三唑类抗真菌药泊沙康唑的临床应用

泊沙康唑（posaconazole）是新型三唑类抗真菌药,对霉菌和酵母菌具有广谱抗菌活性,且抗菌作用强,对难治性或侵袭性真菌感染有效.本文综述其抗真菌机制、药动学、体内外试验、临床研究、用法用量及药物相互作用.     

新生儿药动学与用药特点

新生儿各系统及器官功能未发育完善,药物在体内吸收、分布、代谢、排泄有其特殊性,给药间隔时间、给药方式、给药剂量与年长儿有所不同,这将影响新生儿的药动学。本文就新生儿生理特点与用药关系作粗浅介绍。一、新生儿生理机能、生化功能特点：新生儿体液总量占体重的74％,其中一半是细胞外液。新生儿的细胞外波与体重之比为成人的两倍。新生儿、婴儿的脂肪组织较成人少,仅占体重的15％左右,体表面积与体重之比较成人为大,婴儿的体表面积与体重的比率是成人的2倍[1]。新生儿免疫系统的发育尚未完善,其T细胞、吞噬细胞功能低下,除…     

唑类抗真菌药物手性分离及药代动力学研究进展

唑类抗真菌药物具有手性特征,给药后体内对映体血药浓度及药动学参数显示出差异,具有立体选择性特点,代谢是导致该类药物呈现立体选择性变化的主要环节。而生物样本中对映体定量分析则依赖于手性拆分技术的不断发展。本文综述了近年来唑类抗真菌药物主要手性分析技术及酮康唑、伊曲康唑手性药代动力学研究进展,以期为唑类抗真菌新药研究提供参考。     

儿童患者伏立康唑治疗药物监测研究进展

伏立康唑在成人体内呈现非线性药动学特征，主要在肝脏中代谢，受基因多态性和药物相互作用的影响，个体间及个体内差异较大。因此，治疗药物监测在伏立康唑临床应用中发挥重要作用。相比成人，儿童患者的药动学更加复杂，目前针对儿童群体的研究数据相对较少，对于儿童目标浓度范围及剂量的调整策略尚存在争议，故该群体使用伏立康唑存在较大风险。本文分别从治疗药物监测必要性、监测策略、剂量调整策略共3个方面分析了儿童患者中伏立康唑治疗药物监测研究进展，以期为儿童患者临床抗真菌感染治疗提供参考。     

小儿的临床合理用药

与成年人相比,儿童机体有其不同的生理、生化特点,特别是早产儿、新生儿与成年人的差异尤为悬殊。由于小儿中枢神经系统、胃肠道功能、肝’净功能和内分泌系统的发育尚未健全,导致药物在体内的吸收、分布、代谢、排泄以及机体对药物的反应性等方面与成人有显著差异。本文探讨了药物在小儿体内的药动学及药效学特点,为小儿临床合理用药提供了依据。     

抗真菌药伊曲康唑的药代动力学研究概况

伊曲康唑为三唑类广谱抗真菌药,对浅表真菌、深部真菌感染均有显著疗效,且耐受性良好,临床应用广泛。本文对伊曲康唑在体内的吸收、分布、代谢、排泄的药代动力学特征和影响研究,以及不同患者群体中的药动学作一综述,促进临床合理使用。     

伏立康唑的药动学/药效学及其药物监测

伏立康唑为新一代三唑类抗真菌药,抗菌谱广,抗菌作用强,主要用于治疗患有进展性、可能威胁生命的真菌感染的患者。其药动学呈非线性,个体差异大。本文对伏立康唑药动学影响因素,药动学/药效学特性,血药浓度与治疗效果、不良反应间关系以及不同类患者伏立康唑药物监测作一综述,以指导临床制定个性化给药方案,提高药物治疗效果。     

儿童生理药代动力学模型及其在儿科药物研究中的应用

生理药代动力学(physiologically based pharmacokinetic, PBPK)模型是预测药物在特殊人群中的药代动力学、药效学和安全性的重要工具。尤其对于儿童这类不易开展临床试验的人群, PBPK模型的应用更是能有效促进儿科药物的开发以及儿童的临床用药。目前, PBPK模型在儿科药物开发中的主要应用有以下几种:临床试验设计、药物相互作用(drug-drug interaction, DDI)的风险评估和儿童给药剂量的确立等。本综述简介了儿童生理药动学模型在儿科药物研究中的优越性,总结了PBPK模型如何实现从成人到儿童的外推,儿童生理药动学模型的理论基础,建模过程及所要注意的重要生理参数,列举了目前PBPK模型在儿科药物研究中的一些应用实例。最后简述了儿童PBPK模型当前的局限性和未来发展方向。     

伏立康唑及其临床应用

伏立康唑是最新上市的第2代三唑类广谱抗真菌药物,能有效抑制真菌羊毛甾醇14α去甲基化酶,阻断麦角甾醇生物合成,从而影响细胞膜的流动性、通透性,在体内、外具有广泛的抗真菌活性临床研究结果表明,伏立康唑可用于念珠菌感染和其他药物治疗无效的克柔念珠菌及烟曲菌感染。本文综述了伏立康唑的药效学、药动学特性及临床应用等研究进展。     

静脉营养在儿科病人中的应用

儿科病人包括婴儿（０～２岁）和儿童（２～１２岁）,他们是一个生长发育期的特殊群体。从新生儿到婴儿到儿童,在药效学和药动学方面有很大变化,不能将该年龄段的儿童简单视为成人的缩影,用药剂量方面应有其特点,因此建立不同年龄段儿童用药剂量尤为重要。目前尚缺乏儿科剂量方面的适宜研究。在美国,许多广泛应用于儿科病人的药物甚至是ＦＤＡ不同意使用的,在美国１９８８年做的一次调查中,用于儿童的药物仅有３０％是同意使用的;１９９０年的《医生案头参考书》（ＰＤＲ）仅有７５％的药有儿童禁用或慎用的说明。我国使用较广泛的…     

Pharmacokinetics of famotidine in infants

BACKGROUND: Although famotidine pharmacokinetics are similar in adults and children older than 1 year of age, they differ in neonates owing to developmental immaturity in renal function. Little is currently known about the pharmacokinetics of famotidine in infants aged between 1 month and 1 year, a period when renal function is maturing. OBJECTIVE: To characterise the pharmacokinetics of famotidine in infants. DESIGN: This was a two-part multicentre study with both single dose (Part I, open-label) and multiple dose (Part II, randomised) arms. PATIENTS: Thirty-six infants (20 females and 16 males) who required treatment with famotidine and who had an indwelling arterial or venous catheter for reasons unrelated to the study. METHODS: Infants in Part I were administered a single dose of famotidine 0.5 mg/kg; the dose was intravenous or oral according to the judgement of the attending physician. Infants receiving 0.5 mg/kg intravenously were divided into two groups by age, and pharmacokinetic parameters in infants 0-3 months and >3 to 12 months of age were compared. Infants in Part II were randomised to one of the following treatments: 0.25 mg/kg/dose intravenously or 0.5 mg/kg/dose orally on day 1 and subsequent days, or 0.25 mg/kg/dose intravenously or 0.5 mg/kg/dose orally on day 1 followed by doses of either 0.5 mg/kg/dose intravenously or 1 mg/kg/dose orally on subsequent days. From day 2 onwards, age-adjusted dose administration regimens (once daily in infants <3 months of age and every 12 hours in infants >3 months of age) were used; the total number of famotidine doses ranged from 3 to 11 and the total number of days of dose administration ranged from two to eight. RESULTS: In infants <3 months of age, plasma and renal clearance of famotidine were decreased compared with infants >3 months of age. Pharmacokinetic parameters for the older infants (i.e. those >3 months) were similar to those previously reported for children and adults. Approximate dose-proportionality, no accumulation on multiple dosing and an estimated bioavailability similar to adult values were also observed. CONCLUSION: A short course of famotidine therapy in infants appears generally well tolerated, and the characteristics of famotidine pharmacokinetics during the first year of life are explained to a great degree by the development of renal function, the primary route of elimination for this drug.     

Pharmacokinetic modeling and simulation for dose rationale of doripenem in neonates and infants

The aims of this study were to construct a population pharmacokinetic model of doripenem in neonates and infants and to assess the dosing regimen for patients <3 months of age using Monte-Carlo pharmacokinetic/pharmacodynamic (PKPD) simulations. In the population pharmacokinetic analysis using 187 plasma concentrations from 47 neonates and infants, a two-compartment model well described plasma doripenem concentrations with the most significant covariates of chronological age and gestational age identified for the pharmacokinetics of doripenem. Monte-Carlo simulations suggested that the selected dosages for neonates and infants based on chronological age and gestational age (5 or 10 mg/kg) would provide ≥90% target attainment of 40%fT_>MIC against MIC of 2 μg/mL in all age groups. These results would be useful for understanding the PKPD characteristics of doripenem, which could provide essential information on optimal therapeutic treatment for neonates and infants.     

Single-dose and steady-state pharmacokinetics of piroxicam in elderly vs young adults

Summary Age-dependent changes in pharmacokinetics are considered a possible factor contributing to a higher risk of side-effects from drug treatment in the elderly. However, very little is known about the kinetics and metabolism of most NSAI agents in geriatric subjects. In a prospective age-comparison study, the single dose and steady-state pharmacokinetics of piroxicam 20 mg once daily were determined in 44 subjects ranging in age from 30 to 80 years. Plasma concentrations, elimination half-life, AUC, and volume of distribution were not influenced by age or sex and were in agreement with previously reported results in young adults. Pharmacokinetic parameters in 18 patients with evidence of mild or moderate renal impairment at study entry were not different from those in patients without impairment. Based on this and other studies, elderly patients receiving the recommended dose of piroxicam are not exposed to undue risk related to pharmacokinetic considerations.     

Dopamine and dobutamine in pediatric therapy

Dopamine hydrochloride is widely used to increase blood pressure, cardiac output, urine output, and peripheral perfusion in neonates, infants, and older children with shock and cardiac failure. Its pharmacologic effects are dose dependent, and at low, intermediate, and high dosages include dilation of renal, mesenteric, and cerebral vasculature; inotropic response in the myocardium; and increases in peripheral and renal vascular resistance, respectively. The inotropic response is diminished in neonates compared with older children and adults due to maturational differences in norepinephrine stores. The clearance of dopamine varies widely in the pediatric population, depending on age. Its elimination half-life is approximately 2 minutes in full-term neonates and older children, and may be as long as 4-5 minutes in preterm infants. Due to immaturity of the autonomic nervous system, the drug may produce some adverse respiratory responses at high dose in neonates, the most common being tachycardia and cardiac arrhythmias. Dobutamine resembles dopamine chemically and is an analog of isoproterenol. It is relatively cardioselective at dosages used in clinical practice, with its main action being on beta 1-adrenergic receptors. Unlike dopamine, it does not have any effect on specific dopaminergic receptors. Dobutamine is used to increase cardiac output in infants and children with circulatory failure. Its elimination half-life is about 2 minutes in adults and older children. No information is available about its pharmacokinetics in neonates and infants. Adverse effects such as an increase in heart rate usually occur at high dosages.     

Pharmacokinetics of dexamethasone in premature neonates

Objective: Dexamethasone is frequently used in premature neonates with bronchopulmonary dysplasia, however little is known about its disposition in this population. Methods: We evaluated the pharmacokinetics of dexamethasone in 9 premature neonates with a mean gestational age of 27.3 weeks and a postnatal age of 21.8 days. Results: There was a strong relationship between clearance (4.96 ml·min^–1·kg^–1) and gestational age (r=0.884). Pharmacokinetic parameters were grouped based on a gestational age of less than 27 weeks (Group I) and greater than 27 weeks (Group II). Mean clearance in group I and group II was 1.69 and 7.57 ml·min^–1·kg^–1, respectively. Mean distribution volume in group I and II was 1.26 and 2.19 l·kg^–1, respectively. No significant relationships were noted between the disposition of dexamethasone and ventilator requirements or adverse effects. Conclusion: The pharmacokinetics of dexamethasone in premature neonates was related to gestational age.     

Antifungal agents in neonates: issues and recommendations

Fungal infections are responsible for considerable morbidity and mortality in the neonatal period, particularly among premature neonates. Four classes of antifungal agents are commonly used in the treatment of fungal infections in pediatric patients: polyene macrolides, fluorinated pyrimidines, triazoles, and echinocandins. Due to the paucity of pediatric data, many recommendations for the use of antifungal agents in this population are derived from the experience in adults. The purpose of this article was to review the published data on fungal infections and antifungal agents, with a focus on neonatal patients, and to provide an overview of the differences in antifungal pharmacology in neonates compared with adults. Pharmacokinetic data suggest dosing differences in children versus adult patients with some antifungals, but not all agents have been fully evaluated. The available pharmacokinetic data on the amphotericin B deoxycholate formulation in neonates exhibit considerable variability; nevertheless, the dosage regimen suggested in the neonatal population is similar to that used in adults. More pharmacokinetic information is available on the liposomal and lipid complex preparations of amphotericin B and fluconazole, and it supports their use in neonates; however, the optimal dosage and duration of therapy is difficult to establish. All amphotericin-B formulations, frequently used in combination with flucytosine, are useful for treating disseminated fungal infections and Candida meningitis in neonates. Fluconazole, with potent in vitro activity against Cryptococcus neoformans and almost all Candida spp., has been used in neonates with invasive candidiasis at dosages of 6 mg/kg/day, and for antifungal prophylaxis in high-risk neonates. There are limited data on itraconazole, voriconazole, and posaconazole use in neonates. Caspofungin, which is active against Candida spp. and Aspergillus spp., requires higher doses in children relative to adults, and dosing is best accomplished based on body surface area. Micafungin shows a clear trend toward lower levels in the smallest patients. There are no data on the use of other new antifungal drugs (ravuconazole and anidulafungin) in neonates. In summary, the initial data suggest dosage differences in neonates for some antifungal agents, although the newer agents have not been fully tested for optimal administration in these patients.     

Application of routine monitoring data for determination of the population pharmacokinetics and enteral bioavailability of phenytoin in neonates and infants with seizures

This study investigated the population pharmacokinetics and the enteral bioavailability of phenytoin (PTN) in neonates and infants with seizures. Data from 83 patients were obtained retrospectively from medical records. A 1-compartment model was fitted to the log-transformed concentration data using NONMEM. Between-subject variability and interoccasion variability were modelled exponentially together with a log transform, both-sides exponential residual unexplained variance model. Covariates in nested models were screened for significance. Model robustness was assessed by bootstrapping with replacement (n = 500) from the study data. The parameters of the final pharmacokinetic model were clearance (L/h) = 0.826.[weight (WT, kg) / 70].[1 + 0.0692.(postnatal age (d) - 11)]; volume of distribution (L) = 74.2.[WT (kg) / 70]; absolute enteral bioavailability = 0.76; absorption rate constant (h) = 0.167. The between-subject variability for clearance and volume of distribution was 74.2% and 65.6%, respectively. The interoccasion variability for clearance was 54.4%. The unexplained variability was 51.1%. Final model parameter values deviated from median bootstrap estimates by less than 9%. Phenytoin disposition in neonates and infants can be described satisfactorily by linear pharmacokinetics. The values of allometrically scaled clearance and volume were similar to adult values, suggesting no major kinetic differences between adults and infants on the basis of size alone. Postnatal age independently influenced clearance. Switching from enteral to intravenous routes may require a dosage adjustment. The results of this study provide a basis for more rational prescribing of phenytoin in infants and neonates.     

Evaluation of an empirical dosing schedule for gentamicin in neonates

The standard gentamicin dosing recommendations for neonates appear to be inappropriate because they fail to consider the influence of neonatal development on gentamicin pharmacokinetics. Recent reports have emphasized that the standard regimens of 2.5 mg/kg q8-12h produce steady-state trough serum concentrations greater than 2 micrograms/ml in up to 91 percent of preterm infants of less than 35 weeks' gestation. A new dosing schedule based on postconceptional age (PCA) was developed to provide a better guideline for initiating and maintaining gentamicin therapy in neonates: PCA greater than 34 weeks, 2.5 mg/kg iv q12h; PCA 28-34 weeks, 2.5 mg/kg iv q16h; PCA less than 28 weeks, 2.5 mg/kg iv q24h. The new dosing schedule reduced the number of neonates with elevated trough concentrations (greater than 2 micrograms/ml) from 68.4 percent to 33-40 percent. Pharmacokinetic parameters for gentamicin in the various PCA groups were determined. Volume of distribution was constant across age groups (0.5 +/- 0.09 L/kg). Elimination rate constants (kel), half-lives, and clearance rates (Cl) ranged from 0.069 +/- 0.02 to 0.14 +/- 0.04 h-1, 10.71 +/- 2.92 to 6.04 +/- 1.24 h, and 0.58 +/- 0.25 to 0.93 +/- 0.24 ml/kg/min, respectively. Significant relationships were found between kel and Cl and patient age and weight; significant correlations were found between actual and estimated (based on PCA and weight) kel and Cl. Variability in kel and Cl estimated was considerable in spite of the correlations. The observed variability stresses again the need for pharmacokinetic monitoring of gentamicin therapy in neonates.     

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.