Population Pharmacokinetics of Fluconazole in Young Infants

Wade, Kelly C.; Wu, Di; Kaufman, David; Ward, Robert M.; Benjamin, Daniel K.; Sullivan, Janice E.; Ramey, N.; Jayaraman, Bhuvaneswari; Hoppu, Kalle; Adamson, Peter C.; Gastonguay, Marc R.; Barrett, Jeffrey S.

doi:10.1128/aac.00569-08

Cited by 155 publications

(148 citation statements)

References 22 publications

(21 reference statements)

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“…Of note, we could have reasonably related weight to clearance using linear or power scaling terms, despite the convention for using a scaling exponent of 0.75. 19,26 We could not demonstrate any relationship between teicoplanin clearance and PMA, eGFR or serum creatinine. This is somewhat surprising because teicoplanin is almost completely renally (98%) cleared by glomerular filtration.…”

Section: Discussionmentioning

confidence: 65%

Population pharmacokinetics and pharmacodynamics of teicoplanin in neonates: making better use of C-reactive protein to deliver individualized therapy

Ramos-Martín

Neely

McGowan

et al. 2016

J. Antimicrob. Chemother.

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Objectives: There is uncertainty about the optimal teicoplanin regimens for neonates. The study aim was to determine the population pharmacokinetics (PK) of teicoplanin in neonates, evaluate currently recommended regimens and explore the exposure-effect relationships.Methods: An open-label PK study was conducted. Neonates from 26 to 44 weeks post-menstrual age were recruited (n ¼ 18). The teicoplanin regimen was a 16 mg/kg loading dose, followed by 8 mg/kg once daily. Therapeutic drug monitoring and dose adjustment were not conducted. A standard two-compartment PK model was developed, followed by models that incorporated weight. A PK/pharmacodynamic (PD) model with C-reactive protein serial measurements as the PD input was fitted to the data. Monte Carlo simulations (n¼ 5000) were performed using Pmetrics. The AUCs at steady state and the proportion of patients achieving the recommended drug exposures (i.e. C min .15 mg/L) were determined. The study was registered in the European Clinical Trials Database Registry (EudraCT: 2012-005738-12).Results: The PK allometric model best accounted for the observed data. The PK parameters medians were:). The individual time-course of C-reactive protein was well described using the Bayesian posterior estimates for each patient. The simulated median AUC 96-120 was 302.3 mg . h/L and the median C min at 120 h was 12.9 mg/L; 38.8% of patients attained a C min .15 mg/L by 120 h.Conclusions: Teicoplanin population PK is highly variable in neonates, weight being the best descriptor of PK variability. A low percentage of neonates were able to achieve C min .15 mg/L. The routine use of therapeutic drug monitoring and improved knowledge on the PD of teicoplanin is required.

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Section: Discussionmentioning

confidence: 65%

Population pharmacokinetics and pharmacodynamics of teicoplanin in neonates: making better use of C-reactive protein to deliver individualized therapy

Ramos-Martín

Neely

McGowan

et al. 2016

J. Antimicrob. Chemother.

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“…Preliminary data obtained through opportunistic studies have served in the design of phase I to III trials in children. For example, through the infrastructure of the Pediatric Pharmacology Research Unit funded by the National Institutes of Health, Wade et al obtained timed and scavenged plasma samples to characterize the PK of fluconazole in premature neonates (15). This PK analysis led to the dose selection for a phase III randomized, placebocontrolled trial of fluconazole prophylaxis in premature neonates (clinicaltrials.gov, NCT00734539).…”

Section: Discussionmentioning

confidence: 99%

“…Given the inherent difficulties with multiple blood draws to acquire blood samples in neonates, capitalizing on standard-ofcare procedures (such as biological sample collection from neonates already receiving drugs per routine medical care) has produced meaningful PK data, resulting in improved dosing recommendations for neonates (15). Opportunistic study designs offer an advantage over traditional PK studies given the low risk to participants and higher enrollment rates in a very difficult-tostudy population such as neonates.…”

mentioning

confidence: 99%

Characterization of the Population Pharmacokinetics of Ampicillin in Neonates Using an Opportunistic Study Design

Tremoulet

Lê

Poindexter

et al. 2014

Antimicrob Agents Chemother

106

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iAlthough ampicillin is the most commonly used drug in neonates, developmental pharmacokinetic (PK) data to guide dosing are lacking. Ampicillin is primarily renally eliminated, and developmental changes are expected to influence PK. We conducted an open-label, multicenter, opportunistic, prospective PK study of ampicillin in neonates stratified by gestational age (GA) (<34 or >34 weeks) and postnatal age (PNA) (<7 or >7 days). Drug concentrations were measured by tandem mass spectrometry. PK data were analyzed using population nonlinear mixed-effects modeling in NONMEM 7.2. Monte Carlo simulations were conducted to determine the probability of target attainment for the time in which the total steady-state ampicillin concentrations remained above the MIC (T>MIC) for 50%, 75%, and 100% of the dosing interval. A total of 142 PK samples from 73 neonates were analyzed (median [range] GA, 36 [24 to 41] weeks; PNA, 5 [0 to 25] days). The median ampicillin dose was 200 (100 to 350) mg/kg/day. Postmenstrual age and serum creatinine were covariates for ampicillin clearance (CL). A simplified dosing regimen of 50 mg/kg every 12 h for GA of <34 weeks and PNA of <7 days, 75 mg/kg every 12 h for GA of <34 weeks and PNA of >8 and <28 days, and 50 mg/kg every 8 h for GA of >34 weeks and PNA of <28 days achieved the prespecified surrogate efficacy target in 90% of simulated subjects. Ampicillin CL was associated with neonatal development. A simplified dosing regimen stratified by GA and PNA achieves the desired surrogate therapeutic target in the vast majority of neonates.

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“…Pharmacokinetic data have recently been published for fluconazole, micafungin, and caspofungin [14][15][16][17][18][19][20][21][22][23] . With studies examining pharmacokinetic data targeting comparable levels in adults, neonatal data are needed regarding safety.…”

Section: Treatment Of Invasive Fungal Infectionsmentioning

confidence: 99%

“…Studies of liposomal AmB products indicate that 5 mg/kg should be the starting dose and administered over 2 hours 27,28 . Recent publications of fluconazole demonstrate that a dose of 12 mg/kg is comparable to adult dosing; however, the safety of this dosing has not yet been studied in neonates 19,20 . The echinocandins may have effects that are unknown; monitoring of liver function tests, electrolytes, blood urea nitrogen, creatinine, calcium, phosphorus, and magnesium should be done daily for several days initially and then periodically if normal throughout treatment.…”

Section: Treatment Of Invasive Fungal Infectionsmentioning

confidence: 99%

Challenging issues in neonatal candidiasis

Kaufman

2010

Current Medical Research and Opinion

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In an era of quality improvement and 'getting to zero (infections and/or related mortality),' neonatal candidiasis is ripe for evidence-based initiatives. Knowledge of each institution's invasive Candida infection (ICI) incidence and infection-related mortality is critical to evaluate disease burden and effective interventions. Evidenced-based interventions include: antifungal prophylaxis, starting with appropriate dosing, and prompt removal of central venous catheters (CVC). There is A-I evidence supporting antifungal prophylaxis with fluconazole, and it should be considered in every neonatal intensive care unit (NICU). The literature supports targeting infants51000 g and/or 27 weeks, because this group has high infection-related mortality and neurodevelopmental impairment in 57% of survivors. Antifungal prophylaxis has been shown to nearly eliminate infection-related mortality. Interventions start with prenatal initiatives, with women being treated for vaginal candidiasis, especially with preterm labor or complications. Targeting modifiable risk factors, including restriction policies for use of third-and fourth-generation cephalosporins, carbapenems, H2-antagonists, proton pump inhibitors, and postnatal steroids; guidelines for CVC care and removal; and feeding practices, with promotion of early feedings and breast milk, may also reduce risk. A few studies have emerged on empiric antifungal therapy with sepsis evaluations for preterm infants 51500 g and other high-risk patients that have shown favorable effects of eliminating mortality, but these have not been compared to appropriate antifungal therapy and central line removal. Further study of empiric therapy, prospective treatment studies with higher targeted dosing of amphotericin B preparations, fluconazole, and new antifungals with prompt CVC removal may contribute to a 100% survival rate for those infants41000 g and 28 weeks not receiving antifungal prophylaxis. Evaluation of ICI incidence and mortality by gestational age and birth week should be followed in each NICU, to evaluate infection control and prevention.

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Population Pharmacokinetics of Fluconazole in Young Infants

Cited by 155 publications

References 22 publications

Population pharmacokinetics and pharmacodynamics of teicoplanin in neonates: making better use of C-reactive protein to deliver individualized therapy

Population pharmacokinetics and pharmacodynamics of teicoplanin in neonates: making better use of C-reactive protein to deliver individualized therapy

Characterization of the Population Pharmacokinetics of Ampicillin in Neonates Using an Opportunistic Study Design

Challenging issues in neonatal candidiasis

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