新生儿万古霉素群体药动学模型建立的必要性评价

目的:观察研究万古霉素在新生儿中的临床应用及血药谷浓度达标情况,评价新生儿万古霉素群体药动学模型建立的必要性。方法:回顾性收集苏州市立医院本部新生儿科2011年7月-2014年8月使用万古霉素的病史材料,对其感染部位、病原学检查、疗程、疗效、合并用药、血药浓度监测结果进行统计与分析。结果:入选71例患儿,90.14%为多部位混合感染,最常见的是呼吸道合并血流感染(43.66%);病原学送检率100%,首次培养阳性率80.28%,以葡萄球菌属为主(87.67%);万古霉素首次用药后血药谷浓度达标(10~20 mg·L^-1)率28.17%,未达标患者中有43.14%进行剂量调整,调整后达标率50%;万古霉素总临床有效率为90.14%,血药谷浓度未达标组的临床有效率为42.25%,达标组有效率为47.62%;首次经验性用药未进行剂量调整组万古霉素疗程为(13.41±4.41)d,经验性剂量调整组为(18.73±9.52)d(P=0.00188)。结论:万古霉素治疗新生儿感染疗效确切,但经验性用药后血药谷浓度达标率低,未达标者临床疗效差,经验性多次调整万古霉素用法显著延长患儿治疗时间,因此有必要建立新生儿万古霉素群体药动学模型以实现个体化给药治疗。     

Population pharmacokinetic and pharmacodynamic model of norvancomycin

去甲万古霉素群体药代动力学与药效学研究@张菁$Institute of Antibiotics, Huashan Hospital, Fudan University!Shanghai 200040, China @张婴元$Institute of Antibiotics, Huashan Hospital, Fudan University!Shanghai 200040, China @施耀国$Institute of Antibiotic     

External evaluation of population pharmacokinetic models of vancomycin in neonates: the transferability of published models to different clinical settings

Aims

Vancomycin is one of the most evaluated antibiotics in neonates using modeling and simulation approaches. However no clear consensus on optimal dosing has been achieved. The objective of the present study was to perform an external evaluation of published models, in order to test their predictive performances in an independent dataset and to identify the possible study-related factors influencing the transferability of pharmacokinetic models to different clinical settings.

Method

Published neonatal vancomycin pharmacokinetic models were screened from the literature. The predictive performance of six models was evaluated using an independent dataset (112 concentrations from 78 neonates). The evaluation procedures used simulation-based diagnostics [visual predictive check (VPC) and normalized prediction distribution errors (NPDE)].

Results

Differences in predictive performances of models for vancomycin pharmacokinetics in neonates were found. The mean of NPDE for six evaluated models were 1.35, −0.22, −0.36, 0.24, 0.66 and 0.48, respectively. These differences were explained, at least partly, by taking into account the method used to measure serum creatinine concentrations. The adult conversion factor of 1.3 (enzymatic to Jaffé) was tested with an improvement in the VPC and NPDE, but it still needs to be evaluated and validated in neonates. Differences were also identified between analytical methods for vancomycin.

Conclusion

The importance of analytical techniques for serum creatinine concentrations and vancomycin as predictors of vancomycin concentrations in neonates have been confirmed. Dosage individualization of vancomycin in neonates should consider not only patients'' characteristics and clinical conditions, but also the methods used to measure serum creatinine and vancomycin.     

Developmental pharmacokinetics of propylene glycol in preterm and term neonates

AIM

Propylene glycol (PG) is often applied as an excipient in drug formulations. As these formulations may also be used in neonates, the aim of this study was to characterize the pharmacokinetics of propylene glycol, co-administered intravenously with paracetamol (800 mg PG/1000 mg paracetamol) or phenobarbital (700 mg PG/200 mg phenobarbital) in preterm and term neonates.

METHODS

A population pharmacokinetic analysis was performed based on 372 PG plasma concentrations from 62 (pre)term neonates (birth weight (bBW) 630–3980 g, postnatal age (PNA) 1–30 days) using NONMEM 6.2. The model was subsequently used to simulate PG exposure upon administration of paracetamol or phenobarbital in neonates (gestational age 24–40 weeks).

RESULTS

In a one compartment model, birth weight and PNA were both identified as covariates for PG clearance using an allometric function (CL_i= 0.0849 × {(bBW/2720)^1.69× (PNA/3)^0.201}). Volume of distribution scaled allometrically with current bodyweight (V_i= 0.967 × {(BW/2720)^1.45}) and was estimated 1.77 times higher when co-administered with phenobarbital compared with paracetamol. By introducing these covariates a large part of the interindividual variability on clearance (65%) as well as on volume of distribution (53%) was explained. The final model shows that for commonly used dosing regimens, the population mean PG peak and trough concentrations range between 33–144 and 28–218 mg l⁻¹ (peak) and 19–109 and 6–112 mg l⁻¹ (trough) for paracetamol and phenobarbital formulations, respectively, depending on birth weight and age of the neonates.

CONCLUSION

A pharmacokinetic model was developed for PG co-administered with paracetamol or phenobarbital in neonates. As such, large variability in PG exposure may be expected in neonates which is dependent on birth weight and PNA.     

Rectal and sublingual administration of tacrolimus: a single-dose pharmacokinetic study in healthy volunteers

AimsThe immunosuppressant tacrolimus is usually administered orally. When this is not feasible, other routes of administration may be useful. Previous research suggested that tacrolimus may be applied sublingually or rectally. Pharmacokinetic data are sparse. The aim of this study was to investigate and compare the pharmacokinetics of these alternative formulations with orally administered tacrolimus.MethodsThree single, fixed-dose formulations of tacrolimus were administered in a random sequence in 18 healthy subjects, using a cross-over study design. For sublingual administration, 3 mg of powder obtained from oral capsules was applied under the tongue for a period of 15 min without swallowing, with mouth rinsing afterwards. For rectal administration, a suppository containing 15 mg of the oral powder was used. Oral administration consisted of 7 mg of instant-release tacrolimus capsules (Prograf). Main pharmacokinetic outcome parameters were compared by anova.ResultsSublingual administration showed no clinically significant exposure, contrary to rectal administration, where all subjects had clinically relevant exposure, with a lower relative bioavailability (78%), a lower maximal blood concentration and a later time of maximal blood concentration compared with oral administration.ConclusionsSublingual administration of a single dose of tacrolimus does not result in systemic exposure if care is taken not to swallow saliva and to rinse the oral cavity afterwards. Rectal administration of tacrolimus results in clinically relevant systemic exposure and might represent an alternative formulation in case oral administration is not feasible. When used as a topical agent, systemic side-effects should be considered.     

Inherent Correlation Between Dose and Clearance in Therapeutic Drug Monitoring Settings: Possible Misinterpretation in Population Pharmacokinetic Analyses

During the course of therapeutic drug monitoring (TDM), doses are adjusted to attain a target concentration range and a correlation between clearance (CL) and dose is introduced. In population pharmacokinetic analyses of such TDM data, CL has frequently been modeled as a function of dose. This paper demonstrates by simulation methodology that the TDM process does indeed introduce a correlation between dose and CL which can be interpreted as a nonlinearity. Using literature values of carbamazepine pharmacokinetics, three steady-state concentrations were simulated following a standard 1000 mg total daily dose (TDD) regimen in 100 in silico subjects. A set of clinical rules was established to adjust the TDD based on these three concentrations, as might be done in the clinical setting. Another set of concentrations using these TDM-derived TDDs for each subject (600–1600 mg) was simulated. A standard population pharmacokinetic analysis of the post-TDM data was conducted using NONMEM. This process was replicated 100 times to estimate the type II error rate. When CL was modeled without TDD, plots of WRES versus PRED demonstrated a clear pattern, as did the delta plots of CL (CL minus TVCL) versus TDD, suggesting the covariate TDD should be incorporated into the model. After TDD was included in the model for CL, the objective function value decreased by an average of 75.7 (p < 0.001). In addition, the inter-individual variability in CL expressed as a coefficient of variation decreased by an average of 9.9% and the diagnostic plots improved. Although CL was simulated to be independent of TDD, it was identified as an important covariate using standard approaches in a simulated TDM setting in 100% of the replicated simulation studies. The TDM process introduces a correlation between CL and TDD that can be misinterpreted as nonlinearity in the system     

Population pharmacokinetics of clozapine and its primary metabolite norclozapine in Chinese patients with schizophrenia

Aim:

To develop a combined population pharmacokinetic model (PPK) to assess the magnitude and variability of exposure to both clozapine and its primary metabolite norclozapine in Chinese patients with refractory schizophrenia via sparse sampling with a focus on the effects of covariates on the pharmacokinetic parameters.

Methods:

Relevant patient concentration data (eg, demographic data, medication history, dosage regimen, time of last dose, sampling time, concentrations of clozapine and norclozapine, etc) were collected using a standardized data collection form. The demographic characteristics of the patients, including sex, age, weight, body surface area, smoking status, and information on concomitant medications as well as biochemical and hematological test results were recorded. Persons who had smoked 5 or more cigarettes per day within the last week were defined as smokers. The concentrations of clozapine and norclozapine were measured using a HPLC system equipped with a UV detector. PPK analysis was performed using NONMEM. Age, weight, sex, and smoking status were evaluated as main covariates. The model was internally validated using normalized prediction distribution errors.

Results:

A total of 809 clozapine concentration data sets and 808 norclozapine concentration data sets from 162 inpatients (74 males, 88 females) at multiple mental health sites in China were included. The one-compartment pharmacokinetic model with mixture error could best describe the concentration-time profiles of clozapine and norclozapine. The population-predicted clearance of clozapine and norclozapine in female nonsmokers were 21.9 and 32.7 L/h, respectively. The population-predicted volumes of distribution for clozapine and norclozapine were 526 and 624 L, respectively. Smoking was significantly associated with increases in the clearance (clozapine by 45%; norclozapine by 54.3%). The clearance was significantly greater in males than in females (clozapine by 20.8%; norclozapine by 24.2%). The clearance of clozapine and norclozapine did not differ significantly between Chinese patients and American patients.

Conclusion:

Smoking and male were significantly associated with a lower exposure to clozapine and norclozapine due to higher clearance. This model can be used in individualized drug dosing and therapeutic drug monitoring.     

How to use vancomycin optimally in neonates: remaining questions

In neonates, vancomycin, a narrow-spectrum antibiotic, is the first choice of treatment of late-onset sepsis predominantly caused by Gram-positive bacteria (coagulase-negative staphylococci and enterococci). Although it has been used for >50 years, prescribing the right dose and dosing regimen remains a challenge in neonatal intensive care units for many reasons including high pharmacokinetic variability, increase in the minimal inhibition concentration against staphylococci, lack of consensus on dosing regimen and way of administration (continuous or intermittent), duration of treatment, use of therapeutic drug monitoring, limited data on short- and long-term toxicity, risk of mutant selection and errors of administration linked to concentrated formulations. This article highlights and discusses future research directions, with specific attention given to dosing optimization of vancomycin, including the advantages of modeling and simulation approaches.     

Population pharmacokinetics of caffeine in premature neonates

Objective: To determine population pharmacokinetic parameters of caffeine in premature neonates. Methods: This population analysis was done using 145 serum concentration measurements gathered from 75 hospitalized patients during their routine clinical care. The data were analysed by use of NONMEM (mixed effects modelling) according to a one-compartment open model with either zero or first-order absorption and first-order elimination. The effect of a variety of developmental, demographic and clinical factors (gender, birth weight, current weight, gestational age, postnatal age, postconceptional age and concurrent treatment with phenobarbital and parenteral nutrition) on clearance and volume of distribution was investigated. Forward selection and backward elimination regression identified significant covariates. Results: The final pharmacostatistical model with influential covariates were as follows: clearance (ml · h⁻¹) =5.81 · current weight (kg) + 1.22 · postnatal age (weeks), multiplied by 0.757 if gestational age ≤ 28 weeks and 0.836 if the current primary source of patients' nutrition is parenteral nutrition, and volume of distribution (ml) = 911 · current weight (kg). The interindividual variability in clearance and the residual variability, expressed as coefficients of variation, were 14.87% and 18.44%, respectively. Due to the lack of information on the data set we were unable to characterize the interindividual variability for volume of distribution. Conclusion: In this study, which involved on average only two serum concentrations of caffeine per patient, the use of NONMEM gave us significant and consistent information about the pharmacokinetic profile of caffeine when compared with available bibliographic information. Additionally, parenteral nutrition and low gestational age (≤ 28 weeks) may even come to be considered as risk factors, and their presence may serve as an indicator of the need for periodic monitoring of caffeine concentrations in premature infants. Received: 27 July 1996 / Accepted in revised form: 26 November 1996     

多黏菌素B的群体药动学研究进展

多黏菌素是糖肽类抗生素,对多药耐药革兰阴性菌有效。近年来多黏菌素的群体药动学研究不断丰富。本文对当前已发表的多黏菌素B群体药动学研究进行综述,为其临床应用和进一步研究提供参考。目前已有报道共15项,分别在多药耐药革兰阴性菌感染等重症感染、不同肾功能、接受肾脏移植、接受持续性肾脏替代治疗、体外肺膜氧合、肥胖及囊性纤维化等患者中开展了多黏菌素B的群体药动学研究,其中7项研究将患者肌酐清除率纳入多黏菌素B药物清除率的协变量,3项将患者体质量纳入最终模型作为协变量。与早期的群体药动学研究结论相反,近期研究结果显示,患者的肌酐清除率是显著影响多黏菌素B血浆清除率的因素之一;目前多黏菌素B给药剂量是基于患者体质量设置,但体质量与药物清除率的相关性目前尚存争议。因此,为达到目标药物暴露量并避免肾脏毒性发生,有必要在患者用药期间进行血药浓度监测。     

Population pharmacokinetics of domperidone in preterm neonates

Purpose  A population pharmacokinetic analysis was performed to define domperidone pharmacokinetic parameters in preterm neonates, as no pharmacokinetic data are available in this population. Methods  An oral domperidone solution was administered (0.75 mg/kg per day) in 32 preterm neonates (64 samples). Domperidone plasma concentration was measured by high-performance liquid chromatography (HPLC) assay, and a one-compartment model with first-order absorption was fitted to the data using NONMEM version V level 1.1. Results  The mean peak and trough plasma concentration values of domperidone were, respectively, 25.3 ± 20.5 ng/ml and 15.4 ± 11.4 ng/ml (mean ± standard deviation). The pharmacokinetic parameters (interindividual variability%) were clearance (Cl/F) = 0.92 L/h (51.6%), volume of distribution (Vd/F) = 0.405 L (68%), and absorption constant rate (Ka) = 0.0843 h⁻¹ (55.8%). The clearance is not lower than values reported in adults. No influence of covariates (postnatal age, prematurity, weight, gender) on domperidone pharmacokinetic parameters was found. Conclusion  This pilot study designed with a limited sampling strategy showed that domperidone plasma concentrations were consistent with those reported in adults, suggesting that domperidone dosage regimen currently used in preterm neonates is suitable.     

左旋多巴中国人群药动学模型的建立

目的:建立中国人群左旋多巴/苄丝肼复合制剂中左旋多巴的群体药动学模型。方法:前瞻性收集服用多巴丝肼片的帕金森病(PD)门诊患者稳态谷浓度97例102个血样和健康志愿者13例153个密集血样,高效液相色谱-电化学(HPLC-ECD)法测定左旋多巴(LD)血药浓度。应用NONMEM软件进行群体药动学数据分析,Bootstrap重复抽样用于模型的内部验证。另收集20例PD患者22个血样点作为验证组进行模型外部验证,计算最简模型和最终模型对验证组的平均预测误差(MPE)和平均绝对误差(MAE)对模型进行外部验证。结果:数据采用一房室模型拟合,年龄(AGE)对LD清除率有显著影响,性别(SEX)、体质量(WT)、给药剂量(TAMT)、合并用药不影响LD的药动学参数。LD的基础模型为:CL(CL/F)(L.h-1)=18.2×EXP[ETA(1)],V(V/F)(L)=48.4,ka(h-1)=2.13×EXP[ETA(2)];最终模型为:CL(CL/F)(L.h-1)=17.9×(55/AGE)0.59×(EXP[ETA(1)],V(V/F)(L)=47.5,ka(h-1)=2.14×EXP[ETA(2)]。CL、V、ka的群体典型值分别为17.9 L.h-1、47.5 L、2.14 h-1。Bootstrap重复抽样显示所建立的最终模型稳定、可靠,最终模型对验证组的MPE和MAE较最简模型有显著改善,显示模型有效,且有一定代表性。结论:根据患者的生理用药资料,结合上述模型,可估算个体药动学参数,为临床个体化给药提供参考。     

Population pharmacokinetic modelling of gentamicin and vancomycin in patients with unstable renal function following cardiothoracic surgery

AIMS: To describe the population pharmacokinetics of gentamicin and vancomycin in cardiothoracic surgery patients with unstable renal function. METHODS: Data collected during routine care were analyzed using NONMEM. Linear relationships between creatinine clearance (CL(Cr)) and drug clearance (CL) were identified, and two approaches to modelling changing CL(Cr) were examined. The first included baseline (BCOV) and difference from baseline (DCOV) effects and the second allowed the influence of CL(Cr) to vary between individuals. Final model predictive performance was evaluated using independent data. The data sets were then combined and parameters re-estimated. RESULTS: Model building was performed using data from 96 (gentamicin) and 102 (vancomycin) patients, aged 17-87 years. CL(Cr) ranged from 9 to 172 ml min(-1) and changes varied from -76 to 58 ml min(-1) (gentamicin) and -86 to 93 ml min(-1) (vancomycin). Inclusion of BCOV and DCOV improved the fit of the gentamicin data but had little effect on that for vancomycin. Inclusion of interindividual variability (IIV) in the influence of CL(cr) resulted in a poorly characterized model for gentamicin and had no effect on vancomycin modelling. No bias was seen in population compared with individual CL estimates in independent data from 39 (gentamicin) and 37 (vancomycin) patients. Mean (95% CI) differences were 4% (-3, 11%) and 2% (-2, 6%), respectively. Final estimates were: CL(Gent) (l h(-1)) = 2.81 x (1 + 0.015 x (BCOV(CLCr)-BCOV(CLCr Median)) + 0.0174 x DCOV(CLCr)); CL(Vanc) (l h(-1)) = 2.97 x (1 + 0.0205 x (CL(Cr)-CL(Cr Median))). IIV in CL was 27% for both drugs. CONCLUSIONS: A parameter describing individual changes in CL(cr) with time improves population pharmacokinetic modelling of gentamicin but not vancomycin in clinically unstable patients.     

Population kinetics of gentamicin in neonates

A population kinetic analysis was carried out on sparse plasma gentamicin (GE) concentration data from 469 neonates obtained as part of a routine therapeutic drug monitoring (TDM) programme in the hospital neonatology unit.The best predictors of the kinetic parameters of the monoexponential model, volume of distribution (Vd) and clearance (CL), were the weight (WT) and gestational age (GA). Vd of the neonates was only related to WT, whereas the half-life was only related to the GA.     

Population pharmacokinetic model of canrenone after intravenous administration of potassium canrenoate to paediatric patients

AIMS

To characterize the population pharmacokinetics of canrenone following administration of potassium canrenoate to paediatric patients.

METHODS

Data were collected prospectively from 23 paediatric patients (2 days to 10 years of age; median weight 4 kg, range 2.16–28.0 kg) who received intravenous potassium canrenoate (K-canrenoate) as part of their intensive care therapy for removal of retained fluids, e.g. in pulmonary oedema due to chronic lung disease and for the management of congestive heart failure. Plasma samples were analyzed by HPLC for determination of canrenone (the major metabolite and pharmacologically active moiety) and the data subjected to pharmacokinetic analysis using NONMEM.

RESULTS

A one compartment model best described the data. The only significant covariate was weight (WT). The final population models for canrenone clearance (CL/F) and volume of distribution (V/F) were CL/F (l h⁻¹) = 11.4 × (WT/70.0)^0.75 and V/F (l) = 374.2 × (WT/70) where WT is in kg. The values of CL/F and V/F in a 4 kg child would be 1.33 l h⁻¹ and 21.4 l, respectively, resulting in an elimination half-life of 11.2 h.

CONCLUSIONS

The range of estimated CL/F in the study population was 0.67–7.38 l h⁻¹. The data suggest that adjustment of K-canrenoate dosage according to body weight is appropriate in paediatric patients.     

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.     

Busulfan dosing algorithm and sampling strategy in stem cell transplantation patients

Aim

The aim of this investigation was to develop a model-based dosing algorithm for busulfan and identify an optimal sampling scheme for use in routine clinical practice.

Methods

Clinical data from an ongoing study (n = 29) in stem cell transplantation patients were used for the purposes our analysis. A one compartment model was selected as basis for sampling optimization and subsequent evaluation of a suitable dosing algorithm. Internal and external model validation procedures were performed prior to the optimization steps using ED-optimality criteria. Using systemic exposure as parameter of interest, dosing algorithms were considered for individual patients with the scope of minimizing the deviation from target range as determined by AUC(0,6 h).

Results

Busulfan exposure after oral administration was best predicted after the inclusion of adjusted ideal body weight and alanine transferase as covariates on clearance. Population parameter estimates were 3.98 h^–1, 48.8 l and 12.3 l h^–1 for the absorption rate constant, volume of distribution and oral clearance, respectively. Inter-occasion variability was used to describe the differences between test dose and treatment. Based on simulation scenarios, a dosing algorithm was identified, which ensures target exposure values are attained after a test dose. Moreover, our findings show that a sparse sampling scheme with five samples per patient is sufficient to characterize the pharmacokinetics of busulfan in individual patients.

Conclusion

The use of the proposed dosing algorithm in conjunction with a sparse sampling scheme may contribute to considerable improvement in the safety and efficacy profile of patients undergoing treatment for stem cell transplantation.     

群体药代动力学在万古霉素治疗药物监测的应用

群体药代动力学(PPK)应用统计学原理,可综合评价影响药代动力学个体间及个体内差异的各种因素,并进一步利用Bayesian反馈,能较为准确地预测患者个体药代动力学参数。PPK在万古霉素治疗药物监测、给药方案设计调整及药动-药效研究中均有广泛应用。     

基于群体药代动力学模型仿真探索氨磺必利有效浓度范围

目的:以群体药动学模型仿真为基础,探索氨磺必利有效浓度范围,解决临床实际应用中血药浓度超过治疗参考范围的问题。方法:回顾性收集广州医科大学附属脑科医院2019至2020年接受氨磺必利治疗的精神科患者的治疗药物监测(therapeutic drug monitoring,TDM)数据及相关病历资料,采用非线性混合效应模型对氨磺必利血药浓度数据进行拟合分析,通过协变量筛选评估获得最终模型,模拟仿真各种剂量下氨磺必利血药浓度分布范围。结果:121名患者的330个血药浓度数据的68%可信区间血药浓度范围是185.59~650.94ng·mL^-1,采用建立的一室模型[最终模型:CL/F=61.1×(AGE/32)^-0.624,L·h^-1],模拟仿真发现当给药剂量在200~400mg·d^-1时,氨磺必利的平均血药浓度范围在《神经精神科治疗药物监测共识指南(2017版)》推荐有效浓度范围(100~320ng·mL^-1)内,在给药剂量400~800mg·d^-1时,平均血药浓度为300~600ng·mL^-1。结论:可根据临床治疗情况,将氨磺必利有效浓度范围暂定100~600ng·mL^-1,对应的推荐给药剂量为200~800mg·d^-1。     

Lopinavir/ritonavir population pharmacokinetics in neonates and infants

AIMS

Because of immature hepatic metabolism, lopinavir could present specific pharmacokinetics in the first weeks of life. We aimed at determining the optimal dosing regimen in neonates and infants weighing 1 to 10.5 kg.

METHODS

Lopinavir/ritonavir (LPV/r) pharmacokinetics were studied in 96 infants using a population approach.

RESULTS

A one-compartment model described LPV/r pharmacokinetics. Normalized to a 70 kg adult using allometry, clearance (CL/F) and distribution volume (V/F) estimates were 5.87 l h⁻¹ 70 kg⁻¹ and 91.7 l 70 kg⁻¹. The relative bioavailabilty, F, increased with post-menstrual age (PMA) and reached 50% of the adult value at 39.7 weeks.

CONCLUSIONS

Size and PMA explained some CL/F and V/F variability in neonates/infants. Based upon trough concentration limitations, suggested LPV/r dosing regimens were 40 mg 12 h⁻¹, 80 mg 12 h⁻¹ and 120 mg 12 h⁻¹ in the 1–2 kg, 2–6 kg and 6–10 kg group, respectively.