomycin CL showed a significant dependence on patient age and renal function whereas Cr_Se > 1 mg dl⁻¹ increased V more than twofold. For our representative ICU patient, 61 years, 73 kg, Cr_Se= 1.4 mg dl⁻¹, measured CL_Cr= 74.7 ml min⁻¹, the estimated values were CL = 1.06 ml min⁻¹ kg⁻¹ and V= 2.04 l kg⁻¹. The cumulative fraction of response for a standard vancomycin dose (2 g day⁻¹) was less than 25% for VISA strains, and 33% to 95% for susceptible S. aureus, depending on patient characteristics.

CONCLUSIONS

Simulations provide useful information regarding the initial assessment of vancomycin dosing, the conventional dosing regimen probably being suboptimal in adult ICU patients. A graphic approach provides the recommended dose for any selected probability of attaining the PK/PD efficacy target or to evaluate the cumulative fraction of response for any dosing regimen in this population.     

布洛芬混悬液联合氢化可的松治疗早产儿动脉导管未闭的临床研究

目的探讨布洛芬混悬液联合醋酸氢化可的松片治疗早产儿动脉导管未闭的临床疗效。方法选取2013年8月—2016年8月天津市蓟州区人民医院儿科收治的动脉导管未闭早产儿134例作为研究对象,依据患者治疗方式不同分为布洛芬组(44例)、氢化可的松组(44例)和联合组(46例)。布洛芬组口服布洛芬混悬液,首次剂量10 mg/kg,第2、3剂量5 mg/kg,每次间隔24 h,共3次。氢化可的松组口服醋酸氢化可的松片,1片/次,1次/d,治疗3 d。联合组给予布洛芬混悬液和醋酸氢化可的松片治疗,方法同上。观察3组的临床疗效,比较3组的前列腺素E2(PGE2)、N末端B型脑钠肽(NT-pro BNP)、内皮素-1(EF-1)和心功能指标。结果治疗后,布洛芬组、氢化可的松组和联合治疗组动脉导管未闭关闭率分别为84.09%、79.55%、93.48%,联合治疗组动脉导管未闭关闭率高于布洛芬组和氢化可的松组,3组比较差异有统计学意义(P0.05)。治疗后,3组血浆PGE2、尿PGE2、NT-pro BNP和EF-1水平均明显下降,同组治疗前后比较差异具有统计学意义(P0.05);且联合组这些观察指标明显低于布洛芬组和氢化可的松组,差异具有统计学意义(P0.05)。治疗后,3组左心室收缩末前后径(LVESD)、左心室舒张末前后径(LVEDD)、左心室收缩末容量(LVESV)和左心室舒张末容量(LVEDV)均明显下降,同组治疗前后比较差异有统计学意义(P0.05);且联合组这些观察指标明显低于布洛芬组和氢化可的松组,差异具有统计学意义(P0.05)。联合组高胆红素血症、消化道出血发生率均低于布洛芬组和氢化可的松组,3组比较差异具有统计学意义(P0.05)。结论布洛芬混悬液联合醋酸氢化可的松片治疗早产儿动脉导管未闭具有较好的临床疗效,降低了患儿PGE_2、NT-pro BNP、EF-1水平,改善患儿心功能指标,安全性较好,具有一定的临床推广应用价值。     

Mechanisms of oxygen sensing: a key to therapy of pulmonary hypertension and patent ductus arteriosus

Specialized tissues that sense acute changes in the local oxygen tension include type 1 cells of the carotid body, neuroepithelial bodies in the lungs, and smooth muscle cells of the resistance pulmonary arteries and the ductus arteriosus (DA). Hypoxia inhibits outward potassium current in carotid body type 1 cells, leading to depolarization and calcium entry through L-type calcium channels. Increased intracellular calcium concentration ([Ca+ +]i) leads to exocytosis of neurotransmitters, thus stimulating the carotid sinus nerve and respiration. The same K+ channel inhibition occurs with hypoxia in pulmonary artery smooth muscle cells (PASMCs), causing contraction and providing part of the mechanism of hypoxic pulmonary vasoconstriction (HPV). In the SMCs of the DA, the mechanism works in reverse. It is the shift from hypoxia to normoxia that inhibits K+ channels and causes normoxic ductal contraction. In both PA and DA, the contraction is augmented by release of Ca+ + from the sarcoplasmic reticulum, entry of Ca+ + through store-operated channels (SOC) and by Ca+ + sensitization. The same three 'executive' mechanisms are partly responsible for idiopathic pulmonary arterial hypertension (IPAH). While vasoconstrictor mediators constrict both PA and DA and vasodilators dilate both vessels, only redox changes mimic oxygen by having directly opposite effects on the K+ channels, membrane potential, [Ca(++)]i and tone in the PA and DA. There are several different hypotheses as to how redox might alter tone, which remain to be resolved. However, understanding the mechanism will facilitate drug development for pulmonary hypertension and patent DA.     

Changes in urinary PGE<Subscript>2</Subscript> after ibuprofen treatment in preterm infants with patent ductus arteriosus

Purpose  To investigate changes in urinary PGE₂ after ibuprofen treatment in preterm infants with patent ductus arteriosus (PDA). Methods  Twenty preterm infants with a hemodynamically significant PDA (gestational age, 28.6 ± 2.3 weeks) and 20 controls (gestational age, 30.4 ± 1.5 weeks) were prospectively enrolled at 48–72 h of life. After enrollment, the former underwent conventional ibuprofen-lysine treatment. At 48–72 h (T₀) and 108–144 h of life (T₁), urine samples were noninvasively collected in both groups to measure urinary PGE₂ concentrations (enzyme immunoassay method), and renal function was investigated. Results  Urinary PGE₂ decreased significantly both in ibuprofen-treated patients (66.95 ± 16.78 vs. 27.15 ± 17.92 pg/mL, P < 0.001) and in controls (71.7 ± 16.2 vs. 53.2 ± 18.4 pg/mL, P < 0.001) from T₀ to T₁. However, urinary PGE₂ at T₁ was significantly lower (P < 0.001) in the ibuprofen group compared to the control group. Acute renal failure occurred in three ibuprofen-treated patients (15%). Conclusions  Ibuprofen markedly reduces (59.4%) urinary PGE₂ and may alter renal function in the newborn.     

胸骨左缘第二肋间切口微创治疗动脉导管未闭31例

摘要： 目的 评估经胸骨左缘第二肋间切口微创治疗动脉导管未闭的临床疗效和可靠性。方法 收集2014年1 月—2017年11月我科对31例婴儿期患儿行动脉导管结扎术的临床资料, 所有手术均采用经胸骨左缘第二肋间切口入路, 总结该术式的手术过程, 分析其临床转归。结果 本组病例手术过程顺利, 手术切口长度 （2.5±1.0） cm, 手术时间 （1.5±0.2） h, 术中出血不超过5 mL, 术后平均住院日 （15.1±4.2） d, 未出现死亡、 大出血等重大并发症, 术后无需放置胸腔引流管。术后随访1个月~4年, 无导管再通及动脉瘤形成。结论 胸骨左缘第二肋间切口微创治疗动脉导管未闭是一种安全可靠的方法, 并发症少, 远期疗效满意。     

Indications for a ceftriaxone dosing regimen in Japanese paediatric patients using population pharmacokinetic/pharmacodynamic analysis and simulation

Objectives The objective of this study was to build a ceftriaxone population pharmacokinetic model for Japanese paediatric patients and to examine the dosing regimen of ceftriaxone based on pharmacokinetic/pharmacodynamic (PK/PD) analysis. Methods The population pharmacokinetic analysis using NONMEM was based on published serum concentrations of ceftriaxone. A Monte Carlo simulation was examined to evaluate the time above the minimum inhibitory concentration (TAM) in 20 and 60 mg/kg body weight dose regimen using the population pharmacokinetic parameters. Key findings The time course of the serum concentration of ceftriaxone in paediatric patients was fitted to a two‐compartment model and body weight was incorporated to pharmacokinetic parameters as the covariate. Based on the percent TAM estimated from the final population pharmacokinetic model and the minimum inhibitory concentration (MIC) of ceftriaxone in 2004, we have predicted that the once daily administration of 20 mg/kg ceftriaxone would be effective on various infecting organisms. Conclusions A population pharmacokinetic model of ceftriaxone was built for Japanese paediatric patients based on the available data. The estimated PK/PD result confirmed the appropriateness of once daily dose of 20 mg/kg. In some patients for whom no efficacy was observed at 20 mg/kg, an increase to 60 mg/kg may be required.     

介入治疗动脉导管未闭和房间隔缺损及其疗效评价

目的 :评价介入治疗先天性心脏病动脉导管未闭和心房间隔缺损的初步疗效。方法 :16例病人 ,其中动脉导管未闭 (PDA) 7例 ,房间隔缺损 (ASD) 9例。所有病例均经食道超声 (TEE)证实为PDA或ASD ,并在透视或 (和 )TEE下置入Amplatzer封堵器。术后 2 4h、1、3mon和 1年分别经胸超声、心电图(ECG)和X线胸片检查评价治疗效果。结果 :7例PDA病人 ,选择封堵器的直径为 (9.71± 2 .93)mm(6～ 14mm) ;9例ASD病人 ,球囊测量值为 (2 7.30±6 .82 )mm (16～ 36mm)选择的封堵器的直径为(2 9.33± 8.12 )mm (18～ 38mm)。技术成功率为10 0 % ;术中未发现任何并发症 ,无急诊手术病例。术后即刻造影或TEE显示 4例存在少量分流 ,术后2 4h、1、3mon和 1年TTE检查所有病例无残余分流和再通 ,右房室缩小 ,肺动脉压下降。结论 :经导管置入封堵器治疗PDA和ASD是一种有效的微创方法 ,具有操作简单、安全、技术成功率高及封堵效果好等优点 ,适合于各年龄的继发孔型ASD和各种类型PDA的介入治疗。     

用模型和模拟方法设计氨氯地平的群体药动学研究方案

合理的采样设计是建立可靠群体药动学模型的重要基础。应用非线性混合效应模型的群体药动学研究,是一种有效利用稀疏血样数据估算群体药动学参数的方法。本研究根据D最优化设计和贝叶斯法设计采样方案。以已报道的氨氯地平群体药动学模型为基础,根据临床研究的目的、给药方案和随访时间等设计几套采样方案,采用WinPOPT软件计算优化采样方案,用蒙特卡罗法(Monte Carlo)对各优化的采样方案分别建立一套含400个患者的NONMEM数据文件,用NONMEM7.2软件模拟氨氯地平的浓度数据,然后估算其重要药动学参数(CL/F,V/F和Ka),并计算其平均预测误差(MPE)和平均绝对预测误差(MAPE)。在6个采样方案中,以方案6和3对CL/F估算的准确度和精密度较优,MPE分别为0.1%和0.6%,MAPE均为0.7%。对V的估算,各采样方案间无明显差异。因此,选用氨氯地平拟合药动学参数的准确度和精密度较优,且采样点个数较少的方案3为最佳临床研究方案。本研究旨在为开展氨氯地平在肾功能损害合并高血压患者的群体药动学研究提供科学、有效的采样方法,为群体PK/PD研究提供一种优化设计临床研究方案的科学方法。     

Target concentration intervention is needed for tobramycin dosing in paediatric patients with cystic fibrosis--a population pharmacokinetic study

Aim

The primary aim was to estimate the population pharmacokinetic parameters of once-daily intravenous (i.v.) tobramycin in paediatric cystic fibrosis (CF) patients and to investigate the influence of covariates. The second aim was to assess the need for target concentration intervention (TCI) for tobramycin in this patient group.

Methods

Retrospective demographic, dosing and concentration data were collected from 35 CF patients (21 female, 14 male) aged 0.5–17.8 years, from whom 318 tobramycin plasma concentrations were available. NONMEM was used to estimate the population pharmacokinetics of tobramycin. Simulations were performed using weight-based dosing with a weight from a covariate distribution model to evaluated current dosing schedules and monitoring practices.

Results

A two-compartment model best described the data with population parameter estimates for clearance of central compartment (CL) of 6.37 l h⁻¹ per 70 kg; volume of central compartment (V_c) of 18.7 l per 70 kg; intercompartmental clearance (Q) of 0.393 l h⁻¹; and volume of peripheral compartment (V_per) of 1.32 l. The inclusion of total body weight as covariate reduced the random component of between-subject variability in CL from 50.1% to 11.7% and in V_c from 62.2% to 11.6%. The between-occasion variability on CL was estimated in the final model as 6.5%. Simulations show that one dose does not fit all and TCI and dose adjustment are required.

Conclusions

This study provides the first pharmacokinetic model of once-daily i.v. tobramycin for the use of target concentration intervention in paediatric CF patients.

What is already known about this subject

• Two recent papers have been published which have attempted to build a full population pharmacokinetic model for tobramycin in children with cystic fibrosis.
• However, neither study was able to provide any information about between-subject variability (BSV) and between-occasion variability (BOV), which is necessary to justify and draw conclusions about the use of target concentration intervention (TCI).
• In the publications no simulations were provided to show any new directions or evaluate current therapy.

What this study adds

• This study provides sound evidence that TCI must be undertaken in this patient group, as the BOV is significantly less than the BSV.
• The simulations from this model clearly show that current dosing and monitoring methods will not achieve the necessary targets to maximize the pharmacokinetic–pharmacodynamic relationships of aminoglycosides in this patient group.
• The model presented is able to be easily incorporated into Bayesian dose individualization software, e.g. Abbottbase or TCIworks, to achieve dosing targets more accurately.

     

A survey of population analysis methods and software for complex pharmacokinetic and pharmacodynamic models with examples

An overview is provided of the present population analysis methods and an assessment of which software packages are most appropriate for various PK/PD modeling problems. Four PK/PD example problems were solved using the programs NONMEM VI beta version, PDx-MCPEM, S-ADAPT, MONOLIX, and WinBUGS, informally assessed for reasonable accuracy and stability in analyzing these problems. Also, for each program we describe their general interface, ease of use, and abilities. We conclude with discussing which algorithms and software are most suitable for which types of PK/PD problems. NONMEM FO method is accurate and fast with 2-compartment models, if intra-individual and interindividual variances are small. The NONMEM FOCE method is slower than FO, but gives accurate population values regardless of size of intra- and interindividual errors. However, if data are very sparse, the NONMEM FOCE method can lead to inaccurate values, while the Laplace method can provide more accurate results. The exact EM methods (performed using S-ADAPT, PDx-MCPEM, and MONOLIX) have greater stability in analyzing complex PK/PD models, and can provide accurate results with sparse or rich data. MCPEM methods perform more slowly than NONMEM FOCE for simple models, but perform more quickly and stably than NONMEM FOCE for complex models. WinBUGS provides accurate assessments of the population parameters, standard errors and 95% confidence intervals for all examples. Like the MCPEM methods, WinBUGS's efficiency increases relative to NONMEM when solving the complex PK/PD models.     

Development of a Korean‐specific virtual population for physiologically based pharmacokinetic modelling and simulation

Physiologically based pharmacokinetic (PBPK) modelling and simulation is a useful tool in predicting the PK profiles of a drug, assessing the effects of covariates such as demographics, ethnicity, genetic polymorphisms and disease status on the PK, and evaluating the potential of drug–drug interactions. We developed a Korean‐specific virtual population for the SimCYP® Simulator (version 15 used) and evaluated the population's predictive performance using six substrate drugs (midazolam, S‐warfarin, metoprolol, omeprazole, lorazepam and rosuvastatin) of five major drug metabolizing enzymes (DMEs) and two transporters. Forty‐three parameters including the proportion of phenotypes in DMEs and transporters were incorporated into the Korean‐specific virtual population. The simulated concentration–time profiles in Koreans were overlapped with most of the observed concentrations for the selected substrate drugs with a < 2‐fold difference in clearance. Furthermore, we found some drug models within the SimCYP® library can be improved, e.g., the minor allele frequency of ABCG2 and the fraction metabolized by UGT2B15 should be incorporated for rosuvastatin and lorazepam, respectively. The Korean‐specific population can be used to evaluate the impact of ethnicity on the PKs of a drug, particularly in various stages of drug development.