Departments of 1 Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, and 2 Pharmacy Service; 3 Neonatology Unit, Pediatrics Service, University Hospital, University of Salamanca, Salamanca, Spain
Received 25 November 2003; returned 21 January 2004; revised 5 March 2004; accepted 4 April 2004
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Abstract |
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Patients and methods: The population pharmacokinetics of gentamicin was studied retrospectively in a population of 113 neonates divided into two groups: one for computing the population model (n=97) and another for validation (n=36). A one-compartment pharmacokinetic model and non-linear mixed-effects modelling were used to assess the population pharmacokinetic model.
Results: Weight (W) and postnatal age (PA) were the covariates that influenced the pharmacokinetic parameters of gentamicin. The final population model obtained was: distribution volume, V (L)=0.636 x W (kg)0.852; clearance, Cl (L/h)=0.032 x W (kg)1.482+0.0024 x PA (days). The predictive performance of the model in the population validation was adequate for clinical purposes. The optimized population model allowed us to simulate gentamicin serum levels and their variability, in this kind of patient, when extended-interval dosage administration regimens were implemented.
Conclusions: According to our pharmacokinetic population model, initial doses of gentamicin of 10 mg/kg, and dosage intervals between 3648 h, appear to be appropriate to achieve target peak and trough serum levels of 1520 and <0.5 mg/L, respectively, when extended-interval dosage regimens are implemented in newborns. The half-life of gentamicin in premature babies of very low weight and gestational age <31 weeks is long. Thus, to achieve serum concentrations in the 110 mg/L range, the use of dosage regimens of 5 mg/kg at 3648 h dosage intervals seems suitable.
Keywords: population pharmacokinetics , extended-interval dosage regimens , aminoglycosides
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Introduction |
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Currently, the dosage regimens of aminoglycosides in this kind of patient are based either on conventional administration (812 h dosage interval) or on extended-interval dosage administration (once daily). Nevertheless, there is no consensus concerning current criteria for gentamicin dosing regimens in neonates.6 In patients with high distribution volumes and prolonged gentamicin serum half-lives, as in the case of neonates, the standard guidelines for extended-interval dosage administration as applied to adults are not applicable, and specific pharmacokinetic considerations are required for such situations.
The aim of the present work was to characterize the population pharmacokinetics of gentamicin in neonates, in order to determine the kinetic profile of this drug when extended-interval dosage regimens are used and to facilitate a MAP Bayesian approach in clinical practice.
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Patients and methods |
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A retrospective review of pharmacokinetic data of gentamicin was conducted in 133 newborn patients admitted during 19992003 in the Neonatology Unit of the University Hospital in Salamanca (Spain). These data were obtained as part of our routine therapeutic drug monitoring (TDM) of aminoglycoside therapy in paediatric patients. They were suffering from severe infective processes, proven (11%) or suspected, and were being treated with gentamicin either alone or in combination with other antibiotics. Patients were included if their postnatal age was 30 days, and if data were available for the following: at least two serum gentamicin concentrations (2 and 24 h), sampling times, GA, PA, weight and dosing schedule. The patients were divided into two groups: one for building the population model (n=97) and the other for validation (n=36). Table 1 summarizes the patients' characteristics. Plasma creatinine levels were not included because in the first 2 weeks of life this parameter does not reflect a patient's renal function.5
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Gentamicin was administered to patients suspected of suffering from infection due to Gram-negative microorganisms, regardless of whether this had been confirmed in the antibiogram.
Gentamicin was dispensed in the form of an intravenous (iv) infusion of a 1 mg/mL solution over 3060 min at GA-dependent doses and intervals. In patients with GA <31 weeks, initial doses of 5 mg/kg at dosage intervals of 36 h (GA 2630 weeks) or 48 h (GA <26 weeks) were used to target peak and trough levels of 710 and 12 mg/L, respectively. In patients with GA >31 weeks, initial doses of 10 mg/kg at 36 h dosage intervals (term newborns) or 12 mg/kg at 48 h dosage intervals (GA 3138 weeks) were used to produce the desired peak and trough levels of 1520 mg/L and <0.5 mg/L, respectively. These dosage recommendations were designed on the basis of the pharmacokinetic parameters of gentamicin published previously.7
Two blood samples (2 and 24 h after the end of the infusion) for drug levels were collected routinely by venipuncture after the administration of the second dose of the treatment. We monitored intermediate levels, bearing in mind that trough levels could be below the sensitivity level of the analytical technique. Serum gentamicin levels were measured by fluorescence polarization immunoassay AXYM (Abbott Laboratories, Chicago, IL, USA). The sensitivity limit of this method is 0.3 mg/L, the variation coefficient <5% and the calibration range 0.310 mg/L. On the basis of these levels, individual adjustments of the dose or dosage interval to achieve target levels were performed by a computer-assisted MAP Bayesian approach (Abbottbase pharmacokinetic systems; Program PKS; Abbott Laboratories, Chicago, IL, USA).
Population pharmacokinetic analysis
For the population pharmacokinetic analysis, the serum levels data were fitted to a one-compartment kinetic model with first-order elimination. The pharmacokinetic parameters of the model were clearance (Cl) and the apparent distribution volume (V).
The basic structural model for the pharmacokinetic parameter (P) initially considered was P=, where
represents the fixed-effect parameter of the structural model to be estimated. Selection of a final population model was accomplished by evaluating the incorporation of continuous covariates in different linear and non-linear ways, according to the following general equation:
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The statistical model used to describe intersubject variability in the clearance and apparent distribution volume of gentamicin was proportional:
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To describe the residual error in the concentration, an additive model was chosen:
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The fixed and random parameters of gentamicin were estimated using non-linear mixed-effects modelling, as implemented in the WINNONMIX software package (Pharsight Corp., Mountain View, CA, USA) bundled with the Compaq Visual Fortran compiler (Compaq Computer Corp., Houston, TX, USA). The mixed-effects modelling estimation was accomplished using a first-order estimation method.
Statistical comparison of different population models was based on a 2 test of the difference in the objective function. The final regression model was developed using the forward inclusion and backward elimination technique. Each covariate was incorporated stepwise, either linearly or non-linearly, into the basic population model (forward inclusion). Changes in the objective function upon addition of a covariate approximate the
2 distribution with 1 degree of freedom. A decrease in the objective function (P<0.05) was considered significant during the forward inclusion analysis. The full model was created by incorporating all covariates, which led to a significant decrease in the objective function. The objective function of the full model was used to test the effect of removing each covariate (backward elimination). Only covariates showing an increase in the objective function (P<0.01) upon removal from the full model were retained. The goodness of fit of each analysis run was also assessed by the examination of scatterplots of predicted versus measured gentamicin concentrations, weighted residuals versus dependent and independent variables, the variation coefficient of the mean parameter, changes in the estimates of interindividual and residual variability resulting from the addition or deletion of a covariate and Akaike's Information Criterion.8,9
Using the final population model, individual estimates of the pharmacokinetic parameters were obtained based on fixed-effects population parameters and subject-specific random effects.
The final population model obtained was used to predict a priori serum gentamicin concentrations in the validation population. Predicted peak and intermediate serum gentamicin concentrations were compared with measured concentrations to determine the predictive performance of the final model. Correlation analysis, standardized mean prediction error and standard deviation of standardized mean prediction error10 were used. The predictive performance of our population model (model 1) was compared with two other previously published population pharmacokinetic models of gentamicin in neonates using mixed-effects modelling (model 211 and model 312).
The other models tested were the following: Model 211: Cl (L/h)=0.120x[weight (kg)/2.4]1.36; V (L)=0.429 x weight (kg). Model 312: Cl (L/h)=0.001 x birthweight (kg) x GA (weeks) x P (where P = 1.2 for girls and 1.0 for boys); V (L)=0.472 x birthweight (kg).
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Results |
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Discussion |
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The behaviour of gentamicin in this population allows one to evaluate the use of extended-interval dosage regimens in neonates from the pharmacokinetic perspective. In two recent reviews, in which once-daily dosing in infants was analysed, it is reported that most authors use varying dosing intervals in the range of 2448 h in newborns and premature infants, although extended-interval dosage regimens in neonates usually dose gentamicin every 24 h.18,19 Regarding the doses employed, most authors working with newborn infants with GA >29 weeks use doses between 2.55 mg/kg, with mean peak levels of 5.411.2 mg/L and mean trough levels between 0.81.7 mg/L being achieved.13,2022 These dosage regimens achieve serum levels that resemble those obtained with the conventional dosage regimens in adults.
The pharmacological basis of extended-interval dosage regimens is to achieve levels that are 810 times the MIC, so target peak levels must occur around 1520 mg/L, increasing the post-antibiotic effect. Trough levels of <0.5 mg/L are desirable to guarantee the efficacy and safety of treatment.23 There are other published studies of extended interval-dosage regimens in paediatrics in which the peak and trough serum levels were >15 and <0.5 mg/L, respectively, these serum drug levels being similar to those obtained in adults with this kind of regimen, and the treatments were safe and effective.23,24
In view of the pharmacokinetic behaviour of gentamicin in neonatessupported by our population model and characterized by high distribution volumes and long half-livesfor peak serum levels between 1520 mg/L and trough levels <0.5 mg/L to be attained it is necessary to employ doses 10 mg/kg and dosage intervals >24 h. Figure 4 shows the correlation between the individual value of the half-life of gentamicin and the GA of the patients in our population. It may also be seen that the half-life of gentamicin reaches values >10 h in neonates with a very low weight and with a GA of <31 weeks, and thereafter decreases steadily until values of 56 h are attained in term newborns. The progressive evolution of the half-life of gentamicin with the GA or with the weight of the patient makes it necessary progressively to increase the gentamicin dosing interval up to 3648 h in order to attain similar peak and trough serum levels. In adult patients, extended-interval dosage regimens of aminoglycosides with high peaks and intervals up to 48 h are used in patients with moderate renal impairment (ClCR 2039 mL/min).25 The neonate population shows gentamicin serum half-lives that are very similar to those of adult patients with a moderate degree of renal impairment. As a result, as may be seen in Figure 5, for target peak serum levels between 1520 mg/L and trough serum levels <0.5 mg/L of gentamicin to be reached in neonatessimilar to those seen in adults with extended-interval dosage regimensthe dosing intervals should initially range between 3648 h. Nevertheless, the final adjustment of the interval may depend on the results of the monitoring of serum gentamicin levels.
From the pharmacokinetic point of view, most dosage recommendations in neonates based on the use of extended intervals and doses in the 35 mg/kg range provide peak and trough serum gentamicin levels similar to those obtained with conventional regimens used in adults and based on two to three daily administrations. The common practice of using fixed intervals of 24 h, especially in very low-weight and low GA neonates, may produce potentially toxic trough levels >2 mg/L.
In conclusion, the pharmacokinetic behaviour of gentamicin in neonates is characterized by high distribution volumes and long half-lives. In order to achieve peak serum levelsbased on the concepts that support the benefit of extended-interval dosage regimens aimed at achieving higher peak/MIC ratiosinitial doses of 10 mg/kg or higher, and dosage intervals >24 h, would be necessary in neonates with a GA of 31 weeks. However, in neonates with a GA of <31 weeks, characterized by half-lives of >10 h, dosage regimens of 5 mg/kg at 3648 h dosage intervals would be appropriate. This would aim to reach trough and peak gentamicin serum concentrations in the range of 0.52 mg/L and 710 mg/L, respectively. Later monitoring (TDM) of serum gentamicin levels would use MAP Bayesian strategies on the basis of the population pharmacokinetic parameters. After adaptation of the model to typical TDM computer programs, such as PKS among others, this would permit adjustment of the dose and dosing interval to achieve the peak and trough serum levels of gentamicin associated with extended-interval dosage regimens.
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Footnotes |
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References |
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2 . Vervelde, M. L., Rademaker, C. M. A., Krediet, T. G. et al. (1999). Population pharmacokinetics of gentamicin in preterm neonates: evaluation of a once-daily dosage regimen. Therapeutic Drug Monitoring 21, 51419.[CrossRef][ISI][Medline]
3 . Hayani, K. C., Hatzopoulos, F. K., Fank, A. L. et al. (1997). Pharmacokinetics of once-daily dosing of gentamicin in neonates. Journal of Pediatrics 131, 7680.[ISI][Medline]
4 . Rodvold, K. A., Gentry, C. A., Plank, G. S. et al. (1993). Prediction of gentamicin concentrations in neonates and infants using a Bayesian pharmacokinetic model. Developmental Pharmacology and Therapeutics 20, 21119.[ISI][Medline]
5 . Stolk, L. M., Degraeuwe, P. L., Nieman, F. H. et al. (2002). Population pharmacokinetics and relationship between demographic and clinical variables and pharmacokinetics of gentamicin in neonates. Therapeutic Drug Monitoring 24, 52731.[CrossRef][ISI][Medline]
6
.
Agarwal, G., Rastogi, A., Pyati, S. et al. (2002). Comparison of once-daily versus twice-daily gentamicin dosing regimens in infants 2500 g. Journal of Perinatology 22, 26874.[CrossRef][Medline]
7 . Izquierdo, M., Lanao, J. M., Cervero, L. et al. (1992). Population pharmacokinetics of gentamicin in premature infants. Therapeutic Drug Monitoring 14, 17783.[ISI][Medline]
8 . Davidian, M. & Giltinan, D. M. (1995). Monographs on Statistics and Applied Probability. Vol. 62. Nonlinear Models for Repeated Measurement Data, Chapman & Hall, London, UK.
9 . Martin, E. S. (1991). The population pharmacokinetics of theophylline during the early postnatal period. Journal of Pharmacokinetics and Biopharmaceutics 19, Suppl, 59S77S.
10 . Vozeh, S., Maitre, P. O. & Stanski, D. R. (1990). Evaluation of population (NONMEM) pharmacokinetic parameter estimates. Journal of Pharmacokinetics and Biopharmaceutics 18, 16173.[ISI][Medline]
11 . Jensen, P. D., Edgren, B. E. & Brundage, R. C. (1992). Population pharmacokinetics of gentamicin in neonates using a nonlinear, mixed-effects model. Pharmacotherapy 12, 17882.[ISI][Medline]
12 . Botha, J. H., du Preez, M. J. & Adhikari, M (2003). Population pharmacokinetics of gentamicin in South African newborns. European Journal of Clinical Pharmacology 59, 7559.[CrossRef]
13 . Thomson, A. H., Kokwaro, G. O., Muchohi, S. N. et al. (2003). Population pharmacokinetics of intramuscular gentamicin administered to young infants with suspected severe sepsis in Kenya. British Journal of Clinical Pharmacology 56, 2531.[CrossRef][ISI][Medline]
14 . Rocha, M. J., Almeida, A. M., Afonso, E. et al. (2000). The kinetic profile of gentamicin in premature neonates. Journal of Pharmacy and Pharmacology 52, 10917.[ISI][Medline]
15 . Ohler, K. H., Menke, J. A. & Fuller, F. (2000). Use of higher dose extended interval aminoglycosides in a neonatal intensive care unit. American Journal of Perinatology 17, 28590.[CrossRef][ISI][Medline]
16 . Faura, C. C., Garcia, M. R. & Horga, J. F. (1991). Changes in gentamicin serum levels and pharmacokinetic parameters in the newborn in the course of treatment with aminoglycoside. Therapeutic Drug Monitoring 13, 27780.[ISI][Medline]
17
.
Stickland, M. D., Kirkpatrick, C. M., Begg, E. J. et al. (2001). An extended interval dosing method for gentamicin in neonates. Journal of Antimicrobial Chemotherapy 48, 88793.
18
.
Chattopadhyay, B. (2002). Newborns and gentamicin-how much and how often? Journal of Antimicrobial Chemotherapy 49, 136.
19 . Miron, D. (2001). Once daily dosing of gentamicin in infants and children. Pediatric Infectious Disease Journal 20, 116973.[CrossRef][ISI][Medline]
20 . Skopnik, H., Wallraf, R., Nies, B. et al. (1992). Pharmacokinetics and antibacterial activity of daily gentamicin. Archives of Disease in Childhood 67, 5761.[Abstract]
21 . de Alba Romero, C., Castillo, E. G., Secades, C. M. et al. (1998). Once daily gentamicin dosing in neonates. Pediatric Infectious Disease Journal 17, 116970.[CrossRef][ISI][Medline]
22 . Skopnik, H. & Heimann, G. (1995). Once daily aminoglycoside in full term neonates. Pediatric Infectious Disease Journal 14, 712.[ISI][Medline]
23 . Bass, K. D., Larkin, S. E., Paap, C. et al. (1998). Pharmacokinetics of once-daily gentamicin dosing in pediatric patients. Journal of Pediatrics Surgery 33, 11047.
24 . Carapetis, J. R., Jaquiery, A. L., Buttery, J. P. et al. (2001). Randomized, controlled trial comparing once daily and three times daily gentamicin in children with urinary tract infections. Pediatric Infectious Disease Journal 20, 2406.[CrossRef][ISI][Medline]
25 . Nicolau, D. P., Freeman, C. D., Belliveau, P. P. et al. (1995). Experience with a once-daily aminoglycoside program administered to 2,184 adult patients. Antimicrobial Agents and Chemotherapy 39, 6505.[Abstract]
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