Caspofungin Population Pharmacokinetic Analysis in Plasma and Peritoneal Fluid in Septic Patients with Intra-Abdominal Infections: A Prospective Cohort Study

Objectives: To describe the pharmacokinetics (PK) of micafungin in plasma and peritoneal fluid in septic patients with intra-abdominal infections. Methods: Twelve patients with secondary peritonitis in septic shock receiving 100 mg micafungin once daily were included. Total micafungin plasma and peritoneal fluid were subject to a population pharmacokinetic analysis using Pmetrics®. Monte Carlo simulations were performed considering total AUC0-24h/MIC ratios in plasma. Results: Micafungin concentrations in both plasma and peritoneal exudate were best described by a three-compartmental PK model with the fat free mass (FFM) as a covariate of clearance (CL) and volume of the central compartment (Vc). The mean parameter estimates (standard deviation, SD) were 1.18 (0.40) L/h for CL and 12.85 (4.78) L for Vc. The mean peritoneal exudate/plasma ratio (SD) of micafungin was 25% (5%) on day 1 and 40% (8%) between day 3-5. Dosing simulations supported the use of standard 100 mg daily dosing for C. albicans (FFM < 60 kg), C. glabrata (FFM < 50 kg) and C. tropicalis (FFM < 30 kg) on the second day of therapy. Conclusions: There is a moderate penetration of micafungin into peritoneal cavity (25 to 40%). For empirical treatment, a dose escalation of at least a loading dose of 150 mg depending on the FFM of patients and Candida species is suggested to be effective from the first day of therapy.

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Interventional cohort study of prolonged use (>72 hours) of paracetamol in neonates: protocol of the PARASHUTE study

BMJ Paediatrics Open ◽

10.1136/bmjpo-2018-000427 ◽

2019 ◽

Vol 3 (1) ◽

pp. e000427 ◽

Cited By ~ 1

Author(s):

Sissel Sundell Haslund-Krog ◽

Steen Hertel ◽

Kim Dalhoff ◽

Susanne Poulsen ◽

Ulla Christensen ◽

...

Keyword(s):

Cohort Study ◽

Neonatal Intensive Care ◽

Plasma Concentrations ◽

Population Pharmacokinetic Analysis ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Concomitant Treatment ◽

Pain Scores ◽

Postmenstrual Age ◽

Dosing Strategies

IntroductionAnticipated or actual pain in neonates results in use of paracetamol for prolonged pain relief in many neonatal intensive care units. Clinical trials examining safety of paracetamol exposure in neonates have been of short duration (1–3 days) and hepatic biomarkers and paracetamol metabolism are rarely reported in the same studies.We aim to investigate the safety (hepatic tolerance) and effectiveness of prolonged paracetamol exposure in neonates by measuring hepatic biomarkers, plasma concentrations of paracetamol and its metabolites and pain scores. In addition, we study a possible interaction between ethanol and paracetamol.Methods and analysisA multicentre interventional cohort study.Neonates of any gestational age and up to 44 weeks postmenstrual age, treated with oral or intravenous paracetamol can be included.Alanine aminotransferase (ALT) and bilirubin are measured at baseline or within 24 hours after treatment initiation. P-paracetamol and metabolites are measured at steady state and every 2 days (opportunistically) together with ALT and bilirubin and lastly after discontinuation of treatment. COMFORT neo pain scores are collected longitudinally. COMFORT neo pain scores and population pharmacokinetic analysis of paracetamol samples will be analysed simultaneously using non-linear mixed effects models. One and two compartment models with first-order elimination will be tested for disposition. In addition, plasma ethanol is measured if the patient receives concomitant treatment with intravenous or oral phenobarbital containing ethanol as an excipient.Ethics and disseminationInclusion of patients can be postponed 24 hours after the first paracetamol dose. This is intended to make the inclusion process less stressful for parents. This study uses standard dosing strategies. The potential risks are additional blood samples, which are collected opportunistically to reduce additional heel pricks.Trial registrationnumberEthics Comittee: H-17027244, EudraCT no: 2017-002724-25, BFH-2017–106, 05952.

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