Developmental Pharmacokinetics of Gentamicin in Preterm and Term Neonates

ABSTRACT. We consider dosing regimens designed to cure patients by eradicating colony forming units (CFU) such as bacteria. In the field of "population" pharmaco-kinetics/dynamics (PK/PD), interindividual variability (IIV) of patients is estimated using model parameter statistical distributions. We consider a more probabilistic approach to IIV called stochastic process theory, motivated by the fact that tumor treatment planning uses both approaches. Stochastic process PD can supply additional insights and suggest different dosing regimens due to its emphasis on the probability of complete CFU eradication and its predictions on "pure chance" fluctuations of CFU number per patient when treatment has reduced this integer to less than~100. To exemplify the contrast between stochastic process PD models and standard deterministic PD models, which track only average CFU number, we analyze, neglecting immune responses, neonatal intravenous gentamicin dosing regimens directed against Escherichia coli. Our stochastic calculations predict that the first dose is crucial for CFU eradication. For example, a single 6 mg/kg dose is predicted to have a higher eradication probability than four daily 4 mg/kg doses. We conclude: (1) neonatal gentamicin dosing regimens with larger first doses but smaller total doses deserve investigation; (2) in general, if standard PK/PD models predict average CFU number drops substantially below 100, the models should be modified to incorporate stochastic effects more accurately, and will then usually make more favorable, or less unfavorable, predictions for front boosting ("hit hard early"). Various caveats against over-interpreting the calculations are given.

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“…Our calculations extend two papers (8,9) on PK/PD modeling of neonatal gentamicin treatments. Figure 2 is a condensed summary.…”

Section: Deterministic and Stochastic Neonatal Gentamicin Pk/pd Modelingsupporting

confidence: 68%

“…One PK/PD approach to modeling gentamicin treatment of E. coli in neonates is given in (8,9). The approach takes into account drug-induced "adaptive resistance," which is reversible within days [reviewed in (4,10)]; it does not consider irreversible resistance caused, e.g., by bacterial mutations (11,12).…”

Section: Pk/pd Modelingmentioning

confidence: 99%

Stochastic Process Pharmacodynamics: Dose Timing in Neonatal Gentamicin Therapy as an Example

Radivoyevitch

Siranart

Hlatky

et al. 2015

AAPS J

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“…Routine monitoring of the C peak is not indicated when gentamicin is administered once daily, as it is expected to reach levels above those when given twice daily. According to the references, therapeutic gentamicin concentration C peak is ranging from 15-25 mg/l, but it often exceeds 25 mg/l, which is not associated with adverse effects on clinical outcome [1,15]. However, concentrations below 15 mg/l could be linked with the potential inefficiency due to C peak :MIC ratio <8:1 [3,11].…”

Section: Discussionmentioning

confidence: 99%

“…However, wide inter-individual variability was observed. In the study by Mannan et al, difference in the renal function between pre-and full-term neonates was explained by gestational age [9], while Nielsen et al showed that bodyweight, and both gestational and postnatal age were found to be main factors contributing to variability in gentamicin CL in neonates [15]. Furthermore, Knight et al, revealed significant difference between the mean trough concentrations assessed on day 2 versus days 3 or 4 [20].…”

Section: Discussionmentioning

confidence: 99%

Clinical pharmacokinetics in optimal gentamicin dosing regimen in neonates

Vučićević

Rakonjac

Janković³

et al. 2014

Open Medicine

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AbstractGentamicin is readily used for suspected or proven sepsis in neonates, yet it shows considerable inter-individual pharmacokinetic variability, which limits achievements of therapeutic levels. Hence, the aim of this study was to compare peak and trough gentamicin concentrations according to dosing regimen, to evaluate pharmacokinetic parameters, and to consider adjustments of dosing regimen. Babies with infection were treated with 1 h infusion, and daily dose of 5 or 7.5 mg/kg depending on the age. Patients were randomized into two groups: I — dosing interval 12 h (n=8), II — 24 h (n=11). Two steady-state blood samples were obtained. Pharmacokinetic parameters were calculated using one-compartment model. The results showed a difference (p<0.05) in peak gentamicin concentrations between the groups, and tendency of lower trough levels in the group II. Calculated pharmacokinetic parameters included the volume of distribution (Vd) 0.52±0.47 l/kg, clearance (CL) 0.055±0.036 l/hkg and a half-life (t1/2) of 6.89±3.21 h. Based on the method for dosing regimen adjustments, there was a need to extend dosing interval to 36 h in 6 patients

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“…The approach to dosing in newborns has been suggested to be based on their body weight, gestational age (GA), and postnatal age as these characteristics reflect the pharmacokinetics (PK) in this population (43). A three-compartment PK model of gentamicin disposition in preterm and term newborn infants was recently described based on a prospective study (35).…”

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confidence: 99%

Pharmacokinetic-Pharmacodynamic Model for Gentamicin and Its Adaptive Resistance with Predictions of Dosing Schedules in Newborn Infants

Mohamed

Nielsen

Cars

et al. 2012

Antimicrob Agents Chemother

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Gentamicin is commonly used in the management of neonatal infections. Development of adaptive resistance is typical for aminoglycosides and reduces the antibacterial effect. There is, however, a lack of understanding of how this phenomenon influences the effect of different dosing schedules. The aim was to develop a pharmacokinetic-pharmacodynamic (PKPD) model that describes the time course of the bactericidal activity of gentamicin and its adaptive resistance and to investigate different dosing schedules in preterm and term newborn infants based on the developed model. In vitro time-kill curve experiments were conducted on a strain of Escherichia coli (MIC of 2 mg/liter). The gentamicin exposure was either constant (0.125 to 16 mg/liter) or dynamic (simulated concentration-time profiles in a kinetic system with peak concentrations of 2.0, 3.9, 7.8, and 16 mg/liter given as single doses or as repeated doses every 6, 12, or 24 h). Semimechanistic PKPD models were fitted to the bacterial counts in the NONMEM (nonlinear mixed effects modeling) program. A model with compartments for growing and resting bacteria, with a function allowing the maximal bacterial killing of gentamicin to reduce with exposure, characterized both the fast bactericidal effect and the adaptive resistance. Despite a lower peak concentration, preterm neonates were predicted to have a higher bacterial killing effect than term neonates for the same per-kg dose because of gentamicin's longer half-life. The model supported an extended dosing interval of gentamicin in preterm neonates, and for all neonates, dosing intervals of 36 to 48 h were as effective as a 24-h dosing interval for the same total dose.

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Developmental Pharmacokinetics of Gentamicin in Preterm and Term Neonates

Cited by 78 publications

References 48 publications

Stochastic Process Pharmacodynamics: Dose Timing in Neonatal Gentamicin Therapy as an Example

Stochastic Process Pharmacodynamics: Dose Timing in Neonatal Gentamicin Therapy as an Example

Clinical pharmacokinetics in optimal gentamicin dosing regimen in neonates

Pharmacokinetic-Pharmacodynamic Model for Gentamicin and Its Adaptive Resistance with Predictions of Dosing Schedules in Newborn Infants

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