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.

Pharmacokinetics and safety of prolonged paracetamol treatment in neonates: An interventional cohort study.

AIMS: To investigate the pharmacokinetics and safety of prolonged paracetamol use (>72 h) for neonatal pain. METHODS: Neonates were included if they received paracetamol orally or intravenously for pain treatment. A total of 126 samples were collected. Alanine aminotransferase and bilirubin were measured as surrogate liver safety markers. Paracetamol and metabolites were measured in plasma. Pharmacokinetic parameters for the parent compound were estimated with a nonlinear mixed-effects model. RESULTS: Forty-eight neonates were enrolled (38 received paracetamol for >72 h). Median gestational age was 38 weeks (range 25-42), and bodyweight at inclusion was 2954 g (range 713-4750). Neonates received 16 doses (range 4-55) over 4.1 days (range 1-13.8). The median (range) dose was 10.1 mg/kg (2.9-20.3). The median oxidative metabolite concentration was 14.6 µmol/L (range 0.12-113.5) and measurable >30 h after dose. There was no significant difference (P > .05) between alanine aminotransferase and bilirubin measures at <72 h or >72 h of paracetamol treatment or the start and end of the study. Volume of distribution and paracetamol clearance for a 2.81-kg neonate were 2.99 L (% residual standard error = 8, 95% confidence interval 2.44-3.55) and 0.497 L/h (% residual standard error = 7, 95% confidence interval 0.425-0.570), respectively. Median steady-state concentration from the parent model was 50.3 µmol/L (range 30.6-92.5), and the half-life was 3.55 h (range 2.41-5.65). CONCLUSION: Our study did not provide evidence of paracetamol-induced liver injury nor changes in metabolism in prolonged paracetamol administration in neonates.

Assessment of the Relationship Between Gastric-Acid Suppressants and the Risk of Esophageal Adenocarcinoma: A Systematic Review and Meta-Analysis.

Background: Esophageal cancer is a cancerous tumor that develops in the esophagus. It is the 10th most common cancer and has a low survival rate. Esophageal adenocarcinoma (EAC) is increasing in incidence globally. Those with EAC are affected by Barrett's esophagus metaplasia, which is attributed to genetic predisposition and is more common in men. Studies suggest that gastric acid suppressants, like proton pump inhibitors and histamine-2 receptor antagonists, have anticancer properties and reduce EAC. However, other research has suggested that they are not cancer-protective, and the use of antisecretory drugs is a risk factor for developing EAC. Objective: This systematic review and meta-analysis investigated the properties and risk factors associated with using gastric acid suppressants in patients with EAC. Methods: This meta-analysis used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist. Information from selected articles, including the lead author's name, year of publication, study setting, sample size, and gender, was extracted and recorded into an Excel (Microsoft, Redmond, Washington) form. Statistical data included odds ratio, hazard ratio, and/or risk ratio, with a 95% CI associated with patients with EAC and receiving gastric acid suppressants. Data were compared with individuals not receiving treatment. Publication bias was assessed using Begg's and Egger's tests. Statistical analyzes used Stata 14.0 (Stata LLC, College Station, Texas). Results: The initial electronic literature search retrieved 3761 titles/abstracts. Extensive screening selected 20 articles for analysis. Odds ratios associated with EAC in the individuals using gastric acid suppressants were 0.77 (95% CI, 0.49-1.22; P = 0.274) and 0.67 (95% CI, 0.39-1.29; P = 0.240) for proton pump inhibitors and 1.02 (95% CI, 0.44-2.36; P = 0.967) for histamine-2 receptor antagonists. Conclusions: The results found that gastric acid suppressants do not have a protective role in EAC and are not risk factors. Future studies of confounding variables and risk factors are needed to understand what affects EAC development.

Relationship between serum vitamin D and hip fracture in the elderly: a systematic review and meta-analysis.

INTRODUCTION: This study investigated the relationship between serum 25-hydroxyvitamin D (25OHD) levels and the occurrence of hip fractures in the elderly using a systematic review and meta-analysis approach. MATERIALS AND METHODS: PubMed, Web of Science, and Scopus were used to identify studies that outlined an association between serum 25OHD and the occurrence of a hip fracture in a geriatric patient. The analysis calculated odds ratios (OR) for a hip fracture using a random-effects model. RESULTS: In this study, 28 studies were included, 61,744 elderlies and 9767 cases (15.81%) of hip fractures. In the lowest vs. highest categories of vitamin D in the elderly, pooled OR of hip fractures was 1.80 (95% CI 1.56-2.07, P ≤ 0.001), and modified OR was equal to 1.40 (95% CI 1.20-1.63 P ≤ 0.001). A subgroup analysis showed that the OR of a hip fracture was 2.16 (1.49-3.11, P ≤ 0.001) in case-control studies; 1.52 (1.29-1.79, P = 0.001) in cohort studies; and 1.41 (1.18-1.70, P ≤ 0.001) in case-cohort studies. CONCLUSION: Low serum vitamin D levels in the elderly are associated with an increase in the odds of hip fracture.

Oral drug dosing following bariatric surgery: General concepts and specific dosing advice.

Bariatric or weight-loss surgery is a popular option for weight reduction. Depending on the surgical procedure, gastric changes like decreased transit time and volume and increased pH, decreased absorption surface in the small intestine, decreased exposure to bile acids and enterohepatic circulation, and decreased gastrointestinal transit time may be expected. In the years after bariatric surgery, patients will also substantially lose weight. As a result of these changes, the absorption, distribution, metabolism and/or elimination of drugs may be altered. The purpose of this article is to report the general influence of bariatric surgery on oral drug absorption, and to provide guidance for dosing of commonly used drugs in this special population. Upon oral drug administration, the time to maximum concentration is often earlier and this concentration may be higher with less consistent effects on trough concentrations and exposure. Additionally, prescription of liquid formulations to bariatric patients is supported by some reports, even though the high sugar load of these suspensions may be of concern. Studies on extended-release medications result in an unaltered exposure for a substantial number of drugs. Also, studies evaluating the influence of timing after surgery show dynamic absorption profiles. Although for this group specific advice can be proposed for many drugs, we conclude that there is insufficient evidence for general advice for oral drug therapy after bariatric surgery, implying that a risk assessment on a case-by-case basis is required for each drug.

Population pharmacokinetics of olanzapine in children.

AIMS: The aim of this study was to evaluate the population pharmacokinetics (PopPK) of olanzapine in children and devise a model-informed paediatric dosing scheme. METHODS: The PopPK of olanzapine was characterized using opportunistically collected plasma samples from children receiving olanzapine per standard of care for any indication. A nonlinear mixed effect modelling approach was employed for model development using the software NONMEM (v7.4). Simulations from the developed PopPK model were used to devise a paediatric dosing scheme that targeted comparable plasma exposures to adolescents and adults. RESULTS: Forty-five participants contributed 83 plasma samples towards the analysis. The median (range) postnatal age and body weight of participants were 3.8 years (0.2-19.2) and 14.1 kg (4.2-111.7), respectively. The analysis was restricted to pharmacokinetic (PK) samples collected following enteral administration (oral and feeding tube). A one-compartment model with linear elimination provided an appropriate fit to the data. The final model included the covariates body weight and postmenstrual age (PMA) on apparent olanzapine clearance (CL/F). Typical CL/F and apparent volume of distribution (scaled to 70 kg) were 16.8 L/h (21% RSE) and 663 L (13% RSE), respectively. Developed dosing schemes used weight-normalized doses for children ≤6 months postnatal age or <15 kg and fixed doses for children ≥15 kg. CONCLUSION: We developed a paediatric PopPK model for enterally-administered olanzapine. To our knowledge, this analysis is the first study to characterize the PK of olanzapine in participants ranging from infants to adolescents. Body weight and PMA were identified as influential covariates for characterizing developmental changes in olanzapine apparent clearance.

Impact of Disease on Amikacin Pharmacokinetics and Dosing in Children.

BACKGROUND: Amikacin is widely used to treat severe Gram-negative bacterial infections. Its peak concentration in plasma is associated with treatment efficacy. Amikacin pharmacokinetics (PK) is influenced by disease conditions, in addition to other patient characteristics. In this retrospective study, we evaluated the impact of clinical characteristics and disease condition on amikacin PK in children with burn injuries and those with cancer. METHODS: Amikacin PK data from 66 children with burn injuries and 112 children with cancer were analyzed. A population PK model was developed using the nonlinear mixed-effects modeling approach. Models were developed using NONMEM 7.3 (ICON Development Solutions, LLC, Ellicott City, MD). Data processing and visualization was performed using R packages. RESULTS: The amikacin PK data were best described by a 2-compartment model. The parameters were estimated with mean values (95% confidence intervals) as follows: central volume of distribution (V1), 5.70 L (4.64-6.76 L); central clearance, 2.12 L/h (1.79-2.46 L/h); peripheral volume of distribution (V2), 4.79 L (2.36-7.22 L); and distribution clearance (Q), 0.71 L/h (0.25-1.16 L/h). The final model identified the disease condition as a significant covariate and indicated 55% (28%-82%) higher central clearance and 17% (1%-34%) higher V1 in burn patients compared with cancer patients. Volume of distribution was significantly influenced by age and body weight. Clearance was significantly influenced by age, body weight, and creatinine clearance. Using the final PK model, we developed a workflow for selecting optimal dosing strategies for 3 representative pediatric patient profiles. CONCLUSIONS: Disease condition was significant in influencing amikacin PK in children. To reach the same target concentrations (64 mg/L peak concentration) with a daily-dose plan, burn patients need higher doses than cancer patients. Future investigations are needed to explore the impact of other diseases on amikacin disposition in children, and to prospectively validate the proposed dosing strategy.

Cost-effectiveness of early cancer surveillance for patients with Li-Fraumeni syndrome.

INTRODUCTION: Patients with germline TP53 pathogenic variants (Li-Fraumeni syndrome [LFS]) are at extremely high lifetime risk of developing cancer. Recent data suggest that tumor surveillance for patients with LFS may improve survival through early cancer detection. The objective of this study was to assess the cost-effectiveness of a cancer surveillance strategy for patients with LFS compared with those whose tumors present clinically. METHODS: A Markov decision analytic model was developed from a third-party payer perspective to estimate cost-effectiveness of routine cancer surveillance over a patient's lifetime. The model consisted of four possible health states: no cancer, cancer, post-cancer survivorship, and death. Model outcomes were costs (2015 United States Dollars [USD]), effectiveness (life years [LY] gained), and incremental cost-effectiveness ratio (ICER; change in cost/LY gained). One-way sensitivity analyses and probabilistic sensitivity analyses examined parameter uncertainty. RESULTS: The model showed a mean cost of $46 496 and $117 102 and yielded 23 and 27 LY for the nonsurveillance and surveillance strategies, respectively. The ICER for early cancer surveillance versus no surveillance was $17 125 per additional LY gained. At the commonly accepted willingness to pay threshold of $100 000/life-year gained, surveillance had a 98% probability of being the most cost-effective strategy for early cancer detection in this high-risk population. CONCLUSIONS: Presymptomatic cancer surveillance is cost-effective for patients with germline pathogenic variants in TP53. Lack of insurance coverage or reimbursement in this population may have significant consequences and leads to undetected cancers presenting in later stages of disease with worse clinical outcomes.

Population pharmacokinetic model of transdermal nicotine delivered from a matrix-type patch.

AIMS: Nicotine addiction is an issue faced by millions of individuals worldwide. As a result, nicotine replacement therapies, such as transdermal nicotine patches, have become widely distributed and used. While the pharmacokinetics of transdermal nicotine have been extensively described using noncompartmental methods, there are few data available describing the between-subject variability in transdermal nicotine pharmacokinetics. The aim of this investigation was to use population pharmacokinetic techniques to describe this variability, particularly as it pertains to the absorption of nicotine from the transdermal patch. METHODS: A population pharmacokinetic parent-metabolite model was developed using plasma concentrations from 25 participants treated with transdermal nicotine. Covariates tested in this model included: body weight, body mass index, body surface area (calculated using the Mosteller equation) and sex. RESULTS: Nicotine pharmacokinetics were best described with a one-compartment model with absorption based on a Weibull distribution and first-order elimination and a single compartment for the major metabolite, cotinine. Body weight was a significant covariate on apparent volume of distribution of nicotine (exponential scaling factor 1.42). After the inclusion of body weight in the model, no other covariates were significant. CONCLUSIONS: This is the first population pharmacokinetic model to describe the absorption and disposition of transdermal nicotine and its metabolism to cotinine and the pharmacokinetic variability between individuals who were administered the patch.

Clinical pharmacokinetics of magnesium sulfate in the treatment of children with severe acute asthma.

PURPOSE: Intravenous (IV) magnesium sulfate (MgSO4) is used as adjunct therapy to treat acute asthma exacerbations. Despite its clinical use, there is a limited understanding of the disposition of magnesium in children. METHODS: To explore the pharmacokinetics (PK) of IV MgSO4 in this population, we collected retrospective data from 54 children who received IV MgSO4 for treatment of an acute asthma exacerbation at Primary Children's Hospital in Salt Lake City, UT. These data were analyzed using population PK modeling techniques in NONMEM® to determine sources of variability affecting the disposition of magnesium, as well as to predict the dose of IV MgSO4 needed to achieve clinical benefit. RESULTS: The covariate analysis found that only weight was a significant predictor of magnesium concentrations in children. Estimated model parameters suggested that magnesium exhibits a short serum half-life (2.7 h) in children. The average endogenous magnesium concentration (prior to administration of IV MgSO4) was estimated to be 21 mg/L. Simulated data suggested that doses between 50 and 75 mg/kg are required to achieve concentration-time profiles within a hypothesized target therapeutic range between 25 and 40 mg/L. CONCLUSIONS: These results provide new insight into the disposition of IV MgSO4 in children and provide dosing guidelines for future prospective studies of IV MgSO4 in children with acute asthma.

The impact of exposure to antidepressant medications during pregnancy on neonatal outcomes: a review of retrospective database cohort studies.

INTRODUCTION: Concerns with prescription antidepressant use in pregnant women have instigated the examination of potential associations between fetal exposure to antidepressant medication and outcomes including preterm delivery, congenital malformations, perinatal and post-natal adverse events, persistent pulmonary hypertension, and mortality. The retrospective cohort model is an often utilized study design. The objective of this review is to evaluate the literature on antidepressant use in pregnancy conducted as retrospective cohorts in national/regional medical, or claims databases that assess neonatal and infant outcomes for agreement between studies, ultimately providing a methodological and outcomes summary for future scientific endeavors. METHODS: PubMed was searched for literature relating to antidepressant use and infant outcomes from the earliest available date through July 15, 2016. Studies with a retrospective cohort design and conducted in national/regional medical or claims databases were included. Searched outcomes included preterm delivery, congenital malformations, low birth weight, small for gestational age, persistent pulmonary hypertension of the newborn, and other select adverse events comprising low Apgar score (5 min), convulsions/seizures, respiratory distress/problems, fetal mortality, and infant mortality. RESULTS: Of the 784 studies identified, 36 retrospective cohort studies met eligibility criteria. An increase in preterm delivery and respiratory distress/problems and no increase in congenital malformation or fetal and infant death were associated with prenatal use of prescription antidepressants by majority consensus (at least 2/3 [67%] of studies). CONCLUSIONS: While consensus indicates that perinatal prescription antidepressant use has consequences for the fetus and infant, there are notable inconsistencies in the literature. More investigations that address prenatal exposure to depression and other important covariates are needed.

Towards Rational Dosing Algorithms for Vancomycin in Neonates and Infants Based on Population Pharmacokinetic Modeling.

Because of the recent awareness that vancomycin doses should aim to meet a target area under the concentration-time curve (AUC) instead of trough concentrations, more aggressive dosing regimens are warranted also in the pediatric population. In this study, both neonatal and pediatric pharmacokinetic models for vancomycin were externally evaluated and subsequently used to derive model-based dosing algorithms for neonates, infants, and children. For the external validation, predictions from previously published pharmacokinetic models were compared to new data. Simulations were performed in order to evaluate current dosing regimens and to propose a model-based dosing algorithm. The AUC/MIC over 24 h (AUC24/MIC) was evaluated for all investigated dosing schedules (target of >400), without any concentration exceeding 40 mg/liter. Both the neonatal and pediatric models of vancomycin performed well in the external data sets, resulting in concentrations that were predicted correctly and without bias. For neonates, a dosing algorithm based on body weight at birth and postnatal age is proposed, with daily doses divided over three to four doses. For infants aged <1 year, doses between 32 and 60 mg/kg/day over four doses are proposed, while above 1 year of age, 60 mg/kg/day seems appropriate. As the time to reach steady-state concentrations varies from 155 h in preterm infants to 36 h in children aged >1 year, an initial loading dose is proposed. Based on the externally validated neonatal and pediatric vancomycin models, novel dosing algorithms are proposed for neonates and children aged <1 year. For children aged 1 year and older, the currently advised maintenance dose of 60 mg/kg/day seems appropriate.

Salivary caffeine concentrations are comparable to plasma concentrations in preterm infants receiving extended caffeine therapy.

AIMS: Caffeine concentrations in preterm infants are usually measured in the blood. However, salivary assays may provide a valid and practical alternative. The present study explored the validity and clinical utility of salivary caffeine concentrations as an alternative to blood concentrations and developed a novel plasma/salivary caffeine distribution model. METHODS: Paired salivary and plasma samples were obtained in 29 infants. Salivary samples were obtained using a commercially available salivary collection system. Caffeine concentrations in the saliva and plasma were determined using high-performance liquid chromatography. A population pharmacokinetic (PK) model was developed using NONMEM 7.3. RESULTS: The mean (± standard deviation) gestational age (GA) at birth and birth weight were 27.9 ± 2.1 weeks and 1171.6 ± 384.9 g, respectively. Paired samples were obtained at a mean postmenstrual age (PMA) of 35.5 ± 1.1 weeks. The range of plasma caffeine concentrations was 9.5-54.1 µg ml(-1) , with a mean difference (95% confidence interval) between plasma and salivary concentrations of -0.18 µg ml(-1) (-1.90, 1.54). Salivary and plasma caffeine concentrations were strongly correlated (Pearson's correlation coefficient = 0.87, P < 0.001). Caffeine PK in plasma and saliva was simultaneously described by a three-compartment recirculation model. Current body weight, birth weight, GA, PMA and postnatal age were not significantly correlated with any PK parameter. CONCLUSIONS: Salivary sampling provides an easy, non-invasive method for measuring caffeine concentrations. Salivary concentrations correlate highly with plasma concentrations. Caffeine PK in saliva and plasma are well described by a three-compartment recirculation model.

Darbepoetin administration to neonates undergoing cooling for encephalopathy: a safety and pharmacokinetic trial.

BACKGROUND: Despite therapeutic hypothermia, neonates with encephalopathy (NE) have high rates of death or disability. Darbepoetin alfa (Darbe) has comparable biological activity to erythropoietin, but has extended circulating half-life (t(1/2)). Our aim was to determine Darbe safety and pharmacokinetics as adjunctive therapy to hypothermia. STUDY DESIGN: Thirty infants (n = 10/arm) ≥36 wk gestation undergoing therapeutic hypothermia for NE were randomized to receive placebo, Darbe low dose (2 µg/kg), or high dose (10 µg/kg) given intravenously within 12 h of birth (first dose/hypothermia condition) and at 7 d (second dose/normothermia condition). Adverse events were documented for 1 mo. Serum samples were obtained to characterize Darbe pharmacokinetics. RESULTS: Adverse events (hypotension, altered liver and renal function, seizures, and death) were similar to placebo and historical controls. Following the first Darbe dose at 2 and 10 µg/kg, t(1/2) was 24 and 32 h, and the area under the curve (AUC(inf)) was 26,555 and 180,886 h*mU/ml*, respectively. In addition, clearance was not significantly different between the doses (0.05 and 0.04 l/h). At 7 d, t(1/2) was 26 and 35 h, and AUC(inf) was 10,790 and 56,233 h*mU/ml*, respectively (*P < 0.01). CONCLUSION: Darbe combined with hypothermia has similar safety profile to placebo with pharmacokinetics sufficient for weekly administration.

Evaluation of Vancomycin Use in Late-Onset Neonatal Sepsis Using the Area Under the Concentration-Time Curve to the Minimum Inhibitory Concentration ≥400 Target.

AIM: To develop a vancomycin population pharmacokinetic model and assess the probability of attaining a pharmacodynamic target associated with clinical and microbiological success, a ratio of the 24-hour area under the concentration-time curve to the minimum inhibitory concentration (MIC) ≥ 400, in a 5-year clinical cohort of preterm and term neonatal patients with late-onset staphylococcal sepsis. METHODS: Therapeutic drug monitoring data were obtained from septic neonates with ≥1 vancomycin concentration(s) from January 2006 to September 2011. Only neonates with a postnatal age of >72 hours and a positive microbiological culture were included. Population pharmacokinetic model was developed using nonlinear mixed effects modeling (NONMEM 7.2). Eleven demographic characteristics were evaluated as covariates. Probabilities of achieving the pharmacodynamic target were evaluated. RESULTS: A 1-compartment model with first-order elimination was constructed from 528 vancomycin concentrations collected from 152 preterm and term neonates. Body weight, creatinine clearance (CL), and postmenstrual age were identified as significant covariates. Estimated vancomycin CL and volume of distribution for typical neonates were 0.068 ± 0.03 L·h·kg and 0.62 ± 0.13 L/kg, respectively. Coagulase-negative staphylococci (85.5%) and Staphylococcus aureus (14.5%) were the common pathogenic organisms. The distribution of vancomycin MIC breakpoints was composed of approximately 70% MIC breakpoint of ≤2 mcg/mL. Approximately 54% of neonates, with a median serum creatinine concentration of 0.44 mg/dL, achieved the target ratio of 24-hour area under the concentration-time curve to the MIC ≥ 400 with a median daily dose of 30 (interquartile range, 21-42) mg/kg. CONCLUSIONS: Body weight, creatinine CL, and postmenstrual age significantly influenced vancomycin CL. The current vancomycin doses are acceptable at MICs ≤1 mcg/mL because they are likely to achieve the pharmacodynamic target in the majority of neonatal patients, although higher doses may be considered for more resistant staphylococcal infections.

Development of an optimal sampling schedule for children receiving ketamine for short-term procedural sedation and analgesia.

BACKGROUND: Intravenous racemic ketamine is commonly administered for procedural sedation, although few pharmacokinetic studies have been conducted among children. Moreover, an optimal sampling schedule has not been derived to enable the conduct of pharmacokinetic studies that minimally inconvenience study participants. METHODS: Concentration-time data were obtained from 57 children who received 1-1.5 mg·kg(-1) of racemic ketamine as an intravenous bolus. A population pharmacokinetic analysis was conducted using nonlinear mixed effects models, and the results were used as inputs to develop a D-optimal sampling schedule. RESULTS: The pharmacokinetics of ketamine were described using a two-compartment model. The volume of distribution in the central and peripheral compartments were 20.5 l∙70 kg(-1) and 220 l∙70 kg(-1), respectively. The intercompartmental clearance and total body clearance were 87.3 and 87.9 l·h(-1) ∙70 kg(-1), respectively. Population parameter variability ranged from 34% to 98%. Initially, blood samples were drawn on 3-6 occasions spanning a range of 14-152 min after dosing. Using these data, we determined that four optimal sampling windows occur at 1-5, 5.5-7.5, 10-20, and 90-180 min after dosing. Monte Carlo simulations indicated that these sampling windows produced precise and unbiased ketamine pharmacokinetic parameter estimates. CONCLUSION: An optimal sampling schedule was developed that allowed assessment of the pharmacokinetic parameters of ketamine among children requiring short-term procedural sedation.

Optimal design in pediatric pharmacokinetic and pharmacodynamic clinical studies.

It is not trivial to conduct clinical trials with pediatric participants. Ethical, logistical, and financial considerations add to the complexity of pediatric studies. Optimal design theory allows investigators the opportunity to apply mathematical optimization algorithms to define how to structure their data collection to answer focused research questions. These techniques can be used to determine an optimal sample size, optimal sample times, and the number of samples required for pharmacokinetic and pharmacodynamic studies. The aim of this review is to demonstrate how to determine optimal sample size, optimal sample times, and the number of samples required from each patient by presenting specific examples using optimal design tools. Additionally, this review aims to discuss the relative usefulness of sparse vs rich data. This review is intended to educate the clinician, as well as the basic research scientist, whom plan on conducting a pharmacokinetic/pharmacodynamic clinical trial in pediatric patients.

Absence of P-glycoprotein transport in the pharmacokinetics and toxicity of the herbicide paraquat.

Genetic variation in the multidrug resistance gene ABCB1, which encodes the efflux transporter P-glycoprotein (P-gp), has been associated with Parkinson disease. Our goal was to investigate P-gp transport of paraquat, a Parkinson-associated neurotoxicant. We used in vitro transport models of ATPase activity, xenobiotic-induced cytotoxicity, transepithelial permeability, and rhodamine-123 inhibition. We also measured paraquat pharmacokinetics and brain distribution in Friend leukemia virus B-type (FVB) wild-type and P-gp-deficient (mdr1a(-/-)/mdr1b(-/-)) mice following 10, 25, 50, and 100 mg/kg oral doses. In vitro data showed that: 1) paraquat failed to stimulate ATPase activity; 2) resistance to paraquat-induced cytotoxicity was unchanged in P-gp-expressing cells in the absence or presence of P-gp inhibitors GF120918 [N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide] and verapamil-37.0 [95% confidence interval (CI): 33.2-41.4], 46.2 (42.5-50.2), and 34.1 µM (31.2-37.2)-respectively; 3) transepithelial permeability ratios of paraquat were the same in P-gp-expressing and nonexpressing cells (1.55 ± 0.39 and 1.39 ± 0.43, respectively); and 4) paraquat did not inhibit rhodamine-123 transport. Population pharmacokinetic modeling revealed minor differences between FVB wild-type and mdr1a(-/-)/mdr1b(-/-) mice: clearances of 0.47 [95% confidence interval (CI): 0.42-0.52] and 0.78 l/h (0.58-0.98), respectively, and volume of distributions of 1.77 (95% CI: 1.50-2.04) and 3.36 liters (2.39-4.33), respectively; however, the change in clearance was in the opposite direction of what would be expected. It is noteworthy that paraquat brain-to-plasma partitioning ratios and total brain accumulation were the same across doses between FVB wild-type and mdr1a(-/-)/mdr1b(-/-) mice. These studies indicate that paraquat is not a P-gp substrate. Therefore, the association between ABCB1 pharmacogenomics and Parkinson disease is not attributed to alterations in paraquat transport.

A neonatal amikacin covariate model can be used to predict ontogeny of other drugs eliminated through glomerular filtration in neonates.

PURPOSE: Recently, a covariate model characterizing developmental changes in clearance of amikacin in neonates has been developed using birth bodyweight and postnatal age. The aim of this study was to evaluate whether this covariate model can be used to predict maturation in clearance of other renally excreted drugs. METHODS: Five different neonatal datasets were available on netilmicin, vancomycin, tobramycin and gentamicin. The extensively validated covariate model for amikacin clearance was used to predict clearance of these drugs. In addition, independent reference models were developed based on a systematic covariate analysis. RESULTS: The descriptive and predictive properties of the models developed using the amikacin covariate model were good, and fairly similar to the independent reference models (goodness-of-fit plots, NPDE). Moreover, similar clearance values were obtained for both approaches. Finally, the same covariates as in the covariate model of amikacin, i.e. birth bodyweight and postnatal age, were identified on clearance in the independent reference models. CONCLUSIONS: This study shows that pediatric covariate models may contain physiological information since information derived from one drug can be used to describe other drugs. This semi-physiological approach may be used to optimize sparse data analysis and to derive individualized dosing algorithms for drugs in children.