The bioavailability and maturing clearance of doxapram in preterm infants.

BACKGROUND: Doxapram is used for the treatment of apnea of prematurity in dosing regimens only based on bodyweight, as pharmacokinetic data are limited. This study describes the pharmacokinetics of doxapram and keto-doxapram in preterm infants. METHODS: Data (302 samples) from 75 neonates were included with a median (range) gestational age (GA) 25.9 (23.9-29.4) weeks, bodyweight 0.95 (0.48-1.61) kg, and postnatal age (PNA) 17 (1-52) days at the start of continuous treatment. A population pharmacokinetic model was developed using non-linear mixed-effects modelling (NONMEM®). RESULTS: A two-compartment model best described the pharmacokinetics of doxapram and keto-doxapram. PNA and GA affected the formation clearance of keto-doxapram (CLFORMATION KETO-DOXAPRAM) and clearance of doxapram via other routes (CLDOXAPRAM OTHER ROUTES). For a median individual of 0.95 kg, GA 25.6 weeks, and PNA 29 days, CLFORMATION KETO-DOXAPRAM was 0.115 L/h (relative standard error (RSE) 12%) and CLDOXAPRAM OTHER ROUTES was 0.645 L/h (RSE 9%). Oral bioavailability was estimated at 74% (RSE 10%). CONCLUSIONS: Dosing of doxapram only based on bodyweight results in the highest exposure in preterm infants with the lowest PNA and GA. Therefore, dosing may need to be adjusted for GA and PNA to minimize the risk of accumulation and adverse events. For switching to oral therapy, a 33% dose increase is required to maintain exposure. IMPACT: Current dosing regimens of doxapram in preterm infants only based on bodyweight result in the highest exposure in infants with the lowest PNA and GA. Dosing of doxapram may need to be adjusted for GA and PNA to minimize the risk of accumulation and adverse events. Describing the pharmacokinetics of doxapram and its active metabolite keto-doxapram following intravenous and gastroenteral administration enables to include drug exposure to the evaluation of treatment of AOP. The oral bioavailability of doxapram in preterm neonates is 74%, requiring a 33% higher dose via oral than intravenous administration to maintain exposure.

Enantiomer specific pharmacokinetics of ibuprofen in preterm neonates with patent ductus arteriosus.

AIMS: Racemic ibuprofen is widely used for the treatment of preterm neonates with patent ductus arteriosus. Currently used bodyweight-based dosing guidelines are based on total ibuprofen, while only the S-enantiomer of ibuprofen is pharmacologically active. We aimed to optimize ibuprofen dosing for preterm neonates of different ages based on an enantiomer-specific population pharmacokinetic model. METHODS: We prospectively collected 210 plasma samples of 67 preterm neonates treated with ibuprofen for patent ductus arteriosus (median gestational age [GA] 26 [range 24-30] weeks, median body weight 0.83 [0.45-1.59] kg, median postnatal age [PNA] 3 [1-12] days), and developed a population pharmacokinetic model for S- and R-ibuprofen. RESULTS: We found that S-ibuprofen clearance (CLS , 3.98 mL/h [relative standard error {RSE} 8%]) increases with PNA and GA, with exponents of 2.25 (RSE 6%) and 5.81 (RSE 15%), respectively. Additionally, a 3.11-fold higher CLS was estimated for preterm neonates born small for GA (RSE 34%). Clearance of R-ibuprofen was found to be high compared to CLS (18 mL/h [RSE 24%]), resulting in a low contribution of R-ibuprofen to total ibuprofen exposure. Current body weight was identified as covariate on both volume of distribution of S-ibuprofen and R-ibuprofen. CONCLUSION: S-ibuprofen clearance shows important maturation, especially with PNA, resulting in an up to 3-fold increase in CLS during a 3-day treatment regimen. This rapid increase in clearance needs to be incorporated in dosing guidelines by adjusting the dose for every day after birth to achieve equal ibuprofen exposure.

Faecal calprotectin in suspected paediatric inflammatory bowel disease.

OBJECTIVES: The diagnostic accuracy of faecal calprotectin (FC) concentration for paediatric inflammatory bowel disease (IBD) is well described at the population level, but not at the individual level. We reassessed the diagnostic accuracy of FC in children with suspected IBD and developed an individual risk prediction rule using individual patient data. METHODS: MEDLINE, EMBASE, DARE, and MEDION databases were searched to identify cohort studies evaluating the diagnostic performance of FC in paediatric patients suspected of having IBD. A standard study-level meta-analysis was performed. In an individual patient data meta-analysis, we reanalysed the diagnostic accuracy on a merged patient dataset. Using logistic regression analysis we investigated whether and how the FC value and patient characteristics influence the diagnostic precision. A prediction rule was derived for use in clinical practice and implemented in a spreadsheet calculator. RESULTS: According to the study-level meta-analysis (9 studies, describing 853 patients), FC has a high overall sensitivity of 0.97 (95% confidence interval [CI] 0.92-0.99) and a specificity of 0.70 (0.59-0.79) for diagnosing IBD. In the patient-level pooled analysis of 742 patients from 8 diagnostic accuracy studies, we calculated that at an FC cutoff level of 50 µg/g there would be 17% (95% CI 15-20) false-positive and 2% (1-3) false-negative results. The final logistic regression model was based on individual data of 545 patients and included both FC level and age. The area under the receiver operating characteristic curve of this derived prediction model was 0.92 (95% CI 0.89-0.94). CONCLUSIONS: In high-prevalence circumstances, FC can be used as a noninvasive biomarker of paediatric IBD with only a small risk of missing cases. To quantify the individual patients' risk, we developed a simple prediction model based on FC concentration and age. Although the derived prediction rule cannot substitute the clinical diagnostic process, it can help in selecting patients for endoscopic evaluation.

Non-invasive markers for early diagnosis and determination of the severity of necrotizing enterocolitis.

OBJECTIVES: To improve diagnosis of necrotizing enterocolitis (NEC) by noninvasive markers representing gut wall integrity loss (I-FABP and claudin-3) and gut wall inflammation (calprotectin). Furthermore, the usefulness of I-FABP to predict NEC severity and to screen for NEC was evaluated. METHODS: Urinary I-FABP and claudin-3 concentrations and fecal calprotectin concentrations were measured in 35 consecutive neonates suspected of NEC at the moment of NEC suspicion. To investigate I-FABP as screening tool for NEC, daily urinary levels were determined in 6 neonates who developed NEC out of 226 neonates included before clinical suspicion of NEC. RESULTS: Of 35 neonates suspected of NEC, 14 developed NEC. Median I-FABP, claudin-3, and calprotectin levels were significantly higher in neonates with NEC than in neonates with other diagnoses. Cutoff values for I-FABP (2.20 pg/nmol creatinine), claudin-3 (800.8 INT), and calprotectin (286.2 microg/g feces) showed clinically relevant positive likelihood ratios (LRs) of 9.30, 3.74, 12.29, and negative LRs of 0.08, 0.36, 0.15, respectively. At suspicion of NEC, median urinary I-FABP levels of neonates with intestinal necrosis necessitating surgery or causing death were significantly higher than urinary I-FABP levels in conservatively treated neonates. Of the 226 neonates included before clinical suspicion of NEC, 6 developed NEC. In 4 of these 6 neonates I-FABP levels were not above the cutoff level to diagnose NEC before clinical suspicion. CONCLUSIONS: Urinary I-FABP levels are not suitable as screening tool for NEC before clinical suspicion. However, urinary I-FABP and claudin-3 and fecal calprotectin are promising diagnostic markers for NEC. Furthermore, urinary I-FABP might also be used to predict disease severity.

Intrauterine Growth Restriction and Patent Ductus Arteriosus in Very and Extremely Preterm Infants: A Systematic Review and Meta-Analysis.

It is generally accepted that intrauterine growth restriction (IUGR) increases morbidity and mortality among very preterm neonates. However, evidence is hampered by the widespread practice of using the terms small for gestational age (SGA) and IUGR as synonyms. We conducted a systematic review of studies reporting on the association between IUGR/SGA and patent ductus arteriosus (PDA). PubMed/MEDLINE and EMBASE databases were searched. Of 993 studies reviewed, 47 (50,790 infants) were included. Studies were combined using a random effects model and sources of heterogeneity were determined by subgroup and meta-regression analyses. Meta-analysis of all included studies showed a significantly reduced risk of PDA in the SGA/IUGR group with an odds ratio (OR) of 0.82, and a 95% confidence interval (CI) of 0.70 to 0.96 (p = 0.015). Of the 47 studies, only 7 used a definition for growth restriction that went beyond birth weight (BW) for gestational age (GA). When pooled, meta-analysis could not demonstrate a significant effect size (OR 1.31, 95% CI 0.75 to 2.27, p = 0.343). Moreover, the significantly reduced risk of PDA was found in the 25 studies defining SGA as BW <10th percentile (OR 0.81, 95% CI 0.66 to 0.98, p = 0.032), but not in the 6 studies defining SGA as BW <3rd (OR 1.09, 95% CI 0.70 to 1.71, p = 0.694), or in the 27 studies using a more refined definition of PDA (i.e., hemodynamically significant PDA or PDA requiring treatment, OR 0.87, 95% CI 0.72 to 1.04, p = 0.133). In addition, we found that GA was significantly higher in the SGA/IUGR group (18 studies, mean difference 0.63 weeks, 95% CI 0.24 to 1.03, p = 0.002). Meta-regression analysis confirmed the correlation between this difference in GA and PDA risk. In summary, we observed marked heterogeneity across studies in the definition of growth restriction and PDA, and we found differences between the control and growth-restricted groups in relevant baseline characteristics, such as GA. Therefore, our meta-analysis could not provide conclusive evidence on the association between growth restriction and PDA.

Model-based clinical dose optimization for phenobarbital in neonates: An illustration of the importance of data sharing and external validation.

BACKGROUND: Particularly in the pediatric clinical pharmacology field, data-sharing offers the possibility of making the most of all available data. In this study, we utilize previously collected therapeutic drug monitoring (TDM) data of term and preterm newborns to develop a population pharmacokinetic model for phenobarbital. We externally validate the model using prospective phenobarbital data from an ongoing pharmacokinetic study in preterm neonates. METHODS: TDM data from 53 neonates (gestational age (GA): 37 (24-42) weeks, bodyweight: 2.7 (0.45-4.5) kg; postnatal age (PNA): 4.5 (0-22) days) contained information on dosage histories, concentration and covariate data (including birth weight, actual weight, post-natal age (PNA), postmenstrual age, GA, sex, liver and kidney function, APGAR-score). Model development was carried out using NONMEM® 7.3. After assessment of model fit, the model was validated using data of 17 neonates included in the DINO (Drug dosage Improvement in NeOnates)-study. RESULTS: Modelling of 229 plasma concentrations, ranging from 3.2 to 75.2mg/L, resulted in a one compartment model for phenobarbital. Clearance (CL) and volume (Vd) for a child with a birthweight of 2.6kg at PNA day 4.5 was 0.0091L/h (9%) and 2.38L (5%), respectively. Birthweight and PNA were the best predictors for CL maturation, increasing CL by 36.7% per kg birthweight and 5.3% per postnatal day of living, respectively. The best predictor for the increase in Vd was actual bodyweight (0.31L/kg). External validation showed that the model can adequately predict the pharmacokinetics in a prospective study. CONCLUSION: Data-sharing can help to successfully develop and validate population pharmacokinetic models in neonates. From the results it seems that both PNA and bodyweight are required to guide dosing of phenobarbital in term and preterm neonates.

Chorioamnionitis appears not to be a Risk Factor for Patent Ductus Arteriosus in Preterm Infants: A Systematic Review and Meta-Analysis.

The contribution of chorioamnionitis (CA) to mortality and morbidity in preterm infants is difficult to assess because observational studies frequently present significant differences in baseline characteristics of the infants exposed or non-exposed to CA. In an attempt to perform a thorough assessment of the possible association between CA and patent ductus arteriosus (PDA) in preterm infants, we conducted a meta-analysis in which adjusted odds ratios (ORs) were pooled and we analyzed the effects of potential confounders, such as gestational age (GA) or birth weight (BW). We identified 45 relevant studies (27186 patients, 7742 CA cases). Random effects meta-analysis of crude ORs showed a significant positive association between CA and PDA (OR 1.352, 95% CI 1.172 to 1.560). Adjusted ORs were reported in 11 studies (19577 infants). Meta-analysis of these studies showed a significant negative association between CA and PDA (OR 0.802, 95% CI 0.751 to 0.959). Meta-regression showed that the differences in GA or BW between the CA-exposed and non-exposed groups were significantly correlated with the effect size of the association between PDA and CA. In conclusion, our study confirms that confounders need to be taken into account when assessing the association between CA and clinical outcomes in preterm infants.

A failed attempt to conduct an individual patient data meta-analysis.

A study-level meta-analysis has shown that proton magnetic resonance spectroscopy is a promising prognostic marker in neonatal hypoxic-ischemic encephalopathy. An individual patient data meta-analysis could yield a prognostic tool with improved accuracy enabling well-founded clinical decisions. Our request to share patient data remained unanswered by five out of 18 research groups. Another four declined collaboration for various reasons, including own reanalysis of the data, and lack of parental consent. With less than 40% of the individual patient data available, we refrained from pursuing the proposed study. As future patients may benefit from it, policies mandating data sharing should be introduced.

Pleural effusion due to intra-abdominal extravasation of parenteral nutrition.

An 8-week-old preterm boy experienced respiratory deterioration due to unilateral pleural effusion. Intra-abdominal extravasation of parenteral fluid with leakage into the pleural cavity was suspected based on biochemical analysis of the effluent. Perforation of the central venous catheter in the peritoneal cavity was subsequently confirmed by contrast roentgenography. As in peritoneal dialysis and hepatic hydrothorax, pleuroperitoneal communication needs to be considered in patients exhibiting pleural effusion with a central venous line below the diaphragm.

Protein binding of flucloxacillin in neonates.

The isoxazolyl penicillins, including flucloxacillin, have the highest levels of plasma protein binding among the semisynthetic penicillins. Because only the free fraction of the penicillin is pharmacologically active, it would be useful to measure both protein-bound and free flucloxacillin to determine its protein binding. Until now, flucloxacillin protein binding in newborn infants has been investigated in only two studies with relatively small populations. In the present study, flucloxacillin protein binding was investigated in 56 (preterm) infants aged 3 to 87 days (gestational age, 25-41 weeks). Surplus plasma samples from routine gentamicin assays of each infant were collected and combined to obtain a sufficiently large sample for analysis. Free flucloxacillin was separated from protein-bound flucloxacillin using ultrafiltration. Reversed-phase high-performance liquid chromatography with ultraviolet detection was used to measure free flucloxacillin concentrations in ultrafiltrate and total flucloxacillin concentrations in pooled plasma. Flucloxacillin protein binding was 74.5% +/- 13.1% (mean +/- standard deviation) with a high variability among the infants (34.3% to 89.7%). High Pearson correlations were found between protein binding and the covariates-plasma albumin concentration (r = 0.804, P < 0.001, n = 18) and plasma creatinine concentration (r = -0.601, P < 0.001, n = 45). Statistically significant but less striking correlations were found between protein binding and gestational age, postconceptional age, body weight, and triglyceride concentration. Because of the high variability of protein binding among infants, it is difficult to devise a flucloxacillin dosage regimen effective for all infants. Individualized dosing, based on free flucloxacillin concentrations, might help to optimize treatment of late-onset neonatal sepsis, but practical obstacles will probably prevent analysis of free flucloxacillin concentrations in newborn infants on a routine basis.

Pharmacokinetics of intravenous rifampicin (rifampin) in neonates.

Few reports have addressed neonatal rifampicin plasma concentrations and data on neonatal rifampicin pharmacokinetics are completely lacking. Therefore, plasma concentrations of rifampicin and its main metabolite 25-O-desacetylrifampicin (DES) were measured in 123 surplus plasma samples from routine vancomycin monitoring in 21 neonates using reversed-phase HPLC. Rifampicin peak and trough plasma concentrations were 4.66 +/- 1.47 mg/L and 0.21 +/- 0.20 mg/L, respectively, after a dose of 8.5 +/- 2.1 (mean +/- SD) mg/kg per day. A significant linear relationship between rifampicin dose and peak plasma concentrations was found, but inter-patient variability was high. Pharmacokinetic parameters of rifampicin were calculated according to a one-compartment open model with iterative two-stage Bayesian fitting (MW\PHARM 3.60, Mediware, The Netherlands). First-order elimination constant, volume of distribution corrected for weight, total body clearance corrected for weight (CL/W), and elimination half-life were 0.16 +/- 0.06 h(-1), 1.84 +/- 0.59 L/kg, 0.28 +/- 0.11 Lkg(-1) h(-1), and 4.9 +/- 1.7 h, respectively. A high Pearson correlation was found between CL/W rifampicin and the covariates plasma creatinine and CL/W gentamicin of a preceding gentamicin treatment course, r = 0.728 (n = 17) and r = 0.837 (n = 12), respectively. DES was detected in each plasma sample. Therefore, rifampicin seems to be eliminated by both renal and metabolic pathways in neonates. In 8 study patients, plasma concentrations of rifampicin and DES were measured again after two weeks of therapy. CL/W rifampicin was significantly higher (67 +/- 50%). The authors suggest maintaining the current dose regimen of 10 mg/kg once a day. Because of the large inter-patient variability in rifampicin plasma concentrations and CL/W increase during therapy, the authors suggest monitoring rifampicin peak and trough plasma concentrations to avoid low plasma concentrations. More research is needed to determine well-founded dosing guidelines.

Population pharmacokinetics and dosing of amoxicillin in (pre)term neonates.

Amoxicillin plasma concentrations, pharmacokinetic parameters, and the influence of demographic, anthropometric, and clinical covariates were investigated in 150 neonates. Gestational age (GA) ranged from 25 to 42 weeks and mean postnatal age (PNA) was 0.8 days. Amoxicillin concentrations were measured with reversed-phase HPLC in surplus plasma from routine assays of coadministered gentamicin. Mean total body clearance corrected for body weight (CL/W) was 0.096 +/- 0.036 L/kg(-1)h(-1), mean elimination half-life (t(1/2)) was 5.2 +/- 1.9 hours, and mean volume of distribution corrected for body weight (V/W) was 0.65 +/- 0.13 L/kg. Multiple regression equations were calculated for the prediction of CL/W amoxicillin. CL/W gentamicin, V/W gentamicin, and GA were significant predictors of CL/W amoxicillin. Amoxicillin peak and trough concentrations after the second dose and the time the concentration exceeds the minimum inhibitory concentration (T>MIC), reached with the current dosage regimen, were evaluated. Toxic plasma concentrations were reached in several patients. Therefore, the authors have proposed a lower dosage regimen, based on GA, population pharmacokinetic parameters, bacterial susceptibility (T>MIC), and possible toxicity: 15 mg/kg per 8 hours and 20 mg/kg per 8 hours for neonates with GA < or = 34 and GA>34 weeks, respectively. Simulation with this new dosage regimen indicated that satisfactory plasma concentrations were reached in all 150 neonates. Therefore, use of therapeutic drug monitoring and pharmacokinetic calculations for dosage adjustment is generally not necessary.

Population pharmacokinetics and dosing of flucloxacillin in preterm and term neonates.

In total 235 flucloxacillin total (free+protein bound) plasma concentrations were determined in 55 neonates (gestational age 26 to 42 weeks, postnatal age 0 to 44 days) with reversed-phase HPLC in surplus plasma samples from routine gentamicin assays. Population pharmacokinetic parameters were calculated according to an one compartment open model with iterative two-stage Bayesian fitting (MWPHARM 3.50, Mediware, The Netherlands). Mean clearance corrected for weight was 0.18+/-0.10 L kgh and volume of distribution corrected for weight was 0.54+/-0.17 L/kg. Pearson correlations between the individual pharmacokinetic parameters and covariates, like gestational age, plasma creatinine, and gentamicin clearance, were low and therefore not relevant for use in clinical practice. Total plasma concentrations above 200 mg/L were considered toxic and T>MIC (time above minimum inhibitory free plasma concentration) of more than 40% was considered effective. Protein binding was assumed to be 86.3% in all neonates, based on literature. The current dosage regimen, 25 or 50 mg/kg every 8 or 12 hours, did not result in effective plasma concentrations for the treatment of Staphylococcus aureus in 17 (31%) of the 55 neonates. Therefore, the authors suggest an initial dose of 25 mg/kg/4 h for all neonates, irrespective of their age, based on the breakpoint MIC value of flucloxacillin for Staphylococcus aureus (2.0 mg/L). After isolation of the causative agent of infection, flucloxacillin administration ought to be reconsidered based on the expected susceptibility pattern of the isolate. When oxacillin sensitive coagulase negative staphylococci are isolated, the initial dose should be reduced to 10 mg/kg/6 h, based on the breakpoint MIC value of 0.25 mg/L. Simulation with these new dosage regimens indicated that satisfactory plasma concentrations were reached in 52 of the 55 neonates. However, the regimens need prospective verification. Moreover, the exact role of neonatal protein binding needs to be further investigated.

Vascular reactivity of pulmonary arteries from premature lambs subjected to liquid ventilation.

This study aimed to evaluate the effect of tidal liquid ventilation (TLV) and liquid assisted high frequency oscillatory ventilation (LA-HFOV) on the contractile and relaxing properties of fetal ovine pulmonary arteries. 0.85 term lambs were subjected, after surfactant instillation, to 5 h of TLV or LA-HFOV (5 ml.kg(-1) perfluorocarbon liquid). After euthanasia of the animals, intrapulmonary arteries (fourth branch) were dissected and mounted in a myograph for isometric tension recording. Arteries from unventilated age-matched fetuses were also studied. The contractions induced by K(+), and the thromboxane A(2) mimetic U46619 were not significantly different in the TLV and the LA-HFOV groups. Acetylcholine-induced relaxation was absent after TLV and LA-HFOV but present in unventilated animals. Sodium nitroprusside-induced relaxation was also similar after TLV and LA-HFOV, but reduced when the two groups were compared with unventilated fetuses. We conclude that after TLV and LA-HFOV the pulmonary arterial responses to receptor- and non receptor-mediated contraction and to endothelium-dependent and -independent relaxation were similar.