I.V. acetaminophen pharmacokinetics in neonates after multiple doses

Palmer, Greta M; Atkins, M. E.; Anderson, Brian J.; Smith, Katherine R.; Culnane, T. J.; McNally, Clare; Perkins, Elizabeth; Chalkiadis, George; Hunt, Rod W.

doi:10.1093/bja/aen208

Cited by 141 publications

(94 citation statements)

References 26 publications

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“…This suggests that piperacillin-tazobactam dosing guidelines for premature infants must consider developmental differences in the drugs' CL similar to what has been successfully achieved using PMA-based dosing for other therapeutics (e.g., metronidazole [9,28], amikacin [29], vancomycin [30], and acetaminophen [31]). Other piperacillin dosing regimens using an array of body weight and PNA have been recently developed for infants (7); however, these target lower MICs and are challenging to implement clinically.…”

Section: Discussionmentioning

confidence: 99%

Developmental Pharmacokinetics of Piperacillin and Tazobactam Using Plasma and Dried Blood Spots from Infants

Cohen‐Wolkowiez

Watt

Zhou

et al. 2014

Antimicrob Agents Chemother

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f Piperacillin-tazobactam is often given to infants with severe infection in spite of limited pharmacokinetics (PK) data. We evaluated piperacillin-tazobactam PK in premature and term infants of ages <61 days with suspected systemic infection. Infants received intravenous piperacillin-tazobactam (80 to 100 mg/kg of body weight every 8 h [q 8 h]) based on gestational and postnatal age. Sparse plasma samples were obtained after first and multiple doses. Drug concentrations were measured by tandem mass spectrometry. PK data were analyzed using population nonlinear mixed-effect modeling. Target attainment rates for the time unbound piperacillin concentrations remained above the MIC for 50% and 75% of the dosing interval at steady state were evaluated. Bias in population PK parameter estimates was assessed for dried blood spot (DBS) samples, and a comparability analysis was performed for DBS and plasma drug concentrations using linear regression. We obtained 128 plasma samples from 32 infants, median gestational age of 30 weeks (range, 23 to 40 weeks) and postnatal age of 8 days (range, 1 to 60). Piperacillin and tazobactam PK models included body weight (WT) and postmenstrual age (PMA) as covariates for clearance and WT for volume of distribution and were used to optimize dosing in infants. DBS drug concentrations were 50 to 60% lower than those in plasma, but when combined with plasma concentrations and a matrix effect, the data generated PK model parameters similar to those for plasma alone. With PMA-based dosing (100 mg/kg q 8 h, 80 mg/kg q 6 h, and 80 mg/kg q 4 h for PMA of <30, 30 to 35, and 35 to 49 weeks, respectively), 90% of simulated infants achieved the surrogate therapeutic target of time above the MIC (<32 mg/liter) for 75% of the dosing interval. P iperacillin-tazobactam is approved by the U.S. Food and Drug Administration for the treatment of adults and children of Ͼ2 months of age with infections due to susceptible bacteria; however, the drug is not approved for use in younger infants, including those born prematurely. In spite of this, piperacillin-tazobactam is extensively used "off-label" in young infants for treatment of systemic infections, including bacteremia and complicated intra-abdominal infections, such as necrotizing enterocolitis (1). Because these infections in premature infants are associated with devastating outcomes, such as death and neurodevelopmental impairment (2, 3), appropriate dosing recommendations for agents such as piperacillin-tazobactam are needed. Recommended piperacillin-tazobactam dosing for young infants in sources like Neofax (4) and The Harriet Lane Handbook (5) rely on combinations of birth weight, gestational age, postmenstrual age (PMA), and postnatal age (PNA), which are cumbersome to implement clinically and more importantly are supported by very small and limited clinical trials in this population.The pharmacokinetics (PK) of piperacillin-tazobactam has not been well characterized for premature infants. The drug is primarily renally eliminated by glomerular fi...

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Section: Discussionmentioning

confidence: 99%

Developmental Pharmacokinetics of Piperacillin and Tazobactam Using Plasma and Dried Blood Spots from Infants

Cohen‐Wolkowiez

Watt

Zhou

et al. 2014

Antimicrob Agents Chemother

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“…Postnatal changes in the pharmacokinetic profile of a number of analgesic drugs (eg morphine and paracetamol [acetaminophen]) resulted in significant agerelated changes in dose requirements during infancy and childhood (Bouwmeester et al, 2004;Palmer et al, 2008;Prins et al, 2008). In addition, changes in nociceptive processing may have significant effects on the pharmacodynamic response to analgesics in early life (Walker, 2008).…”

Section: Developmental Neurobiology Of Painmentioning

confidence: 99%

Acupuncture for analgesia in the emergency department: a multicentre, randomised, equivalence and non‐inferiority trial

Cohen

Smit

Andrianopoulos³

et al. 2017

Medical Journal of Australia

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Objectives: This study aimed to assess analgesia provided by acupuncture, alone or in combination with pharmacotherapy, to patients presenting to emergency departments with acute low back pain, migraine or ankle sprain. Design: A pragmatic, multicentre, randomised, assessor‐blinded, equivalence and non‐inferiority trial of analgesia, comparing acupuncture alone, acupuncture plus pharmacotherapy, and pharmacotherapy alone for alleviating pain in the emergency department. Setting, participants: Patients presenting to emergency departments in one of four tertiary hospitals in Melbourne with acute low back pain, migraine, or ankle sprain, and with a pain score on a 10‐point verbal numerical rating scale (VNRS) of at least 4. Main outcome measures: The primary outcome measure was pain at one hour (T1). Clinically relevant pain relief was defined as achieving a VNRS score below 4, and statistically relevant pain relief as a reduction in VNRS score of greater than 2 units. Results: 1964 patients were assessed between January 2010 and December 2011; 528 patients with acute low back pain (270 patients), migraine (92) or ankle sprain (166) were randomised to acupuncture alone (177 patients), acupuncture plus pharmacotherapy (178) or pharmacotherapy alone (173). Equivalence and non‐inferiority of treatment groups was found overall and for the low back pain and ankle sprain groups in both intention‐to‐treat and per protocol (PP) analyses, except in the PP equivalence testing of the ankle sprain group. 15.6% of patients had clinically relevant pain relief and 36.9% had statistically relevant pain relief at T1; there were no between‐group differences. Conclusion: The effectiveness of acupuncture in providing acute analgesia for patients with back pain and ankle sprain was comparable with that of pharmacotherapy. Acupuncture is a safe and acceptable form of analgesia, but none of the examined therapies provided optimal acute analgesia. More effective options are needed. Trial registration: Australian New Zealand Clinical Trials Registry, ACTRN12609000989246.

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“…PMA-based dosing offers an advantage over current recommendations by simplifying dosing regimens and potentially providing desired metronidazole concentrations over a wider age range. PMA-based dosing has not been systematically evaluated for metronidazole; however, it has proven successful for other therapeutics in preterm infants (11,13,15).…”

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confidence: 99%

Population Pharmacokinetics of Metronidazole Evaluated Using Scavenged Samples from Preterm Infants

Cohen‐Wolkowiez

Ouellet

Smith

et al. 2012

Antimicrob Agents Chemother

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g Pharmacokinetic (PK) studies in preterm infants are rarely conducted due to the research challenges posed by this population. To overcome these challenges, minimal-risk methods such as scavenged sampling can be used to evaluate the PK of commonly used drugs in this population. We evaluated the population PK of metronidazole using targeted sparse sampling and scavenged samples from infants that were <32 weeks of gestational age at birth and <120 postnatal days. A 5-center study was performed. A population PK model using nonlinear mixed-effect modeling (NONMEM) was developed. Covariate effects were evaluated based on estimated precision and clinical significance. Using the individual Bayesian PK estimates from the final population PK model and the dosing regimen used for each subject, the proportion of subjects achieving the therapeutic target of trough concentrations >8 mg/liter was calculated. Monte Carlo simulations were performed to evaluate the adequacy of different dosing recommendations per gestational age group. Thirty-two preterm infants were enrolled: the median (range) gestational age at birth was 27 (22 to 32) weeks, postnatal age was 41 (0 to 97) days, postmenstrual age (PMA) was 32 (24 to 43) weeks, and weight was 1,495 (678 to 3,850) g. The final PK data set contained 116 samples; 104/116 (90%) were scavenged from discarded clinical specimens. Metronidazole population PK was best described by a 1-compartment model. The population mean clearance (CL; liter/h) was determined as 0.0397 ؋ (weight/1.5) ؋ (PMA/32) 2.49 using a volume of distribution (V) (liter) of 1.07 ؋ (weight/1.5). The relative standard errors around parameter estimates ranged between 11% and 30%. On average, metronidazole concentrations in scavenged samples were 30% lower than those measured in scheduled blood draws. The majority of infants (>70%) met predefined pharmacodynamic efficacy targets. A new, simplified, postmenstrual-age-based dosing regimen is recommended for this population. Minimal-risk methods such as scavenged PK sampling provided meaningful information related to development of metronidazole PK models and dosing recommendations. P reterm infant pharmacokinetic (PK) studies are exceptionally scarce due to the research challenges posed by this population, such as limited blood volume for PK sampling, difficulty in timing of PK samples due to the critical medical condition of the infants, difficult access to obtain samples, and low rates of informed parental consent. Feasibility issues also are imposed by traditional PK study designs, which require large numbers of specifically timed PK blood samples. These difficulties have encouraged investigators to explore novel minimal-risk methods to evaluate the PK of antimicrobials in this population. One proposed method is the use of scavenged samples left over from the normal clinical care of infants. The use of scavenged samples for PK studies in preterm infants offers several advantages over traditional timed PK trials. These include avoiding the need for heel sticks specif...

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I.V. acetaminophen pharmacokinetics in neonates after multiple doses

Abstract: The parameter estimates are similar to those described for propacetamol. There was no evidence of hepatotoxicity. Unconjugated hyperbilirubinaemia impacts upon CL, dictating dose reduction.

Cited by 141 publications

References 26 publications

Developmental Pharmacokinetics of Piperacillin and Tazobactam Using Plasma and Dried Blood Spots from Infants

Developmental Pharmacokinetics of Piperacillin and Tazobactam Using Plasma and Dried Blood Spots from Infants

Acupuncture for analgesia in the emergency department: a multicentre, randomised, equivalence and non‐inferiority trial

Population Pharmacokinetics of Metronidazole Evaluated Using Scavenged Samples from Preterm Infants

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