Age-dependent Pharmacokinetics Research Articles

Modelling Shows the Negative Impact of Age Dependent Pharmacokinetics on the Efficacy of Oxytetracycline in Young Steers.

The effect of age dependent pharmacokinetics (PK) on the clinical efficacy of oxytetracycline (OTC) against Bovine Respiratory Disease (BRD) in beef cattle was studied, using a Physiologically Based Pharmacokinetic (PBPK) model. The model includes a bodyweight dependent renal clearance. To mimic/reproduce the long terminal half-live a bone forming tissue compartment was considered. Data for the development, calibration and validation of the model were obtained from public literature. To integrate the PK with the pharmacodynamics (PD) of OTC, Monte Carlo simulations were performed using this PBPK model to predict time-concentration curves for two commonly used dosing regimens of short-acting and long-acting injectable OTC formulations in virtual populations of 5,000 steer calves of 100 kg and 400 kg. These curves were then used to calculate the value of the PKPD index for OTC, which is the ratio of the area under the concentration-time curve for 24 h (AUC24h) over the minimum inhibitory concentration (MIC) of the target pathogen (AUC24h/MIC). The MIC values were for Mannheimia haemolytica, the dose-limiting pathogen for BRD. This integration of PBPK and PD for OTC used for the treatment of BRD in calves indicated that the Probability of Target Attainment (PTA) was sufficient for efficacy in calves of 400 kg, but insufficient for calves of 100 kg, when using a long acting dosing regimen of 20 mg/kg BW, twice, with a 48-h interval. The use of a dosing regimen of 10 mg/kg BW/day for 4 days predicted sufficient PTAs in both age groups.

Anticoagulation in Pediatric Patients.

Special aspects of anticoagulation in children include the different epidemiology of thrombosis, developmental changes in the coagulation system, age-dependent pharmacokinetics of anticoagulants, risk of bleeding, and practical hurdles to anticoagulation. The classical anticoagulants so far used in children have several limitations, resulting in the need for regular monitoring. The pharmacological properties of direct oral anticoagulants (DOACs) and the special challenges of anticoagulation in children make the DOACs particularly attractive for children. All DOACs have pediatric development programs, targeting various indications for prevention and treatment of thrombosis. Child-appropriate formulations have been developed, age-specific dosing information generated, and safety and efficacy evaluated in ongoing phase 3 trials. Rivaroxaban and dabigatran have already been authorized for children for treatment of acute venous thrombosis and for extended secondary prevention. Their safety and efficacy have been demonstrated comparable to that of standard-of-care anticoagulants, without need for monitoring. Further studies are ongoing, which are expected to lead to pediatric authorizations of DOACs for primary venous thromboembolic event prevention in some high-risk settings. More real-life data will be necessary from postmarketing studies and registries to complement the evidence base for DOAC use in children, particularly in the youngest age groups and special disease populations.

Ontogeny of Hepatic Transporters and Drug-Metabolizing Enzymes in Humans and in Nonclinical Species.

The liver represents a major eliminating and detoxifying organ, determining exposure to endogenous compounds, drugs, and other xenobiotics. Drug transporters (DTs) and drug-metabolizing enzymes (DMEs) are key determinants of disposition, efficacy, and toxicity of drugs. Changes in their mRNA and protein expression levels and associated functional activity between the perinatal period until adulthood impact drug disposition. However, high-resolution ontogeny profiles for hepatic DTs and DMEs in nonclinical species and humans are lacking. Meanwhile, increasing use of physiologically based pharmacokinetic (PBPK) models necessitates availability of underlying ontogeny profiles to reliably predict drug exposure in children. In addition, understanding of species similarities and differences in DT/DME ontogeny is crucial for selecting the most appropriate animal species when studying the impact of development on pharmacokinetics. Cross-species ontogeny mapping is also required for adequate translation of drug disposition data in developing nonclinical species to humans. This review presents a quantitative cross-species compilation of the ontogeny of DTs and DMEs relevant to hepatic drug disposition. A comprehensive literature search was conducted on PubMed Central: Tables and graphs (often after digitization) in original manuscripts were used to extract ontogeny data. Data from independent studies were standardized and normalized before being compiled in graphs and tables for further interpretation. New insights gained from these high-resolution ontogeny profiles will be indispensable to understand cross-species differences in maturation of hepatic DTs and DMEs. Integration of these ontogeny data into PBPK models will support improved predictions of pediatric hepatic drug disposition processes. SIGNIFICANCE STATEMENT: Hepatic drug transporters (DTs) and drug-metabolizing enzymes (DMEs) play pivotal roles in hepatic drug disposition. Developmental changes in expression levels and activities of these proteins drive age-dependent pharmacokinetics. This review compiles the currently available ontogeny profiles of DTs and DMEs expressed in livers of humans and nonclinical species, enabling robust interpretation of age-related changes in drug disposition and ultimately optimization of pediatric drug therapy.

Area-under-the-Curve-Based Mycophenolate Mofetil Dosage May Contribute to Decrease the Incidence of Graft-versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation in Pediatric Patients.

Acute graft-versus-host disease (GvHD) remains the second leading cause of death, after disease relapse, in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). The medical records of 112 pediatric patients who underwent allo-HSCT from matched unrelated and haploidentical donors were analyzed. Patients were divided into two groups, according to the GvHD prophylactic regimen used. In the control group, GvHD prophylaxis consisted of cyclosporine A (CsA) and methotrexate (MTX) or CsA and mycophenolate mofetil (MMF) at a standard daily dose of 30 mg/kg. All subjects in the study group received tacrolimus (FK506) and MMF. In this group, MMF was subjected to therapeutic drug monitoring (TDM) through mycophenolic acid (MPA) area under the curve AUC0–12. We found a statistically significant difference in both overall acute GvHD (p < 0.0001) and overall chronic GvHD (p < 0.05) incidence between the study and the control group. The initial daily MMF dose and the age at transplant in the study group proved to be inversely correlated (r = −0.523, p < 0.0001). The children under six years of age required a significantly higher daily MMF dose (p < 0.008). This study showed that pharmacological monitoring of MPA AUC0–12 concentration allowed a reduction in the incidence of acute and chronic GvHD. MMF showed age-dependent pharmacokinetics due to greater drug clearance in younger children.

Impact of Older Age on the Exposure of Paclitaxel: a Population Pharmacokinetic Study.

Limited available data suggest that older patients are more prone to develop paclitaxel-induced toxicity than their younger peers. It remains unclear whether this is related to age-dependent pharmacokinetics (PK) of paclitaxel. Primary objective of this study was to determine the influence of older age on the PK of paclitaxel. PK data of patients aged ≥70years who received paclitaxel intravenously at the Netherlands Cancer Institute (NKI) and the Radboud University Medical Center between September 2012 and May 2017 were collected. These prospectively collected data were pooled with previously published databases from multiple clinical trials conducted at the NKI and Erasmus MC Cancer Institute. A previously developed 3-compartment population PK model with saturable distribution and elimination was used to describe paclitaxel plasma concentration-time data. Hereafter, influence of age on paclitaxel PK was assessed in a previously established full covariate model. In total, paclitaxel PK data from 684 patients were available, consisting of 166 patients ≥70years (24%). Median age of the cohort was 61years (range 18 to 84years). The impact of age, either treated as a continuous or dichotomous covariate (<70 versus ≥70years), on the elimination of paclitaxel was only marginal but statistically significant (both p < 0.001 with no clinically relevant decrease in interindividual variability). For a typical patient, maximal elimination capacity decreased by only 5% for a 10-year increment of age. In this extensive multi-center dataset, which included a considerable number of older patients, older age had no clinically relevant impact on paclitaxel PK.

Effect of Age on The Hepatocellularity Number for Wistar rats.

Recently there has been a substantial increase in the number of juvenile animal toxicity studies that are conducted to support pediatric drug safety evaluation. Adequate design of juvenile toxicity studies in rats, for instance with respect to dose levels per age group, requires an understanding of age-dependent pharmacokinetics. In vitro-in vivo extrapolation (IVIVE) and physiologically based pharmacokinetic (PBPK) modeling can help to anticipate age-dependent drug exposure in juvenile toxicity studies provided age-dependent profiles for animal physiology and scaling factors are available. For instance, when hepatocytes are used to predict hepatic drug clearance, the hepatocellularity (number of hepatocytes per gram liver, HPGL) is required as one of the scaling factors. Although HPGL is known for adult rats, information on the influence of age on HPGL is missing. The present work profiles the hepatocellularity number in male Wistar rats as a function of age. Using the NADPH-cytochrome P450 reductase (NCR) activity method, the mean HPGL for the adult rat (8 weeks) was 104 × 10(6) cells/gram liver (relative standard deviation 17%). This value was calculated as a ratio between NRC activities in liver homogenates and suspended hepatocytes. The HPGL values were significantly higher (p <0.001) for rat pups until 3 weeks of age compared with adults. Our results revealed that the HPGL value showed a rapid decrease after 3 weeks (end of weaning), essentially reaching adult values by 4 weeks. This age-dependent HPGL profile will be instrumental for hepatic drug clearance prediction when designing juvenile toxicity studies in Wistar rats.

HEPATIC TRANSPORTER PROTEIN EXPRESSION IN FETUSES, NEONATES AND YOUNG INFANTS

BackgroundTransporters are membrane-bound proteins involved in trafficking substrates (e.g. drugs) across membranes of among others hepatocytes. Limited data exists on the developmental expression. We aim to study protein expression of transporters in fetal, neonatal and infantile liver.MethodsTransporter protein expression (ABCB1, ABCG2, ABCC2, ABCC3, BSEP, GLUT1, MCT1, OATP1B1, OATP2B1, OCTN2) was quantified using UPLC-MS-MS, on snap-frozen post mortem livers (Erasmus MC tissuebank) and adult control livers (UMC-Groningen). Protein expression was determined in isolated crude membrane and quantified using stable-isotope-labelled peptides. Age groups were compared with Mann-Whitney test and post hoc Bonferroni-correction (significance p&lt;0.05). Data was compared to mRNA expression.Results25 liver samples were studied. 10 fetal [median gestational age 23.2 weeks (range 16.4–37.9)], 12 pediatric [postnatal age 1 week (0–11.4) and gestational age at birth 35.1 weeks (27.1–41.0)], and 3 adult liver samples. ABCB1, ABCC2, OATP1B1, OATP2B1 expressions appeared similar in fetuses, pediatrics and adults. MCT1 expression was similar in fetuses and adults, but higher in pediatrics. BSEP expression was lower in fetuses and pediatrics than in adults. ABCC3 expression was lower level in fetuses than in adults, but not in pediatrics compared to adults. ABCG2, GLUT1, OCTN2 expressions were higher in fetuses than in adults, but similar in pediatrics and adults.ConclusionHepatic transporters appear in different developmental expression profiles. ABCB1, ABCC2, OATP1B1 protein expression appears stable. This contrast previous mRNA expression data, which showed lower expression in fetus/neonate. The age-related differences in transporter expression may result in age-dependent pharmacokinetics of substrates.

Meta-analysis of hepatic cytochrome P450 ontogeny to underwrite the prediction of pediatric pharmacokinetics using physiologically based pharmacokinetic modeling.

The accurate prediction of pharmacokinetics (PK) is fundamental to underwriting safety and efficacy in pediatric clinical trials; age-dependent PK may be observed with pediatrics because of the growth and maturation processes that occur during development. Understanding the ontogeny of drug-metabolizing enzymes is a critical enabler for pediatric PK prediction, as enzyme expression or activity may change with age. Although ontogeny functions for the cytochrome P450s (CYPs) have been developed, disconnects between ontogeny functions for the same CYP may exist, depending on whether the functions were derived from in vitro or in vivo data. This report describes the development of ontogeny functions for all the major hepatic CYPs based on in vitro or in vivo data; these ontogeny functions were subsequently incorporated into a physiologically based pharmacokinetic model and evaluated. Pediatric PK predictions based on in vivo-derived ontogeny functions performed markedly better than those developed from in vitro data for intravenous (100% versus 51% within 2-fold, respectively) and oral (98% versus 67%, respectively) dosing. The verified models were then applied to complex pediatric scenarios involving active metabolites, CYP polymorphisms and physiological changes because of critical illness; the models reasonably explained the observed age-dependent changes in pediatric PK.

A human life-stage physiologically based pharmacokinetic and pharmacodynamic model for chlorpyrifos: Development and validation

Sensitivity to some chemicals in animals and humans are known to vary with age. Age-related changes in sensitivity to chlorpyrifos have been reported in animal models. A life-stage physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model was developed to predict disposition of chlorpyrifos and its metabolites, chlorpyrifos-oxon (the ultimate toxicant) and 3,5,6-trichloro-2-pyridinol (TCPy), as well as B-esterase inhibition by chlorpyrifos-oxon in humans. In this model, previously measured age-dependent metabolism of chlorpyrifos and chlorpyrifos-oxon were integrated into age-related descriptions of human anatomy and physiology. The life-stage PBPK/PD model was calibrated and tested against controlled adult human exposure studies. Simulations suggest age-dependent pharmacokinetics and response may exist. At oral doses ⩾0.6mg/kg of chlorpyrifos (100- to 1000-fold higher than environmental exposure levels), 6months old children are predicted to have higher levels of chlorpyrifos-oxon in blood and higher levels of red blood cell cholinesterase inhibition compared to adults from equivalent doses. At lower doses more relevant to environmental exposures, simulations predict that adults will have slightly higher levels of chlorpyrifos-oxon in blood and greater cholinesterase inhibition. This model provides a computational framework for age-comparative simulations that can be utilized to predict chlorpyrifos disposition and biological response over various postnatal life stages.

Abstract 2219: The European Paediatric Oncology off-patent medicines Consortium (EPOC) pharmacokinetic/pharmacodynamic study of doxorubicin.

Abstract Background: Doxorubicin is a key component of a number of treatment regimens used in paediatric oncology despite the very limited pharmacology data on which current dosing regimens are based. In recognition of this, doxorubicin was included on the EMA priority list for paediatric off-patent medicines for which more information was required, particularly on pharmacokinetics. Methods: The EPOC consortium, with collaborators in the UK, France, Germany and Italy, performs paediatric oncology pharmacology clinical trials. This study is a multicentre, multinational phase II pharmacokinetic study investigating age-dependency in the clearance of doxorubicin in children with solid tumours and leukaemia. All patients are being treated according to a tumour-specific national or European therapeutic trial. The aim was to recruit 100 patients, with a particular focus on children less than 3 years. The plasma levels of markers such as troponin T, are being measured to evaluate their use as clinical markers for cardiotoxicity. Data is being analysed using a population pharmacokinetic approach and the impact of pharmacogenetics is being investigated. Results: The study has been open to recruitment in 20 clinical centres across the four participating countries. The target 100 patients have been recruited from all the contributing study protocols, with 26 patients less than 3 years. Of these 26 patients, 5 patients are less than 1 year. An interim pharmacokinetic analysis has been performed on the data from the first 31 patients. The results of the analysis are consistent with the primary aims of the overall study. Conclusion: The data generated during this study should provide comparative data on the age-dependent pharmacokinetics and pharmacogenetics of doxorubicin. The results will contribute to optimising the safe use of doxorubicin in children with cancer. Acknowledgements: Study funded under the seventh framework programme of the European Commission (FP7) Citation Format: Alan V. Boddy, Alison J. Steel, Joachim Boos, Miriam Krischke, Nicolas Andre, Gianni Bisogno, Georg Hempel, Gerlind Bode, Maurizio D'Incalci, Nina Kontny. The European Paediatric Oncology off-patent medicines Consortium (EPOC) pharmacokinetic/pharmacodynamic study of doxorubicin. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2219. doi:10.1158/1538-7445.AM2013-2219

Prediction and evaluation of route dependent dosimetry of BPA in rats at different life stages using a physiologically based pharmacokinetic model

Bisphenol A (BPA) has received considerable attention throughout the last decade due to its widespread use in consumer products. For the first time a physiologically based pharmacokinetic (PBPK) model was developed in neonatal and adult rats to quantitatively evaluate age-dependent pharmacokinetics of BPA and its phase II metabolites. The PBPK model was calibrated in adult rats using studies on BPA metabolism and excretion in the liver and gastrointestinal tract, and pharmacokinetic data with BPA in adult rats. For immature rats the hepatic and gastrointestinal metabolism of BPA was inferred from studies on the maturation of phase II enzymes coupled with serum time course data in pups. The calibrated model predicted the measured serum concentrations of BPA and BPA conjugates after administration of 100μg/kg of d6-BPA in adult rats (oral gavage and intravenous administration) and postnatal days 3, 10, and 21 pups (oral gavage). The observed age-dependent BPA serum concentrations were partially attributed to the immature metabolic capacity of pups. A comparison of the dosimetry of BPA across immature rats and monkeys suggests that dose adjustments would be necessary to extrapolate toxicity studies from neonatal rats to infant humans.

Concentrations of Stiripentol in Children and Adults With Epilepsy

Stiripentol (STP) was approved as an orphan drug in 2007 in Europe as adjunctive therapy with valproic acid (VPA) and clobazam (CLB) for Dravet syndrome. Dravet syndrome is a highly pharmacoresistant form of epilepsy, which starts in early childhood. Data about STP pharmacokinetics and interactions are still limited and in part inconsistent. The aim of our study was to analyze the effect of age, gender, daily STP dose per body weight (milligrams per kilogram), VPA, CLB, and enzyme-inducing antiepileptic drugs on STP concentration-to-dose ratio (CDR), STP clearance, and STP trough concentrations. Retrospectively, 220 STP serum concentrations in 75 patients from 3 German Epilepsy Centers were analyzed. Analysis of variance, regression analysis, and generalized estimating equations were used for statistical analysis. Our findings confirm the nonlinear STP pharmacokinetics. At steady state, STP CDR increased with daily STP doses. Compared with patients older than 12 years, STP concentrations were decreased by 39.6% in children aged 6-12 years (P < 0.001) and by 57.5% in children younger than 6 years (P < 0.001). Phenobarbital and phenytoin decreased STP concentrations by 63.2%. This effect was highly significant (P < 0.001), despite the small number of patients (n = 7) treated with phenobarbital or phenytoin. VPA had no significant effect on STP serum concentrations, whereas STP serum concentrations were moderately but significantly increased by CLB (24.6%, P = 0.011). Therapeutic drug monitoring of STP seems to be useful because of the wide variation of STP CDR, the nonlinear concentration-to-dose relationship, age-dependent pharmacokinetics, and drug-drug interactions.

Development of a Physiologically Based Model for Oseltamivir and Simulation of Pharmacokinetics in Neonates and Infants

Physiologically based pharmacokinetic (PBPK) modelling can assist in the development of drug therapies and regimens suitable for challenging patient populations such as very young children. This study describes a strategy employing PBPK models to investigate the intravenous use of the neuraminidase inhibitor oseltamivir in infants and neonates with influenza. Models of marmoset monkeys and humans were constructed for oseltamivir and its active metabolite oseltamivir carboxylate (OC). These models incorporated physicochemical properties and in vitro metabolism data into mechanistic representations of pharmacokinetic processes. Modelled processes included absorption, whole-body distribution, renal clearance, metabolic conversion of the pro-drug, permeability-limited hepatic disposition of OC and age dependencies for all of these processes. Models were refined after comparison of simulations in monkeys with plasma and liver concentrations measured in adult and newborn marmosets after intravenous and oral dosing. Then simulations with a human model were compared with clinical data taken from intravenous and oral studies in healthy adults and oral studies in infants and neonates. Finally, exposures after intravenous dosing in neonates were predicted. Good simulations in adult marmosets could be obtained after model optimizations for pro-drug conversion, hepatic disposition of OC and renal clearance. After adjustment for age dependencies, including reductions in liver enzyme expression and renal function, the model simulations matched the trend for increased exposures in newborn marmosets compared with those in adults. For adult humans, simulated and observed data after both intravenous and oral dosing showed good agreement and although the data are currently limited, simulations in 1-year-olds and neonates are in reasonable agreement with published results for oral doses. Simulated intravenous infusion plasma profiles in neonates deliver therapeutic concentrations of OC that closely mimic the oral profiles, with 3-fold higher exposures of oseltamivir than those observed with the same oral dose. This work exemplifies the utility of PBPK models in predicting pharmacokinetics in the very young. Simulations showed agreement with a wide range of observational data, indicating that the processes determining the age-dependent pharmacokinetics of oseltamivir are well described.

Age-dependent pharmacokinetics and effect of roscovitine on Cdk5 and Erk1/2 in the rat brain

Roscovitine is a cyclin-dependent kinase (Cdk) and signal-regulated kinase (Erk1/2) inhibitor that has been shown to be effective against several cancer types including brain tumors. We have shown previously that roscovitine crosses the blood brain barrier (BBB) and is rapidly eliminated from both plasma and brain in adult rats. However, age-dependent kinetics and its effects on the brain have not been reported. In the present study, we investigated the pharmacokinetics of roscovitine in adult and in 14 days old rats after the administration of a single dose of 25 mg/kg. Moreover, we studied the effect of the drug on Cdk5 and Erk1/2 activities in three brain regions, hippocampus, frontal cortex and cerebellum. The pharmacokinetics of roscovitine followed a two-compartment model in both plasma and brain in both adult and young rats. The terminal elimination half-life was 7 h in brain as well as in plasma in rat pups compared to <0.5 h observed in adult rats. Brain exposure expressed as AUC brain/AUC plasma was 100% in rat pups compared to 20% found in adult rats. Roscovitine induced a significant Cdk5 inhibition and significant Erk1/2 activation in all studied pups brain regions at 2 h. This is the first study describing age-dependent pharmacokinetics of roscovitine and showing the high brain exposure of infant rats to the drug. Thus, roscovitine may be a promising candidate for the treatment of brain tumors in children.

Age-Dependent Pharmacokinetics of Lansoprazole in Neonates and Infants

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

Etoposide pharmacokinetics in children treated for acute myeloid leukemia

We studied the pharmacokinetics of etoposide in 45 children treated for newly diagnosed acute myeloid leukemia. Etoposide, 100 mg/m body surface area/24 h, was administered by 96-h continuous intravenous infusion. Concomitantly, the children received cytarabine 200 mg/m/24 h by intravenous infusion and 6-thioguanine 100 mg/m twice daily orally. Median total body clearance in children 0.5-1.8 (n=4) and 2.3-17.7 years old (n=36) without Down's syndrome was 17.1 and 17.6 ml/min/m, respectively (P=0.96). Five children with Down's syndrome had a median clearance of 13.6 ml/min/m (P=0.067 compared with non-Down's syndrome children). Eighteen of the children received a second identical treatment course 3-4 weeks later; there was a significant correlation between individual clearance values (rho=0.56; P=0.017). We found no significant correlation between etoposide pharmacokinetics and the remission rate or the relapse rate. In conclusion, our findings indicate that special dose-calculation guidelines for infants above 3 months old are not substantiated by age-dependent pharmacokinetics of etoposide. Down's syndrome children might be candidates for dose reduction if our data are confirmed in larger numbers of patients. Low course-to-course variability indicates that pharmacokinetically guided dosing of etoposide might be clinically relevant, if larger studies can demonstrate that this approach decreases toxicity or increases response rates.

Linear Pharmacokinetics of Micafungin and Its Active Metabolites in Japanese Pediatric Patients with Fungal Infections

The objective of this study was to propose the appropriate dosage regimen of micafungin for pediatric use, considering the effects of dose-linearity, age and other cofactors on the pharmacokinetics. Pharmacokinetic analysis of micafungin and its active metabolites (M1 and M2) after intravenous infusion at doses of 1 to 3 mg/kg was conducted for 19 Japanese pediatric patients (3 infants, 7 toddlers, and 9 pupils) with deep mycosis caused by either Aspergillus or Candida species. One patient was given the maximum dose of 6 mg/kg. The Cmax of micafungin increased in proportion to the dose. The mean values (S.D.) were 5.03 (2.33), 10.25 (4.45), 14.8 (5.52) and 21.1 microg/ml at 1, 2 , 3 and 6 mg/kg, respectively. These parameters were comparable to those seen in adults when the parameter was normalized by body weight. The elimination half life (t1/2) of micafungin over the dose range was apparently constant with the value of 13.1 h. There was no difference between the age groups observed. In fact, the metabolite concentrations were almost the same as those obtained for non-pediatric patients. Thus, micafungin showed the same dose-proportional pharmacokinetics in pediatric patients as it did in adults. No age dependent pharmacokinetics were observed in this study. It was concluded that the body weight adjustment was adequate for the treatment of micafungin in pediatric patients.

Conventional and Atypical Antipsychotics in the Elderly

Psychoses are major mental disorders marked by derangement of personality and loss of contact with reality, and are common in the elderly. Various hypotheses suggest the pivotal role of abnormal neurotransmitter and neuropeptide systems in psychotic patients, the most studied of which are the dopaminergic, serotonergic and glutamatergic systems. In particular, long-term treatment with antagonists at dopamine (D) and serotonin (5-hydroxytryptamine; 5-HT) receptors and agonists at glutamate receptors may improve symptoms. Treatment with antipsychotics is very common in the elderly and often indispensable. However, for successful treatment it is essential to have an adequate multidimensional assessment of the geriatric patient and of his or her polypathology and polypharmacy, together with knowledge of age-dependent pharmacokinetics and pharmacodynamic changes and drug-drug interactions.Conventional antipsychotics such as haloperidol, chlorpromazine, promazine, tiapride and zuclopenthixol are D(2)-receptor antagonists and inhibit dopaminergic neurotransmission in a dose-related manner. They decrease the intensity of all psychotic symptoms, although not necessarily to the same extent and with the same time course. Negative symptoms may persist to a much more striking extent than delusions, hallucinations and thought disorders, and there is a dose-related incidence of extrapyramidal side effects (EPS). Newer antipsychotics, such as clozapine, olanzapine, risperidone, quetiapine and ziprasidone, have a different receptor-binding profile, interacting with both D and 5-HT receptors; they less frequently cause EPS and are better tolerated in the elderly. Their use is advantageous because they are effective both on positive and negative symptoms of schizophrenia and may also be used in the treatment of behavioural disturbances in elderly and/or demented individuals. The use of clozapine is limited by the onset of agranulocytosis, whereas olanzapine, risperidone, quetiapine and, more recently, ziprasidone are widely used, with good results in the above-mentioned diseases.

Age-dependent differential responses of monoaminergic systems to high doses of methamphetamine.

Abuse of methamphetamine (METH) by adolescents is a major public health issue in the U.S.A. Because of the neurotoxic potential of METH, we examined the response of CNS monoaminergic systems in young (adolescent) animals [postnatal day (PND) 40] to high-dose treatments (10 mg/kg, four injections, 2-h intervals) of this drug and contrasted these effects to those seen in older (young adult) rats (PND 90). Consistent with previous reports, we observed that PND 40 animals did not manifest the long-term (7-day) deficits in extrapyramidal dopamine (DA) parameters observed in PND 90 rats. In contrast, METH-induced rapid (1-h) reduction in the activity of striatal DA transporters occurred in both age groups. In addition, both persistent (7-day) and rapid (1-h) deficits in serotonergic systems (measured as reductions in tryptophan hydroxylase activity) were observed in PND 40 and 90 rats. Age-related differences in METH-induced hyperthermia did not appear to be a principal cause for our observations; however, age-dependent pharmacokinetics of this drug might have contributed to the differential METH monoaminergic responses by PND 40 and 90 animals.

Age and sex dependent pharmacokinetics of cyclosporine in the rat after a single intravenous dose

The dependency of cyclosporine (CyA) pharmacokinetics on the age (10 and 40-week-old) and the gender was studied in Wistar rats who were given 10 mg/kg dose of the drug intravenously. CyA levels in whole blood were analyzed by a specific fluorescence polarization immunoassay (Abbot TDx). Blood concentration vs time profiles were characterized by resorting to compartmental and noncompartmental methods. The first approach showed that the best model fitting experimental data was a three-compartment open model with first-order kinetics. It indicated that the drug undergoes extensive distribution in a wide variety of tissues. The mean half-lives corresponding to λ 1 and λ 2 phases coincided in all groups and lasted on average 0.22 and 4.30 h, respectively. The mean volume of distribution at steady-state depended mainly on the rats gender and age, indicating values of 2.64±0.37 l/kg for older males as compared to 2.03±0.29, 1.71±0.12, and 1.87±0.16 l/kg for young males and females and 40-week-old females, respectively. Drug elimination rates ranged from 0.019 to 0.123 h −1 and manifested a marked dependency on both, the gender and the age. The bioavailability (AUC 0−∞) was higher for males (81.06±8.31 and 139.62±41.34 μg·h per ml vs 50.19±2.10 and 49.65±5.68 μg·h per ml) while the systemic blood clearance (CL) was significantly lower for males than for females (85±19 and 109±3 ml/h per kg vs 198±9 and 205±29 ml/h per kg). No statistically significant differences were detected between compartmental and noncompartmental parameters by paired t-tests. Therefore, the results demonstrate that female rats clear CyA faster than males, probably due to differences in drug metabolism.