2011 - Athens - Greece

PAGE 2011: Infection
Sarah Alghanem

Development of a Tobramycin Dosage Adjustment Nomogram for Patients with Cystic Fibrosis

Alghanem S(1), Paterson I(2), Thomson AH(1)

(1)Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde Glasgow, (2)Cystic Fibrosis Unit, NHS Greater Glasgow and Clyde, Pharmacy and Prescribing Support Unit, NHS Greater Glasgow and Clyde

Objectives: A tobramycin dose of 10 mg/kg every 24 hours is recommended for patients with cystic fibrosis. However, there is no nomogram currently available to help clinicians interpret measured concentrations and determine dosage adjustments. This study used data collected during routine therapeutic drug monitoring over 16 years to determine within-subject variability (WSV) and the influence of covariates on aminoglycoside pharmacokinetic parameters in patients with cystic fibrosis. The population model was then used to develop a dose adjustment nomogram for this patient group.

Methods: The study involved a retrospective analysis of the aminoglycoside database for patients with cystic fibrosis and covered the period 1993 to 2009. The data were analysed by NONMEM (version 7) (1). One and two compartment models were compared and the influence of covariates, including a range of methods for estimating renal function, was examined. WSV was investigated with the assumption that one course of therapy represented one occasion. Internal validation was conducted with 1000 bootstrap samples and a prediction-corrected VPC. Typical concentration-time profiles were used to generate the nomogram.

Results: Aminoglycoside concentrations (n = 2238) were available from 166 patients aged 14 to 66 years (median 23 years). Peak concentrations measured within the first 2 hours after the infusion ranged from 2.6 to 18 mg/L (median 9.3 mg/L). Trough concentrations ranged from 0.1 to 3.5 mg/L (median 0.48 mg/L). The number of occasions available ranged from 1 to 28 with a median of 5. Data were fitted with a two compartment model and the inclusion of WSV on CL produced a further improvement in fit. The final covariate model for CL included creatinine clearance estimated by the Cockcroft and Gault equation (2), with the minimum serum creatinine concentration fixed to 60 µmol/L.  Between-subject variability (BSV) in CL was 18.5% and WSV was 11%. V1 was best described using height, which reduced BSV from 16% to 12%. BSV could not be estimated for V2 and Q. Internal methods supported the validity of the final model. A nomogram was developed to aid in the interpretation of tobramycin concentrations with extended interval dosing.

Conclusions: Since unexplained WSV in the handling of aminoglycoside antibiotics in patients with cystic fibrosis is low, patients can be started on a previous individualised dosage regimen if a new course of therapy is required. A tobramycin dosage adjustment nomogram may help in the interpretation of measured tobramycin concentrations.

[1] Beal S, Sheiner LB, Boeckman A, Bauer R. NONMEM User's Guides (1989-2009). Ellicott City, MD, USA: Icon Development Solutions 2009.
[2] Cockcroft D, Gault M. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31-41.

Reference: PAGE 20 (2011) Abstr 2077 [www.page-meeting.org/?abstract=2077]
Poster: Infection