Comparative Analysis of Machine Learning Algorithms Evaluating the Single Nucleotide Polymorphisms of Metabolizing Enzymes with Clinical Outcomes Following Intravenous Paracetamol in Preterm Neonates with Patent Ductus Arteriosus.

AIMS: Pharmacogenomics has been identified to play a crucial role in determining drug response. The present study aimed to identify significant genetic predictor variables influencing the therapeutic effect of paracetamol for new indications in preterm neonates. BACKGROUND: Paracetamol has recently been preferred as a first-line drug for managing Patent Ductus Arteriosus (PDA) in preterm neonates. Single Nucleotide Polymorphisms (SNPs) in CYP1A2, CYP2A6, CYP2D6, CYP2E1, and CYP3A4 have been observed to influence the therapeutic concentrations of paracetamol. OBJECTIVES: The purpose of this study was to evaluate various Machine Learning Algorithms (MLAs) and bioinformatics tools for identifying the key genotype predictor of therapeutic outcomes following paracetamol administration in neonates with PDA. METHODS: Preterm neonates with hemodynamically significant PDA were recruited in this prospective, observational study. The following SNPs were evaluated: CYP2E1*5B, CYP2E1*2, CYP3A4*1B, CYP3A4*2, CYP3A4*3, CYP3A5*3, CYP3A5*7, CYP3A5*11, CYP1A2*1C, CYP1A2*1K, CYP1A2*3, CYP1A2*4, CYP1A2*6, and CYP2D6*10. Amongst the MLAs, Artificial Neural Network (ANN), C5.0 algorithm, Classification and Regression Tree analysis (CART), discriminant analysis, and logistic regression were evaluated for successful closure of PDA. Generalized linear regression, ANN, CART, and linear regression were used to evaluate maximum serum acetaminophen concentrations. A two-step cluster analysis was carried out for both outcomes. Area Under the Curve (AUC) and Relative Error (RE) were used as the accuracy estimates. Stability analysis was carried out using in silico tools, and Molecular Docking and Dynamics Studies were carried out for the above-mentioned enzymes. RESULTS: Two-step cluster analyses have revealed CYP2D6*10 and CYP1A2*1C to be the key predictors of the successful closure of PDA and the maximum serum paracetamol concentrations in neonates. The ANN was observed with the maximum accuracy (AUC = 0.53) for predicting the successful closure of PDA with CYP2D6*10 as the most important predictor. Similarly, ANN was observed with the least RE (1.08) in predicting maximum serum paracetamol concentrations, with CYP2D6*10 as the most important predictor. Further MDS confirmed the conformational changes for P34A and P34S compared to the wildtype structure of CYP2D6 protein for stability, flexibility, compactness, hydrogen bond analysis, and the binding affinity when interacting with paracetamol, respectively. The alterations in enzyme activity of the mutant CYP2D6 were computed from the molecular simulation results. CONCLUSION: We have identified CYP2D6*10 and CYP1A2*1C polymorphisms to significantly predict the therapeutic outcomes following the administration of paracetamol in preterm neonates with PDA. Prospective studies are required for confirmation of the findings in the vulnerable population.

Is fat-free mass-based gentamicin dosing regimen preferable than whole-body weight in neonates?

Importance: Body fluid dynamics and renal maturation status vary during the neonatal period. We hypothesized that differences in peak and trough gentamicin concentrations could be expected. Objective: To predict the peak and trough gentamicin concentrations in critically ill neonates and to predict the changes in the predicted peak plasma concentrations of gentamicin following fat-free mass dosing. Methods: Critically ill neonates that received gentamicin and have gentamicin concentration measured were recruited. Fat mass was estimated using skinfold thicknesses. Changes in the peak plasma concentrations (Cmax) using whole-body weight (estimated using the current dosing regimen) and predicted concentrations following the fat-free mass-based dosing were the outcome measures. Results: Eighty-nine critically ill neonates were recruited. Sub-therapeutic Cmax was estimated using the current dosing regimen in 32.6%, and 22.5% neonates following the first and second doses of gentamicin. Preterm neonates had significantly higher fat mass compared to term neonates. All except one had Cmax above 12 µg/ml after the first dose and all had after the second gentamicin dose following the predicted fat-free mass-based gentamicin dosing. The recommended doses are as follows: extreme preterm: 7.95 mg/kg every 48 h; very preterm: 7.30 mg/kg every 36-48 h; late preterm: 5.90 mg/kg every 36-48 h; and term neonates at 5.10 mg/kg every 24 h. Interpretation: Fat-free mass dosing may be considered for obtaining optimal therapeutic effects in the neonatal population.

Cumulative Doses Predict the Risk of Furosemide-Induced Electrolyte Abnormalities in Critically Ill Neonates.

Background: Furosemide has limited indications in the term neonates. Its use in preterm neonates is off-label. Considering the dearth of data, we carried out a retrospective study evaluating the furosemide use and its effects on the electrolyte abnormalities in critically ill neonates. Methods: Critically ill neonates receiving at least one dose of furosemide during their stay in the NICU were recruited. The following details were obtained: demographic characteristics and furosemide details (dose, frequency, route, and duration). Urine output, body weight, serum creatinine, electrolytes (sodium, potassium, calcium, bicarbonate, chloride, and magnesium) during furosemide therapy were extracted. Results: Ninety neonates were recruited. Elevated serum creatinine was observed in 21.1% of the patients, and electrolyte disturbances were observed in 52.2%. Those with electrolyte disturbances had significantly greater cumulative doses compared to those without [5.5 (1-34) vs 3.9 (0.9-30.2) mg/kg; p = 0.01]. Cumulative doses adjusted to body-weight were significantly lower in very preterm and extremely preterm neonates compared to late preterm category. A significant area-under-the-curve was observed for the cumulative dose (0.66; 95% CI: 0.54-0.78; p = 0.01) in predicting the risk of electrolyte abnormalities with a cut-off value of 4 mg/kg. Eight neonates received more than 10 mg/kg cumulative dose of furosemide of which one died. No significant differences were observed between the proportion of neonates with electrolyte disturbances with cumulative furosemide dose above 10 mg/kg (p = 0.3) and with mortality (p = 0.3). Conclusion: We observed that our critically ill neonates received relatively higher cumulative doses of furosemide and electrolyte disturbances were observed in nearly half of the population. A cumulative dose of 4 mg/kg increases the risk of electrolyte abnormalities, particularly in preterm neonates. More diligence in the dose titration coupled with deprescribing and intense monitoring of all the potential adverse effects in this vulnerable population is needed.

Evaluation of urinary acetaminophen metabolites and its association with the genetic polymorphisms of the metabolising enzymes, and serum acetaminophen concentrations in preterm neonates with patent ductus arteriosus.

Acetaminophen is gaining importance as a first-line drug for treating patent ductus arteriosus (PDA) in neonates. Predominant metabolites of acetaminophen in preterm neonates vary from that of adults; and the drug is predominantly metabolised by conjugation and partly by Cytochrome P450 (CYP) enzymes.We carried out the present study to identify the principal urine metabolites of acetaminophen (glucuronide/sulphate) in preterm neonates with hemodynamically significant PDA receiving intravenous acetaminophen, and to evaluate the prevalence of single nucleotide polymorphisms (SNPs) in the key CYP enzymes (CYP1A2*3, CYP1A2*4, CYP1A2*1C, CYP1A2*1K, CYP1A2*6, CYP2D6*10, CYP2E1*2, CYP2E1*5B, CYP3A4*1B, CYP3A4*2, CYP3A4*3, CYP3A5*3, CYP3A5*7, and CYP3A5*11) and their effect on urinary metabolites and serum acetaminophen concentrations.Nineteen (32.8%) neonates had heterozygous CYP1A2*1C, two (3.3%) with heterozygous CYP1A2*1K, 15 (27.8%) and two (3.7%) had heterozygous and homozygous CYP2D6*10, two (3.7%) had heterozygous CYP2E1*5B, seven (12.3%) and three (5.3%) had heterozygous and homozygous CYP3A4*1B, and three (5.5%) had CYP3A5*7 amongst the study population. Acetaminophen sulphate predominated over glucuronide metabolite at all time points. Postnatal days of life was significantly associated with an increase in the urine acetaminophen metabolites with decreased serum acetaminophen concentrations.A significant prevalence of SNPs in the key CYP enzymes related to acetaminophen metabolism was observed in our neonatal population. Population pharmacokinetic-pharmacodynamic modelling incorporating genetic and metabolite data is urgently needed for implementation of precision medicine in this vulnerable population.

Off-label drug use and the risk of medication errors in critically ill neonates: A conceptual pilot study.

BACKGROUND: Off-label drug (OLD) use is common in neonates. OBJECTIVE: There is a dearth of information associating the OLD use and the risk of medication errors in critically ill neonates. Hence, the present study was carried out. METHODS: Drug prescriptions in neonates admitted to the intensive care unit of a tertiary care hospital between September 2018 and June 2019 were evaluated. Details on their demographics, reason for admission in intensive care unit, drug-related information and serum creatinine were extracted. United States Food and Drug Administration approved drug labels were compared. World Health Organization (WHO) anatomy, therapeutic and chemical (ATC) classification was used for drug categorization. We assessed the risk of medication errors in the adult population using a validated tool: medication risk score (MERIS). RESULTS: One hundred and seventy-one neonates with 2394 prescriptions were included in this study. Seventy one percent of the neonates in the present study received at least one OLD/unlicensed prescription item. A trend in increased numbers of OLD/unlicensed drug use in more premature and lower birth weight neonates were observed. Medication risk score was significantly higher in neonates receiving OLD/unlicensed drugs compared to those with only labelled drugs. Very and extreme pre-term (along with very low and extremely low birth weight) neonates were at higher risk of medication errors compared to others. Presence of OLD/unlicensed prescribed items is associated with a potentially increased risk of medication errors by an odds ratio of 20.4 compared to labelled drugs. CONCLUSION: Significant proportions of critically ill neonates received at least one OLD/unlicensed drug and such use was associated with potentially increased risk of medication errors.

Intravenous acetaminophen (at 15 mg/kg/dose every 6 hours) in critically ill preterm neonates with patent ductus arteriosus: A prospective study.

WHAT IS KNOWN AND OBJECTIVES: Acetaminophen has been increasingly used in treating patent ductus arteriosus (PDA) in preterm neonates. Variations were observed in the dosing regimen of acetaminophen across the studies. There is hardly any data available for a relatively higher dose of intravenous acetaminophen (15 mg/kg/dose every 6 hours) in the preterm population. We present here the results of a prospective study with this dose of intravenous acetaminophen for treating PDA in critically ill preterm neonates. METHODS: Preterm neonates (≤37 weeks of gestational age) with haemodynamically significant PDA were enrolled. Intravenous acetaminophen at 15 mg/kg/dose every 6 hours was administered. Echocardiographic monitoring, liver and renal function tests were carried out. Standard definitions were adhered for defining acute kidney injury (AKI) and hepatotoxicity. RESULTS: Fifty-five neonates were recruited. Following the first dose, less than half had their serum acetaminophen concentrations in the therapeutic range. Extreme preterm neonates were less likely to have a sustained therapeutic acetaminophen concentration after the first dose. Following multiple doses and at steady state, 97.2% and 98.8% respectively were in the therapeutic range. Forty-three (78.2%) neonates had successful closure of the ductus arteriosus of which 22 were extreme preterm, 17 were very preterm and 4 were late preterm neonates; and considering their birthweights, 21 were extremely low, 16 were very low and 6 were low birthweight categories. Ten neonates had elevated alanine aminotransferase levels with three in the low-to-moderate risk of hepatotoxicity category. Eight neonates had altered renal function tests indicating AKI. WHAT IS NEW AND CONCLUSION: Intravenous acetaminophen at 15 mg/kg/dose every 6 hours was efficacious in 78.2% of the preterm neonates with PDA. We observed a lower incidence of hepatotoxicity, and AKI in the study population. No association was observed between the serum acetaminophen concentrations and PDA closure.

Drug utilisation in adult, paediatric and neonatal intensive care units, with an emphasis on systemic antimicrobials.

INTRODUCTION: Critically ill adults, children and neonates receive drugs that are often administered parenterally and in infusions. Considering patient illness severity, empirical broad-spectrum antimicrobials are commonly used. We conducted the present study to evaluate the drug use in this population, with a special focus on antimicrobials. MATERIAL AND METHODS: A prospective cross-sectional study was implemented in adult, paediatric and neonatal intensive care units. Various prescribing and supplemental indicators were used for drug comparisons. The World Health Organisation's list of essential drugs, the national drug formulary and critically important antimicrobial drugs were assessed. Proportions and median (range) were used to represent categorical and numerical values. RESULTS: Four hundred and ninety-six critically ill patients were enrolled in the study, with 5,636 prescribed drugs used for 31,993 patient-days. Critically ill adults received significantly more drugs compared to children and the neonatal population (11 [8-16], 9 [6-17] and 5 [3-12] respectively). Critically ill neonates received significantly fewer of the drugs listed in the national formulary compared to older children and adults (94.1% [10.1], 92.4% [32.4] and 80.1% [20.4]). Critically ill neonates received fewer antimicrobials (82% compared to 91.3% in adults and 98% in children). Furthermore, critically ill adults received more broad-spectrum antimicrobials compared to neonates. Prolonged empirical antimicrobial use was observed more in critically ill children (52%) compared to adults (29.8%). A large majority of the antimicrobials were critically important for 87.7%, 83.9% and 86.5% of patients in the adult, paediatric and neonatal intensive care units. CONCLUSIONS: We observed significant differences in terms of drug classes predominantly used in various age groups of critically ill patients, particularly regarding the nature and type of antimicrobial drugs and the duration of antimicrobial therapy.

Possible effects of excipients used in the parenteral drugs administered in critically ill adults, children, and neonates.

BACKGROUND: Critically ill patients receiving parenteral drugs are at an increased risk of exposure to various excipients administered simultaneously and at increased amounts. Hence, we carried out the present study. RESEARCH DESIGN AND METHODS: Patients admitted in the adult, pediatric, and neonatal intensive care units were recruited following their consent. Details on their demographics, diagnoses, and drugs administered and the excipients were collected. RESULTS: Almost all the critically ill patients received drugs containing at least one excipient. Significant numbers of critically ill neonates received at least one of either known to be harmful or potentially harmful excipients. Critically ill neonates had significantly greater daily exposure of macrogol than children and adults; and benzyl alcohol (v/v) and propyl paraben compared to adults. Critically ill neonates and children had greater exposure to benzyl alcohol (w/v), methyl paraben, sodium metabisulfite than adults did. Benzyl alcohol exposure was likely to be several-fold high in critically ill patients. Exposures to benzyl alcohol and propylene glycol were possibly linked to increased risk of mortality particularly in neonates. CONCLUSION: Critically ill neonates and children are likely to receive a significantly greater quantity of harmful excipients than critically ill adults. Benzyl alcohol and propylene glycol exposure are likely to be associated with increased risk of mortality in critically ill.

Dose Optimization of Gentamicin in Critically Ill Neonates.

BACKGROUND: Appropriate dosing of gentamicin in critically ill neonates is still debated. OBJECTIVE: To assess the peak concentration (Cmax) and area-under-the-time-concentration curve (AUC0-24) of gentamicin and to simulate the recommended doses using the Monte Carlo method. METHODS: This was a retrospective study on critically ill neonates carried over a one-year period. The demographic characteristics, dosage regimen and gentamicin concentrations were recorded for each neonate. Using Bayesian pharmacokinetic modeling, Cmax and AUC0-24 were predicted. Dose recommendations for the target Cmax (µg/ml) of 12 were obtained, and Monte Carlo simulation (100,000 iterations) was used for predicting the pharmacokinetic parameters and recommended doses for various birth weight categories. RESULTS: Eighty-two critically ill neonates (with an average gestational age of 33.7 weeks; and birth weight of 2.1 kg) were recruited. Higher Cmax and AUC0-24 values were predicted in premature neonates, with greater cumulative AUCs in extremely preterm neonates. The average administered dose was 4 mg/kg/day and 75% of the participants had Cmax greater than 12 µg/ml following a single dose, and 85% were found to be at steady state. On the contrary, only 25% of the study population had the recommended AUC0-24 (above 125 µg-hr/ml). Simulation tests indicate that 90% of the critically ill neonates would achieve recommended Cmax with doses ranging between 5 and 6 mg/kg/day. CONCLUSION: Currently used dose of 4 mg/kg/day is adequate to maintain Cmax in a large majority of the study population, with one-fourth population reporting the recommended AUC0-24. Increasing the dose to 5-6 mg/kg/day will more likely help to achieve both the recommended Cmax and AUC0-24 values.