Pharmacokinetics of once-a-day netilmicin (6 mg/kg ...

Journal of Antimicrobial Chemotherapy (1996) 38, 499-505

Pharmacokinetics of once-a-day netilmicin (6 mg/kg) in neonates J. J. Ettiinger*, K. A. Bedford*, A. M. Lovering*, D. S. Reeves', B. D. Speidel* and A. P. MacGowan**

'Department of Neonatal Medicine;bBristol Centre for Antimicrobial Research & Evaluation, Southmead Health Services NHS Trust and the University of Bristol, Department of Medical Microbiology, Southmead Hospital, Westbury-on-Trym, Bristol, BSW 5NB, UK

Introduction The pharmacokinetics of netilmicin in neonates has been examined before and the main conclusion to be drawn from these studies is the large interpatient variability in observed serum concentrations in this group (Bergan & Michalsen, 1982; Kuhn et al., 1986). Previously serum half-life, volume of distribution, absolute plasma clearance and 'peak' serum concentration have been related to weight and gestational age (Siegel et al., 1979). Others have been able to relate absolute plasma clearance to chronological age (Kuhn et al., 1986). However, such correlations have not always been possible, presumably due to the variable handling of aminoglycosides by neonates (Bergan & Michalsen, 1986). Once-daily aminoglycoside therapy has been shown to be clinically effective and possibly less toxic if compared with multiple doses, not only in a wide variety of mainly adult patients (Parker & Davey, 1993; MacGowan & Reeves, 1994; MacGowan, 1994; Barza et al., 1996) but also in children (Kafetzis et al., 1991; Viscoli et al., 1991). However, although aminoglycosides play an important role in the antimicrobial •Corresponding author. Tel: +44-{117>950-5050; Fax: + 44-(117>959-3154; E-mail: [email protected] 0305-7453/96/090499 + 07 $12.00/0

499 © 1996 The British Society for Antimicrobial Chemotherapy

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The pharmacokinetics of once a day netilmicin (6 mg/kg) was studied in 21 neonates. The babies were divided into three groups according to gestational age: group I aged >36 weeks; group II between 34-36 weeks and group III 2 mg/L. There were also large patient-to-patient variations in serum half-life, volume of distribution, area under the curve and relative plasma clearance such that these parameters could not be correlated to gestational age or weight. Absolute plasma clearance was correlated with both gestational age and weight. There was evidence of accumulation between the first and second dose for all three patient groups and for patients of gestational age < 34 weeks (group III) these observations were statistically significant. A netilmicin dosage of 4.5 mg/kg once a day may be more suitable for all neonates supported by assay of serum concentrations.

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therapy of neonatal sepsis, limited data are available concerning the pharmacokinetics, efficacy and toxicity of once daily aminoglycosides in neonates. For example, Langeandnes et al. (1993) confirmed the safety of once daily over twice daily amikacin in 22 male neonates but no data exist on the pharmacokinetics or clinical efficacy. In common with other clinical areas where aminoglycosides are used, once-daily therapy would provide an opportunity to simplify dosing, perhaps reduce the number of aminoglycoside assays and lessen toxicity in neonates. This study was designed to investigate the pharmacokinetics of netilmicin (6 mg/kg) given iv once a day to neonates of varying gestational age who required admission to our Special Care Baby Unit. Patients and methods

Results The babies were divided into three groups depending on gestational age. Group I were more than 36 weeks old (n = 7), group II between 36 and 34 weeks (n = 6) and group III less than 34 weeks (n = 8). There were more males than females in each group but the chronological age in days when therapy started was similar (Table I). Birth weight was lower in premature babies than those delivered at term and unsurprisingly gestational age was well correlated with weight (r = 0.91, P < 0.01). The mean netilmicin concentration (range; S.D.) 4 h after the first dose was 6.6 (4.9-10.2; 1.7) in group I, 6.2 (5.5-6.7; 0.5) in group II and 5.0 (3.7-5.9; 0.7) in group III. Concentrations 24 h after the first dose ranged from 0.8 to 3.8 mg/L with only two


Neonates requiring iv antimicrobials were included in the study. Babies were excluded if they were thought to have renal imparement or had a urine output of less than l.OmL/kg/h. In addition to netilmicin (6 mg/kg), every 24 h patients also received a /J-lactam, usually penicillin, flucloxacillin or cefotaxime. Netilmicin was administered by slow iv injection and blood samples taken 4 h and 24 h after the first dose and 2, 4, 8, 16 and 24 h after the second dose. Netilmicin was assayed using a fluorescence polarisation method (TDx, Abbott Laboratories) employing the reverse dilution protocol we previously described for concentrations of 2 mg/L. Although the mean netilmicin concentration ± s.D. at 2 h post dose on day 2 decreased from 10.6 + 1.2 mg/L in group I, to 9.9 + 1.0 mg/L in group II and 9.2 ± 1.1 mg/L in group III, the 2 h post dose netilmicin concentration could not be correlated with gestational age or weight. Similarly while the mean netilmicin concentrations at 24 h post dose were higher in groups II and III than group I, 24 h post dose concentrations could not be correlated to gestational age or weight, either on day 1 or day 2 of therapy.

Group I Group II Group III

10.6 (9.1-13.2; 1.4) 9.9 (8.9-11.6; 1.0) 9.2 (7.4-10.6; 1.1)

7.4(5.2-11.2; 1.8) 7.8 (5.6-10.0; 1.6) 7.1 (5.7-8.4; 1.2)

4.6(3.4-7.5; 1.3) 6.0 (5.2-6.9; 0.6) 5.6 (3.6-7.6; I.I)

2.7 (1.8-6.6; 1.7) 4.0 (2.8-4.7; 0.6) 3.5 (2.5-4.6; 0.6)

4.6 (2.8-7.5; 1.3) 15.4 (8.0-24.0; 5.5) 0.41 (0.36-0.48; 0.05) 199.6 (107.4-469.8; 123.7) 2.38 (0.64-3.26; 0.95) 0.64 (0.35-0.92; 0.24)

group I

6.7 (2.5-11.4; 2.6) 15.6 (11.0-20.0; 3.0) 0.46 (0.33-0.54; 0.08) 226.9 (123.7-286.0; 37.8) 1.07 (0.56-1.4; 0.29) 0.45 (0.39-0.56; 0.08)

Mean (range; s.D.) group II

6.6 (3.5-13.0; 2.9) 19.0 (10.5-31.0; 5.9) 0.52 (0.43-0.67; 0.09) 237.1 (170.4-364.3; 63.1) 0.61 (0.37-1.06; 0.21) 0.45 (0.27-0.61; 0.11)

group III

a g

5-

1.9(0.9-5.0; 1.4) * 2.8 (1.9-4.1; 0.8) a 2.7 (1.5-3.5; 0.6) P-

24

8 29.4 (26-33; 2.8) 0/8 1.39 (0.90-1.93; 0.36) 1.5 ± 2 . 6 8.3 (6.1-11.6; 2.1)

Table III. Pharmacokinetics of once a day netilmicin (6 mg/kg/day) in neonates of varying ages

T,pp (h) Tmy (h) Vo (L/kg) AUC-» (mg/L/h) C/ p (mL/min) C/p (mL/min/kg)

Parameter

6 35.5 (35-36; 0.5) 1/5 2.36 (1.45-2.8; 0.43) 1.0 ±2.2 14.2 (8.7-16.8; 2.6)

III (36 weeks)

Table I. Patient information (mean (range; s.D.)) on the three groups analysed (gestational age in parenthesis against group number Downloaded from jac.oxfordjournals.org by guest on July 17, 2011

Netihnicin pharmacokinetics in neonates

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large patient to patient variation in pharmacokinetic parameters we observed which werefive-to-six-foldfor T\a$, two-fold for VD, four-to-five-fold for AUC and three-tofour-fold for weight-corrected plasma clearance. The reasons for this marked variation is unknown and was not observed in a similar study we performed in febrile adult neutropenic patients (MacGowan et al., 1994). Presumably, new born neonates have unpredictable changes in renal function and proportion of body water which account for these variations. The confirmation of such variations in patients who receive single daily doses of netilmicin is important as it indicates that gestational age is not a reliable predictor of pharmacokinetic parameters and that a single dose corrected for weight supported by serum netilmicin determination will be the best clinical approach to once daily therapy—as it is for thrice or twice a day dosing. Our data do, however, show a trend to increasing Ti., VD and AUC and reducing relative plasma clearance with decreasing gestational age or weight, and others have been able to show Ti and VD were inversely related to gestational age or weight (Siegel et al., 1979). This is not surprising as glomerular filtration rate is directly related to gestational age, hence the half-life of renally excreted drugs is likely to be longer in premature infants. Such babies also have a higher relative extracellular fluid volume, and hence aminoglycoside volumes of distribution will be larger in premature infants compared to older or term neonates (Edwards, 1986). The more surprising observation is that such changes are not translated into predictable changes in pharmacokinetic parameters. A deep aminoglycoside compartment has been previously described in neonates with an elimination half life of 62.4 h and our data supports the presence of a deep compartment but is insufficient to make an accurate assessment of the Tipy. However, it is likely to be longer than the mean Tll2y in the range 15.4-19 h we were able to estimate (Siegel et al., 1979). No studies have addressed the netihnicin serum concentrations associated with efficacy or toxicity in neonates. However, by extrapolation from adult pharmacokinetic data and clinical trials performed in adults with other aminoglycosides (Noone, Pattison & Garfield, 1974; Moore, Smith & Lietman, 1984) peak levels of >6mg/L may be


Figure . Serum concentrations of netilmicin in neonates following administration of 6 mg/kg IV. • , Patient group I data point; O . patient group II data point; A , patient group III data point; — • — , patient group mean point; •••••••, patient group II mean point; — A — , patient group III mean point.

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Acknowledgement

We wish to thank the medical and nursing staff of Southmead Special Care Unit for helping to perform this study. References Barza, M., Ioannidis, J. P. A., Cappelleri, J. C. & Lou, J. (1996). Single or multiple daily doses of aminoglycosides: a meta-analysis. British Medical Journal 312, 338-48. Bergan, T. & Michalsen, H. (1982). Pharmacokinetic assessment of netilmicin in newborns and older children. Infection 10, 153-8. Edwards, C. (1986). Pharmacokinetics in the neonate 3. Gentamicin Pharmaceutical Journal 25, 518-9. Kafetzis, D. A., Signidou, L., Vlachos, E., Davros, J., Balramis, Y., Papandreou, E. et al. (1991). Clinical and pharmacokinetic study of single daily dose amikacin in paediatric patient with severe gram-negative infections. Journal of Antimicrobial Chemotherapy 27, Suppl. C, 105-12. Kuhn, R. J., Nahata, M. C , Powell, D. A. & Bickers, R. G. (1986). Pharmacokinetics of netilmicin in premature infants. European Journal of Clinical Pharmacology 29, 635-7. Langhendries, J. P., Battisti, O. Bertrand, J. M., Francois, A., et al. (1993). Once-a-day administration of amikacin in neonates: assessment of nephrotoxicity and ototoxicity. Developmental Pharmacology and Therapeutics 20, 220-30. MacGowan, A. P. (1994). Once-daily aminoglycoside therapy: serum monitoring and clinical indication. Syra Drug Monitor 1, 1-6.


optimal in patients receiving twice or thrice daily dosing. Serum concentrations associated with either nephrotoxicity or ototoxicity have also been difficult to establish but trough levels of < 2 mg/L may minimise risks (MacGowan & Reeves, 1994). It is also unknown if such a concentration also applies to neonates. The serum netilmicin concentrations obverved in our patients are very different to those observed with once-daily netilmicin therapy in adults. In particular the vast majority of adult patients with normal renal function have concentrations of < 1 mg/L at 24 h post dose. In this study only two babies had 24 h post dose levels of < 1 mg/L after the first dose. In addition and also unlike adults, neonatal patients showed a marked trend towards drug accumulation between the first and second doses and this was statistically significant with the youngest group of infants (group III). The 24 h post-dose netilmicin remains above the MIGw of most likely pathogens, but this is not required for aminoglycoside efficacy. It is unknown how long it would take for serum concentrations to drop below 1 mg/L as it was difficult for us to assess the elimination Ti from the deep compartment. To produce serum-time curves similar to adults who receive once daily aminoglycoside therapy, that is high post-dose ( > 10 mg/L) and low ( < 1 mg/L) 24 h post-dose concentrations is impossible in the neonate, due to their longer serum half-life and lower plasma clearance. If a 6 mg/kg dose is used in neonates a longer dosing interval such as 48 h would be possible, alternatively a smaller dose such as 3 mg/kg could be employed every 24 h, but then the peak concentration may be too low. However, as there are no established correlations between serum concentrations and efficacy or toxicity it may be reasonable to propose keeping 24 h trough concentration below 2 mg/L, the equivalent of a sustained trough level of 2 mg/L in twice or thrice daily dosing, and, perhaps use a daily dose of 4.5 mg/kg. Clearly such a dosing schedule would have to be validated pharmacokinetically and in terms of its clinical efficacy and potential toxicity in a neonatal population.

Netilmicin phannacokinetics in neonates

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(Received 3 January 1995; returned 18 February 1995; revised 8 March 1996; accepted 2 May 1996)


MacGowan, A. P., Bedford, K. A., Blundell, E., Brown, N. M., Habib, F., Hows, J. el al. (1994). The phannacokinetics of once-daily gentamicin in neutropcnic adults with hacmatological malignancy. Journal of Antimicrobial Chemotherapy 34, 809-12. MacGowan, A. P. & Reeves, D. S. (1994). Serum monitoring of once-daily aminoglycoside dosing. Journal of Antimicrobial Chemotherapy 33, 349-50. MacGowan, A. P. & Reeves, D. S. (1994). Serum aminoglycoside concentrations: the case for routine monitoring. Journal of Antimicrobial Chemotherapy 34, 829-37. Moore, R. D., Smith, C. R. & Lietman, P. S. (1984). The association of aminoglycoside plasma levels with mortality in patients with Gram-negative bacteraemia. Journal of Infectious Diseases 149, 443-8. Noone, P., Pattison, J. R. & Garfield, D. (1974). The effective use of gentamicin in life threatening sepsis. Postgraduate Medical Journal 50, Suppl. 7, 9-16. Parker, S. E. & Davey, P. G. (1993). Practicalities of once-daily aminoglycoside dosing. Journal of Antimicrobial Chemotherapy 31, 4-8. Siegel, J. D., McCracken, G. H., Thomas, M. L. & Threlkeld, N. (1979). Pharmacokinetic properties of netilmicin in new born infants. Antimicrobial Agents and Chemotherapy 15, 246-53. Viscoli, C , Dudley, M., Ferrea, G., Boni, L., Castagnola, E., Barretta, M. A. et al. (1991). Serum concentration and safety of single daily dosing of amikacin in children undergoing bone marrow transplantation. Journal of Antimicrobial Chemotherapy 27, Suppl. C, 113-20. White, L. O., MacGowan, A. P., Lovering, A. M., Holt, H. A., Reeves, D. S. & Ryder, D. (1994). Assay of low trough serum gentamicin concentrations by fluorescence polarisation immunoassay. Journal of Antimicrobial Chemotherapy 33, 1068—70.