Population pharmacokinetics and pharmacodynamics of dobutamine in neonates on the first days of life.

AIMS: To describe the pharmacokinetics (PK) and concentration-related effects of dobutamine in critically ill neonates in the first days of life, using nonlinear mixed effects modelling. METHODS: Dosing, plasma concentration and haemodynamic monitoring data from a dose-escalation study were analysed with a simultaneous population PK and pharmacodynamic model. Neonates receiving continuous infusion of dobutamine 5-20 µg kg-1 min-1 were included. Left ventricular ejection fraction (LVEF) and cardiac output of right and left ventricle (RVO, LVO) were measured on echocardiography; heart rate (HR), mean arterial pressure (MAP), peripheral arterial oxygen saturation and cerebral regional oxygen saturation were recorded from patient monitors. RESULTS: Twenty-eight neonates with median (range) gestational age of 30.4 (22.7-41.0) weeks and birth weight (BW) of 1618 (465-4380) g were included. PK data were adequately described by 1-compartmental linear structural model. Dobutamine clearance (CL) was described by allometric scaling on BW with sigmoidal maturation function of postmenstrual age (PMA). The final population PK model parameter mean typical value (standard error) estimates, standardised to median BW of 1618 g, were 41.2 (44.5) L h-1 for CL and 5.29 (0.821) L for volume of distribution, which shared a common between subject variability of 29% (17.2%). The relationship between dobutamine concentration and RVO/LVEF was described by linear model, between concentration and LVO/HR/MAP/cerebral fractional tissue oxygen extraction by sigmoidal Emax model. CONCLUSION: In the postnatal transitional period, PK of dobutamine was described by a 1-compartmental linear model, CL related to BW and PMA. A concentration-response relationship with haemodynamic variables has been established.

Population Pharmacokinetics and Dosing of Milrinone After Patent Ductus Arteriosus Ligation in Preterm Infants.

OBJECTIVES: The postoperative course of patent ductus arteriosus ligation is often complicated by postligation cardiac syndrome, occurring in 10-45% of operated infants. Milrinone might prevent profound hemodynamic instability and improve the recovery of cardiac function in this setting. The present study aimed to describe the population pharmacokinetics of milrinone in premature neonates at risk of postligation cardiac syndrome and give dosing recommendations. DESIGN: A prospective single group open-label pharmacokinetics study. SETTINGS: Two tertiary care neonatal ICUs: Tallinn Children's Hospital and Tartu University Hospital, Estonia. PATIENTS: Ten neonates with postmenstrual age of 24.6-30.1 weeks and postnatal age of 5-27 days undergoing patent ductus arteriosus ligation and at risk of postligation cardiac syndrome, based on echocardiographic assessment of left ventricular output of less than 200 mL/kg/min 1 hour after the surgery. INTERVENTIONS: Milrinone at a dose of 0.73 µg/kg/min for 3 hours followed by 0.16 µg/kg/min for 21 hours. Four blood samples from each patient for milrinone plasma concentration measurements were collected. MEASUREMENTS AND MAIN RESULTS: Concentration-time data of milrinone were analyzed with nonlinear mixed-effects modeling software (NONMEM Version 7.3 [ICON Development Solutions, Ellicott City, MD]). Probability of target attainment simulations gave a dosing schedule that maximally attains concentration targets of 150-250 µg/L. Milrinone pharmacokinetics was described by a one-compartmental linear model with allometric scaling to bodyweight and an age maturation function of glomerular filtration rate. Parameter estimates for a patient with the median weight were 0.350 (L/hr) for clearance and 0.329 (L) for volume of distribution. The best probability of target attainment was achieved with a loading dose of 0.50 µg/kg/min for 3 hours followed by 0.15 µg/kg/min (postmenstrual age < 27 wk) or 0.20 µg/kg/min (postmenstrual age ≥ 27 wk). CONCLUSIONS: Population pharmacokinetic modeling and simulations suggest a slow loading dose followed by maintenance infusion to reach therapeutic milrinone plasma concentrations within the timeframe of the postligation cardiac syndrome.

Retention of acidic and basic analytes in reversed phase column using fluorinated and novel eluent additives for liquid chromatography-tandem mass spectrometry.

This research focuses on retention mechanisms in a LC column with C18 stationary phase when novel eluent additives (HFIP, HFTB and TFE as well as NFTB and perfluoropinacol) are used. The retention factors between novel eluent additives and conventional ones like ammonium acetate and ammonium bicarbonate at different eluent pH values were compared. A simple set of drug-like molecules, widely spread over different logP values, containing protonated and deprotonated acids and bases was selected for this investigation. HFIP, HFTB, NFTB and PP demonstrated strong influence on basic polar analytes in basic medium. These additives drastically increased retention. A decrease in retention was observed for acidic analytes when novel eluent additives were used. Additionally, for the first time, the absolute pH (pHabs) scale was used for expressing the mobile phase pH.

A sensitive method for the simultaneous UHPLC-MS/MS analysis of milrinone and dobutamine in blood plasma using NH4F as the eluent additive and ascorbic acid as a stabilizer.

The purpose of this work was to develop and validate an HPLC-MS/MS method suitable for quantifying two important cardiovascular drugs, milrinone and dobutamine, in neonatal and paediatric patients' blood plasma samples. Sufficiently low LLOQ levels were required to obtain adequate pharmacokinetic data for the evaluation of optimal dosing. Since the specifics of the patient group set some restrictions on the available sample volume, the method was designed to use only 20 µL of plasma for the analysis. Analytes were separated chromatographically in a biphenyl column using a conventional water-methanol-formic acid eluent with the addition of ammonium fluoride. The latter provided a significant signal enhancement in positive ion mode detection for both analytes allowing the LLOQ to reach below 1 ng/mL. Matrix matched calibration was linear in the range of 1-300 ng/mL, between-run accuracy remained within 107-115%, and precision within 4.8-7.4% for both analytes over the calibration range (including LLOQ level). Dobutamine degradation in plasma samples was prevented by the usage of ascorbic acid. The method was applied to plasma samples of neonates from two pharmacokinetic/pharmacodynamics studies (n = 38).

Utilization of data below the analytical limit of quantitation in pharmacokinetic analysis and modeling: promoting interdisciplinary debate.

Traditionally, bioanalytical laboratories do not report actual concentrations for samples with results below the LOQ (BLQ) in pharmacokinetic studies. BLQ values are outside the method calibration range established during validation and no data are available to support the reliability of these values. However, ignoring BLQ data can contribute to bias and imprecision in model-based pharmacokinetic analyses. From this perspective, routine use of BLQ data would be advantageous. We would like to initiate an interdisciplinary debate on this important topic by summarizing the current concepts and use of BLQ data by regulators, pharmacometricians and bioanalysts. Through introducing the limit of detection and evaluating its variability, BLQ data could be released and utilized appropriately for pharmacokinetic research.

A highly sensitive method for the simultaneous UHPLC-MS/MS analysis of clonidine, morphine, midazolam and their metabolites in blood plasma using HFIP as the eluent additive.

In intensive care units, the precise administration of sedatives and analgesics is crucial in order to avoid under- or over sedation and for appropriate pain control. Both can be harmful to the patient, causing side effects or pain and suffering. This is especially important in the case of pediatric patients, and dose-response relationships require studies using pharmacokinetic-pharmacodynamic modeling. The aim of this work was to develop and validate a rapid ultra-high performance liquid chromatographic-tandem mass spectrometric method for the analysis of three common sedative and analgesic agents: morphine, clonidine and midazolam, and their metabolites (morphine-3-glucuronide, morphine-6-glucuronide and 1'-hydroxymidazolam) in blood plasma at trace level concentrations. Low concentrations and low sampling volumes may be expected in pediatric patients; we report the lowest limit of quantification for all analytes as 0.05ng/mL using only 100µL of blood plasma. The analytes were separated chromatographically using the C18 column with the weak ion-pairing additive 1,1,1,3,3,3-hexafluoro-2-propanol and methanol. The method was fully validated and a matrix matched calibration range of 0.05-250ng/mL was attained for all analytes In addition, between-day accuracy for all analytes remained within 93-108%, and precision remained within 1.5-9.6% for all analytes at all concentration levels over the calibration range.