When will the Glomerular Filtration Rate in Former Preterm Neonates Catch up with Their Term Peers?

AIMS: Whether and when glomerular filtration rate (GFR) in preterms catches up with term peers is unknown. This study aims to develop a GFR maturation model for (pre)term-born individuals from birth to 18 years of age. Secondarily, the function is applied to data of different renally excreted drugs. METHODS: We combined published inulin clearance values and serum creatinine (Scr) concentrations in (pre)term born individuals throughout childhood. Inulin clearance was assumed to be equal to GFR, and Scr to reflect creatinine synthesis rate/GFR. We developed a GFR function consisting of GFRbirth (GFR at birth), and an Emax model dependent on PNA (with GFRmax, PNA50 (PNA at which half of GFR max is reached) and Hill coefficient). The final GFR model was applied to predict gentamicin, tobramycin and vancomycin concentrations. RESULT: In the GFR model, GFRbirth varied with birthweight linearly while in the PNA-based Emax equation, GA was the best covariate for PNA50, and current weight for GFRmax. The final model showed that for a child born at 26 weeks GA, absolute GFR is 18%, 63%, 80%, 92% and 96% of the GFR of a child born at 40 weeks GA at 1 month, 6 months, 1 year, 3 years and 12 years, respectively. PopPK models with the GFR maturation equations predicted concentrations of renally cleared antibiotics across (pre)term-born neonates until 18 years well. CONCLUSIONS: GFR of preterm individuals catches up with term peers at around three years of age, implying reduced dosages of renally cleared drugs should be considered below this age.

Age-Related Changes in Vancomycin Protein Binding: Is it Time to Take it Seriously?

BACKGROUND: Vancomycin (VAN) protein binding in plasma is influenced by illness and age; hence, doses titrated according to total concentrations are fraught. In this study, model-estimated free VAN concentrations (EFVC) were compared with assumed free VAN concentrations (AFVC) in neonates, children, and adults in the intensive care unit and those on dialysis. METHODS: Patient cohorts were identified from the hospital database. Demographics, clinical characteristics, total VAN concentrations, and laboratory variables were obtained from electronic health records. EFVC was derived from 6 models identified in the literature. For all models, total VAN concentration was the most important predictor; other predictors included albumin, total protein, and dialysis status. The AFVC was calculated as 50% of the total concentration (ie, assumption of 50% bound). RESULTS: Differences between EFVC and AFVC in adults were insignificant; however, differences in pediatric intensive care unit patients, according to 2 different models, were significant: mean ± SD = 4.1 ± 1.58 mg/L and 4.7 ± 2.46 mg/L (P < 0.001); the percentages within the free VAN trough range = 30.4% versus 55.1% and 30% versus 55.1%; and the supratherapeutic percentages = 65.2% versus 31.9% and 66.7% versus 31.9%, respectively. In neonates, the difference between EFVC and AFVC was mean ± SD = 6.9 ± 1.95 mg/L (P < 0.001); the percentages within the free VAN trough range for continuous and intermediate dosing were 0% versus 81.3% and 14.3% versus 71.4%, and the supratherapeutic percentages were 100% versus 6.25% and 71.4% versus 0%, respectively. CONCLUSIONS: The fraction of free unbound VAN is higher in sick children and neonates than in adults. Therefore, total VAN concentrations do not correlate with the pharmacologically active free VAN concentrations in the same manner as in adults. Adjusting VAN doses in neonates and children to target the same total VAN concentration as the recommended therapeutic range for adults may result in toxicfree concentrations.

Personalised dosing of vancomycin: A prospective and retrospective comparative quasi-experimental study.

AIMS: The 2019 update to the US consensus guideline for vancomycin therapeutic monitoring advocates using Bayesian-guided personalised dosing to maximise efficacy and minimise toxicity of vancomycin. We conducted an observational cohort study of the implementation of bed-side Bayesian-guided vancomycin dosing in vascular surgery patients. METHODS: Over a 9-month prospective study period, vascular surgery patients were dosed vancomycin using Bayesian-guided dosing decision tool (DoseMeRx) and compared retrospectively with a control group admitted to the same ward in the 14 months prior to the study and dosed using a standard algorithmic approach. Primary endpoints were proportion of patients achieving mean area under the curve in 24 hours (AUC24 ) in the acceptable range 350-450 mg/L• h and percentage time in acceptable range (%TTR). Secondary endpoints focused on clinical outcomes including incidence of acute kidney injury. RESULTS: A significantly higher proportion of DoseMeRx patients achieved mean AUC24 values in the acceptable range compared to the control group; 71/104 (68.3%) vs 58/139 (41.7%), P < .005. The median %TTR was also greater in DoseMeRx patients compared to the control group (57.1 vs 30.0%, P < .00001). Patients in the DoseMeRx group missed an average of 0.23 doses per course compared to 1.04 doses in the control group (P < .00001). No difference was observed in secondary (clinical) outcomes between the 2 groups. CONCLUSION: Bedside Bayesian-guided personalised dosing of vancomycin increases the proportion of patients achieving target AUC24 and the %TTR.

Personalised Warfarin Dosing in Children Post-cardiac Surgery.

Warfarin dosing is challenging due to a multitude of factors affecting its pharmacokinetics (PK) and pharmacodynamics (PD). A novel personalised dosing algorithm predicated on a warfarin PK/PD model and incorporating CYP2C9 and VKORC1 genotype information has been developed for children. The present prospective, observational study aimed to compare the model with conventional weight-based dosing. The study involved two groups of children post-cardiac surgery: Group 1 were warfarin naïve, in whom loading and maintenance doses were estimated using the model over a 6-month duration and compared to historical case-matched controls. Group 2 were already established on maintenance therapy and randomised into a crossover study comparing the model with conventional maintenance dosing, over a 12-month period. Five patients enrolled in Group 1. Compared to the control group, the median time to achieve the first therapeutic INR was longer (5 vs. 2 days), to stable anticoagulation was shorter (29.0 vs. 96.5 days), to over-anticoagulation was longer (15.0 vs. 4.0 days). In addition, median percentage of INRs within the target range (%ITR) and percentage of time in therapeutic range (%TTR) was higher; 70% versus 47.4% and 83.4% versus 62.3%, respectively. Group 2 included 26 patients. No significant differences in INR control were found between model and conventional dosing phases; mean %ITR was 68.82% versus 67.9% (p = 0.84) and mean %TTR was 85.47% versus 80.2% (p = 0.09), respectively. The results suggest model-based dosing can improve anticoagulation control, particularly when initiating and stabilising warfarin dosing. Larger studies are needed to confirm these findings.

Population pharmacokinetics of cefazolin before, during and after cardiopulmonary bypass to optimize dosing regimens for children undergoing cardiac surgery.

Objectives: The objective of this study was to characterize cefazolin serum pharmacokinetics in children before, during and after cardiopulmonary bypass (CPB), in order to derive an evidence-based dosing regimen. Patients and methods: This study included children who received cefazolin before surgical incision, before cessation of CPB and after surgery. Blood samples of total and unbound cefazolin concentrations were collected before, during and after CPB. The cefazolin concentration-time profiles were analysed using population pharmacokinetic modelling and predictors for interindividual variability in pharmacokinetic parameters were investigated. Subsequently, optimized dosing regimens were developed using stochastic simulations. Clinicaltrials.gov: NCT02749981. Results: A total of 494 total and unbound cefazolin concentrations obtained from 56 children (aged 6 days to 15 years) were included. A two-compartment model with first-order elimination plus an additional compartment for the effect of CPB best described the data. Clearance (1.56 L/h), central volume (1.93 L) and peripheral volume (2.39 L) were allometrically scaled by body weight. The estimated glomerular filtration rate (eGFR) was identified as a covariate on clearance and the serum albumin concentration was associated with maximum protein binding capacity. Our simulations showed that an additional bolus dose at the start of CPB improves the PTA in typical patients from 59% to >94%. Prolonged surgery and preserved renal function (i.e. drop in eGFR <25%) had a negative impact on PTA. Conclusions: We propose an optimized dosing regimen for cefazolin during cardiac surgery in paediatric patients to avoid treatment failure due to inadequate antibiotic prophylaxis.

'Acceptability' of a new oral suspension formulation of mercaptopurine in children with acute lymphoblastic leukaemia.

AIM: The aim of this questionnaire-based survey was to determine the 'acceptability' of Xaluprine®, a new oral liquid formulation of mercaptopurine, when administered chronically to children during the maintenance treatment phase of acute lymphoblastic leukaemia. PATIENTS AND METHODS: This was a single centre survey of children (aged 3 to 16 years) and their parents at a routine follow-up visit during the maintenance phase of acute lymphoblastic leukaemica treatment. The questionnaire probed for their views on overall acceptability such as taste, smell, incidences of vomiting, ease and willingness to take Xaluprine® on a daily basis, and utilised a 5-point facial hedonic scale (1 = bad, 5 = good) as well as open/closed questions. RESULTS: Twenty-two children were recruited; 17 (77%) scored taste between 3 and 5 ('okay' to 'good') and 20 (91%) scored smell between 3 and 5. Only four children (18%) reported an aftertaste. Of the five children (23%) who scored taste as 1 or 2 ('bad'), three found taking all oral medicines difficult. Six children (27%) reported vomiting, but this was not considered related to Xaluprine®. Seven children (32%) sometimes complained that they did not want to take Xaluprine®; 15 (68%) never complained. In response to the question, 'How easy is it for you to take Xaluprine®?' 18 children (82%) reported that it was 'Easy all the time.' This was more favourable than other oral liquid medicines that they were taking concurrently. CONCLUSION: The results of this survey show that Xaluprine® has good overall acceptability in the paediatric population and suggests that Xaluprine® is an important, alternative, age-appropriate formulation of mercaptopurine.

High variability in the dosing of commonly used antibiotics revealed by a Europe-wide point prevalence study: implications for research and dissemination.

BACKGROUND: Antibiotic dosing in neonates varies between countries and centres, suggesting suboptimal exposures for some neonates. We aimed to describe variations and factors influencing the variability in the dosing of frequently used antibiotics in European NICUs to help define strategies for improvement. METHODS: A sub-analysis of the European Study of Neonatal Exposure to Excipients point prevalence study was undertaken. Demographic data of neonates receiving any antibiotic on the study day within one of three two-week periods from January to June 2012, the dose, dosing interval and route of administration of each prescription were recorded. The British National Formulary for Children (BNFC) and Neofax were used as reference sources. Risk factors for deviations exceeding ±25% of the relevant BNFC dosage recommendation were identified by multivariate logistic regression analysis. RESULTS: In 89 NICUs from 21 countries, 586 antibiotic prescriptions for 342 infants were reported. The twelve most frequently used antibiotics - gentamicin, penicillin G, ampicillin, vancomycin, amikacin, cefotaxime, ceftazidime, meropenem, amoxicillin, metronidazole, teicoplanin and flucloxacillin - covered 92% of systemic prescriptions. Glycopeptide class, GA <32 weeks, 5(th) minute Apgar score <5 and geographical region were associated with deviation from the BNFC dosage recommendation. While the doses of penicillins exceeded recommendations, antibiotics with safety concerns followed (gentamicin) or were dosed below (vancomycin) recommendations. CONCLUSIONS: The current lack of compliance with existing dosing recommendations for neonates needs to be overcome through the conduct of well-designed clinical trials with a limited number of antibiotics to define pharmacokinetics/pharmacodynamics, efficacy and safety in this population and by efficient dissemination of the results.

Simultaneous pharmacokinetic modeling of gentamicin, tobramycin and vancomycin clearance from neonates to adults: towards a semi-physiological function for maturation in glomerular filtration.

PURPOSE: Since glomerular filtration rate (GFR) is responsible for the elimination of a large number of water-soluble drugs, the aim of this study was to develop a semi-physiological function for GFR maturation from neonates to adults. METHODS: In the pharmacokinetic analysis (NONMEM VI) based on data of gentamicin, tobramycin and vancomycin collected in 1,760 patients (age 1 day-18 years, bodyweight 415 g-85 kg), a distinction was made between drug-specific and system-specific information. Since the maturational model for clearance is considered to contain system-specific information on the developmental changes in GFR, one GFR maturational function was derived for all three drugs. RESULTS: Simultaneous analysis of these three drugs showed that maturation of GFR mediated clearance from preterm neonates to adults was best described by a bodyweight-dependent exponent (BDE) function with an exponent varying from 1.4 in neonates to 1.0 in adults (ClGFR = Cldrug*(BW/4 kg)(BDE) with BDE = 2.23*BW(-0.065)). Population clearance values (Cldrug) for gentamicin, tobramycin and vancomycin were 0.21, 0.28 and 0.39 L/h for a full term neonate of 4 kg, respectively. DISCUSSION: Based on an integrated analysis of gentamicin, tobramycin and vancomycin, a semi-physiological function for GFR mediated clearance was derived that can potentially be used to establish evidence based dosing regimens of renally excreted drugs in children.

Dried blood spots and sparse sampling: a practical approach to estimating pharmacokinetic parameters of caffeine in preterm infants.

AIMS: Dried blood spots (DBS) alongside micro-analytical techniques are a potential solution to the challenges of performing pharmacokinetic (PK) studies in children. However, DBS methods have received little formal evaluation in clinical settings relevant to children. The aim of the present study was to determine a PK model for caffeine using a 'DBS/microvolume platform' in preterm infants. METHODS: DBS samples were collected prospectively from premature babies receiving caffeine for treatment of apnoea of prematurity. A non-linear mixed effects approach was used to develop a population PK model from measured DBS caffeine concentrations. Caffeine PK parameter estimates based on DBS data were then compared with plasma estimates for agreement. RESULTS: Three hundred and thirty-eight DBS cards for caffeine measurement were collected from 67 preterm infants (birth weight 0.6-2.11 kg). 88% of cards obtained were of acceptable quality and no child had more than 10 DBS samples or more than 0.5 ml of blood taken over the study period. There was good agreement between PK parameters estimated using caffeine concentrations from DBS samples (CL = 7.3 ml h⁻¹ kg⁻¹; V = 593 ml kg⁻¹; t(½) = 57 h) and historical caffeine PK parameter estimates based on plasma samples (CL = 4.9-7.9 ml h⁻¹ kg⁻¹; V = 640-970 ml kg⁻¹; t(½) = 101-144 h). We also found that changes in blood haematocrit may significantly confound estimates of caffeine PK parameters based on DBS data. CONCLUSIONS: This study demonstrates that DBS methods can be applied to PK studies in a vulnerable population group and are a practical alternative to wet matrix sampling techniques.

Pharmacokinetics of buccal and intranasal lorazepam in healthy adult volunteers.

PURPOSE: To investigate the plasma-concentration profile of lorazepam when administered by the intranasal and buccal routes to determine their utility for the treatment of prolonged seizures. METHODS: On two occasions separated by at least 7 days washout, 12 healthy adult male volunteers received 2 mg of lorazepam via the intranasal or buccal route. Blood samples were collected at time periods from 0 to 48 h, and pharmacokinetic parameters were determined. RESULTS: Lorazepam was well absorbed from both administration routes; however, there was a more pronounced lag phase with the buccal route and absorption was more rapid from the intranasal route. CONCLUSIONS: Intranasal lorazepam has more favourable pharmacokinetics than buccal lorazepam when considering the need for the rapid blood concentrations required for seizure termination. Further clinical evaluation of this route is required.

Infliximab: a single-centre, prospective, observational evaluation of TDM data in patients with IBD.

OBJECTIVES: Therapeutic drug monitoring of infliximab (IFX) is important to optimise treatment of inflammatory bowel disease (IBD). A recent IBD consensus statement recommends targeting trough serum concentrations of >3 µg/mL, higher than our local recommendation of >1 µg/mL. We therefore investigated the relationship between IFX trough concentrations and C reactive protein (CRP), faecal calprotectin (FCP), clinical outcomes and anti-IFX antibody (AB) development as well as the influence of concomitant thiopurine treatment. METHODS: Observational data, prospectively collected in a cohort of adult patients with IBD newly initiated on IFX at a single centre. RESULTS: IFX concentrations >3 µg/mL were associated with a greater reduction in CRP (% change from baseline) and lower FCP; mean (SD) 47 (33.8) % vs 102.3 (136.9) % and 233.9 (505.1) µg/g vs 416.3 (613.5) µg/g, respectively. Lower IFX concentrations were observed in patients who developed AB than those who did not, mean (range) 6.2 (1.1-10) µg/mL vs 0.9 (0.4-4.9) µg/mL, respectively, and also in patients who stopped/switched therapy compared with those who continued, 2.4 (2.9) µg/mL vs 6.5 (2.8) µg/mL; p=0.0002. Patients taking a concomitant thiopurine were found to have higher IFX concentrations; mean (range) 6.4 (0.7-10) µg/mL vs 3.9 (0.4-10) µg/mL. CONCLUSIONS: IFX concentrations are correlated with biomarkers, clinical response and AB development in patients with IBD. Concomitant thiopurine therapy appears to be associated with higher IFX concentrations and reduced likelihood of AB development.

Inflammation and cardiovascular status impact midazolam pharmacokinetics in critically ill children: An observational, prospective, controlled study.

Altered physiology caused by critical illness may change midazolam pharmacokinetics and thereby result in adverse reactions and outcomes in this vulnerable patient population. This study set out to determine which critical illness-related factors impact midazolam pharmacokinetics in children using population modeling. This was an observational, prospective, controlled study of children receiving IV midazolam as part of routine care. Children recruited into the study were either critically-ill receiving continuous infusions of midazolam or otherwise well, admitted for elective day-case surgery (control) who received a single IV bolus dose of midazolam. The primary outcome was to determine the population pharmacokinetics and identify covariates that influence midazolam disposition during critical illness. Thirty-five patients were recruited into the critically ill arm of the study, and 54 children into the control arm. Blood samples for assessing midazolam and 1-OH-midazolam concentrations were collected opportunistically (critically ill arm) and in pre-set time windows (control arm). Pharmacokinetic modeling demonstrated a significant change in midazolam clearance with acute inflammation (measured using C-Reactive Protein), cardio-vascular status, and weight. Simulations predict that elevated C-Reactive Protein and compromised cardiovascular function in critically ill children result in midazolam concentrations up to 10-fold higher than in healthy children. The extremely high concentrations of midazolam observed in some critically-ill children indicate that the current therapeutic dosing regimen for midazolam can lead to over-dosing. Clinicians should be aware of this risk and intensify monitoring for oversedation in such patients.

A phase 1 dose-sparing, randomized clinical trial of seasonal trivalent inactivated influenza vaccine combined with MAS-1, a novel water-in-oil adjuvant/delivery system.

BACKGROUND: New influenza vaccines are needed to increase vaccine efficacy. Adjuvants may allow hemagglutinin (HA) dose-sparing with enhanced immunogenicity. MAS-1 is an investigational low viscosity, free-flowing, water-in-oil emulsion-based adjuvant/delivery system comprised of stable nanoglobular aqueous droplets. METHODS: A phase 1, double-blind, safety and immunogenicity, HA dose escalation, randomized clinical trial was conducted. MAS-1 adjuvant with 1, 3, 5 or 9 µg per HA derived from licensed seasonal trivalent high dose inactivated influenza vaccine (IIV, Fluzone HD 60 µg per HA) in a 0.3 mL dose were compared to standard dose IIV (Fluzone SD, 15 µg per HA). Safety was measured by reactogenicity, adverse events, and clinical laboratory tests. Serum hemagglutination inhibition (HAI) antibody titers were measured for immunogenicity. RESULTS: Seventy-two subjects, aged 18-47 years, received one dose of either 0.3 mL adjuvanted vaccine or SD IIV intramuscularly. Common injection site and systemic reactions post-vaccination were mild tenderness, induration, pain, headache, myalgia, malaise and fatigue. All reactions resolved within 14 days post-vaccination. Safety laboratory measures were not different between groups. Geometric mean antibody titers, geometric mean fold increases in antibody titer, seroconversion rates and seroprotection rates against vaccine strains were in general higher and of longer duration (day 85 and 169 visits) with MAS-1-adjuvanted IIV at all doses of HA compared with SD IIV. Adjuvanted vaccine induced higher antibody responses against a limited number of non-study vaccine influenza B and A/H3N2 viruses including ones from subsequent years. CONCLUSION: MAS-1 adjuvant in a 0.3 mL dose volume provided HA dose-sparing effects without safety concerns and induced higher HAI antibody and seroconversion responses through at least 6 months, demonstrating potential to provide greater vaccine efficacy throughout an influenza season in younger adults. In summary, MAS-1 may provide enhanced, more durable and broader protective immunity compared with non-adjuvanted SD IIV. Clinical Trial Registry: ClinicalTrials.gov # NCT02500680.

MAS-1, a novel water-in-oil adjuvant/delivery system, with reduced seasonal influenza vaccine hemagglutinin dose may enhance potency, durability and cross-reactivity of antibody responses in the elderly.

BACKGROUND: Increased influenza vaccine efficacy is needed in the elderly at high-risk for morbidity and mortality due to influenza infection. Adjuvants may allow hemagglutinin (HA) dose-sparing with enhanced immunogenicity. MAS-1 is an investigational water-in-oil emulsion-based adjuvant/delivery system comprised of stable nanoglobular aqueous droplets. METHODS: A phase 1, randomized, double-blind, safety and immunogenicity, adjuvant dose escalation trial was conducted in persons aged 65 years and older. MAS-1 adjuvant dose volumes at 0.3 mL or 0.5 mL containing 9 µg per HA derived from licensed seasonal trivalent influenza vaccine (IIV, Fluzone HD 60 µg per HA, Sanofi Pasteur) were compared to high dose (HD) IIV (Fluzone HD). Safety was measured by reactogenicity, adverse events, and safety laboratory measures. Immunogenicity was assessed by serum hemagglutination inhibition (HAI) antibody titers. RESULTS: Forty-five subjects, aged 65-83 years, were randomly assigned to receive 9 µg per HA in 0.3 mL MAS-1 (15 subjects) or HD IIV (15 subjects) followed by groups randomly assigned to receive 9 µg per HA in 0.5 mL MAS-1 (10 subjects) or HD IIV (5 subjects). Injection site tenderness, induration, and pain, and headache, myalgia, malaise and fatigue were common, resolving before day 14 post-vaccination. Clinically significant late-onset injection site reactions occurred in four of ten subjects at the 0.5 mL adjuvant dose. Safety laboratory measures were within acceptable limits. MAS-1-adjuvanted IIV enhanced mean antibody titers, mean-fold increases in antibody titer, and seroconversion rates against vaccine strains for at least 168 days post-vaccination and enhanced cross-reactive antibodies against some non-study vaccine influenza viruses. CONCLUSION: MAS-1 adjuvant provided HA dose-sparing without safety concerns at the 0.3 mL dose, but the 0.5 mL dose caused late injection site reactions. MAS-1-adjuvanted IIV induced higher HAI antibody responses with prolonged durability including against historical strains, thereby providing greater potential vaccine efficacy in the elderly throughout an influenza season. Clinical Trial Registry: ClinicalTrials.gov # NCT02500680.

Pharmacokinetics and Safety of a Novel Oral Liquid Formulation of 13-cis Retinoic Acid in Children with Neuroblastoma: A Randomized Crossover Clinical Trial.

(1) Background: 13-cis-retinoic acid (13-CRA) is a key component of neuroblastoma treatment protocols. This randomized crossover study compares the pharmacokinetics (PK), safety and palatability of a novel oral liquid formulation to the current method of extracting 13-CRA from capsules. (2) Methods: Pharmacokinetics was evaluated in two consecutive treatment cycles. Patients were randomized to receive either liquid or capsule formulation on cycle 1 and then crossed over to the alternative formulation on cycle 2. The daily dose was 200 mg/m2, reduced to 160 mg/m2 in patients with weight ≤ 12 kg. (3) Results: A total of 20 children, median (range) age 4.3 (1-11.6) y were recruited. Pharmacokinetic data were pooled and a population model describing the disposition of 13-CRA and 4-oxo-13-CRA was developed. Bioavailability of the liquid formulation was estimated to be 65% higher (95% CI; 51-79%) than the extracted capsule. CmaxSS and AUC(0-12)SS estimates were also significantly higher; mean (95% CI) differences were 489 (144-835) ng/mL and 3933 (2020-5846) ng/mL·h, respectively (p < 0.01). There were no significant differences in reported adverse effects. Parents found dosing considerably easier with liquid formulation. (4) Conclusions: The pharmacokinetics, safety and palatability of a new liquid formulation of 13-CRA compares favorably to 13-CRA extracted from capsules. Clinical Trial Registration: clinicaltrial.gov NCT03291080.

Extended-interval gentamicin: population pharmacokinetics in pediatric critical illness.

OBJECTIVES: Once-daily gentamicin therapy is becoming increasingly common in pediatric practice; however, little is known about pharmacokinetics in critical illness. Gentamicin exhibits concentration dependant killing; thus, peak serum concentrations at least eight times higher than minimum inhibition concentration of the target organism have been recommended. We wanted to derive pharmacokinetic parameters for gentamicin in critical illness and to evaluate whether a dose of 8 mg/kg provides an adequate peak serum concentration (>16 mg/L). PATIENTS AND INTERVENTIONS: Population-based pharmacokinetic analyses were undertaken using therapeutic drug monitoring data collected prospectively in an intensive care unit over 6 months (n = 50 children). Monte Carlo simulations were used to estimate the probability of achieving 1) peak concentrations >16 mg/L; and 2) trough concentrations <2 mg/L at 24 and 36 hrs. MEASUREMENTS AND MAIN RESULTS: The optimal pharmacokinetic model was of two-compartment disposition with zero order input and additive residual error. Weight was associated nonlinearly with clearance and linearly with volume, and age was a significant covariate for clearance. An 8-mg/kg dose provided near 100% probability of achieving adequate peak concentrations at all ages. However this probability decreased rapidly at doses <7 mg/kg with neonates being the most susceptible. Approximately 50% of nonpremature neonates within the first week of life, 25% of infants, and 10% of children are likely to need a dose interval >24 hrs. CONCLUSIONS: A gentamicin dose of 8 mg/kg is highly likely to achieve peak concentrations >16 mg/L in critically ill children. A considerable proportion will require dose intervals >24 hrs; thus, therapeutic drug monitoring is essential.

Validation of methods for determining pediatric midazolam using wet whole blood and volumetric absorptive microsampling.

Aim: Collection and quantitative analysis in dry blood using volumetric absorptive microsampling (VAMS™) potentially offers significant advantages over conventional wet whole blood analysis. This manuscript explores their use for pediatric sampling and explores additional considerations for the validation of the bioanalytical method. Results: HPLC-MS/MS methods for the determination of midazolam and its major metabolite 1-OH midazolam in both whole wet blood, and dry blood collected on VAMS were developed, validated, and used to support an observational clinical study to compare pharmacokinetic parameters in pediatric patients. Conclusion: Validation data met internationally accepted guideline criteria. A strong correlation was observed in calculated concentrations between wet and dry test samples, indicating that VAMS is a suitable technique for use in pediatric clinical studies.

Case Report on a Rare Intraoperative Finding of Ectopic Liver Tissue Attached to Gallbladder Wall during Laparoscopic Cholecystectomy.

INTRODUCTION: Ectopic liver is a rare finding (Corsy, 1922; Kubota et al., 2007) that is usually discovered intraoperatively or during an autopsy (Bassis and Izenstark, 1956). Preoperative diagnosis of ectopic liver is also uncommon. The most common site of ectopic liver is on the gall bladder, although there are reports of other sites such as the adrenal glands and esophagus. The management of ectopic liver is en-bloc resection due to the high risk of hepatocellular carcinoma. CASE PRESENTATION: We describe the case of a 42-year-old female who presented with recurrent abdominal pain. She was found to have a smooth fragment of a reddish brown tissue attached to the anterior surface of the gallbladder during an elective laparoscopic cholecystectomy. The tissue was removed with the gallbladder, and histopathology showed normal ectopic liver tissue. CONCLUSION: Due to the possibility of malignant transformation into hepatocellular carcinoma, en-bloc resection is the choice of management.

Personalised dosing of medicines for children.

OBJECTIVES: Doses for most drugs are determined from population-level information, resulting in a standard ?one-size-fits-all' dose range for all individuals. This review explores how doses can be personalised through the use of the individuals' pharmacokinetic (PK)-pharmacodynamic (PD) profile, its particular application in children, and therapy areas where such approaches have made inroads. KEY FINDINGS: The Bayesian forecasting approach, based on population PK/PD models that account for variability in exposure and response, is a potent method for personalising drug therapy. Its potential utility is even greater in young children where additional sources of variability are observed such as maturation of eliminating enzymes and organs. The benefits of personalised dosing are most easily demonstrated for drugs with narrow therapeutic ranges such as antibiotics and cytotoxics and limited studies have shown improved outcomes. However, for a variety of reasons the approach has struggled to make more widespread impact at the bedside: complex dosing algorithms, high level of technical skills required, lack of randomised controlled clinical trials and the need for regulatory approval. SUMMARY: Personalised dosing will be a necessary corollary of the new precision medicine initiative. However, it faces a number of challenges that need to be overcome before such an approach to dosing in children becomes the norm.