NextDose: A web-based Bayesian dose forecasting tool

Last updated 2 May 2023

Gentamicin, Tobramycin, Amikacin and Vancomycin

Target Concentration

Gentamicin

Aminoglycoside targets are murkily defined (Matthews, Kirkpatrick et al. 2004). But it is reasonable to consider there are two target concentrations for gentamicin. An acceptable range for peak concentration after the first dose is 10 to 15 mg/L (target of 12.5 mg/L). This initial target is based on in vitro studies which indicate that most of the bacterial killing effect can be attributed to the first dose (Barclay, Begg et al. 1994). The risk of toxicity associated with this concentration is considered small because of the short duration of high concentrations and the saturable uptake mechanism for aminoglycosides into the cochlear hair cells (Hiel, Erre et al. 1993) and renal tubules (Barclay, Kirkpatrick et al. 1999). Vestibular toxicity is more often recognized (Ahmed, Hannigan et al. 2012), however, reversible hearing loss occurs and is associated with higher exposure and higher trough concentrations of gentamicin (Abdel Jalil, Hawwa et al. 2013).

The second target is an average steady state concentration of 3 mg/L with an acceptable range of 2.4 to 3.75 mg/L (Matthews, Kirkpatrick et al. 2004). This target is equivalent to a 24 hour AUC of 72 m/L*h. Higher initial peak concentrations and 24 h AUC have been recommended (Health Queensland 2018).

Intermittent 24 h dosing is widely used. This minimizes ototoxicity and renal toxicity despite high peak concentrations (see above) but is effective even though trough concentrations at 24 h may be undetectable in patients with good renal function. Figure 1 shows first dose predictions using a steady state target of 3 mg/L and a dosing interval or 24 h in a 30 y old 70 kg man with normal renal function for his weight and age. The steady state concentration at 8 h after the dose is 2 mg/L and at 24 h after the dose is 0.4 mg/L. The initial peak concentration is close to the target of 12.5 mg/L.

Figure 1

Tobramycin

In children with cystic fibrosis the target peak concentration of tobramycin is 30 mg/L (acceptable range 24-38 mg/L). A 24 h target AUC of 100 mg/L*h has been recommended (acceptable range 80 mg/L*h to 125 mg/L*h) (Hennig, Norris et al. 2008).

Amikacin

Exposure targets are hard to find in the literature. The target concentration for amikacin is also not clearly defined. A peak concentration target with an acceptable range of 45-60 mg/L (Health Queensland 2018) has been suggested which leads to peak concentration target value of 52.5 mg/L. Amikacin targets are typically around 3 times bigger than gentamicin so a possible target is 3 times the average steady state target of 3 mg/L which might be rounded up to 10 mg/L. An average steady state target of 10 mg/L (24 h AUC 240 mg/L*h) and a 24 h dosing interval achieves a peak within the acceptable range in a 30 y old 70 kg man with normal renal function with a 24 h trough concentration of 1.1 mg/L (Figure 2).

Figure 2

Vancomycin

The recommended target for vancomycin is a steady state 24 h AUC of 515 mg/L*h (average steady state target of 21.5 m/L) with an acceptable range of 400 to 600 mg/L*h (Rybak, Le et al. 2020). This AUC target (AUCssDI) achieves a peak of 68 mg/L with a 24 h trough concentration of 4.2 mg/L in a 30 y old 70 kg man with normal renal function if the dosing interval is 24 h (Figure 3).

Figure 3

The guideline AUC target for vancomycin is defined by an integration interval of 24 h. However, the dosing interval for vancomycin is more commonly 12 h which leads to a different profile.

If you select the target type option “mg/L*h (AUCssDI)” then this means the AUC value you enter will depend on the chosen dosing interval (DI). Occasionally users struggle with the guideline 400 mg/L*h over 24 h AUC target when the actual (or planned) dosing interval is not 24 h. if you plan to dose every 12 h you need to half the target value to 200 mg/L*h in order to get to the guideline target of 400 mg/L*h over 24 h.

There is another option in the NextDose drop down list of target types. It now includes “mg/L*h (AUCss24)” with a default value of 400. If you use this option then you do not need to change the AUC value if you have used (or plan to use) a dosing interval such as 12 h. You can specify any dosing interval you want and NextDose will then figure out the dose for that dosing interval to achieve the steady state AUC target of 400 mg/L*h over 24 h. You may, of course, change the target value e.g. to 600 with your choice of dosing interval and the proposed dose will achieve the steady state AUC target of 600 mg/L*h over 24 h.

This AUC target of 257.5 mg/L*h over 12 h achieves a peak of 38.6 mg/L with a 12 h trough concentration of 8.8 mg/L in a 30 y old 70 kg man with normal renal function if the dosing interval is 12 h (Figure 4).

Figure 4

Note that the steady state average concentration (21.5 mg/L) is the same for both 24 h and 12 h dosing intervals. The calculation of the AUC appropriate for the dosing interval can be simply avoided by specifying the average steady state concentration (CssAvg) and entering the proposed dosing interval.

NextDose Model

The use of TCI for gentamicin, amikacin and vancomycin has been widely used in clinical practice for a long time. The clinical benefits of measuring concentrations are generally accepted but without evidence from a randomized concentration controlled trial to show that TCI is effective for these antibiotics.

A pharmacokinetic model has been developed from a pooled data analysis of gentamicin, amikacin and vancomycin. A joint analysis of data for these three drugs was undertaken with the assumption that there are common features influencing the pharmacokinetics and that sources of predictable and unpredictable variability may be similar.

The key differences for the gentamicin, amikacin and vancomycin models are the total clearance, the fraction of total clearance accounted for by differences in renal function and the volume of distribution. The residual unidentified variability in concentrations is drug specific.

Clearance is based on a combination of non-renal function predicable clearance and renal function predictable clearance. Both of these clearance components use normal fat mass which is a combination of fat free mass and a fraction of fat mass (similar to the adjusted body weight method often recommended for dosing). The PK parameters determining distribution (central volume, peripheral volume and inter-compartmental clearance) are also based on normal fat mass.

The model shares common size components for all 3 drugs based on theory based allometry and normal fat mass.

Maturation of clearance, predictable from renal-function and not predictable from renal function, use sigmoid functions of post-menstrual age with different parameters for renal and non-renal maturation.

An empirical decrease in non-renal function clearance with age was estimated from gentamicin data and assumed to be similar for vancomycin and amikacin.

Changes in volume of distribution after birth use the same exponential decrease model but with drug specific parameters describing the magnitude and time course of approaching the adult size standardized values.

NextDose calculates the loading dose which achieves the same peak concentration after the first dose as that predicted at steady state from the maintenance dose and dosing interval. The loading dose depends on all the PK parameters. The principle is to achieve as rapidly as possible a concentration profile similar to that which will eventually be obtained at steady state.

The gentamicin version of the model and parameters is used for tobramycin calculations because the PK of gentamicin and tobramycin are essentially the same (Regamey, Gordon et al. 1973).

References

Abdel Jalil, M. H., A. F. Hawwa, P. J. McKiernan, M. D. Shields and J. C. McElnay (2013). "Population pharmacokinetic and pharmacogenetic analysis of tacrolimus in paediatric liver transplant patients." British Journal of Clinical Pharmacology: n/a-n/a.

Ahmed, R. M., I. P. Hannigan, H. G. MacDougall, R. C. Chan and G. M. Halmagyi (2012). "Gentamicin ototoxicity: a 23-year selected case series of 103 patients." Medical Journal of Australia 196(11): 701-704.

Barclay, M. L., E. J. Begg and K. G. Hickling (1994). "What is the evidence for once-daily aminoglycoside therapy?" Clinical Pharmacokinetics 27(1): 32-48.

Barclay, M. L., C. M. Kirkpatrick and E. J. Begg (1999). "Once daily aminoglycoside therapy. Is it less toxic than multiple daily doses and how should it be monitored?" Clinical Pharmacokinetics 36(2): 89-98.

Health Queensland (2018). "Aminoglycoside dosing in adults https://www.health.qld.gov.au/__data/assets/pdf_file/0019/713323/aminoglycoside-guidelines.pdf."

Hennig, S., R. Norris and C. M. J. Kirkpatrick (2008). "Target concentration intervention is needed for tobramycin dosing in paediatric patients with cystic fibrosis – a population pharmacokinetic study." British Journal of Clinical Pharmacology 65(4): 502-510.

Hiel, H., P. Erre and C. Aurousseau (1993). "Gentamicin Uptake by Cochlear Hair Cells Precedes Hearing Impairment during Chronic Treatment." Audiology 32(1): 78-87.

Matthews, I., C. Kirkpatrick and N. Holford (2004). "Quantitative justification for target concentration intervention--parameter variability and predictive performance using population pharmacokinetic models for aminoglycosides." Br J Clin Pharmacol 58(1): 8-19.

Regamey, C., R. C. Gordon and W. M. Kirby (1973). "Comparative pharmacokinetics of tobramycin and gentamicin." Clin Pharmacol Ther 14(3): 396-403.

Rybak, M. J., J. Le, T. P. Lodise, D. P. Levine, J. S. Bradley, C. Liu, B. A. Mueller, M. P. Pai, A. Wong-Beringer, J. C. Rotschafer, K. A. Rodvold, H. D. Maples and B. M. Lomaestro (2020). "Therapeutic monitoring of vancomycin for serious methicillin-resistant Staphylococcus aureus infections: A revised consensus guideline and review by the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists." Am J Health Syst Pharm 77(11): 835-864.