Population pharmacokinetic and exposure-response analyses of d-amphetamine after administration of lisdexamfetamine dimesylate in Japanese pediatric ADHD patients

Lisdexamfetamine dimesylate, a prodrug of d-amphetamine, has been approved for treatment of attention-deficit/hyperactivity disorder (ADHD). The purposes of this study were constructing a population pharmacokinetic model of d-amphetamine after dosing of lisdexamfetamine dimesylate and assessing influential factors on the pharmacokinetics of d-amphetamine in Japanese pediatric patients with ADHD. Additionally, the exposure-response relationship was evaluated for Japanese pediatric patients with ADHD using a clinical rating scale, the ADHD Rating Scale IV (ADHD RS-IV, efficacy endpoint) total score as a response index. A total of 1365 points of plasma d-amphetamine concentrations from pediatric patients (6–17 years) with ADHD in clinical studies conducted in Japan and the US were employed for the population pharmacokinetic analysis. The plasma concentrations of d-amphetamine in pediatric patients with ADHD were well described by a one-compartment model with first-order absorption and lag time. The effects of body weight and ethnicity (Japanese or non-Japanese) on apparent total body clearance and the effect of body weight on apparent volume of distribution were incorporated into the final model. No clear exposure-dependent reduction was evident from the ADHD RS-IV total score, whereas the reductions were greater for the lisdexamfetamine dimesylate treatment groups compared with the placebo group regardless of exposure to d-amphetamine.     

Distinguishing the efficacy and sedative effects of guanfacine extended release in children and adolescents with attention-deficit/hyperactivity disorder

The present study investigated whether symptom reduction in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) treated with guanfacine extended release (GXR) can be explained by sedative effects of the medication. Data from four double-blind, randomized, placebo-controlled, phase 3 trials of GXR monotherapy (1–7 mg/day; morning administration) in children (aged 6–12 years) and adolescents (aged 13–17 years) with ADHD were analyzed post hoc. Two studies used forced-dose titration and two used flexible-dose titration. Efficacy was determined using ADHD Rating Scale IV (ADHD-RS-IV) scores. Sedative treatment-emergent adverse events (TEAEs) included somnolence, sedation and hypersomnia. The proportion of responders (≥ 30% reduction in ADHD-RS-IV total score) increased from weeks 1 to 4 and remained stable to study endpoint. Sedative TEAEs generally peaked at the first week in which the target dose was achieved and then declined. In subgroup analyses, significant placebo-adjusted improvements in ADHD-RS-IV total scores were observed in participants without any sedative TEAEs in the forced-dose and flexible-dose studies (nominal p < 0.001). In addition, GXR was associated with significant improvements in both inattentive and hyperactive–impulsive symptoms, as assessed by the ADHD-RS-IV subscale scores (nominal p < 0.001) and by the ADHD-RS-IV total score in participants with different ADHD subtypes (nominal p < 0.05). Thus, the efficacy of GXR in children and adolescents with ADHD is not primarily due to sedation, although some contribution to symptom reduction cannot be excluded, especially early in treatment when rates of sedative TEAEs are at their highest.     

Population Pharmacokinetic/Pharmacodynamic Modeling of Guanfacine Effects on QTc and Heart Rate in Pediatric Patients

Using a previously developed population pharmacokinetic model, an exposure-response (ER) model was successfully developed to describe guanfacine plasma concentrations and changes in heart rate (HR) and the QT interval. Guanfacine exposure was associated with small decreases in HR and a small prolongation of the population-corrected QT (QTcP) interval. Based on the final ER model for effect of guanfacine on HR, the estimated population typical decrease in HR would be 2.3% (2.1–2.7%) of the baseline circadian HR for every 1 ng/mL of guanfacine exposure. A QTcP was developed for the analysis using the sampled population. An effect of sex on baseline-corrected QT (BQTP) was the only covariate effect in the final ER model for QTcP, its inclusion resulting in a typical baseline QTcP estimate that is 9 (5–13) ms higher for females. There was no evidence of QT-RR hysteresis. A linear model was used to relate guanfacine plasma concentrations to QTcP. The typical (95% confidence interval) slope parameter was estimated to be 0.941 (0.62–1.25) ms/ng/mL. The final model predicted an approximate 1-ms increase from baseline for every 1 ng/mL of guanfacine in plasma. The main predictor of QTcP prolongation was guanfacine exposure, which decreased with body weight and increased with dose.

Electronic supplementary material

The online version of this article (doi:10.1208/s12248-014-9645-0) contains supplementary material, which is available to authorized users.KEY WORDS: ADHD, guanfacine, pediatric, pharmacodynamics, pharmacokinetic     

Population pharmacokinetics of duloxetine in Japanese pediatric patients with major depressive disorder

The objectives of this analysis were to characterize the pharmacokinetics of duloxetine in Japanese pediatric patients aged 9–17 years with major depressive disorder (MDD) and to explore potential intrinsic factors affecting its pharmacokinetics. A population pharmacokinetic (PK) model was developed with plasma steady-state duloxetine concentrations from Japanese pediatric patients with MDD in an open-label long-term extension trial in Japan (ClinicalTrials.gov Identifier: NCT03395353). Duloxetine pharmacokinetics in Japanese pediatric patients was well described by a one-compartment model with first-order absorption. The population mean estimates of CL/F and V/F of duloxetine were 81.4 L/h and 1170 L, respectively. Patient intrinsic factors were assessed for their potential influence on duloxetine apparent clearance (CL/F). Only sex was identified as a statistically significant covariate of duloxetine CL/F. Duloxetine pharmacokinetic parameters and model-predicted duloxetine concentrations at steady state in the Japanese pediatric population were compared with those in Japanese adults. The mean duloxetine CL/F in pediatrics is slightly higher than adults, it is, however, expected that comparable steady-state duloxetine exposure in pediatric patients can be achieved with the approved dose regimen for adults. The population PK model provides useful information to understand the pharmacokinetic characteristics of duloxetine for Japanese pediatric patients with MDD.ClinicalTrials.gov identifierNCT03395353     

Guanfacine and guanfacine extended release: treatment for ADHD and related disorders

Guanfacine, an alpha(2A) adrenoceptor agonist, is U.S. Food and Drug Administration (FDA)-approved for the treatment of hypertension in adolescents and adults. It also has been used "off-label" for several years in children as a possible treatment for attention-deficit/hyperactivity disorder (ADHD) and pervasive developmental disorders (PDDs). Small placebo-controlled trials support the use of guanfacine for the treatment of ADHD. There is more limited research on the use of guanfacine in treating hyperactivity occurring in children diagnosed with PDD. Recently, guanfacine extended release (GXR), a once-daily formulation has been manufactured and studied in phase III clinical trials. Based on preliminary scientific presentations, it also appears to be efficacious in improving ADHD in children. The most common adverse effects associated with guanfacine and GXR treatment is sedation. Adverse cardiovascular effects are uncommon, although modest reductions in blood pressure and heart rate are common. If GXR is FDA-approved, it would be the first alpha(2A) adrenoceptor agonist marketed for ADHD.     

Population Pharmacokinetics of Baloxavir Marboxil in Japanese Pediatric Influenza Patients

Baloxavir marboxil is a prodrug of baloxavir acid, an inhibitor of cap-dependent endonuclease, and suppresses the replication of influenza virus. The aim of this study was to investigate its pharmacokinetic characteristics in Japanese pediatrics. Population pharmacokinetic analysis was conducted for baloxavir acid with 328 plasma concentration data points in a clinical study of 107 Japanese pediatric influenza patients. The plasma baloxavir acid concentration profiles were well captured by a 2-compartment model including first-order absorption and lag time. Body weight was considered to be the most crucial covariate, which affects clearance and volume of distribution. The body weight–based dose regimen (10 mg for 10 kg to less than 20 kg pediatrics, 20 mg for 20 kg to less than 40 kg pediatrics, and 40 mg for at least 40 kg pediatrics) for Japanese pediatrics can provide comparable exposure to baloxavir acid to that for adults. In conclusion, the population pharmacokinetic model would be useful to comprehend the characteristics of baloxavir acid pharmacokinetics in pediatric patients.     

Pharmacokinetics of Coadministration of Guanfacine Extended Release and Methylphenidate Extended Release

Background

α₂-Adrenoceptor agonists are used adjunctively to psychostimulants in treating attention-deficit/hyperactivity disorder (ADHD) when psychostimulants alone do not sufficiently reduce symptoms. However, data on the pharmacokinetic profiles and safety of combination treatments in ADHD are needed.

Objective

The primary objective of this study was to evaluate the pharmacokinetic profiles of guanfacine extended release (GXR) and methylphenidate hydrochloride (MPH) extended release, alone and in combination.

Study Design

This was an open-label, randomized, three-period crossover, drug–drug interaction study.

Setting

The study was conducted at a single clinical research center.

Participants

Thirty-eight healthy adults were randomized in this study.

Interventions

Subjects were administered single oral doses of GXR (Intuniv^®; Shire Development LLC, Wayne, PA, USA) 4 mg, MPH (Concerta^®; McNeil Pediatrics, Titusville, NJ, USA) 36 mg, or GXR and MPH combined.

Main Outcome Measures

Guanfacine, dexmethylphenidate (d-MPH), and l-methylphenidate (l-MPH) levels were measured with blood samples collected predose and up to 72 h postdose. Safety evaluations included treatment-emergent adverse events (TEAEs), vital signs, and electrocardiograms (ECGs).

Results

Thirty-five subjects completed the study. Analyses of the 90 % confidence intervals (CIs) for the geometric mean ratios of the maximum plasma concentration (C_max) and area under the concentration–time curve extrapolated to infinity (AUC_∞) values for guanfacine and d-MPH following administration of GXR or MPH alone or combined met strict bioequivalence criteria (90 % CIs within the interval of 0.80–1.25). Overall, combining GXR and MPH did not alter the pharmacokinetic parameters of either medication. Sixteen subjects (42.1 %) had at least one TEAE. The most commonly reported TEAEs included headache and dizziness following GXR, MPH, and GXR and MPH combined. Two subjects had clinically significant abnormalities in ECG results following coadministration: both events were mild and resolved the same day.

Conclusions

In this short-term, open-label study of healthy adults, coadministration of GXR and MPH did not result in significant pharmacokinetic drug–drug interactions. No unique TEAEs were observed with coadministration of GXR and MPH compared with either treatment alone.     

Population pharmacokinetics and pharmacodynamics of meropenem in pediatric patients

Meropenem is a highly potent carbapenem antibiotic against gram-positive and gram-negative bacteria. Meropenem plasma concentration data from 99 pediatric patients (aged 0.08-17.3 years) were used to develop a population pharmacokinetic model. Pharmacokinetic analysis was performed using NONMEM with exponential interindividual variability and combinational residual error model. A 2-compartment model was found to fit the data best. Creatinine clearance and body weight were the most significant covariates explaining variabilities in meropenem pharmacokinetics among pediatric patients. The validated final model was used to predict meropenem plasma concentrations in 37 pediatric meningitis patients, receiving 40 mg/kg meropenem, who had minimum inhibitory concentration values of the causative pathogens and outcome available. Since the causative pathogens in all patients were eradicated, no break points for required exposure could be found. The microbiological outcomes indicate that the current clinical dosage regimen provides sufficient drug exposure to eradicate the pathogens commonly involved in pediatric meningitis.     

Population pharmacokinetic analysis of micafungin in Japanese patients with fungal infections

The object of this analysis was to develop a population pharmacokinetic model of micafungin, a new anti-fungal agent of the echinocandin class, to optimize dosing in Japanese patients with fungal infections. Population pharmacokinetics parameters were determined using NONMEM based on pharmacokinetic data from 198 subjects in seven clinical studies, comprising four phase I, two phase II and one pediatric phase III study. The healthy subjects received intravenous infusion of 2.5-150 mg micafungin. Adult and pediatric patients, age range of 8 month to 15 yeras old, were received 25-150 mg and 1-6 mg/kg daily, respectively. A total of 1825 micafungin plasma samples were available for this analysis. Two-compartment pharmacokinetic model was adopted. The clearance of micafungin was influenced by body weight in children and platelet counts (PLT). However the PLT accounted for less than 20% of the variation of micafungin clearance in Japanese subjects. In conclusions, body weight is the primary covariate factor in pediatric patients. The dose adjustment by body weight would be required only pediatric patients for the micafungin therapy in Japanese patients with fungal infection.     

Guanfacine for attention deficit and hyperactivity disorder in pediatrics: A systematic review and meta-analysis

To review the evidence from randomized controlled trials (RCTs) on the safety and efficacy of guanfacine in pediatric attention deficit hyperactivity disorder (ADHD), a bibliographic search up to May 2014 was performed using the Cochrane Library׳s Central Register of Controlled Trials, the Embase, PsycINFO, and Medline databases, and clinical trials registers. The search terms used were: [“guanfacine”] and [“child” or “adolescent” or “pediatrics”] and [“randomized controlled trial”] and [“Attention Deficit Disorder with Hyperactivity” or “Attention Deficit Disorder” or “Attention Hyperactivity Disorder” or “Hyperactivity” or “ADHD”]. A meta-analysis was performed using response, defined as a score≤2 on the Clinical Global Impression Improvement score, as the outcome measure. In all, 7 out of 48 studies were included, for a total of 1752 participants. All studies compared guanfacine versus placebo, with a duration ranging from 6 to 16 weeks. In all, the Clinical Global Impression Improvement score was reported as a secondary measure. Overall, 694/1177 (59.0%) participants in the guanfacine group benefited from the treatment compared to 192/575 (33.3%) in the placebo group (pooled OR 3.2; 95%CI 2.4–4.1). The participants with at least one adverse event were 948 (82.4%) in the guanfacine and 376 (67.9%) in the placebo group (OR 2.6; 95%CI 1.6–4.4). Somnolence (OR 4.9), sedation (OR 2.8), and fatigue (OR 2.2), were the adverse events with the greatest risk of occurrence in the guanfacine versus the placebo group. On the basis of seven randomized, placebo controlled trials guanfacine resulted safe and effective in treating children and adolescents with ADHD     

Population pharmacokinetics of oral busulfan in young Japanese children before hematopoietic stem cell transplantation

The objectives of this study were to develop a population pharmacokinetic model and to determine the covariates affecting the pharmacokinetics of busulfan in Japanese pediatric patients who received high-dose oral busulfan as a conditioning regimen before hematopoietic stem cell transplantation. Population analysis was performed using retrospective therapeutic drug monitoring data (including test dose data) from 103 children. Their ages ranged from 2 months to 11 years old (mean age, 30 months; median age, 18 months). The plasma concentration of busulfan in all 1028 samples was measured with the same high-performance liquid chromatography method. Maximum likelihood estimates were sought for pharmacokinetic parameters with the NONMEM program. The best structural covariate-free model for busulfan was a one-compartment model with an exponential error model to account for intersubject variability and a proportional error model to account for intrasubject variability. The apparent oral clearance was found to be correlated with age, aspartate transaminase, and type of disease (malignant disease or other). The apparent volume of distribution was related to body weight. The busulfan formulation (1% powder form or crystal form) and dose (milligrams per kilogram) influenced the absorption rate constant. It was estimated that oral clearance expressed per kilogram of body weight is low at early infancy, then increases to a maximum at approximately 2 years of age and, thereafter, decreases. In conclusion, we have developed a population pharmacokinetic model of oral busulfan in children, particularly for those younger than 4 years old, that takes into consideration not only body size, but also several other covariates.     

Pharmacokinetics of Coadministered Guanfacine Extended Release and Lisdexamfetamine Dimesylate

Background

In clinical practice, α₂-adrenoceptor agonists have been adjunctively administered with psychostimulants for the treatment of attention-deficit/hyperactivity disorder (ADHD). Two studies have examined the adjunctive use of guanfacine extended release (GXR, Intuniv^®; Shire Development LLC, Wayne, PA, USA) with psychostimulants in children and adolescents with a suboptimal response to psychostimulant treatment. However, the potential for pharmacokinetic drug–drug interactions (DDIs) between GXR and lisdexamfetamine dimesylate (LDX, Vyvanse^®; Shire US LLC, Wayne, PA, USA) has not been thoroughly evaluated.

Objective

The primary objective of this study was to examine the pharmacokinetics of GXR 4 mg and LDX 50 mg given as single doses alone and in combination.

Study Design

This was an open-label, randomized, three-period crossover, DDI study.

Setting

The study was conducted in a single clinical research center.

Participants

Forty-two healthy adults were randomized in this study.

Interventions

Subjects were administered single oral doses of GXR 4 mg, LDX 50 mg, or GXR and LDX in combination.

Main Outcome Measures

Blood samples collected predose and up to 72 h postdose assessed guanfacine, LDX, and d-amphetamine levels. Bioequivalence was defined as the 90 % confidence intervals (CIs) of the geometric mean ratios of the area under the plasma concentration–time curve extrapolated to infinity (AUC_0–∞) and maximum plasma concentration (C_max) falling within the bioequivalence reference interval (0.80–1.25). Safety measures included adverse events, vital signs, and electrocardiograms (ECGs).

Results

Forty subjects completed the study. Following administration of LDX alone or in combination with GXR, the statistical comparisons of the AUC_0–∞ and C_max of d-amphetamine fell entirely within the reference interval. For guanfacine, the 90 % CI of the geometric mean ratio of AUC_∞ for the two treatments was within the bioequivalence criteria, but for C_max the upper bound of the 90 % CI exceeded the standard range for bioequivalence by 7 %. This relatively small change is unlikely to be clinically meaningful. Treatment-emergent adverse events (TEAEs) were reported by 42.9 % of subjects; the most commonly reported TEAEs included dizziness (5.0, 7.3, and 7.3 %) and headache (7.5, 4.9, and 7.3 %) following administration of GXR, LDX, and GXR and LDX in combination, respectively. Clinically significant ECG abnormalities occurred in one subject following administration of LDX and in one subject following coadministration of GXR and LDX.

Conclusions

In healthy adults, coadministration of GXR and LDX did not result in a clinically meaningful pharmacokinetic DDI compared with either treatment alone. No unique TEAEs were observed with coadministration of GXR and LDX compared with either treatment alone.     

Guanfacine extended release for the treatment of attention-deficit/hyperactivity disorder in children and adolescents

Introduction: Guanfacine extended release (GXR) is a selective α_2A-adrenoreceptor agonist originally developed as an antihypertensive agent and now FDA approved for the treatment of attention-deficit/hyperactivity disorder (ADHD) as monotherapy and as adjunctive to psychostimulants in children and adolescents 6 – 17 years old.

Areas covered: Search of the PubMed and PsycInfo databases from 1990 to 2014 using the search term ‘guanfacine’. Studies selected for review were either controlled or open trials of guanfacine or GXR. Shire Pharmaceuticals, Inc. was contacted and supplied a synopsis of all available ADHD studies on GXR for review.

Expert opinion: GXR is an evidence-based treatment for ADHD in children and adolescents. Because this compound has a smaller effect size than psychostimulants for the symptoms of ADHD, it is generally considered a second-line treatment after the psychostimulants or in combination with psychostimulants. Evidence for efficacy is more robust in children than for adolescents. Because of its pharmacodynamic actions in prefrontal cortex, GXR shows considerable promise for other behavioral conditions frequently comorbid with ADHD and potential promise for emotional and behavioral dysregulation secondary to traumatic stress.     

Population Pharmacokinetics of Doripenem in Pediatric Patients and Monte-Carlo Pharmacokinetic-Pharmacodynamic Simulations for Dosing Regimen Assessment

The aims of this study were to evaluate the pharmacokinetics of doripenem (Finibax^®, Doribax^®, S-4661), a parenteral carbapenem antibiotic, in pediatric patients based on concentrations of doripenem in plasma after administration of 20 mg/kg 2 or 3 times daily and to evaluate the dosing regimens by using Monte-Carlo pharmacokinetic-pharmacodynamic simulations. Population pharmacokinetic analysis was performed by using 190 plasma concentrations of doripenem from 99 patients (2 months-13 years old). The two-compartment model well described the doripenem plasma concentrations in pediatric patients. Body weight was found to be the most significant influential factor. Gender was also found to be a significant covariate although the effect was relatively small. Monte-Carlo simulations indicated that 20 mg/kg over 1 h infusion would give 90% probability of target attainment for 40% of time above minimum inhibitory concentration against Haemophilus influenzae and Streptococcus pneumoniae, major causative pathogens in pediatric infections, and that 40 mg/kg, the highest approved dose for Japanese pediatric patients, administered over 3 h infusion achieved 98.6% against 8 μg/mL. The developed population pharmacokinetic model of doripenem and Monte-Carlo simulations for pediatric patients should provide useful information for understanding the pharmacokinetic and pharmacokinetic-pharmacodynamic characteristics of doripenem and for optimal treatment of pediatric patients.     

Efficacy and safety of extended-release guanfacine hydrochloride in children and adolescents with attention-deficit/hyperactivity disorder: A randomized,controlled, Phase III trial

Guanfacine extended-release (GXR), a selective α2A-adrenergic agonist, is a non-stimulant treatment for attention-deficit/hyperactivity disorder (ADHD). This study assessed the efficacy (symptoms and function) and safety of dose-optimized GXR compared with placebo in children and adolescents with ADHD. An atomoxetine (ATX) arm was included to provide reference data against placebo. Patients (6–17 years) were randomized at baseline to dose-optimized GXR (0.05–0.12 mg/kg/day – 6–12 years: 1–4 mg/day; 13–17 years: 1–7 mg/day), ATX (10–100 mg/day) or placebo for 4 or 7 weeks. The primary efficacy measure was change from baseline in ADHD Rating Scale version IV (ADHD-RS-IV). Key secondary measures were Clinical Global Impression-Improvement (CGI-I) and the Weiss Functional Impairment Rating Scale-Parent Report (WFIRS-P; learning and school, and family domains). Safety assessments included treatment-emergent adverse events (TEAEs), electrocardiograms and vital signs. A total of 272 (80.5%) patients from Europe, the USA and Canada completed the study. Significant differences were observed in least squares mean change from baseline in ADHD-RS-IV total score (placebo-adjusted differences) (GXR: [−8.9, p<0.001]; ATX: [−3.8, p<0.05]), the difference from placebo in the percentage of patients showing improvement (1 [‘very much improved’] or 2 [‘much improved’]) for CGI-I (GXR: [23.7, p<0.001]; ATX: [12.1, p<0.05]), WFIRS-P learning and school domain (GXR: [−0.22, p<0.01]; ATX: [−0.16, p<0.05]) and WFIRS-P family domain (GXR: [−0.21, p<0.01]; ATX: [−0.09, p=0.242]). Most common TEAEs for GXR were somnolence, headache and fatigue; 70.1% of GXR subjects reported mild-to-moderate TEAEs. GXR was effective and well tolerated in children and adolescents with ADHD.     

Population pharmacokinetics of peginterferon alfa-2b in pediatric patients with chronic hepatitis C

Purpose

The aim of this study was to characterize the population pharmacokinetics of peginterferon (PEG-IFN) alfa-2b in pediatric patients with chronic hepatitis C and to identify covariates influencing PEG-IFN alfa-2b disposition.

Methods

Pharmacokinetic data from a multicenter open-label study of subcutaneously administered peginterferon alfa-2b (60 μg/m²/wk) plus oral ribavirin (15 mg/kg/day) in patients with chronic hepatitis C aged 3–17 years old was used to develop a population pharmacokinetic nonlinear mixed-effects model.

Results

The final population pharmacokinetic analysis was conducted with the pooled data from 107 pediatric patients. A one-compartment model with first-order absorption, first-order elimination, exponential inter-individual variability on clearance, and a combination additive and proportional residual error model adequately described the PEG-IFN alfa-2b pharmacokinetic profile. Age (apparent clearance and apparent volume of distribution) and sex (apparent clearance) were significant covariates. The mean body surface area normalized apparent clearance of PEG-IFN alfa-2b was 0.56 L/h/m², and was similar when evaluated across the pediatric age groups.

Conclusion

The final population model suggests age-dependent increases in clearance and volume of distribution of PEG-IFN alfa-2b in pediatric patients with chronic hepatitis C. The apparent clearance normalized to body surface area was similar across pediatric age groups, supporting the use of body size–adjusted dosing in pediatric subjects.     

Guanfacine extended-release for attention-deficit/hyperactivity disorder (ADHD)

Importance of the field: Guanfacine extended-release (GXR) is a non-stimulant approved in the US for treatment of attention deficit/hyperactivity disorder (ADHD). GXR is a ‘first in class’ α_2A-adrenoceptor agonist reformulated to optimize efficacy. GXR enters a rapidly growing but crowded ADHD market as an alternative not only to psychostimulants but also to atomoxetine.

Areas covered in this review: Pharmacodynamics, pharmacokinetics, clinical efficacy and safety of GXR are covered based on a literature review (MEDLINE and EMBASE) from 1980 to 2010. Two large pivotal controlled trials are reviewed along with companion safety studies over 24 months. Collateral studies in ADHD children with oppositional symptoms and combination use of GXR in psychostimulant partial-responders are featured.

What the reader will gain: Novel aspects of apparent GXR mechanism of action may complement existing treatments. Study evidence indicates that GXR is a well-tolerated and effective treatment for children and adolescents with ADHD, and appears efficacious to reduce oppositional symptoms in children with these complicating features. The GXR safety database reflects mild and asymptomatic decreases in both blood pressure and heart rate throughout, with most adverse events being somnolence-related and time-limited.

Take home message: This review of GXR will allow the reader to determine the place for GXR in the ADHD treatment landscape.     

头孢哌酮钠舒巴坦钠在儿童群体中的药动学研究和剂量优化

目的： 考察头孢哌酮在儿童群体中的药动学特征,促进个体化用药。方法： 收集140例患儿的临床资料和血药浓度数据。采用非线性混合效应模型法建立头孢哌酮在儿童群体中的群体药动学模型,用拟合优度（Goodness-of-fit）、直观预测检验法（VPC）、正态化预测分布误差（NPDE）验证最终模型的预测性能。采用模拟试验评价不同用药方案的合理性。结果： 最终模型评价结果表明模型稳定、预测结果可靠,得到的头孢哌酮药动学参数为：表观分布容积（V_d）0.86 L,清除率（CL）0.38 L·h^-1。模型结构显示患儿的体质量及肾小球滤过率是影响药动学参数的显著性因素。基于此模型最终确定各年龄段儿童的最优给药方案为：针对大肠埃希菌,新生儿患者为30 mg·kg^-1,qid,静滴2 h;1个月~2岁患儿为20 mg·kg^-1,qid,静滴2 h;2~14岁患儿为10 mg·kg^-1,tid,静滴2 h;针对肺炎克雷伯菌,新生儿患者为10 mg·kg^-1,tid,静滴2 h;1个月~2岁患儿为10 mg·kg^-1,tid,静滴2 h;2~14岁患儿为10 mg·kg^-1,bid,静滴2 h。结论： 本研究成功建立了头孢哌酮在儿童患者中的药动学模型,并借此模型推导出不同年龄段患儿针对大肠埃希菌及肺炎克雷伯菌的最佳给药方案。     

Population pharmacokinetics of phenytoin after intravenous administration of fosphenytoin sodium in pediatric patients, adult patients, and healthy volunteers

Purpose

We performed a population pharmacokinetic analysis of phenytoin after intravenous administration of fosphenytoin sodium in healthy, neurosurgical, and epileptic subjects, including pediatric patients, and determined the optimal dose and infusion rate for achieving the therapeutic range.

Methods

We used pooled data obtained from two phase I studies and one phase III study performed in Japan. The population pharmacokinetic analysis was performed using NONMEM software. The optimal dose and infusion rate were determined using simulation results obtained using the final model. The therapeutic range for total plasma phenytoin concentration is 10–20 μg/mL.

Results

We used a linear two-compartment model with conversion of fosphenytoin to phenytoin. Pharmacokinetic parameters of phenytoin, such as total clearance and central and peripheral volume of distribution were influenced by body weight. The dose simulations are as follows. In adult patients, the optimal dose and infusion rate of phenytoin for achieving the therapeutic range was 22.5 mg/kg and 3 mg/kg/min respectively. In pediatric patients, the total plasma concentration of phenytoin was within the therapeutic range for a shorter duration than that in adult patients at 22.5 mg/kg (3 mg/kg/min). However, many pediatric patients showed phenytoin concentration within the toxic range after administration of a dose of 30 mg/kg.

Conclusions

The pharmacokinetics of phenytoin after intravenous administration of fosphenytoin sodium could be described using a linear two-compartment model. The administration of fosphenytoin sodium 22.5 mg/kg at an infusion rate of 3 mg/kg/min was optimal for achieving the desired plasma phenytoin concentration.