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     

The pharmacokinetics of theophylline in premature neonates during the first few days after birth

The aims of the study were to estimate the pharmacokinetic parameters, clearance rate (CL), and volume of distribution (V) of theophylline in premature neonates during the first few days after birth, and to identify factors contributing to interindividual variability. The authors obtained 263 serum concentrations from 105 apneic premature neonates receiving intravenous (IV) theophylline. Mean (SD) birth weight and postnatal ages were 1.3 (0.3) kg and 1.1 (0.3) days, respectively. The data were analyzed using the nonlinear mixed effects model (NONMEM). A one-compartment model with first order elimination was used. The final models were: CL (L/h) = 0.006 * WGT 0.75 * P, V (L) = 0.63 * WGT, WGT = weight (kg) P = 1.47 with oxygen support and 1.0 without oxygen support. The CL in the study population was low, resulting in long half-lives. After inclusion of the above covariates, as well as interoccasion variability, the interindividual variability in CL was 56% and in V was 47%. Interoccasion variability in CL and V was 34% and 35% respectively. Theophylline pharmacokinetics are variable in the premature neonate during the first week of life, and this high variability makes it difficult to predict drug concentrations with the same degree of accuracy as in other populations.     

Population pharmacokinetics of gentamicin in South African newborns

Objective Gentamicin population pharmacokinetics in newborns were studied with special reference to possible gender effects.Methods Steady-state serum levels (n=139) were obtained from 79 neonates with a mean birth weight of 2.1 kg, mean gestational age of 35.1 weeks and mean age at the time of sampling of 4.2 days. The data were analysed using the non-linear mixed effects model (NONMEM). A one-compartment model was used to fit the data.Results The final models for clearance (CL) and volume of distribution (V) were: CL(l/h)=0.001×WGT×GA×P and V(l)=0.472×WGT, where WGT=birth weight (kg), GA=gestational age (weeks) and P=1.2 for girls and 1.0 for boys. The values of inter-individual variability in CL and V were 34% and 35%, respectively. Intra-individual variability was 5% (proportional) and 7.2% (additive). Mean (95% confidence interval) values of CL and half-life were 0.042 l h^–1 kg^–1 (0.041, 0.043 l h^–1 kg^–1) and 8.0 h (7.7, 8.3 h), while V was 0.472 (0.428, 0.516) l/kg for all patients.Conclusion Mean population pharmacokinetic values were similar to those obtained with NONMEM for gentamicin in other neonates of similar age. Gender was found to be a determinant of CL, with girls clearing faster than boys.     

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.     

A gentamicin pharmacokinetic population model and once-daily dosing algorithm for neonates

STUDY OBJECTIVE: To develop a gentamicin pharmacokinetic population model and once-daily dosing algorithm for neonates younger than 10 days. DESIGN: Prospective, open-label study. SETTING: Neonatal intensive care unit. PATIENTS: One hundred thirty-nine neonates prescribed gentamicin. MEASUREMENTS AND MAIN RESULTS: Gentamicin peak and trough serum concentrations were collected from 139 neonates divided into three groups who were receiving one of the following intravenous 24-hour gentamicin regimens during the first 10 days of life, based on gestational age and birth weight (group 1, < 28 wks, 2.5 mg/kg; group 2, 28-34 wks, 3 mg/kg; and group 3, > 34 wks, 4 mg/kg). A structural model was developed in ADAPT II software using a MAP Bayesian approach. Final population parameter estimates were calculated using iterative two-stage analysis. The median (range) gestational age and birth weight, respectively, were 32 weeks (23-42 wks) and 1.92 kg (0.47-5.00 kg). The final one-compartmental linear model had a median (range) gentamicin total clearance, half-life, and volume of distribution of 0.0709 L/hour (0.0151-0.246 L/hr), 8.59 hours (4.88-16.9 hrs), and 0.262 L (0.0903-0.929 L), respectively. Total clearance increased as gestational age increased (p<0.001). Group 1 (10.2 hrs) had a significantly longer half-life than either group 2 (8.89 hrs, p<0.01) or group 3 (6.98 hrs, p<0.01). Total clearance was associated with gestational age and birth weight: clearance (L/hr) = (0.00504 + [0.00108 x gestational age]) x birth weight (coefficient of determination [r2] = 0.897), and volume of distribution was associated with birth weight (r2 = 0.700). The following dosing algorithm was designed to reach a therapeutic 24-hour area under the curve (87.5 mg/L x hr) in neonates during the first 10 days after birth: 24-hour gentamicin dose (mg) = (0.441 + [0.0945 x gestational age]) x birth weight. CONCLUSION: This dosing algorithm provides a new approach for determining initial gentamicin dosing regimens in neonates; however, clinical validation is required.     

The effect of sepsis upon gentamicin pharmacokinetics in neonates

AIM: To investigate the effect of sepsis upon the volume of distribution (Vd) of gentamicin in neonates. METHODS: A retrospective chart review was conducted of neonates admitted to Dunedin Hospital who had gentamicin concentrations performed between 1st January 2000 and 30th October 2003. Data from 277 neonates, including a total of 576 gentamicin concentrations, were included in the pharmacokinetic analysis. Fifteen (5.4%) of the neonates had confirmed sepsis. Pharmacokinetic analyses were performed with NONMEM using a one compartment first order elimination model. Duration of infusion (D) was included as a parameter in the model. Covariates included sepsis (SEP), chronological age, gestational age (GA), birth weight, current weight, gender, Apgar score at 1 (AP1) and 5 (AP2) minutes, plasma C-reactive protein and serum creatinine. RESULTS: The initial model provided a mean estimates of clearance (CL) of 0.0460 l kg(-1) h(-1), volume of distribution (Vd) of 0.483 l kg(-1) and D of 0.748 h. The magnitudes of interpatient variability, expressed as CV%, were 29.2% for CL, 20.8% for Vd and 71.5% for D. The magnitude of residual variability in gentamicin concentrations was 88.0%. The final pharmacokinetic model was: CL = (0.0177 + 0.00147.(GA-20) + 0.000635.AP2) l kg(-1) h(-1), Vd = (0.483 +0.0656. sepsis) l kg(-1), D = 0.672 h. The interpatient variability (CV%) was 22.8% for CL, 22.8% for Vd and 97.7% for D. The magnitude of residual variability in gentamicin concentrations was 83.3%. CONCLUSIONS: The 14% increase in Vd in septic neonates implies that larger doses may be required to achieve peak therapeutic concentrations in the presence of sepsis. D is an important parameter in neonatal pharmacokinetic models.     

The kinetic profile of gentamicin in premature neonates

The kinetic profile of gentamicin in premature infants has been studied to enable the development of optimized dosage schedules for neonatal intensive-care units and to stress the relationship between the pharmacokinetic parameters and several demographic, developmental and clinical factors which might be associated with changes in gentamicin disposition. Sixty-eight newborn patients of 24- to 34-weeks gestational age and 600-3,100 g current weight in their first week of life, undergoing routine therapeutic drug monitoring of their gentamicin serum levels, were included in this retrospective analysis. Gentamicin pharmacokinetic parameters were determined through non-linear regression by using a single-compartment open model. By regression analysis the current weight (g) was shown to be the strongest co-variate, and both gentamicin clearance (L h(-1)) and volume of distribution (L) had to be normalized. Additionally, gentamicin clearance depended on gestational age with a cut-off at 30 weeks, which allowed the division of the overall population into two subsets (< 30 weeks and between 30-34 weeks of gestational age). The younger neonates (<30 weeks of gestational age) showed a lower gentamicin clearance (0.0288 vs 0.0340 L h(-1) kg(-1)), a slightly higher volume of distribution (0.464 vs 0.435 L kg(-1)), and a longer half-life (11.17 vs 8.88 h) compared with the older subgroup (30-34 weeks of gestational age). On the basis of the pharmacokinetic parameters obtained, we suggest loading doses of 3.7 and 3.5 mg kg(-1) for the two subgroups of neonates (<30 weeks and 30-34 weeks of gestational age), respectively. The appropriate maintenance doses in accordance with the characteristics of the patients should be 2.8 mgkg(-1)/24h and 2.6 mg kg(-1)/18 h for neonates < 30 weeks and between 30-34 weeks of gestational age, respectively. Finally, when compared with previous studies, the information obtained on the pharmacokinetics and determinants of the pharmacokinetic variability of gentamicin in neonates was shown to be consistent.     

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.     

Population pharmacokinetics of tobramycin in hospitalized patients receiving once-daily dosing regimen

The population pharmacokinetics of tobramycin was investigated in a group of 327 adult hospitalized patients receiving once-daily administration of tobramycin at a dose of 7 mg kg(-1). The patients had an average age of 57+/-18 y and an average weight of 65+/-14 kg; 153 of the patients were female. Data, comprised of 575 serum concentrations, were analyzed using a nonlinear mixed-effect model (NONMEM) with a first-order conditional estimation method and were best described with a one-compartment model. The patient covariates including body weight, gender, age and creatinine clearance (CL(CR)) were added in a stepwise fashion to identify their potential influences on tobramycin pharmacokinetics. Results showed that tobramycin clearance (CL) was linearly correlated with CL(CR) (proportionality constant: 0.066+/-0.002 x CL(CR) (ml min(-1))) and the volume of distribution (Vd) was linearly related to body weight (proportionality constant: 0.40+/-0.024 x body weight (1 kg(-1))). The mean population estimates for CL and Vd were 4.53 l h(-1) and 27.3 l, respectively. The half-life of tobramycin was estimated to be 4.2 h. The inter-individual variability in CL and Vd were 37.0 and 28.5%, respectively. The residual error was 1.2 mg l(-1). Based on the results, optimal dosing intervals for renal impaired patients were calculated and were comparable with the intervals derived from the previous established nomogram.     

中国患者异丙酚群体药代动力学(英文)

目的:用NONMEN程序分析中国患者群体药代动力学,并定量研究性别、年龄和体重对异丙酚药代参数的影响。方法:研究了76例择期手术的患者(男37例、女39例、年 龄19-77岁、体重39-86kg),共收集1459个血液标本。用NONMEN方法分析清除率和分布容积的个体间变异以及年龄、体重和性别的影响。结果:可用三室模型模拟异丙酚的药代动力学参数。体重可影响异丙酚的中央室、浅外周室和深外周室的清除率以及中央室的分布容积,而浅外周室和深外周室的分布容积保持不变。体重60kg的成人的上述药代参数的估计值分别为:1.56L/min、0.737L/min、0.360L/min、12.1L、43L、213L。老人随年龄的增大而清除率和中央室的分布容积减少。结论:中国人的异丙酚的药代动力学可用标准三室模型描述,年龄和体重可影响模型参数。因此根据患者的个体药代参数可改善靶控输注的精密度。     

Population pharmacokinetic analysis of vancomycin in neonates. A new proposal of initial dosage guideline

AIM

To determine the population pharmacokinetic parameters of vancomycin in neonatal patients with a wide range of gestational age and birth weight, and subsequently to design an initial dosing schedule for vancomycin in neonates.

METHODS

Using nonlinear mixed-effects modelling (NONMEM VI), the pharmacokinetics of vancomycin were investigated in 70 neonates with postmenstrual age and body weight ranging 25.1–48.1 weeks and 0.7–3.7 kg, respectively. A one-compartment linear disposition model with zero order input and first-order elimination was used to describe the data. Nine demographic characteristics and 21 co-administered drugs were evaluated as covariates of clearance (CL) and distribution volume (V_d) of vancomycin.

RESULTS

Weight-normalized clearance of vancomycin was influenced by postmenstrual age (PMA) and co-administration of amoxicillin-clavulanic acid. Weight-normalized volume of distribution was influenced by co-administration of spironolactone. CL and V_d of the typical individual in this study population (PMA = 34.6 weeks, weight = 1.7 kg) were estimated to be 0.066 l h⁻¹ kg⁻¹ (95% CI 0.059, 0.073 l h⁻¹ kg⁻¹) and 0.572 l kg⁻¹ (95% CI 0.505, 0.639 l kg⁻¹), respectively. This model was used to predict a priori serum vancomycin concentrations in a validation group (n= 41), which were compared with observed concentrations to determine the predictive performance of the model. The 95% confidence interval of mean prediction error included zero for both peak and trough vancomycin concentrations.

CONCLUSIONS

Postmenstrual age, co-administration of amoxicillin-clavulanic acid and spironolactone have a significant effect on the weight-normalized CL and V_d. An initial dosage guideline for vancomycin is proposed for preterm and full-term neonates, whereas the population pharmacokinetic model can be used for dosage individualization of vancomycin.     

Orogastric and intravenous indomethacin administration to very premature neonates with patent ductus arteriosus: population pharmacokinetics, absolute bioavailability, and treatment outcome

A population pharmacokinetic model was developed after administration of orogastric and/or intravenous indomethacin for the treatment of patent ductus arteriosus in preterm infants. Plasma indomethacin concentrations (n=227) were obtained from 90 preterm infants of median gestational age 27 weeks, mean postnatal age of 12 days, and a mean current weight (WT) of 1010 g. Infants received one to three courses of indomethacin (0.1 mg/kg per day for 6 days). A one-compartment model was fitted to the data to obtain estimates of clearance (CL), volume of distribution (V), absorption rate constant (Ka) and orogastric bioavailability (F), using NONMEM. Model robustness was assessed by bootstrapping with replacement (500 samples). The structural model was: CL (L/h)=0.0166 (WT / 0.936)1.54; V (L)=0.484 (WT / 0.936)1.41; F=0.986; Ka (h(-1))=0.786. The interindividual variability for CL and V was 57.7% and 45.6%, respectively. There remained considerable residual unexplained variability (45.4%). Mean (range) conditional estimates from individual infants for CL, V, and elimination half-life were 18.9 (4.7-45.5) mL/h/kg, 509 (191-1120) mL/kg, and 20.0 (12.0-37.3) hours, respectively. Complete ductus closure occurred in 67% of patients. Infants of lower gestational age or birth weight had less chance of successful ductal closure. There was no obvious dose-response relationship between systemic exposure to varying plasma indomethacin concentrations and ductus closure, which does not support individualized indomethacin dosing based on monitoring to a target plasma concentration.     

Population pharmacokinetics of ibuprofen enantiomers in very premature neonates

The objective of the present study was to evaluate the pharmacokinetic parameters for both S- and R-ibuprofen enantiomers in very premature neonates (gestational age strictly inferior to 28 weeks) and possible relationships between the pharmacokinetic parameters and various covariates. Newborns were randomized to receive ibuprofen or placebo for the prophylactic treatment of patent ductus arteriosus (PDA) at an initial dose of 10 mg/kg ibuprofen within 6 hours after birth, followed by two 5-mg/kg doses at 24-hour intervals (n = 52). If a PDA was still present afterwards, a curative course of ibuprofen using the same dosage regimen was administered (n = 10). A sparse sampling strategy was used because only 2 samples were collected after the third prophylactic injection and 1 after the third curative injection. A model including the chiral transformation of R- to S-ibuprofen was fitted to the concentration-time data using a population approach (NONMEM). R- and S-ibuprofen t(1/2) were about 10 hours and 25.5 hours, respectively. After prophylactic treatment, the mean clearance of R-ibuprofen (CLR = 12.7 mL/h) was about 2.5-fold higher than for S-ibuprofen (CLS = 5.0 mL/h). In addition, clearance of R- and S-ibuprofen increased significantly with gestational age. The mean estimation of R-ibuprofen clearance was found to be higher than for S-ibuprofen, and the clearance of both enantiomers increased with gestational age. This should be considered to assess pharmacokinetic-pharmacodynamic relationships of ibuprofen in premature neonates and subsequently to understand and refine the use of ibuprofen in managing PDA either as a prophylactic or curative treatment.     

Development of a Population Pharmacokinetic Model for Taranabant, a Cannibinoid-1 Receptor Inverse Agonist

Taranabant is a cannabinoid-1 receptor inverse agonist developed for the treatment of obesity. A population model was constructed to facilitate the estimation of pharmacokinetic parameters and to identify the influence of selected covariates. Data from 12 phase 1 studies and one phase 2 study were pooled from subjects administered single and multiple oral doses of taranabant ranging from 0.5 to 8 mg. A total of 6,834 taranabant plasma concentrations from 187 healthy and 385 obese subjects were used to develop the population model in NONMEM. A standard covariate analysis using forward selection (α = 0.05) and backward elimination (α = 0.001) was conducted. A three-compartment model with first-order absorption and elimination adequately described plasma taranabant concentrations. The population mean estimates for apparent clearance and apparent steady-state volume of distribution were 25.4 L/h and 2,578 L, respectively. Statistically significant covariate effects were modest in magnitude and not considered clinically relevant (the effects of body mass index (BMI) and creatinine clearance (CrCL) on apparent clearance; BMI, age, CrCL, and gender on apparent volume of the peripheral compartment and age on apparent intercompartmental clearance). The pharmacokinetic profile of taranabant can adequately be described by a three-compartment model with first-order absorption and elimination. Clinical dose adjustment based on covariates effects is not warranted.Key words: NONMEM, obesity, pharmacokinetics, population, taranabant     

Population pharmacokinetics of tobramycin.

1. Population pharmacokinetic parameters of tobramycin were determined in a heterogenous group of 97 patients using serum samples drawn for the routine monitoring of tobramycin concentrations, following multiple dosing regimens. 2. To describe the accumulation kinetics of tobramycin a two-compartment pharmacokinetic model was required. The best fit to the data was obtained when drug clearance (1 h-1) was related linearly to creatinine clearance (proportionality constant: 0.059 +/- 0.002 x CLcr (ml min-1)) and initial volume of distribution (1) was related linearly to body weight (proportionality constant: 0.327 +/- 0.014 x body weight (kg)). The intersubject variability in these two parameters was 32% and 3%, respectively, whilst the residual or intrasubject variability amounted to 21% of the tobramycin concentration. The terminal half-life of tobramycin, 26.6 +/- 9.4 h, was appreciably shorter than previously reported. 3. The population pharmacokinetic model was validated against data obtained from 34 independent patients and the predicted and observed concentrations were found to be in good agreement. The population pharmacokinetic model was used to design a priori dosing recommendations for tobramycin.     

NONMEM and NPEM2 population modeling: a comparison using tobramycin data in neonates

Nonlinear mixed effects modeling (NONMEM) and nonparametric expectation maximization (NPEM2) have both been used in population modeling of tobramycin. We compared both methods for differences in population pharmacokinetic parameters in relation to error models used. Predictive performance was compared between models. A group of 470 neonates who had received tobramycin according to a gestational age (GA)-dependent dosing interval was analyzed according to a one-compartment model with NONMEM and NPEM2. Additional models were constructed where the assay error pattern in NPEM2 mimicked NONMEM residual error and vice versa. Individual pharmacokinetic parameter estimates were compared. Predictive performance was evaluated in a separate group of 61 patients. Population estimates and variation coefficients (CV) for optimal models were NONMEM K(el) 0.071 h(-1) (27%), V(d) 0.59 L/kg (9%); NPEM2 K(el) 0.079 h(-1) (42%), V(d) 0.65 L/kg (48%). Forcing NONMEM to use the NPEM2 error pattern as residual error or vice versa resulted in smaller differences in CVs of the estimates. NONMEM gave less bias (P < 0.05) than NPEM2 and comparable precision with this approach. In conclusion NONMEM and NPEM2 are dissimilar in population estimates. Differences in ranges of pharmacokinetic parameter estimates between NONMEM and NPEM2 are largely determined by the method of incorporating error patterns in both programs.     

Limited predictability of amikacin clearance in extreme premature neonates at birth

AIM: Identify and quantify factors describing variability of amikacin clearance in preterm neonates at birth. METHODS: Population pharmacokinetics of amikacin were estimated in a cohort of 205 extreme preterm neonates [post conception age (PCA) 27.8, SD 1.8, range 24-30 weeks; weight 1.07, SD 0.34, range 0.45-1.98 kg, postnatal age < 72 h]. Covariate analysis included weight, PCA, Apgar score, prophylactic administration of a nonsteroidal anti-inflammatory drug (NSAID) to the neonate, maternal indomethacin and betamethasone administration, and chorioamnionitis. RESULTS: A one-compartment linear disposition model with zero order input (0.3 h i.v. infusion) and first-order elimination was used. The population parameter estimate for volume of distribution (V) was 40.2 l per 70 kg. Clearance (CL) increased from 0.486 l h(-1) per 70 kg at 24 weeks PCA to 0.940 l h(-1) per 70 kg by 30 weeks PCA. The population parameter variability (PPV) for CL and V was 0.336 and 0.451. The use of a NSAID (either aspirin or ibuprofen) in the first day of life reduced amikacin clearance by 22%. Overall 65% of the variability of CL was predictable. Weight explained 48%, PCA 15% and NSAIDs 2%. CONCLUSIONS: Size and post-conception age are the major contributors to clearance variability in extreme premature neonates (<31 weeks PCA). The large (35% of total) unexplained variability in clearance reinforces the need for target concentration intervention to reduce variability in exposure to a safe and effective range.     

Clinical pharmacokinetics of phenobarbital in neonates.

Demographic and clinical pharmacokinetic data collected from term and preterm neonates who were treated with intravenous phenobarbital have been analysed to evaluate the role of patient characteristics in pharmacokinetic parameters. Significant relationships between total body weight (TBW) or body surface area (BSA) and volume of distribution (Vd) and total body clearance (CL) were found. Coefficients of determination were: 0.55 and 0.59 for Vd, and 0.76 and 0.72 for CL against TBW and BSA, respectively. In addition, significant relationships between height of the infants and volume of distribution of phenobarbital and total body clearance were observed. Coefficients of determination were 0.58 for Vd and 0.56 for CL. A weaker but significant correlation existed between gestational age and Vd or CL of phenobarbital. Coefficients of determination were 0.43 and 0.64, respectively. There was no correlation between volume of distribution per kg body weight or total body clearance per kg body weight and any patient parameter investigated. However, these latter pharmacokinetic parameters tended to decrease with increasing gestational age and height of the neonates. The results obtained were used to develop new loading and maintenance doses for phenobarbital in neonates based on total body weight and body surface area and based on height and gestational age for cases that weight is not available.     

The population pharmacokinetics of theophylline in neonates and young infants

The population pharmacokinetics of theophylline were evaluated using 391 theophylline serum concentration measurements from 108 neonates and young infants (postnatal age 0-26 weeks), who received theophylline for the treatment of neonatal apnea. A one-compartment pharmacokinetic model with first-order elimination was used, with intravenous aminophylline and oral theophylline administration modeled as zero-order infusions. The effect of a variety of developmental and demographic factors on clearance (CL) and volume (V) were investigated. Hypothesis testing to evaluate potentially significant factors produced a final model in which clearance was based on weight (kg) raised to an exponential power and postnatal age (weeks), with CL (ml/hr) = 17.5 (weight)1.28 + 1.17 (postnatal age). Clearance was reduced by 12% for patients receiving parenteral nutrition. Volume of distribution in this population was adequately described using only weight, with V (L) = 0.858 L/kg. Bioavailability of orally administered drug was not significantly less than unity. Interindividual variability in clearance was modest, with a coefficient of variation for clearance of 16%. An estimate of interindividual variability in volume could not be obtained. As a measure of residual variability in theophylline serum concentrations, the coefficients of variation for theophylline serum concentrations of 5.0, 10.0, and 13.0 mg/L were found to be approximately, 25, 12, and 9%, respectively. The identification of influential patient factors and the quantification of their influence on theophylline disposition allow for a priori estimates of theophylline pharmacokinetic parameters in these patients.