Population pharmacokinetics of gentamicin in neonates using a nonlinear, mixed-effects model.

The population pharmacokinetics of gentamicin in neonates was determined using a nonlinear, mixed-effects model (NONMEM). The final regression equations derived to estimate clearance (Cl) and volume of distribution (Vd) were Cl = 0.120 * (WT/2.4)1.36 L/hr and Vd = 0.429 * (WT) L. The interindividual variability (% CV) for clearance was 26.2% and for volume of distribution 15.9%. Intraindividual variability was 11.0%. In a separate group of 30 neonates, the predictive ability of the NONMEM-generated population variables was compared to the predictions from a standard two-stage population analysis. The trough concentrations predicted using NONMEM-generated parameters were significantly less biased and more precise; there were no significant differences between the methods in predicting peaks. NONMEM is a useful tool for determining population pharmacokinetics and appears to be consistent across populations using routine clinical data and limited observation.     

The effect of sepsis upon gentamicin pharmacokinetics in neonates

AIM: To investigate the effect of sepsis upon the volume of distribution (Vd) of gentamicin in neonates. METHODS: A retrospective chart review was conducted of neonates admitted to Dunedin Hospital who had gentamicin concentrations performed between 1st January 2000 and 30th October 2003. Data from 277 neonates, including a total of 576 gentamicin concentrations, were included in the pharmacokinetic analysis. Fifteen (5.4%) of the neonates had confirmed sepsis. Pharmacokinetic analyses were performed with NONMEM using a one compartment first order elimination model. Duration of infusion (D) was included as a parameter in the model. Covariates included sepsis (SEP), chronological age, gestational age (GA), birth weight, current weight, gender, Apgar score at 1 (AP1) and 5 (AP2) minutes, plasma C-reactive protein and serum creatinine. RESULTS: The initial model provided a mean estimates of clearance (CL) of 0.0460 l kg(-1) h(-1), volume of distribution (Vd) of 0.483 l kg(-1) and D of 0.748 h. The magnitudes of interpatient variability, expressed as CV%, were 29.2% for CL, 20.8% for Vd and 71.5% for D. The magnitude of residual variability in gentamicin concentrations was 88.0%. The final pharmacokinetic model was: CL = (0.0177 + 0.00147.(GA-20) + 0.000635.AP2) l kg(-1) h(-1), Vd = (0.483 +0.0656. sepsis) l kg(-1), D = 0.672 h. The interpatient variability (CV%) was 22.8% for CL, 22.8% for Vd and 97.7% for D. The magnitude of residual variability in gentamicin concentrations was 83.3%. CONCLUSIONS: The 14% increase in Vd in septic neonates implies that larger doses may be required to achieve peak therapeutic concentrations in the presence of sepsis. D is an important parameter in neonatal pharmacokinetic models.     

Pharmacokinetic analysis of cefozopran in neonatal infections--population pharmacokinetics using nonmem

This report describes the results on pharmacokinetics, efficacy and safety of cefozopran (CZOP) in neonatal patients. Enrolled patients were 136 in total whose informed consents to enter this study had been given by their parents. Among them, blood samples were collected from 42 neonates to analyze concentrations of CZOP by population pharmacokinetics (PPK) methods. Based on this analysis, the average pharmacokinetic parameters of CZOP and the variabilities of them in different morbid pharmacological backgrounds and in different subjects were evaluated. This PPK analysis showed that clearance (CL) and distribution volume (Vd) of CZOP could be estimated by the following equations; CL = 0.0452 x WT1.75 (in the case of the postnatal age of over than 1 day) CL = 0.623 x 0.0452 WT1.75 (in the case of the postnatal age of 1 day or less) Vd = 0.455 x WT where WT indicates body weight in kg. The coefficients of variation among individual subjects on CL and Vd were found to be 20.7% and 20.0%, respectively. From this PPK analysis it was indicated that the elimination of CZOP is dependent on the postnatal age and is approximately 38% lower in the younger group than in the older group. Therefore, it could be concluded that, though the cases of evaluation were small in number, adjustment of dosing of CZOP is necessary, particularly in prolongation of intervals of administration, in cases of postnatal age of 1 day or less.     

Clinical pharmacokinetics of phenobarbital in neonates.

Demographic and clinical pharmacokinetic data collected from term and preterm neonates who were treated with intravenous phenobarbital have been analysed to evaluate the role of patient characteristics in pharmacokinetic parameters. Significant relationships between total body weight (TBW) or body surface area (BSA) and volume of distribution (Vd) and total body clearance (CL) were found. Coefficients of determination were: 0.55 and 0.59 for Vd, and 0.76 and 0.72 for CL against TBW and BSA, respectively. In addition, significant relationships between height of the infants and volume of distribution of phenobarbital and total body clearance were observed. Coefficients of determination were 0.58 for Vd and 0.56 for CL. A weaker but significant correlation existed between gestational age and Vd or CL of phenobarbital. Coefficients of determination were 0.43 and 0.64, respectively. There was no correlation between volume of distribution per kg body weight or total body clearance per kg body weight and any patient parameter investigated. However, these latter pharmacokinetic parameters tended to decrease with increasing gestational age and height of the neonates. The results obtained were used to develop new loading and maintenance doses for phenobarbital in neonates based on total body weight and body surface area and based on height and gestational age for cases that weight is not available.     

Pharmacokinetic approach for optimizing gentamicin use in neonates during the first week of life

Introduction:

Gentamicin is an essential drug for the treatment of sepsis in neonates. The current work aims to optimize the use of gentamicin in neonates during the first week of life.

Materials and Methods:

The study was done at King Abdul-Aziz university hospital. Seventy-three neonates who received gentamicin 4-5 mg/kg and dosing interval at 24-48 hr were enrolled. Peak and trough serum levels of gentamicin were determined by immunoassay. Pharmacokinetic parameters were estimated assuming one compartment model and first order elimination kinetic. Analysis of variance was used to test the difference between means using Statistical Package for the Social Sciences (SPSS) Version 13.

Results:

About 73% of the patients attained peak gentamicin level within therapeutic range (6-12μg/ml), while 12% showed potentially toxic trough level (>2 μg /ml). The incidence of trough level was higher among patients receiving the drug every 24 hr. There was no clear correlation between high trough level and serum creatinine. High volume of distribution (Vd) of gentamicin (0.40-0.45) L/kg was observed. Neonates with proven sepsis showed higher mean Vd. Those with extremely low birth weight showed significantly longer half life of 11.5 h. Other neonates showed half life of (8-9) hr.

Conclusions:

Gentamicin dose of 4.5 mg/kg every 36 hr is recommended as simple empirical regimen during the 1^st week of life for neonates with normal or LBW and every 48 hr for those with ELBW.KEY WORDS: Gentamicin, preterm neonates, pharmacokinetics, therapeutic drug monitoring     

Clinical pharmacokinetics of antibacterial drugs in neonates

Neonatal patients are surviving longer due to the rapid advances in medical knowledge and technology. Our understanding of the developmental physiology of both preterm and full term neonates has also increased. It is now apparent that differences in body composition and organ function significantly affect the pharmacokinetics of antibacterial drugs in neonates, and dosage modifications are required to optimise antimicrobial therapy. The penicillins and cephalosporins are frequently used in neonates. Although ampicillin has replaced benzylpenicillin (penicillin G) for empirical treatment of neonatal sepsis, many of the other penicillins may be used in neonates for the management of various infections. Increased volume of distribution (Vd) and decreased total body clearance (CL) affect the disposition of penicillins and cephalosporins. Decreased renal clearance (CLR) due to decreased glomerular filtration and tubular secretion is responsible for the decreased CL for most of the beta-lactams. Aminoglycoside Vd is affected by the increased total body water content and extracellular fluid volume of neonates. The increased Vd, in part, accounts for the extended elimination half-life (t1/2) observed in neonates. Aminoglycoside CL is dependent on renal glomerular filtration which is markedly decreased in neonates, especially those preterm. These drugs appear to be less nephrotoxic and ototoxic in neonates than in older patients, and the role of serum concentration monitoring should be limited to specific neonatal patients. Other antibiotics such as vancomycin, teicoplanin, chloramphenicol, rifampicin, erythromycin, clindamycin, metronidazole and cotrimoxazole (trimethoprim plus sulfamethoxazole) may be used in certain clinical situations. The emergence of staphylococcal resistance to penicillins has increased the need for vancomycin. With the exceptions of vancomycin and chloramphenicol, the efficacy and safety of these other agents in neonates have not been established. The need for serum vancomycin concentration monitoring may be limited, as with aminoglycosides, while safety concerns warrant the routine monitoring of serum chloramphenicol concentrations in neonates. Dosing guidelines are provided, based on the pharmacokinetics of the drugs and previously published recommendations. These dosing guidelines are intended for initial therapy, and close therapeutic monitoring is recommended for maintenance dose requirements to optimise patient outcome. There has been an enormous increase in our knowledge of neonatal physiology and drug disposition. Fortunately, many of the antibacterial drugs used in neonates (e.g. penicillins and cephalosporins) are relatively safe. It will be important to evaluate all newly developed antibiotics in neonates to assure their maximum efficacy and safety.     

Application of routine monitoring data for determination of the population pharmacokinetics and enteral bioavailability of phenytoin in neonates and infants with seizures

This study investigated the population pharmacokinetics and the enteral bioavailability of phenytoin (PTN) in neonates and infants with seizures. Data from 83 patients were obtained retrospectively from medical records. A 1-compartment model was fitted to the log-transformed concentration data using NONMEM. Between-subject variability and interoccasion variability were modelled exponentially together with a log transform, both-sides exponential residual unexplained variance model. Covariates in nested models were screened for significance. Model robustness was assessed by bootstrapping with replacement (n = 500) from the study data. The parameters of the final pharmacokinetic model were clearance (L/h) = 0.826.[weight (WT, kg) / 70].[1 + 0.0692.(postnatal age (d) - 11)]; volume of distribution (L) = 74.2.[WT (kg) / 70]; absolute enteral bioavailability = 0.76; absorption rate constant (h) = 0.167. The between-subject variability for clearance and volume of distribution was 74.2% and 65.6%, respectively. The interoccasion variability for clearance was 54.4%. The unexplained variability was 51.1%. Final model parameter values deviated from median bootstrap estimates by less than 9%. Phenytoin disposition in neonates and infants can be described satisfactorily by linear pharmacokinetics. The values of allometrically scaled clearance and volume were similar to adult values, suggesting no major kinetic differences between adults and infants on the basis of size alone. Postnatal age independently influenced clearance. Switching from enteral to intravenous routes may require a dosage adjustment. The results of this study provide a basis for more rational prescribing of phenytoin in infants and neonates.     

Pharmacokinetics of a netilmicin loading dose on the first postnatal day in preterm neonates with very w gestational age

Objective Pharmacokinetic parameters are important for dose adjustment of aminoglycosides, but they are highly variable in neonates. In this study the pharmacokinetics of a netilmicin loading dose was investigated on the first postnatal day in preterm neonates with very low gestational age (GA).Methods In an open prospective study, 20 neonates with GA between 22.9 and 32.0 weeks and suspected postnatal bacterial infection received an intravenous loading dose of 5 mg/kg netilmicin over 1 h during the first postnatal day. Netilmicin serum concentrations were determined by an enzyme multiplied immunoassay.Results The systemic clearance of netilmicin normalized to body weight (BW) was not significantly different in three GA subgroups (0.59± 0.02 ml/min/kg for GA <24 weeks, 0.72±0.14 ml/min/kg for GA 24–27 weeks, and 0.62±0.19 ml/min/kg for GA 27–32 weeks, P=0.123). Similar results were also obtained for serum elimination half-time and for the distribution volume normalized to BW. Multiple regression analysis showed that systemic clearance and volume of distribution (both not normalized to BW) significantly correlated with BW (P<0.0001) but not with GA. In the entire group, 20% of peak concentrations were below the target of 6 mg/l, and 63% of trough concentrations were above the target of 2 mg/l.Conclusion In neonates with very low GA, the pharmacokinetic parameters of netilmicin determined after an intravenous loading dose were not dependent on GA when normalized to BW. A number of neonates did not reach targeted peak and trough netilmicin serum concentrations, suggesting that a higher loading dose and a prolonged dosing interval might enhance the effectiveness and safety of netilmicin in preterm neonates immediately after birth.     

Clinical pharmacokinetics of aminoglycosides in the neonate: a review

Background  Sepsis is common in neonates and is a major cause of morbidity and mortality. Sixty percent of preterm neonates receive at least one antibiotic, and 43% of the antibiotics administered to these neonates are aminoglycosides. The clearance (Cl), serum half-life (t_1/2), and volume of distribution (Vd) of aminoglycosides change during the neonatal life, and the pharmacokinetics of aminoglycosides need to be studied in neonates in order to optimise therapy with these drugs. Objective  The aim of this work is to review the published data on the pharmacokinetics of aminoglycosides in order to provide a critical analysis of the literature that can be a useful tool in the hands of physicians. Methods  The bibliographic search was performed electronically using PubMed, as the search engine, through July 11th, 2008. Firstly, a Medline search was performed with the keywords “pharmacokinetics of aminoglycosides in neonates” with the limit of “human”. Other Medline searches were performed with the keywords “pharmacokinetics of … in neonates” followed by the name of the aminoglycosides: amikacin, gentamicin, netilmicin and tobramycin. In addition, the book Neofax: A Manual of Drugs Used in Neonatal Care by Young and Mangum (Thomson Healthcare, 2007) was consulted. Results  The aminoglycosides are mainly eliminated by the kidney, and their elimination rates are reduced at birth. As a consequence Cl is reduced and t_1/2 is prolonged in the neonate as compared to more mature infants. The high body-water content of the neonate results in a large Vd of aminoglycosides as these drugs are fairly water soluble. Postnatal development is an important factor in the maturation of the neonate, and as postnatal age proceeds, Cl of aminoglycosides increases. Conclusion  The maturation of the kidney governs the pharmacokinetics of aminoglycosides in the infant. Cl and t_1/2 are influenced by development, and this must be taken into consideration when planning a dosage regimen with aminoglycosides in the neonate. Aminoglycosides are fairly water soluble, and the larger water content of neonates yields a larger Vd in these patients.     

Population pharmacokinetics of gentamicin in preterm neonates: evaluation of a once-daily dosage regimen.

Population pharmacokinetic parameters of gentamicin in preterm neonates on a once-daily dosage regimen of 3.0 mg/kg given intravenously every 24 hours were established prospectively. In 34 preterm neonates with a mean gestational age of 32 +/- 4 (SD), 182 serum gentamicin levels (91 peak/trough pairs) were determined. Individual adjustments of dose or dosage interval were calculated by computer-aided Bayesian forecasting. The parameters Vd, ke, and CL for each patient were obtained by the nonparametric estimation of maximization method. The predictive power of the model was calculated and the pharmacokinetic estimates were statistically analyzed with SPSS/PC. Cluster analysis showed a division into 2 subpopulations (designated 1 and 2) on the basis of postnatal age. The mean +/- SD postnatal age of subpopulation 1 (n = 29) was 6 +/- 2 days (range 1-7) and of subpopulation 2 (n = 5) 15 +/- 4 days (range 12-24). The mean +/- SD gentamicin relative clearances of subpopulation 1 and subpopulation 2 were 0.0515 +/- 0.0128 and 0.1026 +/- 0.0102 L kg(-1) hr(-1), respectively (p < 0.05). The mean +/- SD values for Vd (Lkg(-1)) in both populations 1 and 2 were 0.6916 +/- 0.1670 and 0.7509 +/- 0.1961, respectively (not significantly different). For ke these data were 0.0744 +/- 0.0200 and 0.1366 +/- 0.0522 (p < 0.05). Statistics showed that the data for Vd and ke of subpopulation 1 were normally distributed (Vd and ke skewness 1.61 and 1.46; kurtosis 3.09 and 3.10 respectively). The model yielded a bias of -0.11 mg/L and a precision of 0.36 mg/L. It is recommended that gentamicin be started in a dosage of 3.5 mg/kg intravenously once-daily under close monitoring.     

FPIA法测定不同日龄新生儿庆大霉素药代动力学与肾功能关系的探讨

新生儿肾功能发育不全是影响药代动力学的重要因素,庆大霉素主要经肾排泄;本文运用荧光偏振免疫分析法(FPIA)对24例不同日龄新生儿患者分组测得血清庆大霉素浓度,数据按一室模型回归分析求得每例的药动学参数,探讨与肾功能的关系。数据表明:Vd值各组之间无显著性差异(P>0.05),Ke,(?),C1值A组较B组有显著性差异(P<0.05),A组较C组有非常显著性差异(P<0.01),B,C两组间无显著性差异(P>0.05)。从而得出初步结论,A组肾脏发育很不完全,肾功能低下,B组已有较明显变化,C组肾功能显著增强。     

经颅彩超在新生儿缺氧缺血性脑病中的应用价值

目的：分析经颅多普勒彩色超声在新生儿缺氧缺血性脑病( HIE）的诊断价值。方法：选取我院收治的45例HIE患儿为研究对象,及同期于我院生产的45例健康新生儿为对照组,所有新生儿均于出生后48 h内进行经颅多普勒彩超检查,分析其彩超结果及大脑中动脉附近血流动力学。结果：对照组新生儿脑沟及双侧脉络丛回声较强,脑实质组织回声中等,双侧基底节区回声较均匀。研究组24例轻度患儿脑实质回声均匀度较差,回声表现为略强小点状,16例中、重度患儿超声结果均显示其侧脑室出现狭窄,脑室旁白质回声增强。研究组新生儿Vs、Vd、Vm均显著低于对照组,差异具有统计学意义( P＜0.05）;中、重度组PI显著高于对照组( P＜0.05）;中、重度组RI＞0.72或≤0.55与对照组有统计学意义( P＜0.05）。结论：经颅彩超不仅可较为清晰的显示新生儿颅脑回声情况,还可有效的探测脑血流动力学的变化,为HIE的早期诊断提供丰富的参考数据支持,值得临床进一步实践。     

高压氧对围生期缺氧缺血事件新生儿脑血流的影响

目的通过检测围生期缺氧缺血事件新生儿高压氧（HBO）治疗前后的脑血流,了解高压氧治疗对有围生期缺氧缺血事件新生儿脑灌注的影响。方法于2008年12月-2010年12月在我院住院的有围生期缺氧缺血病史的新生儿中,随机选取30例,用彩色超声多普勒检测每次HBO治疗前后通过大脑中动脉（McA）脑血流情况,连续检测其大脑前动脉的收缩期峰值（VS）、舒张末期速度（Vd）、阻力指数（RI）。所得数据采用SPSS13．0统计软件进行统计分析。结果脑血流速度的改变：HBO治疗的第1、2天,治疗前后脑血流速度无明显改变;治疗第3天,Vs、Vd较前降低,其中Vs差异有显著性（P〈0．05）,Vd差异有极显著性（P〈0．01）;治疗第4天,Vs、Vd较前降低,Vs、Vd差异有极显著性（P〈0．01）。血管阻力指数的变化：HBO治疗的第1、2天,无明显改变;治疗第3天,RI较前升高,RI差异有极显著性垆〈0．01）治疗第4天,RI较前升高,RI差异有极显著性（P〈0．01）。结论对围生期缺氧缺血事件新生儿进行HBO治疗,初期脑灌注影响不明显,治疗后期产生明显影响,可使脑血管收缩并致血流速度减慢,从而影响脑灌注。     

Desmethyldiazepam pharmacokinetics: studies following intravenous and oral desmethyldiazepam, oral clorazepate, and intravenous diazepam

After single 10-mg intravenous (IV) doses of desmethyldiazepam (DMDZ) to 12 healthy human volunteers, (mean age, 62 years) blood samples were obtained over the next 14 or more days. Mean kinetic variables were volume of distribution (Vd), 90 liters; elimination half-life (t1/2), 93 hours; and clearance, 12.3 mL/min. Vd was significantly correlated with body weight (r = .73, P less than .01) and with percent ideal body weight (r = .91, P less than .001). Eleven of the same subjects also received 5- to 15-mg doses of IV diazepam (DZ). Mean kinetic variables were Vd, 180 liters; t1/2, 83 hours; and clearance, 28 mL/min. Clearances of DZ and DMDZ were significantly correlated (r = .73, P less than .02). Based on area analysis, the extent of conversion of DZ to systemic DMDZ averaged 53%. After oral administration of DMDZ in tablet form (10 mg), or of clorazepate dipotassium in capsule form (15 mg), systemic availability of DMDZ from each of the oral dosage forms was not significantly different from 100%.     

小诺米星在新生儿的药物动力学

本文报告２０例患儿（男性１２例，女性８例；日龄１５±ｓ８ｄ）应用小诺米星，Ａ组１０例以４ｍｇ／（ｋｇ·ｄ），Ｂ组１０例以５ｍｇ／（ｋｇ·ｄ），均ｂｉｄ，静脉滴注，观察其药物动力学与肾毒性。单剂０．５ｈ滴毕。结果：血药峰值分别为４．５与４．７μｇ／ｍＬ（Ｐ＞０．０５）。２组药物动力学参数（Ｖｄ，Ｃｌ，ＡＵＣ）与肾毒性参数（β２－ＭＧ，ＢＵＮ）差别均无显著意义（Ｐ＞０．０５）。提示该药用于新生儿，且剂量增至５ｍｇ／（ｋｇ·ｄ）于１ｗｋ内应用是安全的。     

Appropriate usage of antibiotics by therapeutic drug monitoring

Aminoglycosides are mainly distributed in the extracellular fluid, so when they are given to neonates who have a large amount of extracellular fluid, their distribution is increased. In our data, the volume of distribution (Vd) of Arbekacin in the neonates was twice that of the adults, 0.54 l/kg. Therefore, the dose per weight of aminoglycosides to the neonates should be increased more than to the adults. In the renal function of the neonates, differentiation of the nephron is completed within 36 weeks after conception, but it is functionally immature. In our data, renal drug excretion increased rapidly in the post-conceptional ages (PCAs) of 34-35 weeks. Consequently, we based the Arbekacin administration schedule for the neonates on the PCAs. There is excellent correlation between serum level of vancomicin (VCM) and dose x serum creatinine (Scr)/weight in the haemodialysis patients, suggesting that we can use weight and Scr to set the VCM administration schedule for these patients. We also established on administration schedule of Teicoplanin for the haemodialysis patients. In this article, we present the TDM analysis result of the antibiotics in our hospital.     

Population pharmacokinetics of amikacin at birth and interindividual variability in renal maturation

OBJECTIVE: Pharmacokinetic (PK) interindividual variability in amikacin has been shown to be wide in neonates. This study evaluated the evolution of this variability with gestational age (GA) at birth in relation to renal maturation. METHODS: Population PK values of amikacin were studied in 131 newborns (postnatal age 1 day, GA 24-41 weeks) divided into 16 groups, defined by GA, from 24 to 41 weeks (with a mean of 8.2 infants per group). PK variables were Kel/Vol, Ks/Vs, Cl/Vol. Cls/ where: Kel = Kslope x GA + Kintercept, Cl = Clslope x GA + Clintercept, and Vol = Vs x body weight. Ki and Cli were held as constants. The nonparametric distribution of the probability density function (PDF) was obtained, as were mean, median, and SD values of each PK variable for each GA group. RESULTS: Amikacin elimination increased linearly with GA, showing that GA is a good covariate of renal elimination. Amikacin volume of distribution increased with body weight up to a GA of about 38 weeks and then decreased for highest GA values. However, the PDF for the individual GA groups showed a multimodal PK distribution. Kel, Vol, Vs, Cl, and Cl, standard deviations increased linearly with GA, showing differential renal maturation. The higher the GA, the more interindividual PK variability increased. CONCLUSIONS: These results show that amikacin elimination and the volume of distribution are dependent upon GA, and that differential renal maturation in neonates is responsible for the wider PK interindividual variability with high GA. Dosage regimens of amikacin and other aminoglycosides should be revised in newborns with high GA. Bayesian adaptive control of therapeutics might be particularly indicated to obtain efficacy for each neonate as early as the first dose.     

Distribution and disposition associated with compartmentation of body fluid in the developing fetus of the rat.

The relationship between the developmental change of the disposition kinetic character for p-phenylbenzoic acid (PPBA) and compartmentalized fluid of the body was investigated in the rat fetus. [14C]Inulin injected into the umbilical vein attained the steady state distribution at 8 min on Day 17 of gestation and at 10 min on Day 21 of gestation. Inulin space (Vi) on Day 17 of gestation was 0.686 ml/g body wt and decreased to 0.542 ml/g on Day 21 of gestation. [14C]Inulin injected into the fetuses on Days 18 and 21 of gestation remained in the fetal body. Hence a determination method of the apparent volume of distribution (Vd) for PPBA was developed using Vi. Vd on Day 17 of gestation was 0.640 ml/g body wt and decreased to 0.454 ml/g on Day 21 of gestation. Body water based on wet body weight showed no significant change. The analysis of PPBA distribution by the compartmentalization of body fluid suggests that the developmental change of Vd is reflected by that of Vi. The elimination rate (K(el)) from the fetus decreased rapidly in the earlier stages of gestation and slowly in the later stages of gestation. The change of the transplacental clearance (Cl) was mainly reflected by that of K(el) throughout the gestation period. However, the change of Vd partly influenced the change of Cl in the later stage of gestation.     

Population pharmacokinetics and dosing of amoxicillin in (pre)term neonates

Amoxicillin plasma concentrations, pharmacokinetic parameters, and the influence of demographic, anthropometric, and clinical covariates were investigated in 150 neonates. Gestational age (GA) ranged from 25 to 42 weeks and mean postnatal age (PNA) was 0.8 days. Amoxicillin concentrations were measured with reversed-phase HPLC in surplus plasma from routine assays of coadministered gentamicin. Mean total body clearance corrected for body weight (CL/W) was 0.096 +/- 0.036 L/kg(-1)h(-1), mean elimination half-life (t(1/2)) was 5.2 +/- 1.9 hours, and mean volume of distribution corrected for body weight (V/W) was 0.65 +/- 0.13 L/kg. Multiple regression equations were calculated for the prediction of CL/W amoxicillin. CL/W gentamicin, V/W gentamicin, and GA were significant predictors of CL/W amoxicillin. Amoxicillin peak and trough concentrations after the second dose and the time the concentration exceeds the minimum inhibitory concentration (T>MIC), reached with the current dosage regimen, were evaluated. Toxic plasma concentrations were reached in several patients. Therefore, the authors have proposed a lower dosage regimen, based on GA, population pharmacokinetic parameters, bacterial susceptibility (T>MIC), and possible toxicity: 15 mg/kg per 8 hours and 20 mg/kg per 8 hours for neonates with GA < or = 34 and GA>34 weeks, respectively. Simulation with this new dosage regimen indicated that satisfactory plasma concentrations were reached in all 150 neonates. Therefore, use of therapeutic drug monitoring and pharmacokinetic calculations for dosage adjustment is generally not necessary.