Population pharmacokinetics of caffeine in premature neonates (original) (raw)
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BMC pharmacology & toxicology, 2016
This study sought to assess the pharmacokinetic and pharmacodynamic relationships of caffeine citrate therapy in preterm neonates who had therapeutic drug monitoring (TDM) in the post-extubation period. A retrospective observational study was conducted in preterm neonates who received caffeine citrate therapy for apnea of prematurity and had TDM done in the post-extubation period between January 2006 and October 2011. The relationships between pharmacodynamic effects (heart rate, respiratory rate, episodes of apnea, adverse events) and caffeine serum concentrations were explored. A total of 177 blood samples were obtained from 115 preterm neonates with a median (range) gestational age of 29 (24 - 33) weeks and birth weight of 1230 (607 - 2304) kg. Caffeine citrate therapy was initiated at a median (interquartile range) postnatal age of 1 (1 - 3) day and TDM was performed at a postnatal age of 15 (10 - 24) days. No direct correlations were found between respiratory rate or apneic epi...
Pharmacokinetic profile of caffeine in the premature newborn infant with apnea
The Journal of Pediatrics, 1979
The pharmacokinetic profile of caffeine was studied in 32 premature newborn infants with apnea: 12 following a single intravenous dose; 3 after a single oral dose; 7 during treatment with an initial empirical (high) maintenance dose schedule; and 10 during treatment with a revised (lower) dose schedule. Mean (+ SE) A Vd, tt/2, ke~, and clearance following a single intravenous dose were 0.916 +_ 0.070 1/kg, 102.9 + 17.9 hours, 0.009 +_ O.O01/hours and 8.9 +_ 1.5 ml/kg/hour, respectively. Rapid absorption was noted with plasma concentrations of 6 to 10 mg/l achieved within 30 minutes to two hours following an oral dose of lO mg/kg. Cp s" of caffeine in infants given a high empirical dose (il.2 +--1.5 mg/kg/day) ranged from 22.5 to 84.2 mg/l (mean = 45.3) whereas a dose schedule based on kinetic data (2.5 mg/kg/day) yielded plasma concentrations ranging from 7.4 to 19.4 mg/l (mean ~= 13. 7). We suggest a loading dose of 10 mg/kg intravenously or orally followed by a daily maintenance dose of 2.5 mg/ kg/ day administered as a single dose for the treatment and prevention of neonatal apnea.
Serum caffeine concentrations and short-term outcomes in premature infants of ⩽29 weeks of gestation
Journal of perinatology : official journal of the California Perinatal Association, 2014
Objective:Caffeine is effective in the treatment of apnea of prematurity but it is not well known if the therapeutic concentration of the drug has an impact on other neonatal outcomes such as chronic lung disease (CLD). The aim of this study was to determine if there is an association between caffeine concentrations and the incidence of CLD in premature infants of ⩽29 weeks of gestation.Study design:A retrospective chart review of all the infants born ⩽29 weeks of gestation from 2007 to 2011, who survived until discharge or 36 weeks postmenstrual age, was conducted. Caffeine concentrations were obtained weekly on infants getting the drug. Average caffeine concentrations (ACCs) were determined for the duration of caffeine therapy and correlated with CLD, length of stay (LOS), oxygen at discharge (OD), duration of ventilation (DV) and total charges for hospitalization for each patient.Results:Of the 222 eligible infants, 198 met the inclusion criteria. ACC for infants without CLD was ...
Caffeine in apnoeic Asian neonates: a sparse data analysis
British Journal of Clinical Pharmacology, 2002
Aims To monitor plasma caffeine concentrations and adverse effects and to study the pharmacokinetics of caffeine in neonatal apnoea in the local Asian population after intravenous administration of caffeine. Methods Eighteen neonates with apnoea were treated with caffeine citrate at a loading dose of 10 mg caffeine base kg x1 and a maintenance dose of 2.5 mg kg x1 day x1. Blood samples, three after loading and two after the maintenance dose on day 2, 3, 7, 14 and 21 were taken and analysed for caffeine and its main metabolites using solid phase extraction and h.p.l.c. Adverse effects were monitored. Sparse data pharmacokinetic analysis was performed using P-Pharm. Results Mean caffeine concentrations varied from 10 to 20 mg l x1 throughout treatment (range 3.6-28.4 mg l x1). These concentrations were efficacious; less so in those with lower concentrations. Adverse effects included gastrointestinal disturbances, diuresis and hyperglycaemia. Pharmacokinetic parameter estimates [mean (coefficient of variation%)] were CL=0.00628 (17.5%) l h x1 and V=0.961 (20.3%) l. CL (l h x1)=0.004248 * wt(kg)+0.00154; r=0.8, P<0.01, explained 64% of the variation. V (l)=0.6299 * wt(kg)+0.259; r=0.67, P<0.01, explained 45% of variation. Model-predicted compared with observed plasma concentrations in a separate group of 10 neonates were unbiased and of good precision. Conclusions The dosing regimen studied was suitable for our local Asian neonates as it resulted in therapeutic caffeine concentrations for adequate treatment of apnoea. Adverse effects were tolerable. Therefore, to avoid a higher incidence of adverse effects, this regimen should be retained and not increased as proposed by other workers. CL and V were within values of those reported for neonatal apnoea. Sparse data analysis showed that weight alone was adequate as the influential variable for the accurate prediction of individual pharmacokinetic parameters, plasma concentrations and for dosage adjustment if required.
Journal of analytical methods in chemistry, 2018
Caffeine is recognized as the first-line therapeutic agent for apnea of prematurity. The dosage regimen is 10 mg/kg loading dose and 2.5 mg/kg maintenance dose. However, the plasma concentration achieved, not always, is therapeutically useful. It makes necessary to increase the doses to reach plasma concentration up to 30 or 35 g/mL or even higher to attain therapeutic effect. To study why neonates have these differences, and whether these effects are linked to prenatal caffeine exposure, we had to develop an analytical method for an accurate measurement of caffeine and metabolites concentration. The analysis was carried out using fetal bovine serum (FBS) as biological matrix in a high-performance liquid chromatography with an ultraviolet detector method. This method allows acceptable chromatographic resolution between analytes in 15 minutes. It was validated and proved to be linear in the 0.1-40 g/mL range for caffeine, paraxanthine, theobromine, and theophylline in the same chroma...
British journal of clinical pharmacology, 2016
Caffeine concentrations in preterm infants are usually measured in blood. However, salivary assay may provide a valid and practical alternative. This study explores the validity and clinical utility of salivary caffeine concentrations as an alternative to blood concentrations and develops a novel plasma/salivary caffeine distribution model. Paired salivary and plasma samples were obtained in 29 infants. Salivary samples were obtained using a commercially available salivary collection system. Caffeine concentrations in salivary and plasma were determined using high performance liquid chromatography. A population pharmacokinetic (PK) model was developed using NONMEM 7.3. Mean (± SD) gestational age (GA) at birth and birth weight (BW) were 27.9 ± 2.1 weeks and 1171.6 ± 384.9 grams, respectively. Paired samples were obtained at a mean postmenstrual age (PMA) of 35.5 ± 1.1 weeks. The range of plasma caffeine concentrations was 9.5-54.1 µg/ml with a mean difference (95%CI) between plasma ...
DBS–LC–MS/MS assay for caffeine: validation and neonatal application
Bioanalysis, 2016
Aim: DBS might be an appropriate microsampling technique for therapeutic drug monitoring of caffeine in infants. Nevertheless, its application presents several issues that still limit its use. This paper describes a validated DBS–LC–MS/MS method for caffeine. Results: The results of the method validation showed an hematocrit dependence. In the analysis of 96 paired plasma and DBS clinical samples, caffeine levels measured in DBS were statistically significantly lower than in plasma but the observed differences were independent from hematocrit. Conclusion: These results clearly showed the need for extensive validation with real-life samples for DBS-based methods. DBS–LC–MS/MS can be considered to be a good alternative to traditional methods for therapeutic drug monitoring or PK studies in preterm infants.
A Study on Outcome of Early Caffeine Administration in Very Preterm Neonates
Asian Journal of Clinical Pediatrics and Neonatology, 2019
Background: Apnea intervals frequently occur in very preterm infants. Methylxanthenes stimulate breathing efforts and hence have been used for treating apnea of prematurity. Aim: to study the outcome of early caffeine administration in very preterm neonates. Subjects and Methods: The first (1st) group babies received early caffeine within 48 hours of life before developing apnea. The second group (2nd) group babies received caffeine late after 48 hours, after onset of apneic episode. Results: There was no significant difference in the number of episodes of apnea, bradycardia and hypoxemia. Also no significant difference in the incidence of Patent ductus arteriosus (PDA), Intra ventricular hemorrhage (IVH), Necrotizing enterocolitis (NEC), Retinopathy of prematurity (ROP) or Bronchopulmonary dysplsia (BPD). Conclusion: There was no significant difference noted in the number of episodes of apnea, bradycardia and hypoxemia in the group with early caffeine administratration compared to late caffeine administration.