A joint model of the pharmacokinetics of gentamicin, amikacin and vancomycin with a wide dispersion of age, size and renal function was developed by pooling data from around the world. Data was contributed by Karel Allegaert (Belgium), Amilcar Falcao (Portugal), Nicolas Simon (France), Lin Lo (Malaysia), Alison Thomson (Scotland), Catherine Sherwin (New Zealand and USA), Evelyn Aigrain (France), Carolina Llanos-Paez (Australia), Linas Mockas (USA), Carl Kirkpatrick (New Zealand).
Table 1 Studies used to create the GAVamycin data with patient numbers and observations by drug
|
Drug |
Number of patients |
Number of observations |
|
Gentamicin |
5970 |
8878 |
|
Amikacin |
737 |
2106 |
|
Vancomycin |
3233 |
16357 |
|
Total |
9940 |
27341 |
As expected total elimination clearance (CL total) is predicted by renal function (RF) (ratio of individual estimated GFR to nGFR (O’Hanlon, Holford et al. 2023)) but it has two distinct components based on glomerular filtration rate (GFR) (1) Clearance associated with normal glomerular filtration rate (nGFR) and an asymmetrical sigmoid function of RF (CLGFR) and (2) clearance not associated with nGFR but with a linear function of RF (CLNGFR).
Table 2 Major model component selection based on objective function value (OFV)
|
Description |
dOFV |
df |
p |
|
CLNGFR no maturation |
3114.3 |
4 |
0 |
|
CLGFR linear RF |
1409.8 |
9 |
5.96E-298 |
|
CLNGFR no RF |
777.4 |
2 |
1.58E-169 |
|
Volume no PNA increase at birth |
403.5 |
4 |
4.93E-86 |
|
FFM using (Al-Sallami, Goulding et al. 2015) |
158.2 |
7 |
7.82E-31 |
|
Final model |
dOFV=change in OFV from final model, df=degrees of freedom (number of parameters less than final model), p=Chi square(dOFV,df)
The joint model confirmed that elimination of gentamicin, amikacin and vancomycin can be described by accounting by RF but also required consideration of GFR. An increase in central volume of distribution at birth is well known (Fuchs, Guidi et al. 2014). After accounting for body size and composition (O’Hanlon, Sumpter et al. 2023), a previously undescribed slow decrease in both central and peripheral volume of distribution in the first years of life was shown to improve the goodness of fit of all 3 drugs (Table 2).
References
Al-Sallami, H. S., A. Goulding, A. Grant, R. Taylor, N. Holford and S. B. Duffull (2015). “Prediction of Fat-Free Mass in Children.” Clin Pharmacokinet 54(11): 1169-1178.
Fuchs, A., M. Guidi, E. Giannoni, D. Werner, T. Buclin, N. Widmer and C. Csajka (2014). “Population pharmacokinetic study of gentamicin in a large cohort of premature and term neonates.” British Journal of Clinical Pharmacology 78(5): 1090-1101.
O’Hanlon, C. J., N.Holford, A. Sumpter and H. S. Al-Sallami (2023). “Consistent Methods for Fat Free Mass, Creatinine Clearance and Glomerular Filtration Rate to describe Renal Function from Neonates to Adults.” CPT Pharmacometrics Syst Pharmacol Accepted.