Pharmacokinetics In Children Research Articles

Doxylamine pharmacokinetics following single dose oral administration in children ages 2–17 years

To characterize doxylamine pharmacokinetics in children. This study was conducted in 41 subjects, ages 2-17 years. Doxylamine succinate doses based on age/weight ranged from 3.125 to 12.5 mg. A single oral dose was administered with 2 to 4 oz. of water or decaffeinated beverages ∼2 hours after a light breakfast. Plasma samples were obtained before and for 72 hours after dosing and analyzed for doxylamine using HPLC MS/MS. Pharmacokinetic parameters were estimated using non-compartmental methods and relationships with age were assessed using linear regression. Over the fourfold dose range, Cmax was similar while AUC increased only 60%, although not statistically significant (P-value = 0.0517). As expected due to increasing body size, CLo and Vz /F increased with age. Due to a similar increase with age for Clo and Vz /F, no age-related differences in t1/2,z were observed (∼16 hours). Allometric scaling indicated no maturation related changes in CLo ; although Vz /F remained age-dependent, the predicted range decreased ∼70%. Overall, the single doses were well tolerated. Somnolence was the most common reported AE with no apparent differences in incidence noted with age. An age/weight dosing nomogram utilizing a fourfold range of doses achieves similar Cmax , whereas AUC increases only 60%.

Pharmacology of paediatric total intravenous anaesthesia

Adult parameter estimates for pharmacokinetic models over-predict plasma concentrations in children. Parameter sets that describe 3-compartment pharmacokinetic models for propofol have been published and some are now incorporated into commercially available paediatric infusion pumps. Pharmacokinetics in children is influenced by size and age. Other covariates remain poorly understood. There are no integrated pharmacokinetic-pharmacodynamic analyses available. However, methodology exists that enables us to link pharmacokinetic parameter sets with pharmacodynamic data in order to calculate a rate constant linking serum and effect site concentrations. Literature concerning paediatric total intravenous anaesthesia was reviewed to appraise these parameter sets (‘models’) and to outline the pharmacology behind them, their limitations and pitfalls. Los parámetros farmacocinéticos estimados en los modelos de adultos sobreestiman las concentraciones plasmáticas en niños. Se han publicado diversos conjuntos de parámetros que describen modelos de tres compartimentos para propofol y algunos están disponibles para bombas de infusión de uso pediátrico. La farmacocinética en niños está influenciada por el tamaño y la edad. Otras variables siguen siendo pobremente entendidas. No existen análisis integrados farmacocinéticos-farmacodinámicos. Sin embargo, existe la metodología que permite establecer un nexo entre los parámetros farmacocinéticos con datos farmacodinámicos y poder así calcular la constante de velocidad que vincula las concentraciones plasmáticas con las del sitio de efecto. En este estudio se hizo una revisión de la literatura en relación con el tema de anestesia intravenosa en pediatría para evaluar estos parámetros (modelos) y para destacar la farmacología detrás de ellos, sus limitaciones y problemas.

OCT1 Genetic Variants Influence the Pharmacokinetics of Morphine in Children

Large interindividual variability in morphine disposition could contribute to unpredictable variability in morphine analgesia and adverse events. Caucasian children have more adverse effects and slower morphine clearance than African-American children. To study variations in intravenous morphine pharmacokinetics in children, we examined the influence of genetic polymorphisms in OCT1. In 146 children undergoing adenotonsillectomy, 146 concentration-time profiles (2-4 measurements per patient) were available. Population pharmacokinetic analysis characterized the profiles in NONMEM(®) and tested OCT1 variants as covariates. Allometrically scaled post hoc Bayesian morphine clearance in homozygotes of loss-of-function OCT1 variants (n = 9, OCT1*2-*5/*2-*5) was significantly lower (20%) than in wild-type (n = 85, OCT1*1/*1) and heterozygotes (n = 52, OCT1*1/*2-*5; p < 0.05). Besides bodyweight, OCT1 genotypes play a significant role in intravenous morphine pharmacokinetics. Relatively high allelic frequencies of defective OCT1 variants among Caucasians may explain their lower morphine clearance and possibly higher frequencies of adverse events compared with African-American children. Original submitted 21 December 2012; Revision submitted 7 May 2013.

Rituximab pharmacokinetics in children and adolescents with de novo intermediate and advanced mature B‐cell lymphoma/leukaemia: a Children's Oncology Group report

The ANHL01P1 trial was undertaken to determine pharmacokinetics and safety following the addition of rituximab to French-American-British/Lymphome Malins de Burkitt (FAB/LMB96) chemotherapy in 41 children and adolescents with Stage III/IV mature B-cell lymphoma/leukaemia. Patients received rituximab (375 mg/m(2) ) days -2 and 0 of two induction cycles and day 0 of two consolidation cycles. Highest peak levels were achieved following the second dose of each induction cycle [299 ± 19 and 384 ± 25 μg/ml (Group-B); 245 ± 31 and 321 ± 32 μg/ml (Group-C)] with sustained troughs and t½ of 26-29 d. Rituximab can be safely added to FAB chemotherapy with high early rituximab peak/trough levels and a long t½.

Rituximab pharmacokinetics in children and adolescents with de novo intermediate and advanced mature B-cell lymphoma/leukemia: A Children’s Oncology Group (COG) report.

3055 Background: The COG trial ANHL01P1 was undertaken to determine pharmacokinetics (PK) and safety following the addition of rituximab (R) to FAB/LMB 96 chemotherapy in children and adolescents with stage III/IV mature B-NHL and B-ALL±CNS disease. Methods: Patients received R (375mg/m2) on day -2 and 0 of two induction cycles and day 0 of two consolidation cycles. R levels were measured prior to any antibody infusion, during induction cycles (1 hour prior and 30-60 minutes after each R dose) and following consolidation cycles (1, 3, 6 and 9 months after last R dose). R was measured by ELISA with goat anti-rituximab antibody as the capture reagent and goat anti-mouse IgG-conjugated to horseradish peroxidase as the detection reagent. R terminal half-life (t½) was calculated if at least 3 time points after the last dose were measurable in an individual subject. Results: Serum R levels are reported in the Table. Highest peak levels were achieved following the second dose of each induction cycle with sustained troughs and a t½ of 26-29 days. Group C patients tended to have lower R levels than Group B. Patients with LDH ≥2xULN were noted to have lower R levels during induction 1 compared to those with LDH &lt;2xULN. Children (&lt;13 years) exhibited higher peak concentrations, similar trough levels and a shorter t½ than adolescents (≥13 years). None of these differences reached significance after adjusting for multiple comparisons. Conclusions: R can be safely added to FAB chemotherapy with high early R peak/trough levels and a long terminal half-life. The efficacy of R combined with FAB chemotherapy is currently being investigated in an ongoing international intergroup trial. Clinical trial information: NCT00057811. [Table: see text]

A Practical Tranexamic Acid Dosing Scheme Based on Population Pharmacokinetics in Children Undergoing Cardiac Surgery

Pediatric cardiac surgery patients are at high risk for bleeding, and the antifibrinolytic drug tranexamic acid (TA) is often used to reduce blood loss. However, dosing schemes remain empirical as a consequence of the absence of pharmacokinetic study in this population. The authors' objectives were thus to investigate the population pharmacokinetics of TA in pediatric cardiac surgery patients during cardiopulmonary bypass (CPB). Twenty-one patients were randomized to receive TA either continuously (10 mg/kg followed by an infusion of 1 mg · kg · h(-1) throughout the operation, and 10 mg/kg into the CPB) or discontinuously (10 mg/kg, then 10 mg/kg into the CPB and 10 mg · kg · h(-1) at the end of CPB). Serum concentrations were measured at eight time points with chromatography-mass spectrometry and the data were modeled using Monolix (Lixoft, Orsay, France). Tranexamic acid pharmacokinetics was ascribed to a two-compartment open model. The main covariate effects were body weight and CPB. Representative pharmacokinetic parameters adjusted to a 70-kg body weight were as follows: systemic clearance, 2.45 l/h; volume of distribution in the central compartment, 14.1 l; intercompartmental clearance, 5.74 l/h; and peripheral volume, 32.8 l. In accordance with this model, the authors proposed a weight-adjusted dosing scheme to maintain effective TA concentrations in children during surgery, consisting of one loading dose followed by a continuous infusion. The authors report for the first time the pharmacokinetics of TA in children undergoing cardiac surgery with CPB, and propose a dosing scheme for optimized TA administration in those children.

Faster pharmacokinetics and increased patient acceptance of intradermal insulin delivery using a single hollow microneedle in children and adolescents with type 1 diabetes

In an effort to improve compliance with insulin therapy and to accelerate insulin pharmacokinetics, we tested the hypothesis that intradermal insulin delivery using a hollow microneedle causes less pain and leads to faster onset and offset of insulin pharmacokinetics in children and adolescents with type 1 diabetes (T1DM) compared with a subcutaneous, insulin pump catheter. In this repeated measures study, 16 children and adolescents with T1DM received Lispro insulin by microneedle and subcutaneous administration on separate days. Subjects rated the pain of insertion and infusion using a visual analog scale. Blood specimens were collected over 4 h to determine insulin and glucose concentrations. Microneedle insertion pain was significantly lower compared with insertion of the subcutaneous catheter (p = 0.005). Insulin onset time was 22 min faster (p = 0.0004) and offset time was 34 min faster (p = 0.017) after hollow microneedle delivery compared with subcutaneous delivery. In this study, intradermal insulin delivery using a single, hollow microneedle device resulted in less insertion pain and faster insulin onset and offset in children and adolescents with T1DM. A reduction in pain might improve compliance with insulin delivery. The faster onset and offset times of insulin action may enable closed-loop insulin therapy.

A Workflow Example of PBPK Modeling to Support Pediatric Research and Development: Case Study with Lorazepam

The use of physiologically based pharmacokinetic (PBPK) models in the field of pediatric drug development has garnered much interest of late due to a recent Food and Drug Administration recommendation. The purpose of this study is to illustrate the developmental processes involved in creation of a pediatric PBPK model incorporating existing adult drug data. Lorazepam, a benzodiazepine utilized in both adults and children, was used as an example. A population-PBPK model was developed in PK-Sim v4.2® and scaled to account for age-related changes in size and composition of tissue compartments, protein binding, and growth/maturation of elimination processes. Dose (milligrams per kilogram) requirements for children aged 0-18 years were calculated based on simulations that achieved targeted exposures based on adult references. Predictive accuracy of the PBPK model for producing comparable plasma concentrations among 63 pediatric subjects was assessed using average-fold error (AFE). Estimates of clearance (CL) and volume of distribution (V(ss)) were compared with observed values for a subset of 15 children using fold error (FE). Pediatric dose requirements in young children (1-3 years) exceeded adult levels on a linear weight-adjusted (milligrams per kilogram) basis. AFE values for model-derived concentration estimates were within 1.5- and 2-fold deviation from observed values for 73% and 92% of patients, respectively. For CL, 60% and 80% of predictions were within 1.5 and 2 FE, respectively. Comparatively, predictions of V(ss) were more accurate with 80% and 100% of estimates within 1.5 and 2 FE, respectively. Using the presented workflow, the developed pediatric model estimated lorazepam pharmacokinetics in children as a function of age.

Age-related differences in plasma and intracellular tenofovir concentrations in HIV-1-infected children, adolescents and adults

There is limited pediatric information on the complex relationships among the dose of tenofovir disoproxil fumarate (TDF), plasma concentrations of tenofovir (TFV), and intracellular TFV diphosphate (TFV-DP) concentrations. Our objectives were to describe TFV-DP pharmacokinetics in children and adolescents and investigate the effect of age on TFV and TFV-DP concentrations. TFV-DP pharmacokinetics were determined in 47 children and adolescents. TFV and TFV-DP were quantified with validated liquid chromatography/tandem mass spectrometry methods. Data were pooled with other studies in HIV-infected adults (N = 55). Nonlinear mixed effects modeling was used to develop the population model and explore the influence of covariates on TFV. A two-compartment model, partitioned for slow and fast absorbers by age, with weight allometrically scaled for children and adolescents, best described TFV pharmacokinetics. An indirect stimulation of response model best described TFV-DP formation. Apparent oral TFV clearance was significantly faster in patients less than 25 versus 25 years or more. The most significant covariate on apparent TFV oral clearance and central distribution volume was creatinine clearance. The TFV plasma concentration producing 50% of maximal TFV-DP concentrations was almost two-fold lower in patients less than 25 versus 25 years or more. The estimated intracellular TFV-DP half-life for these groups was 70 and 87 h, respectively. These data demonstrate that children and adolescents receiving standard TDF dosing of 300 mg once daily achieve higher intracellular TFV-DP concentrations than adults, despite lower plasma TFV concentrations. This age-related difference appears to arise from an increased sensitivity to formation of TFV-DP.

Safety and efficacy of levetiracetam for the treatment of partial onset seizures in children from one month of age

Epilepsy is a common neurological disorder in the pediatric population, affecting up to one percent of children, and for which the mainstay of treatment is anticonvulsant medication. Despite the frequent use of anticonvulsant drugs, remarkably little is known about the safety and efficacy of most of these medications in the pediatric epilepsy population. Of 34 anticonvulsants currently approved for use by the US Food and Drug Administration (FDA), only 13 have been approved for use in children. Although infants and young children are disproportionately affected by epilepsy, there are currently only three anticonvulsant medications that have been specifically evaluated and approved for use in children younger than 2 years of age. In 2012, the FDA approved levetiracetam as an adjunctive treatment for partial onset seizures in infants and children from one month of age. Here we review the available data on levetiracetam in the pediatric epilepsy population. We first discuss the pharmacological profile of levetiracetam, including its mechanism of action, formulations and dosing, and pharmacokinetics in children. We then review the available efficacy, safety, and tolerability data in children from one month of age with partial onset seizures. We conclude that the current data leading to the approval of levetiracetam for use in infants and children with partial onset seizures is encouraging, although more work needs to be done before definitive conclusions can be drawn about the efficacy of levetiracetam across different pediatric age groups.

Pharmacokinetics (PK) of the chimeric anti-GD2 antibody, ch14.18, in children with high-risk neuroblastoma.

9576 Background: The PK of ch14.18, a chimeric monoclonal antibody (cMoAb) that significantly improves survival in high-risk neuroblastoma, was previously reported to be highly variable in children, and its clearance (CL, 130 mL/h · m2) and volume of distribution (Vdss, 32 L/m2) were &gt;10-fold higher than the CL and Vdss of other cMoAbs. Characterizing the PK of ch14.18 and the factors responsible for its variability could lead to alternative dosing strategies that reduce toxicity. Methods: Detailed PK sampling was performed prior to, during and for 25 d after 4 daily 10 h infusions of 25 mg/m2 of ch14.18 administered with sargramostim (ANBL0032) in children enrolled on an IRB-approved institutional correlative protocol supported by United Therapeutics Corp. Ch14.18 concentrations were measured with a validated ELISA with a lower limit of detection of 0.44 mcg/mL. PK parameters were derived using non-compartmental methods and reported as median (range). Results: 5 males and 4 females, median (range) age 3.5 (1-7) yrs, have been enrolled. Six were studied on cycle 1 (C1), 2 on C5 and 1 on C3; 3 of 6 patients studied on C1 were re-studied on C3. Data from 3 patients are not included because pre-treatment plasma samples contained a substance that interfered with the ELISA. The Cmax after the 4th daily infusion was 14 (10-24) mcg/mL, and ch14.8 was undetectable at day 25 in 3/6 patients. The half-life was 220 (120-390) h, and the CL was 11 (3.8-16) mL/h · m2, which is similar to the average CL of 4 other cMoAbs (11 mL/h · m2). The Vdss of 2.8 (1.2-3.9) L/m2 approximated blood volume and was similar to the Vdss of other cMoAbs (1.7 L/m2) and humanized MoAbs (2.8 L/m2). AUC0-∞ in 2 patients studied twice were 3440 and 1540 mcg · h/mL on C1 and 2760 and 2690 mcg · h/mL on C3. Conclusions: Ch14.18 CL, Vdss and half-life in children are similar to those in adults receiving ch14.18 at the same dose and similar to other cMoAbs. Ch14.18 PK in children was less variable than previously reported. The identity of the interfering substance in the plasma of some patients requires further investigation. A limited sampling strategy will be developed from these data for use in larger multi-institutional PK studies of ch14.18.

Phase I Study of the Tolerability and Pharmacokinetics of Palifermin in Children Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

The maximum tolerated dose of palifermin, a keratinocyte growth factor, in children is not known, and its pharmacokinetics in this population has not been well studied. This is a phase I study of palifermin was designed to evaluate its tolerability at doses of 40, 60, and 90 μg/kg/day in children age 2-18 years of age, receiving a myeloablative preparative regimen for allogeneic hematopoietic stem cell transplantation (HSCT). In each cohort, palifermin was given for 3 consecutive days before the preparative regimen and for 3 days after the stem cell infusion. Twelve patients were enrolled. Palifermin 90 μg/kg/day was tolerated in 6 patients without dose-limiting toxicity. All patients had at least 1 adverse event, mostly National Cancer Institute grade 1 or 2 severity. Skin rash, grade 2 or lower, was the most common adverse event, seen in 67% of patients. Only 3 patients (25%) had mucositis. The area under the concentration-time curve increased proportionally to the dose, and approximately 97% of palifermin exposure occurred in the first 24 hours after administration. Palifermin clearance increased linearly with body weight, supporting dosing by body weight. The mean clearance was 1893 mL/hour/kg, and it did not change significantly between administration of the first and last doses (P=.80). The mean elimination half-life was 4.6 hours. Our datashow that palifermin was tolerated at a dose of 90 μg/kg/day, and exhibits linear pharmacokinetics in children undergoing allogeneic HSCT.

Pharmacokinetics and pharmacodynamics – is there anything new?

Pharmacokinetics and pharmacodynamics – is there anything new?

Perioperative Pharmacokinetics of Methadone in Adolescents

Methadone is frequently administered to adults experiencing anesthesia and receiving pain treatment. Methadone pharmacokinetics in adults are well characterized, including the perioperative period. Methadone is also used in children. There is, however, no information on methadone pharmacokinetics in children of any age. The purpose of this investigation was to determine the pharmacokinetics of intravenous methadone in children undergoing surgery. Perioperative opioid-sparing effects were also assessed. Eligible subjects were children 5-18 yr undergoing general anesthesia and surgery, with an anticipated postoperative inpatient stay exceeding 3 days. Three groups of 10 to 11 patients each received intravenous methadone hydrochloride after anesthetic induction in ascending dose groups of 0.1, 0.2, and 0.3 mg/kg (up to 20 mg). Anesthetic care was not otherwise changed. Venous blood was obtained for 4 days, for stereoselective determination of methadone and metabolites. Pain assessments were made each morning. Daily and total opioid consumption was determined. Perioperative opioid consumption and pain was determined in a second cohort, which was matched to age, sex, race, ethnicity, surgical procedure, and length of stay, but not receiving methadone. The final methadone study cohort was 31 adolescents (14 ± 2 yr, range 10-18) undergoing major spine surgery for a diagnosis of scoliosis. Methadone pharmacokinetics were linear over the dose range 0.1-0.3 mg/kg. Disposition was stereoselective. Methadone administration did not dose-dependently affect postoperative pain scores, and did not dose-dependently decrease daily or total postoperative opioid consumption in spinal fusion patients. Methadone enantiomer disposition in adolescents undergoing surgery was similar to that in healthy adults.

Successful Empirical Antifungal Therapy of Intravenous Itraconazole with Pharmacokinetic Evidence in Pediatric Cancer Patients Undergoing Hematopoietic Stem Cell Transplantation

Abstract 3019▪FN2▪This icon denotes a clinically relevant abstract Introduction:Itraconazole is a widely used antifungal agent with a broad spectrum of activity, but pharmacokinetics has large inter- and intra-individual variability. The optimal usages of itraconazole from numerous pharmacokinetic studies have been proposed in adults. However, application of itraconazole in pediatric patients is limited since its pharmacokinetics in children is less known. This study assessed the efficacy of the empirical use of intravenous (IV) itraconazole in pediatric patients undergoing hematopoietic stem cell transplantation and investigated the pharmacokinetics of repeated-doses of itraconazole and its active metabolite hydroxyitraconazole. Patients & Methods:Efficacy was evaluated in 85 patients undergoing hematopoietic stem cell transplantation (32 allogeneic, 53 autologous). Oral itraconazole prophylaxis (2.5 mg/kg twice daily) was started on the day -2 of the conditioning chemotherapy. Itraconazole was changed to IV form in patients with persistent neutropenic fever over 2 days (5 mg/kg twice daily for 2 days for induction and 5 mg/kg daily for maintenance). Itraconazole was continued until the absolute neutrophil count was over 1, 000/uL, the development of fungal disease, the development of unacceptable drug toxicity or death, or the withdrawal from study. Empirical treatment was considered successful if all of the following criteria were met: successful treatment of baseline fungal infection, absence of breakthrough fungal infection, survival for 7 days after therapy, resolution of neutropenic fever, and no premature discontinuation due to toxicity or lack of efficacy. Full pharmacokinetic study was conducted in 6 patients (1 allogeneic, 5 autologous). For pharmacokinetic study, trough level during oral itraconazole was measured with blood collected before the 5th dose. Blood for trough level of IV administrations were sampled prior to every induction doses and 1–5th IV maintenance doses. For area under the plasma concentration-time curve (AUC) analysis, serial blood samples were collected prior to the 3rd IV maintenance infusion, and 1, 2, 4, 8, 12, 24hr after the infusion. Plasma concentrations of itraconazole and hydroxyitraconazole were determined using a validated HPLC method. Results:The overall success rates fulfilling all criteria were 32.9%. There was no patient with baseline fungal infection, but 1 patient with breakthrough fungal infection, and all patients were survived for 7 days after discontinuation of itraconazole. The rates of resolution of fever in 48 hours after itraconazole were 32.9%, and premature discontinuation occurred in 23.5% of patients. The causes of discontinuation were persistent fever in 17 (20%) patients, and nausea or vomiting in 3 (3.5%) patients. There was no Grade 3–4 toxicity associated with itraconazole.The mean trough plasma concentration of itraconazole after oral prophylaxis and intravenous induction were 577.2 and 1413.3 ng/ml. The median pharmacokinetic values for steady-state itraconazole and hydroxyitraconazole, respectively, were as follows: AUC form 0 to 24 h (AUC24), 42.8 and 63.1 μg · h/ml; clearance (CL) at steady state, 63.5 and 38.5 ml/min; and volume of distribution at steady state (Vdss), 201.8 and 711.2 L. According to the results, sufficient trough level was achieved during oral prophylaxis, and levels were rising rapidly by successive IV inductions so that the steady concentration of twice the level of oral itraconazole was maintained during IV maintenance with this empirical strategy.Compared with a previous pediatric single intravenous study, lower CL for itraconazole and metabolite were observed, which can be explained by saturable drug metabolism with multiple dosing, as found in adults. Dose adjusted steady state AUC24 of itraconazole and metabolite were about twice of those in the adults, and relatively smaller clearance of study drug needs to be considered for pediatric use. Conclusion:IV itraconazole was effective and safe as an empirical antifungal agent in pediatric patients undergoing hematopoietic stem cell transplantation, and this is considered to be due to the fast and satisfactory increase in the drug concentration by switching oral prophylaxis to IV itraconazole. There are considerable pharmacokinetic differences between children and adults with respect to itraconazole and its active metabolite, which should be considered with pediatric usages. Disclosures:No relevant conflicts of interest to declare.

Population pharmacokinetics of atazanavir/ritonavir in HIV-1-infected children and adolescents.

To investigate atazanavir (ATV) population pharmacokinetics in children and adolescents, establish factors that influence ATV pharmacokinetics and investigate the ATV exposure after recommended doses. Atazanavir concentrations were measured in 51 children/adolescents during a mean therapeutic monitoring follow up of 6.6 months. A total of 151 ATV plasma concentrations were obtained, and a population pharmacokinetic model was developed with NONMEM. Patients received ATV alone or boosted with ritonavir. Atazanavir pharmacokinetics was best described by a one-compartment model with first-order absorption and elimination. The effect of bodyweight was added on both apparent elimination clearance (CL/F) and volume of distribution using allometric scaling. Atazanavir CL/F was reduced by ritonavir by 45%. Tenofovir disoproxil fumarate (TDF) co-medication (300 mg) increased significantly by 25% the atazanavir/ritonavir (ATV/r) CL/F. Mean ATV/r CL/F values with or without TDF were 8.9 and 7.1 L h(-1) (70 kg)(-1), respectively. With the recommended 250/100 mg and 300/100 mg ATV/r doses, the exposure was higher than the mean adult steady-state exposure in the bodyweight range of 32-50 kg. To target the mean adult exposure, children should receive the following once-daily ATV/r dose: 200/100 mg from 25 to 39 kg, 250/100 mg from 39 to 50 kg and 300/100 mg above 50 kg. When 300 mg TDF is co-administered, children should receive (ATV/r) at 250/100 mg between 35 and 39 kg, then 300/100 mg over 39 kg.

Physiologically based pharmacokinetic modelling of high- and low-dose etoposide: from adults to children

To evaluate the ability of a physiology-based pharmacokinetic (PBPK) model to predict the systemic drug exposure of high- and low-dose etoposide in children from a model developed with adult data. Simulations were performed with PK-Sim(®) (Bayer Technology Services). Model development was done using data from adult patients receiving etoposide in a conventional and high-dose polychemotherapy regimen before stem cell transplantation. Michaelis-Menten parameters from in vitro experiments reported in the literature were applied to describe the metabolism and excretion processes by P450 enzymes and transporters. The model was scaled down to children and compared to etoposide plasma concentrations in this age group. Simulated plasma concentration-time courses of protein-bound and free etoposide in adults for high- and low-dose schedules agreed with the observed data. Mean simulated total clearance of high- and low-dose etoposide was 0.70ml/min/kg (Cl(observed): 0.70ml/min/kg) versus 0.50ml/min/kg (Cl(observed): 0.60 ml/min/kg), respectively. Integrated Michaelis-Menten kinetics was adequately transformed to age-related pharmacokinetics in children. Predictions of the pharmacokinetics in different age groups were also in good agreement with observed data. Drug interactions triggered by P-glycoprotein inhibitors or nephrotoxic drugs can also be elucidated. The PBPK model matched the pharmacokinetics in different dosing regimens in adults. Furthermore, the scaling procedure from the adult model to children provides useful predictions for paediatric patients. Comedication with drugs influencing the metabolism and excretion has to be taken into account. This approach could be useful for planning pharmacokinetic studies in children.

Factors influencing carbamazepine pharmacokinetics in children and adults: population pharmacokinetic analysis

The aim of the present study was to build population pharmacokinetic models for the clearance of carbamazepine (CBZ) in two separate populations of Serbian patients with epilepsy, children and adults. Analysis was performed using 114 and 53 steady-state concentrations of CBZ collected from 98 children and 53 adult epileptic patients, respectively. Mean values of total body weight and age were 31 ± 13 kg and 8 ± 3 years in the population of children, and 67 ± 13 kg and 32 ± 15 years in the population of adults. The one-compartment model with first order elimination and without absorption was used from the PREDPP (Prediction for Observation Population Pharmacokinetics) library of NONMEM software. The derived final models of CBZ clearance were similar in the target populations. The most important factors which affected typical mean value of CBZ clearance in both populations studied were age of the patients and total daily dose; the CBZ clearance linearly followed increase of these factors. However, the influence of the patients' age was almost 3.4 times higher in the pediatric population than that in adults while the influence of total daily dose of CBZ is similar. On the other hand, final model in the adult population revealed also influence of concomitant therapy with phenobarbital (PB). The magnitude of this effect was +1.61 l h-1. The pharmacokinetic models obtained were validated in groups of 18 children and 13 adults with epilepsy. The derived models describe well CBZ clearance in terms of Serbian pediatric and adult epileptic patient characteristics, offering a basis for rational individualization of CBZ dosage regimens.

Abstract 5447: Investigating the relationship between pharmacogenetic variation in ABCB1 and ABCC2 tagSNPs and actinomycin D pharmacokinetics in children

Abstract Actinomycin D (Act D) has been used successfully to treat adult and childhood cancers for over 30 years. It continues to play a key role in the treatment of Wilms tumour patients, with 5-year survival rates &amp;gt;80% currently observed. While treatment is generally well tolerated, veno-occlusive disease (VOD) is a potentially life-threatening side effect observed in 1.7-13.5% of patients. Dose-intensity of Act D treatment has been highlighted as a possible risk-factor for VOD in paediatric patient populations. ATP binding cassette (ABC) transporters are expressed throughout the body to protect against exogenous compounds. In the liver and kidney, ABC transporters facilitate the removal of compounds via biliary or renal excretion and have previously been shown to play a major role in the transport of anti-cancer agents such as doxorubicin and irinotecan. Common single nucleotide polymorphisms (SNPs) for these transporters have been shown to alter clinical exposure to various anti-cancer agents. We have therefore carried out translational and clinical studies focusing on Act D pharmacokinetics in Wilms tumour patients and pharmacogenetic variation in key ABC transporters. Initial experiments were carried out to determine the potential importance of ABC transporter expression on the in vitro activity and transport of Act D, using MDCKII-WT alongside ABCB1, ABCG2 and ABCC2 over-expressing cell lines. Growth inhibition (GI) and intracellular accumulation experiments were carried out over a range of Act D concentrations (0-10µM). Pharmacokinetic analysis of samples obtained from patients receiving Act D was carried out using a validated LC/MS method and blood samples were obtained from all patients for pharmacogenetic analysis. Finally, the International HapMap database was used to determine tagSNPs for ABCB1 and ABCC2 with minor allele frequencies of greater than 0.1 in a Caucasian population, allowing the link between ABCB1 and ABCC2 haplotypes and Act D exposure to be investigated. GI experiments indicated a 40-fold decrease in Act D sensitivity in cells over-expressing ABCB1 (GI50: 0.85µM) and a 3-fold decrease in cells over-expressing ABCC2 (GI50: 0.06µM) compared to the control cell line (GI50: 0.02µM). Higher intracellular levels of Act D (normalized per mg protein) were observed in the WT parental cell line (650nM) as compared to those over-expressing ABCB1 (215nM), following a 6h incubation with 2µM Act D. This effect was abrogated by use of the ABCB1 inhibitor verapamil. Pharmacokinetic analysis of samples obtained from 56 patients indicated a large inter-patient variability in Act D exposure (AUC0-24h range: 1.6 – 11.4 µg/ml.min). Ongoing investigations into pharmacogenetic variation in ABCB1 and ABCC2 tagSNPs in these patients provide novel preliminary data relating to links between ABCB1 and ABCC2 haplotypes and Act D exposure in children with cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5447. doi:10.1158/1538-7445.AM2011-5447

Exploring the pharmacokinetics of oral ketamine in children undergoing burns procedures

The aim of this study was to describe ketamine pharmacokinetics when administered orally to children suffering from burn injury in >10% body surface area. Children (n = 20) were given ketamine 5 or 10 mg·kg(-1) orally 20 min prior to presentation for surgical procedures. Anesthesia during procedures was maintained with a volatile anesthetic agent. Additional intravenous ketamine was given as a bolus (0.5-1 mg·kg(-1)) to nine children during the procedure while a further nine children were given an infusion (0.1 mg·kg(-1)·h(-1)) continued for 4-19 h after the procedure. Blood was assayed for ketamine and norketamine on six occasions over the study duration of 8-24 h. Data were pooled with those from an earlier analysis (621 observations from 70 subjects). An additional time-concentration profile from an adult given oral ketamine was gleaned from the literature (17 observations). A population analysis was undertaken using nonlinear mixed-effects models. The pooled analysis comprised 852 observations from 91 subjects. There were 20 children who presented for procedures related to burns management (age 3.5 sd 2.1 years, range 1-8 years; weight 14.7 sd 4.9 kg, range 7.9-25 kg), and these children contributed 214 ketamine and norketamine observations. A two-compartment (central, peripheral) linear disposition model fitted data better than a one-compartment model. Bioavailability of the oral formulation was 0.45 (90% CI 0.33, 0.58). Absorption half-time was 59 (90% CI 29.4, 109.2) min and had high between-subject variability (BSV 148%). Population parameter estimates, standardized to a 70-kg person, were central volume 21.1 (BSV 47.1%) l·70 kg(-1), peripheral volume of distribution 109 (27.5%) l·70 kg(-1), clearance 81.3 (46.1%) l·h(-1)·70 kg(-1), and inter-compartment clearance 259 (50.1%) l·h(-1)·70 kg(-1). Under the assumption that all ketamine was converted to norketamine, the volume of the metabolite was 151.9 (BSV 39.1%) l·70 kg(-1) with an elimination clearance of 64.4 (BSV 63.4%) l·h(-1) ·70 kg(-1) and a rate constant for intermediate compartments of 26.2 (BSV 52.1%) h(-1)·70 kg(-1). The ketamine pharmacokinetics in children with minor burns are similar to those without burns. The peak ratio of norketamine/ketamine at 1 h is 2.8 after oral administration allowing an analgesic contribution from the metabolite at this time. There is low relative bioavailability (<0.5) and slow variable absorption. Dose simulation in a child (3.5 years, 15 kg) suggests a dose regimen of oral ketamine 10 mg·kg(-1) followed by intravenous ketamine 1 mg·kg(-1) i.v. with the advent of short-duration surgical dressing change at 45 min.