Vancomycin pharmacokinetics and Bayesian estimation in pediatric patients

The vancomycin pharmacokinetic profile was characterized in six pediatric patients and the potential of nonlinear mixed effects modeling and Bayesian forecasting for vancomycin monitoring was explored using NONMEM V (1.1). Based on steady state serial vancomycin concentrations, the estimates of mean t1/2, Vd, and Cl derived by the Sawchuk and Zaske method (1) were 3.52 hours, 0.57 L/kg, and 0.12 L/h per kg, respectively. NONMEM analysis demonstrated that a weight-adjusted two-compartment model described individual patients' data better than a comparable one-compartment model. The two-compartment estimates of mean t1/2alpha, t1/2beta, Vss, and Cl were 0.80 hour, 5.63 hours, 0.63 L/kg, and 0.11 L/h per kg, respectively. The relatively long mean t1/2alpha suggests that peak vancomycin concentrations measured earlier than 4 hours postdose do not reflect postdistributional serum concentrations. NONMEM population modeling revealed that a weight-adjusted two-compartment model provided a better fit than a comparable one-compartment model. The resulting population parameters and variances were fixed in NONMEM to obtain Bayesian predictions of individual vancomycin serum concentrations. Bayesian estimation with either a single midinterval or trough sample has the potential to provide accurate and precise predictions of vancomycin concentrations. This should be evaluated using a vancomycin population pharmacokinetic model based on a larger sample of pediatric patients.     

Clincial pharmacokinetics in neonates.

Recent concern over toxic effects of drugs in newborns, infants and children have stressed the need for better knowledge of drug kinetics during development. The present review focuses on the available data on clinical pharmacokientics in the neonate. Despite the lack of systematic approaches on drug disposition during the first month of life, the body of data currently available indicates profound differences in drug disposition between neonates and older infants, children and adults. In terms of physiological and anatomical factors the neonate has to be considered as a 'unique drug recipient'. For all the specific variables which govern the drug kinetic pattern (absorption, blood esterase activity, plasma protein binding, metabolic degradation and renal excretion), there are clear difference between neonates and older infants and children. Such differences are not always unidirectional. In the case of absorption, they depend on the maturational stage, but more on the physico-chemical properties of the individual compound. Esterase activiy and renal excretion are also related to the physico-chemical properties of the drug, but are more clearly linked with the development stage. Plasma protein blinding is generally reduced, and depends on several factors, not all of which are as yet clearly identified and understood. Biotransformation activities are usually very low, but may be increased several-fold by exposure to inducing agents. Hydroxylating activity and conjugation with glucronic acid appear to be the two metabolic pathways which are most defective at birth, while sulphate and gylcine conjugation, and dealkylation activities are close to the adult pattern. The material reviewed is fragmentary and does not always permit a comparison of the data obtained in newborns with those reported for adults. Differences in the methodology used and in the kinetic criteria further complicate the matter. It is, however, clearly emerging that drug disposition may vary greatly in the newborn in relation to its developmental age. The reported differences may be relevant for clinical practice and stress the need for more detailed information on drug kinetics in the neonate. Such information may be achieved by carefully planned clinical trials, but more meaningfully, and more profitably for the individual patient, by a very carefully, well integrated monitoring of the neonate a risk. By such an approach, where drug plasma levels are related to drug effects and to the pathophysiological condition, the significance of various factors on drug disportion during development will be better clarified, thus allowing a more rational and safer therapy in the newborn.     

Population pharmacokinetics of cisapride in neonates

OBJECTIVES: We conducted a population pharmacokinetic analysis of cisapride in neonates to study whether metabolic immaturity in this population may lead to increased concentrations. METHODS: Cisapride was administered orally in 91 neonates at the dose of 0.2 mg/kg four times a day. Plasma concentrations were measured using a validated HPLC method. A one-compartment model with first-order absorption was fitted to the data using NONMEM software. RESULTS: One to seven plasma samples were obtained from neonates aged 7-123 days. Cisapride concentrations ranged from 5.5 ng/mL to 172 ng/mL and were not higher than those reported in adults. The absorption constant rate was fixed to 2.5 h-1. Clearance (CL/F) and volume of distribution (V/F) both significantly correlated to weight (WT), but addition of this covariate in V/F did not improve the objective function after it was added in the CL/F covariate model. Prematurity, postnatal age, or coadministered drugs did not affect cisapride clearance. Final population pharmacokinetic parameters (interindividual variability) were: V/F=17,200 mL (90.4%) and CL/F=3.91 x WT(3/4) mL/h (36.3%). CONCLUSIONS: Our finding that cisapride clearance is primarily influenced by weight is in agreement with current recommendations of weight-adjusted doses. This study indicates that no clinically relevant maturational changes in cisapride clearance have to be considered during the first quadrimester of life.     

Reduced variability in tacrolimus pharmacokinetics following intramuscular injection compared to oral administration in cynomolgus monkeys: Investigating optimal dosing regimens

Tacrolimus is one of the most commonly used immunosuppressive agents in animal models of transplantation. However, in these models, oral administration is often problematic due to the lowered compliance associated with highly invasive surgery and due to malabsorption in the intestinal tract. Therefore, we carried out a study to determine the pharmacokinetics of tacrolimus after intramuscular (IM) injection and to determine the optimal IM dosing regimens in primate models. Six male cynomolgus monkeys (Macaca fascicularis) were used in the study. Doses of 0.1 mg/kg and 5 mg were administered via IM injection and oral administration, respectively, once to determine single-dose pharmacokinetics and once daily for 5 days to determine multiple-dose pharmacokinetics. According to pharmacokinetic model estimates, the inter- and intra-individual variabilities in bioavailability following IM injection were remarkably reduced compared with those following oral administration. Monte Carlo simulations revealed that C_peak, C_trough and AUC would also have less variability following IM injection compared with oral administration. In this study, we found that the pharmacokinetic characteristics of tacrolimus were more constant following IM injection compared with oral administration. These results suggest that IM injection can be an alternative route of administration fin non-human primate model studies.     

Age-dependent pharmacokinetics of lansoprazole in neonates and infants

BACKGROUND: Evidence suggests that age may affect the pharmacokinetics of lansoprazole in pediatric patients, but little information is available in neonates and infants. OBJECTIVE: To determine the pharmacokinetics of lansoprazole in neonates and infants <1 year of age with gastroesophageal reflux disease (GERD)-associated symptoms. METHODS: Two single- and repeated-dose, randomized, open-label, multicenter studies were conducted. Studies involved a pretreatment period of 7 or 14 days, a dose administration period of 5 days, and a follow-up period of 30 days for adverse events collection. The studies were conducted in both hospital and private clinic settings. The studies were performed in 24 neonates (aged 28 days, but <1 year) with GERD-associated symptoms diagnosed by medical history and the clinical judgment of the treating physician. Participants received lansoprazole 0.5 or 1.0 mg/kg/day (neonates) or 1.0 or 2.0 mg/kg/day (infants) for 5 days. Plasma pharmacokinetic parameters on dose administration day 1 were calculated, and plasma concentrations on day 5 were obtained. RESULTS: The pharmacokinetics of lansoprazole were approximately dose proportional. After a single dose in neonates, the mean maximum plasma concentrations (C(max)) were 831 and 1672 ng/mL, and the mean area under the plasma concentration-time curve (AUC) values were 5086 and 9372 ng . h/mL for lansoprazole doses of 0.5 and 1.0 mg/kg, respectively. The time to C(max) (t(max)) [3.1 hours] and harmonic mean terminal elimination half-life (t((1/2))) [2.8 hours] were slightly longer in neonates receiving 0.5 mg/kg than the t(max) (2.6 hours) and t((1/2)) (2.0 hours) values observed in neonates receiving 1.0 mg/kg. Mean oral clearance (CL/F) was identical for the two doses (0.16 L/h/kg). After a single 1.0 or 2.0 mg/kg dose in infants, the lansoprazole C(max) values were 959 and 2087 ng/mL and the mean AUC values were approximately 2203 and 5794 ng . h/mL, respectively. The mean t(max) and mean t((1/2)) were 1.8 hours and 0.8 hours, respectively, for both doses (1.0 or 2.0 mg/kg), while mean CL/F was 0.71 and 0.61 L/h/kg, respectively. In both patient groups, mean plasma concentrations on day 5 were similar to day 1 concentrations. No clinically meaningful accumulation was observed following 5 days' dose administration. Plots of lansoprazole pharmacokinetics against chronologic age showed that dose-normalized C(max), t((1/2)), and AUC were two, three, and five times higher, respectively, in study participants aged 10 weeks-1 year. Lansoprazole was well tolerated in all patients. CONCLUSIONS: The pharmacokinetics of lansoprazole in pediatric patients are age dependent, with those aged 10 weeks-1 year. Thus, pediatric patients aged 10 weeks to achieve similar plasma exposure.     

Vancomycin pharmacokinetics in critically ill patients receiving continuous venovenous haemodiafiltration

AIMS: To investigate the pharmacokinetics of vancomycin in critically ill patients on continuous venovenous haemodiafiltration (CVVHDF), a continuous renal replacement therapy (CRRT) and to see if routine measures approximate vancomycin clearance. METHODS: Pharmacokinetic profiles (15) of initial and steady-state doses of 750 mg twice daily intravenous vancomycin were obtained from blood and ultrafiltrate samples from 10 critically ill patients in the intensive care unit, with acute renal failure on CVVHDF (1 l h(-1) dialysate plus 2 l h(-1) filtration solution; 3 l h(-1) effluent; extracorporeal blood flow 200 ml min(-1)). RESULTS: CVVHDF clearance of vancomycin was 1.8 +/- 0.4 l h(-1) (30 +/- 6.7 ml min(-1)). This was 1.3-7.2 times that reported previously for vancomycin using other forms of CRRT. Total vancomycin body clearance was 2.5 +/- 0.7 l h(-1) (41.7 +/- 11.7 ml min(-1)). The clearance of vancomycin by CVVHDF was 76 +/- 16.5% of the total body clearance. CVVHDF removed approximately half the vancomycin dose during the 12-h period (A(CVVHDF) = 413 mg). The fraction eliminated by all routes was 60%. The sieving coefficient for vancomycin was 0.7 +/- 0.1 and for urea was 0.8 +/- 0.06. CONCLUSIONS: Vancomycin is cleared effectively by CVVHDF. Clearance was faster than other forms of CRRT, therefore doses need to be relatively high. Urea clearance slightly overestimates vancomycin clearance. The administered doses of 750 mg every 12 h were too high and accumulation occurred, as only approximately 60% of a dose was cleared over this period. The maintenance dose required to achieve a target average steady-state plasma concentration of 15 mg l(-1) can be calculated as 450 mg every 12 h.     

Population pharmacokinetics of caffeine in premature neonates

Objective: To determine population pharmacokinetic parameters of caffeine in premature neonates. Methods: This population analysis was done using 145 serum concentration measurements gathered from 75 hospitalized patients during their routine clinical care. The data were analysed by use of NONMEM (mixed effects modelling) according to a one-compartment open model with either zero or first-order absorption and first-order elimination. The effect of a variety of developmental, demographic and clinical factors (gender, birth weight, current weight, gestational age, postnatal age, postconceptional age and concurrent treatment with phenobarbital and parenteral nutrition) on clearance and volume of distribution was investigated. Forward selection and backward elimination regression identified significant covariates. Results: The final pharmacostatistical model with influential covariates were as follows: clearance (ml · h⁻¹) =5.81 · current weight (kg) + 1.22 · postnatal age (weeks), multiplied by 0.757 if gestational age ≤ 28 weeks and 0.836 if the current primary source of patients' nutrition is parenteral nutrition, and volume of distribution (ml) = 911 · current weight (kg). The interindividual variability in clearance and the residual variability, expressed as coefficients of variation, were 14.87% and 18.44%, respectively. Due to the lack of information on the data set we were unable to characterize the interindividual variability for volume of distribution. Conclusion: In this study, which involved on average only two serum concentrations of caffeine per patient, the use of NONMEM gave us significant and consistent information about the pharmacokinetic profile of caffeine when compared with available bibliographic information. Additionally, parenteral nutrition and low gestational age (≤ 28 weeks) may even come to be considered as risk factors, and their presence may serve as an indicator of the need for periodic monitoring of caffeine concentrations in premature infants. Received: 27 July 1996 / Accepted in revised form: 26 November 1996     

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.     

Population pharmacokinetics of rectal theophylline in neonates

The population pharmacokinetics of theophylline were studied in 35 neonates receiving aminophylline suppositories for the treatment of apnoea of prematurity. Routinely measured theophylline serum concentrations (n = 138, range 3-20 mg/L) were modelled in NONMEM according to a one-compartment model. The influence of a number of clinical and demographic factors, e.g., weight (range 0.8-2.5 kg) and postnatal age (2-80 days), on clearance/bioavailability (CL/F) and volume/bioavailability (V/F) was investigated. Both these parameters were found to significantly correlate to weight alone in a directly proportional manner: CL/F = 40 +/- 2 ml/h/kg and V/F = 1.3 +/- 0.2 L/kg. The absorption was best described by a first-order process, having a half-life of 1.6 +/- 0.7 h. The interindividual variability in CL/F was 25%, whereas the same estimates in V/F and in the first-order absorption rate constant could not be obtained. The residual variability in theophylline concentrations was modelled with additive error with an estimated standard deviation of 1.78 mg/L. From these results, it was concluded that rectal administration of aminophylline in neonates is a therapeutically acceptable alternative to oral administration. The convenience gained by rectal, compared to oral, administrations may compensate, in many instances, for the possibly slightly higher variability in CL/F of the former.     

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.     

Population pharmacokinetics of domperidone in preterm neonates

Purpose  A population pharmacokinetic analysis was performed to define domperidone pharmacokinetic parameters in preterm neonates, as no pharmacokinetic data are available in this population. Methods  An oral domperidone solution was administered (0.75 mg/kg per day) in 32 preterm neonates (64 samples). Domperidone plasma concentration was measured by high-performance liquid chromatography (HPLC) assay, and a one-compartment model with first-order absorption was fitted to the data using NONMEM version V level 1.1. Results  The mean peak and trough plasma concentration values of domperidone were, respectively, 25.3 ± 20.5 ng/ml and 15.4 ± 11.4 ng/ml (mean ± standard deviation). The pharmacokinetic parameters (interindividual variability%) were clearance (Cl/F) = 0.92 L/h (51.6%), volume of distribution (Vd/F) = 0.405 L (68%), and absorption constant rate (Ka) = 0.0843 h⁻¹ (55.8%). The clearance is not lower than values reported in adults. No influence of covariates (postnatal age, prematurity, weight, gender) on domperidone pharmacokinetic parameters was found. Conclusion  This pilot study designed with a limited sampling strategy showed that domperidone plasma concentrations were consistent with those reported in adults, suggesting that domperidone dosage regimen currently used in preterm neonates is suitable.     

万古霉素不同给药方式所致肾毒性

目的：介绍万古霉素发生肾毒性机制、诊断标准及不同给药方式所致的肾毒性。方法：以"万古霉素"、"肾毒性"等关键词组合中英文查询 Pubmed、CNKI、Elsevier及FMJ的 2016年4月以前相关文献,筛选出万古霉素不同给药方式下有关肾毒性最新最优文献,综合分析万古霉素采用不同给药方式导致肾毒性的差异。结果：万古霉素不同给药方式所致的肾毒性是不同的,以静脉输注最为常见,口服及局部给药几乎无肾毒性。结论：临床医生在静脉输注万古霉素时,应监测血药浓度,以减少肾毒性的发生。     

Lopinavir/ritonavir population pharmacokinetics in neonates and infants

AIMS

Because of immature hepatic metabolism, lopinavir could present specific pharmacokinetics in the first weeks of life. We aimed at determining the optimal dosing regimen in neonates and infants weighing 1 to 10.5 kg.

METHODS

Lopinavir/ritonavir (LPV/r) pharmacokinetics were studied in 96 infants using a population approach.

RESULTS

A one-compartment model described LPV/r pharmacokinetics. Normalized to a 70 kg adult using allometry, clearance (CL/F) and distribution volume (V/F) estimates were 5.87 l h⁻¹ 70 kg⁻¹ and 91.7 l 70 kg⁻¹. The relative bioavailabilty, F, increased with post-menstrual age (PMA) and reached 50% of the adult value at 39.7 weeks.

CONCLUSIONS

Size and PMA explained some CL/F and V/F variability in neonates/infants. Based upon trough concentration limitations, suggested LPV/r dosing regimens were 40 mg 12 h⁻¹, 80 mg 12 h⁻¹ and 120 mg 12 h⁻¹ in the 1–2 kg, 2–6 kg and 6–10 kg group, respectively.     

Population pharmacokinetics and relationship between demographic and clinical variables and pharmacokinetics of gentamicin in neonates

Population pharmacokinetic parameter estimates were calculated from 725 routine plasma gentamicin concentrations obtained in 177 neonates of 24 to 42 weeks' gestational age in their first week of life. Kel increases and V/W decreases with increasing gestational age. Almost identical results were obtained with iterative two-stage Bayesian fitting (MW\PHARM 3.30) as with a non-parametric maximization algorithm (NPEM2). The effect of various covariates on drug disposition was investigated retrospectively using multiple regression analysis. Predictive power for Kel increases with rising gestational age. For neonates 28.5 weeks and 30.9 weeks (r2 = 0.482), with gestational age, postnatal age, and Apgar score at 5 minutes being predictors. A very strong correlation existed between volume of distribution and weight (r2 = 0.83). Volume as a function of weight could be described with low predictivity by gestational age and to a lesser degree by Apgar score at 5 minutes (r2 = 0.298). The developed models need appropriate prospective clinical validation.