Immature Renal Function Research Articles

Using PKPD Modeling to Optimize Gentamicin Dosing in Saudi Neonates

The intricate interplay between pharmacokinetics and pharmacodynamics is pivotal in optimizing gentamicin therapy for neonates, a population characterized by unique physiological developmental considerations and pathophysiological changes in critically ill neonates. Rapid growth, Altered body composition, the immature renal function and premature immune system, significantly influence pharmacokinetic parameters Cl and Vd which aggravate complexities to achieve targets attainment and therapeutic drug monitoring compared to adults, necessitating individualized dosing strategies. The primary aim of this review, highlights the importance of PKPD modeling to optimizing gentamicin dosing in neonates Emerging trends in pediatric pharmacotherapy underscore the urgency for advancing pharmacokinetic-pharmacodynamic (PKPD) modeling to enhance therapeutic efficacy. Future research should focus on integrating real-world data from diverse neonatal populations. Genetic variations may influence the outcomes of PKPD studies, and subsequent dosing recommendations. Conducting PKPD studies in diverse populations is crucial for obtaining more robust and reliable results, which would allow for more representative models that account for physiological variations. Incorporating advanced computational techniques such as machine learning may further refine predictive accuracy, enabling personalized dosing strategies that minimize toxicity while maximizing therapeutic benefits As research evolves, the role of pediatric-specific biomarkers in PKPD modeling warrants closer investigation, potentially leading to breakthroughs that redefine dosing paradigms. By addressing these critical areas, the field can advance toward more effective and individualized pharmacotherapy, reducing adverse outcomes and improving clinical care for vulnerable neonates.

Population pharmacokinetics and dose rationale for aciclovir in term and pre-term neonates with herpes.

Aciclovir is considered the first-line treatment against Herpes simplex virus (HSV) infections in new-borns and infants. As renal excretion is the major route of elimination, in renally-impaired patients, aciclovir doses are adjusted according to the degree of impairment. However, limited attention has been given to the implications of immature renal function or dysfunction due to the viral disease itself. The aim of this investigation was to characterize the pharmacokinetics of aciclovir taking into account maturation and disease processes in the neonatal population. Pharmacokinetic data obtained from 2 previously published clinical trials (n = 28) were analyzed using a nonlinear mixed effects modeling approach. Post-menstrual age (PMA) and creatinine clearance (CLCR) were assessed as descriptors of maturation and renal function. Simulation scenarios were also implemented to illustrate the use of pharmacokinetic data to extrapolate efficacy from adults. Aciclovir pharmacokinetics was described by a one-compartment model with first-order elimination. Body weight and diagnosis (systemic infection) were statistically significant covariates on the volume of distribution, whereas body weight, CLCR and PMA had a significant effect on clearance. Median clearance varied from 0.2 to 1.0 L/h in subjects with PMA <34 or ≥34 weeks, respectively. Population estimate for volume of distribution was 1.93 L with systemic infection increasing this value by almost 3-fold (2.67 times higher). A suitable model parameterization was identified, which discriminates the effects of developmental growth, maturation, and organ function. Exposure to aciclovir was found to increase with decreasing PMA and renal function (CLCR), suggesting different dosing requirement for pre-term neonates.

Physicochemical properties of brand and generic infusion fluid preparations (Part 3): Investigation of type 1 hypotonic infusion fluids.

In Japan, the increasing use of generic drugs has led to a reduction in drug prices, which affect the steady supply of drugs. A "basic drug" system was introduced to rescue these drugs by eliminating gaps in drug prices among preparations with the same constituents. "Type 1" hypotonic infusion fluids, which are potassium-free and commonly used to treat dehydration, meet the definition of a "basic drug" in Japan, and there are no drug price gaps. However, there is a lack of information on the physicochemical properties of "type 1" hypotonic infusion fluids, making it difficult to identify differences among them. Extracellular fluid-replacement solutions and "type 3" hypotonic infusion fluids have different pH and titratable acidity. Here, we measured the pH, titratable acidity, and osmolality of six different "type 1" hypotonic infusion fluids and compared the results with respect to risk avoidance considering metabolic acidosis, changes upon mixing, and vascular pain. There was a significant difference, or trend toward significance, in titratable acidity, which is a risk factor for metabolic acidosis in patients with impaired renal function, and pH, which is a risk factor for change upon mixing, among all combinations except one of the infusion fluids. Thus, the selection of "type 1" hypotonic infusion fluids for children with immature renal function, elderly patients with impaired renal function, and patients with unknown pathophysiology, considering titratable acidity and pH, is an effective strategy for risk avoidance.

Preterm Small Gestational Age Newborns: Impact on Renal Size and Function

OBJECTIVE: The objective of the study was to evaluate the size and function of the kidney in high-risk premature small gestational age (PT/SGA) newborns. Furthermore, estimation of the glomerular filtration rate (GFR) was done by comparing Cystatin C-based method with the creatinine –based method in those preterm newborns.&#x0D; PATIENTS AND METHODS: The study included 20 PT/SGA and controls (20 preterm appropriate for gestational age [PT/AGA] and 20 full-term [FT] newborns). Serum creatinine, blood urea nitrogen, and cystatin C were determined on days 3 and 7 of the study for all newborn infants. GFR was assessed by cystatin C-based method and creatinine-based method. Evaluation of the renal size by ultrasound was done on day 7 of neonatal life.&#x0D; RESULTS: A significant difference was found in the length and transverse diameter of both kidneys, comparing PT/SGA group with PT/AGA and FT group. Cystatin C on day 3 of PT/SGA group had a significant difference than PT/AGA and FT group. Estimation of GFR (eGFR) calculated by filler Zappitelli, Grubb, Larsson, and Dorum formulae of PT/SGA group had a significant difference comparing with PT/AGA and FT group on days 3 and 7.&#x0D; CONCLUSION: PT/SGA newborns have reduced renal size and immature renal function. Cystatin C is a marker for renal function superior to creatinine as it is not affected by body mass index, gestational age, and birth weight. Cystatin C-based eGFR is more accurate and more sensitive to minor changes in GFR than creatinine-based equation.

Prevalence and Risk Factors for Hyponatremia in Preterm Infants.

BACKGROUND:Hyponatremia is the result of a negative sodium balance caused by inadequate salt intake or excessive salt loss due to immature renal or intestinal function in preterm infants.AIM:The aim of our study was to define the incidence of and factors affecting its development in preterm newborns.METHODS:This was a retrospective cohort analysis of 126 preterm infants born before 36 weeks of gestation between June 2016 and July 2018 at Neonatal Intensive Care Unit of Hue Central Hospital, Vietnam. Hyponatremia was defined as a sodium level ≤ 132 mEq/L or 133-135 mEq/L with oral sodium supplementation. We used the serum sodium level to define hyponatremia.RESULTS:There were 37 infants who had hyponatremia, accounting for 29.4% of the infants enrolled in the study. Alower gestational age, the presence of respiratory distress syndrome, the use of furosemide, and feeding with breast milk were significant risk factors for hyponatremia in preterm newborns.CONCLUSION:Hyponatremia occurred at a relatively high frequency. This result exemplifies the importance of serum sodium monitoring and supplementation for the correction of hyponatremia.

Sepsis and Neonatal Acute Kidney Injury

Although the neonatal period is only the first 28 days of life, it accounts globally for in excess of 40% of deaths of children younger than 5 years of age. Sepsis is an important contributor to this burden of neonatal death as well as disease. Sepsis is in addition a leading cause of acute kidney injury (AKI) in neonates. Neonatal AKI independently contributes toward mortality and morbidity with neonates dying because of AKI. The neonates' response to sepsis and AKI is complicated by hemodynamic instability from cardiac and intrapulmonary shunts as well as immature renal function. This review article will examine the at-risk neonatal populations, causes of and risk factors for neonatal sepsis, pathophysiology, fluid overload, prevention, and global perspectives.

Imaging MS in Toxicology: An Investigation of Juvenile Rat Nephrotoxicity Associated with Dabrafenib Administration.

As part of an investigative nephrotoxicity study, kidney tissues from juvenile rats orally administered dabrafenib at different age intervals between postnatal day (PND) 7 to 35 were investigated by MALDI and LDI imaging mass spectrometry (IMS) to determine the chemical composition of tubular deposits. In the youngest age group (PND 7-13), MALDI IMS demonstrated that a dabrafenib carboxylic acid metabolite was diffusely localized to the regions of tubular deposits (medulla and corticomedullary junction); however, no dabrafenib-related material was detected directly from the deposits. Rather, the LDI IMS analysis determined that the deposits were composed primarily of calcium phosphate. Based on these data, the dabrafenib associated nephrotoxicity, including the formation of tubular deposits, was determined to be age dependent. Furthermore, immature renal function was hypothesized to be responsible for the susceptibility of the youngest pups. Graphical ᅟ Electronic supplementary materialThe online version of this article (doi:10.1007/s13361-015-1103-4) contains supplementary material, which is available to authorized users.

Risk factors for late-onset hyponatremia and its influence on neonatal outcomes in preterm infants.

Late-onset hyponatremia (LOH), hyponatremia occurring after two weeks of age with the achievement of full feeding, is the result of a negative sodium balance caused by inadequate salt intake or excessive salt loss due to immature renal or intestinal function in preterm infants. The aims of our study were to identify the risk factors for LOH and its influence on neonatal outcomes. This was a retrospective cohort analysis of 161 preterm infants born before 34 weeks of gestation between June 2009 and December 2010 at Seoul National University Hospital. LOH was defined as a sodium level ≤ 132 mEq/L or 133-135 mEq/L with oral sodium supplementation. LOH occurred in 49 (30.4%) of the studied infants. A lower gestational age, a shorter duration of parenteral nutrition, the presence of respiratory distress syndrome, the use of furosemide, and feeding with breast milk were significant risk factors for LOH. In terms of neonatal outcomes, the infants with LOH had longer hospital stays and higher risks of bronchopulmonary dysplasia and retinopathy of prematurity requiring surgery. LOH lasting at least 7 days significantly increased moderate to severe bronchopulmonary dysplasia, periventricular leukomalacia, and extra-uterine growth retardation. LOH is commonly observed in preterm infants; it may be a risk factor for bronchopulmonary dysplasia and retinopathy of prematurity or a marker of illness severity.

Oseltamivir Dosing in Premature Infants

We conducted a 2-sample pharmacokinetic study of oseltamivir in 12 premature infants. Oseltamivir 1 mg/kg/dose twice daily in infants <38 weeks postmenstrual age (n=8) resulted in oseltamivir carboxylate exposure comparable to previously published pediatric data, which helps prospectively validate this regimen. Oseltamivir 3 mg/kg/dose once daily in premature infants >38 weeks postmenstrual age (born prematurely but chronologically past term, n=4) resulted in similar oseltamivir and oseltamivir carboxylate exposure. Although these results suggest persistence of immature renal function in this subgroup, further pharmacokinetic/pharmacodynamic description is required to confirm the appropriateness of this regimen.

Abstract 809: Prenatal and postnatal management of infants at 100%-risk for developing retinoblastoma

Abstract Purpose: Prenatal diagnosis by amniocentesis of infants at 100%-risk of developing retinoblastoma (RB) is possible when the familial RB1 mutation is known in the parent. Since retinal tumors may develop in the third trimester, we assessed the success of a protocol of early delivery of such infants for early institution of therapy with the aim of optimizing outcome. Methods: Since 1999, we treated ten 100%-risk infants with early delivery in a Special Pregnancy Unit, at 32-37 weeks gestation and when deemed to be safe by their obstetrician. From birth, weekly dilated indirect fundoscopy, and/or contact imaging, and/or optical coherent tomography (OCT) examinations were performed with no sedation, with 3-weekly examinations under anesthesia (EUAs) only started once the first tumor was identified, or by the age of 3 months. The tumors were ablated by focal laser therapy and/or cryotherapy. In selected cases, subtenons topotecan (local chemotherapy that causes little side-effects systemically), was used to reduce the sizes of tumors that were too large, or near the optic nerve, or affecting the macula, for focal therapy ablation. When possible, low-dose or single-agent systemic chemotherapy was avoided to avoid induction of the multidrug resistance (MDR) P-glycoprotein in the tumors. If indicated, short-course but high-dose cyclosporin (CSA) MDR-circumventing high-dose carboplatin-etoposide-vincristine (CEV) chemotherapy was given as soon as the infant's immature renal function normalized. Secondary malignancy-inducing radiation and/or eye enucleation was only used for tumors progressing under this regimen. Results: At median followup of 5.7 years (range 0.7-11.7 years), both eyes were saved in 9 children, seven with 20/20-20/50 vision in at least one eye (two were too young for vision-testing), and only one child required radiation and then enucleation of one eye, but retained 20/30 vision in the remaining radiated eye. Five children were only treated with focal laser therapy and/or cryotherapy, two with added subtenons topotecan, four with 1 to 4-cycle CSA-modulated CEV, and one with 2-cycle non-CSA-modulated/dose-adjusted CEV because of immature renal function. Conclusions: This protocol warrants multicenter trial to confirm the favorable efficacy with low toxicity and excellent vision preservation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 809. doi:1538-7445.AM2012-809

A seven-day study of the pharmacokinetics of intravenous levetiracetam in neonates: marked changes in pharmacokinetics occur during the first week of life

Levetiracetam (LEV) is increasingly used in the treatment of neonatal seizures. The aim of this study was to determine pharmacokinetics in neonates with seizures and to obtain preliminary safety and efficacy data. Eighteen term neonates with seizures persisting after 20 mg/kg of phenobarbital received intravenous LEV for 1 wk. LEV was administered as a 20 or 40 mg/kg bolus followed by 5-10 mg/kg/d. Pharmacokinetic data were analyzed using a nonlinear mixed-effects population approach. Continuous electroencephalogram monitoring allowed preliminary assessment of the efficacy of LEV in this population. LEV clearance (CL) increased from a mean of 0.7 ml/min/kg (SD 0.27 ml/min/kg) on day 1 to 1.33 ml/min/kg (SD 0.35 ml/min/kg) by day 7. Mean half-life was 18.5 h (SD 7.1 h) on day 1 of the study and decreased to 9.1 h (SD 2.0 h) by day 7. The mean volume of distribution was 1.01 l/kg (SD 0.13 l/kg). No study-related serious adverse events were observed. CL of LEV in neonates was higher than expected on the basis of immature renal function in term infants and increased significantly during the first week of life. More frequent dosing of LEV is needed in term infants to maintain serum concentrations in the range seen in children and adults.

Probable association of neonatal death with the use of tramadol to treat labour pain

Tramadol is often used in obstetrics for the relief of labour pain. It has a dual mechanism of action, a monoaminergic effect of tramadol itself and an opioid effect, primarily mediated by its metabolite O-desmethyl tramadol, formed by genetically polymorphic cytochrome P450 2D6. In newborns, elimination of O-desmethyl tramadol is prolonged due to immature renal function. We report on a case of neonatal death following rectal administration of tramadol to treat labour pain to a birth-giving mother. An objective causality assessment using the Naranjo probability scale revealed that the likelihood of tramadol causing respiratory depression was probable. We hypothesize that neonatal death was associated with an increased exposure to O-desmethyl tramadol due to ultrarapid metabolizer cytochrome P450 2D6 genotype of the mother. More evidence is needed to support this association. Nevertheless, in obstetric analgesia, tramadol should be used with more caution until more safety data are available.

Gadolinium in pediatric cardiovascular magnetic resonance: what we know and how we practice.

BackgroundThe association of gadolinium-based contrast agents (GBCAs) with nephrogenic systemic fibrosis (NSF) has led to a heightened awareness towards patients’ renal function. Whereas detailed guidelines exist for the use of GBCAs in adult patients, best practice is less well defined in children, especially in the very young. We aimed at identifying current practice with regards to the use of GBCAs in children who undergo Cardiovascular Magnetic Resonance.MethodsWe conducted a worldwide survey among cardiac imagers with pediatric expertise. The questionnaire contained 21 questions covering the imagers’ work environments, GBCAs used, monitoring of renal function, and a special emphasis was placed on the practice in neonates.ResultsThe survey yielded 70 replies. The single most commonly used GBCA was gadopentetate dimeglumine 34/70 (49%). Among the respondents, the choice of GBCA was more importantly based on availability 26/70 (37%) and approval by a pharmaceutical licensing body that most closely reflects the indication 16/70 (23%) than image quality 7/70 (10%) and side effect profile 8/70 (11%). 55/70 (79%) of respondents performed scans in neonates <1 week of age and 52/55 (95%) of them used GBCA in neonates. 65/70 (93%) respondents at least assess some of their patients’ renal functions. Formula-based estimate of glomerular filtration rate is the most popular assessment method 35/65 (54%). In patients with a glomerular filtration rate < 30 ml/min/1.73 m2 62/70 (89%) of respondents do not administer gadolinium at all. The single most common side effect of gadolinium was noted to be nausea/emesis 34/57 (60%) followed by discomfort at injection site 17/57 (30%).ConclusionsCardiac imagers are aware of the immature renal function and physiological differences of their pediatric patients that place them at risk for NSF. Epidemiological data is needed for pediatric cardiovascular licensure of gadolinium compounds and for the creation of practice guidelines which will replace current-day practice based on individual clinical judgment.

Evaluation of the vancomycin dosage regimen based on serum creatinine used in the neonatal intensive care unit

Vancomycin is frequently used for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections; however, determining the optimal dosage for neonates is difficult because of their immature renal function. Serum creatinine-based dosing was introduced in Kumamoto City Hospital Neonatal Medical Center. Serum trough concentration and therapeutic efficacy of vancomycin were evaluated before and after the introduction of the creatinine-based dosing. When the therapeutic range of serum trough concentration of vancomycin at steady state was set to 5-15 µg/mL, 20 trough concentrations (48.8%) were within the therapeutic range and 21 trough concentrations were outside the therapeutic range before the introduction of the serum creatinine-based dosing. After the introduction of serum creatinine-based dosing, 18 trough concentrations (81.8%) were within the therapeutic range and 4 trough concentrations were not, and there was an increase in the number of patients with trough concentrations in the therapeutic range (P= 0.01; Fisher's exact test). The serum creatinine-based dosing of vancomycin is useful in maintaining the appropriate serum level of vancomycin in neonates.

Simulations of cilengitide PK profiles in pediatric population by means of allometric scaling: Reliability and support to BSA-based dose adjustment strategy.

9548 Background: Cilengitide is a selective αvβ3/αvβ5 integrin inhibitor in clinical development for the treatment of various types of solid tumors. In this study, a population pharmacokinetic (PK) 2-compartment model was developed using data from 3 studies in adult patients (n=136) with advanced solid cancer, NSCLC or advanced unresectable pancreatic cancer. This model was used to simulate the plasma concentration time profiles of cilengitide in pediatric patients of various age/weight. Methods: The population-based PK parameters obtained in adults were allometrically scaled to pediatric populations with average body weight (BW) of 10, 15, 20, 25, 30, 40, 50, and 60 kg (CV 15%). The allometric function used the pediatric BW, a reference adult BW of 70 kg, and a fixed allometric exponent of 0.75 for clearance and of 1 for volume of distribution. Considering that cilengitide clearance is predominantly renal, immature renal function (90% of the mature one) was assumed for children in the 10 kg BW group. Concentration vs. time profiles were simulated for 30 subjects in each group, receiving twice-weekly 1-h infusions of 1800 mg/m2 cilengitide for up to 3 weeks. Results: The dose adjustment based on body surface area (BSA) provided homogeneous predicted cilengitide exposure (AUC0–24h range: 200–1787 μ g·h/mL) and concentration at the end of the 1-h infusion (Cmax range: 100–558 μ g/mL) in a wide range of BW (range: 8–86 kg). For lower BW, BSA-based dose adjustment led to a minimal drift towards higher allometric scaling-predicted concentrations. This was amplified by neglecting renal function immaturity. The simulated profiles compare well with published pediatric profiles (MacDonald et al. 2008), although some slight over-prediction was observed. Conclusions: As corroborated by independent experimental data, cilengitide pediatric PK profiles can reliably be predicted using allometrically-scaled PK parameters derived from adult data. The BSA-based dose adjustment strategy appears justified in children/adolescents, leading to homogenous exposure over a wide range of body weight. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck KGaA, Merck Serono

Guideline to use gadolinium‐based contrast agents at Kyoto University Hospital

Guideline to use gadolinium-based contrast agents (GBCAs) to prevent nephrogenic systemic fibrosis (NSF) at Kyoto University Hospital is presented. This guideline is basically the same as the one issued by the joint committee of the Japan Radiological Society and Japanese Society of Nephrology. In the guideline of the joint committee of Japan Radiological Society and Japanese Society of Nephrology, it is described that GBCAs should be used only when they are indispensable for adequate diagnosis regardless of renal function. In this guideline, it is also described that use of GBCAs should be decided after carefully weighing the risks and benefits for patients with estimated glomerular filtration rate (eGFR) 30-60 mL/min/1.73 m(2), and that use of the smallest possible amount of GBCA is necessary even for patients whose eGFR is greater than 60 mL/min/1.73 m(2). The guideline of Kyoto University Hospital includes regulations for patients who underwent or are waiting for liver transplantations, because patients with liver transplantations are reported to have higher risk for NSF and because several hepatic transplantation surgeries are performed at our hospital. Our guideline also regulates the use for neonates or infants less than 1 year old, because of their immature renal function. J. Magn. Reson. Imaging 2009;30:1364-1365. (c)2009 Wiley-Liss, Inc.

Pharmacometrics-Based Dose Selection of Levofloxacin as a Treatment for Postexposure Inhalational Anthrax in Children

Levofloxacin was recently (May 2008) approved by the U.S. Food and Drug Administration as a treatment for children following inhalational exposure to anthrax. Given that no clinical trials to assess the efficacy of a chosen dose was conducted, the basis for the dose recommendation was based upon pharmacometric analyses. The objective of this paper is to describe the basis of the chosen pediatric dose recommended for the label. Pharmacokinetic (PK) data from 90 pediatric patients receiving 7 mg/kg of body weight levofloxacin and two studies of 47 healthy adults receiving 500 and 750 mg/kg levofloxacin were used for the pharmacometric analyses. Body weight was found to be a significant covariate for levofloxacin clearance and the volume of distribution. Consistently with developmental physiology, clearance also was found to be reduced in pediatric patients under 2 years of age due to immature renal function. Different dosing regimens were simulated to match adult exposure (area under the concentration-time curve from 0 to 24 h at steady state, maximum concentration of drug in serum at steady state, and minimum concentration of drug in serum at steady state) following the approved adult dose of 500 mg once a day. The recommended dose of 8 mg/kg twice a day was found to match the exposure of the dose approved for adults in a manner that permitted confidence that this dose in children would achieve efficacy comparable to that of adults.

Therapeutic monitoring of carboplatin dosing in a premature infant with retinoblastoma

Carboplatin dosing based on renal function and therapeutic monitoring have been previously shown to be beneficial in the treatment of children with cancer. However, the applicability of such approaches to the treatment of premature or newborn infants, where kidney function may change markedly with advancing gestational and postnatal age, is unknown. Diagnosis of retinoblastoma in a preterm infant provided a rare opportunity to carry out adaptive carboplatin dosing in a patient with immature renal function. A preterm female infant born at a gestational age of 32 weeks was diagnosed with bilateral retinoblastoma at 35 weeks. Carboplatin treatment with real-time pharmacokinetic monitoring was initiated on day 26 of life at an initial dose of 6.6 mg/kg. Plasma samples were obtained at specified time points and carboplatin levels quantified by atomic absorption spectrometry. Additional doses of carboplatin were determined by pharmacokinetic monitoring based on the achievement of carboplatin AUC values of 5.2-7.8 mg/ml min on three courses of treatment. Increased carboplatin doses administered on successive courses of treatment reflected a greater than twofold increase in drug clearance, from 3.4-7.1 ml/min over a 7-week period. Pharmacokinetically-guided carboplatin dosing led to the attainment of AUCs within 10% of target values on each course of treatment. The patient completed five courses of carboplatin with both tumours defined as inactive after this treatment period. Data obtained from studying this patient suggests that adaptive carboplatin monitoring represents a feasible and beneficial clinical approach in preterm infants or neonates.

Optimising piperacillin/tazobactam dosing in paediatrics

Piperacillin/tazobactam, an intravenous antibacterial combination product, has recently been approved for paediatric (age 2 months to 17 years) use in the USA. The purpose of this analysis is to describe the basis for the dosing recommendations in this age group. Pharmacokinetic (PK) parameters and demographic covariates from 53 children enrolled in two paediatric studies were used in the analysis. Individual drug clearance (CL) values calculated by non-compartmental methods were available. The influence of demographic covariates on CL was investigated by non-linear regression. The analysis identified CL to be dependent on body weight. CL was also found to be influenced by age in paediatric patients ≤2 years, which is consistent with the expectation based on maturation of renal function. The population PK analysis and simulations, utilising comparable adult exposures as a basis to explore optimal dosing, resulted in the following dosing recommendations: for paediatric patients ≥9 months, a dose of 100/12.5 mg/kg every 8 h showed exposures similar to adults; for paediatric patients aged 2–9 months, the dose of 100/12.5 mg/kg should be reduced by a factor of 0.8 (i.e. 80/10 mg/kg), likely due to immature renal function. Based upon this analysis, dosing recommendations for paediatric patients down to 2 months of age were incorporated in the labelling. No data were available to allow additional recommendations for paediatric patients <2 months of age to be made.

Rasburicase for the Management of Tumor Lysis Syndrome in Neonates

To describe the management of tumor lysis syndrome (TLS) with rasburicase in 2 patients who presented with cancer within the first month of life and compare and contrast both cases with respect to their underlying renal physiology, management, and eventual outcome. TLS developed in 2 neonates born at 38 weeks' gestational age; both were managed in part with rasburicase. One patient was a 21-day-old infant who received 2 days of induction chemotherapy for the treatment of congenital Stage IV-S neuroblastoma. With a single 0.2 mg/kg dose of rasburicase, the serum urate level normalized and the infant completed therapy without incident. The second patient was a 4-day-old neonate with congenital precursor-B cell acute lymphoblastic leukemia who presented with spontaneous TLS complicated by renal dysfunction. Despite several doses of intravenous rasburicase (2 doses of 0.1 mg/kg and 4 doses of 0.2 mg/kg), as well as aggressive supportive therapy, the infant died of complications arising from uncontrolled TLS. Neonates may be at particular risk for TLS given their immature renal function and its predisposition toward metabolic derangements. While rasburicase has the potential to provide a rapid reversal of TLS in this patient population, when TLS is complicated by pre-existing acute renal failure, additional interventions and alternative anti-tumor strategies may be necessary for a successful outcome. When managing TLS in infancy, clinicians must consider the relative degree of renal immaturity and its predisposition toward metabolic derangements. Rasburicase appears to be well tolerated and effective in lowering serum urate concentrations in the treatment of therapy-related TLS in neonates. However, in instances of spontaneous TLS complicated by the normally low glomerular filtration rate in the newborn infant, the use of rasburicase and other supportive care measures may still be inadequate, warranting further study.