Efficacy, nephrotoxicity and ototoxicity of aminoglycosides, mathematically modelled for modelling-supported therapeutic drug monitoring

Therapeutic drug monitoring (TDM) of aminoglycosides has been a topic during the last thirty years. There is a tendency that - because of the once-daily regimen - TDM is considered not necessary anymore. Although once daily dosing has the potential for decreased toxicity, long-term usage can cause severe nephro- and ototoxicity. Furthermore, inadequate plasma concentrations can lead to treatment failure. This work is devoted to the development and application of the first mathematical model of aminoglycosides, which simulates in relation to the pharmacokinetics both their effects on bacteria as well as their nephrotoxicity and cochleotoxicity. Our software system is suitable for TDM. Based on theoretical considerations, a multi-compartment mathematical model in a numerical program in Matlab is derived that incorporates the antimicrobial effects of aminoglycosides, the saturable and active uptake into kidney cells, the reversible nephrotoxicity and the irreversible cochleotoxicity. Using fictitious person data, and an assumed pharmacokinetic and dynamic parameter set obtained from the literature, we simulated the drug concentrations, antibacterial effects, and toxicity over time in virtual patients to illustrate the benefits of optimized, efficacious dosage regimens that minimize (acceptable) nephro- and auditory ototoxicity. Our model confirms that extended-interval dosing seems the most appropriate to achieve this goal. By this manner, the present mathematical model contributes to an increase in our knowledge of how to obtain an optimized dosing strategy for individual patients. With the developed program, we are able to demonstrate that optimal aminoglycoside dosing still needs a sophisticated system of TDM. (C) 2011 Elsevier B.V. All rights reserved

Amoxicillin pharmacokinetics in (preterm) infants aged 10 to 52 days: effect of postnatal age.

The pharmacokinetic parameters of amoxicillin were determined in 32 newborn infants aged 10 to 52 days (mean postnatal age, 24.7 +/- 12.4 days) to improve amoxicillin dosing in this age group. Amoxicillin plasma concentrations were determined using reversed-phase high-performance liquid chromatography in surplus plasma samples from routine gentamicin assays. Amoxicillin pharmacokinetic parameters (mean +/- SD) were as follows: first-order elimination constant (K(el)) = 0.27 +/- 0.10 h(-1), volume of distribution corrected for body weight (V/W) = 0.66 +/- 0.27 L/kg, total body clearance corrected for body weight (CL/W) = 0.18 +/- 0.10 Lkg(-1)h(-1), and elimination half-life (t(1/2)) = 3.0 +/- 1.3 hours. Amoxicillin body clearance was approximately twofold greater in our patients compared with published values in younger neonates (mean postnatal age, 0.76 +/- 1.57 days). Simulation studies using the observed amoxicillin pharmacokinetic data suggest an amoxicillin dose of 40 mg/kg administered every 8 hours in infants older than 9 days postnatal age, independent of gestational age and postconceptional age, to achieve satisfactory target plasma amoxicillin concentrations less than 140 mg/L and time above minimum inhibitory concentration of at least 40%. Prospective evaluation of this suggested new dosage regimen is necessary before implementation in the care of ill neonates.<br/

Role of cytochrome p450 polymorphisms in the development of pulmonary drug toxicity: a case-control study in the Netherlands

BACKGROUND: Drug-induced pulmonary toxicity is a serious and expanding problem with often unknown aetiology. Many drugs are metabolized by cytochrome P450 (CYP) enzymes. OBJECTIVE: To establish whether allelic variation in CYP polymorphic genes contributes to variability in drug response and unexpected toxicity. METHODS: A case-control study was conducted. The cases consisted of patients with drug-induced interstitial lung disease (DI-ILD; n = 59). Two control groups were used: one group of healthy volunteers (n = 173) and one group of patients with idiopathic pulmonary fibrosis (IPF; n = 110). RESULTS: Of the patients with DI-ILD 91.5% (54/59) had at least one of the studied variant genes compared with 70.5% (122/173, p < 0.001) of the healthy volunteers and 69.1% (76/110, p < 0.001) of the IPF patients. The percentage of individuals with one or more variant CYP genes was higher in the DI-ILD group. Odds ratios were significantly increased and ranged from 3.25 to 40.8, indicating a significant association between the development of DI-ILD and the presence of one or more variant CYP genes. CONCLUSION: DI-ILD appeared to be associated with the presence of at least one variant CYP allele. This study supports the potential usefulness of personalized medicine by genotyping aiming to improve efficacy, tolerability and drug safety. AD - Department of Clinical Chemistry, Maastricht University Medical Centre, Maastricht, the Netherlandsild care center, Maastricht University Medical Centre, Maastricht, the Netherlands

Five-year fracture risk estimation in patients with Parkinson's disease

BackgroundPrevious studies have shown that patients with Parkinson's disease (PD) are at increased risk of fractures. However, no specific prediction model for fracture estimation among PD patients is currently available. Therefore, the aim of this study was to develop a simple score for estimating the 5-year osteoporotic and hip fracture risks among patients with PD.MethodsThe UK Clinical Practice Research Datalink (1987–2011) was used to identify incident PD patients. Cox proportional-hazards models were used to calculate the 5-year risks of osteoporotic and hip fracture among PD patients. The regression model was fitted with various risk factors for fracture and the final Cox model was converted into integer risk scores.ResultsWe identified 4411 incident PD patients without a history of osteoporotic treatment. The 5-year risks of osteoporotic and hip fracture were plotted in relation to the risk score. Risk scores increased with age, female gender, history of renal disease and history of dementia. The C-statistic, which is a parameter to test the internal validity of the model, was reasonable for the prediction of osteoporotic fracture (0.69) and hip fracture (0.73).ConclusionIn this study, we developed a simple model to estimate 5-year fracture risk among incident PD patients. It may be useful in daily practice after external validation.<br/

Use of biguanides and the risk of colorectal cancer: a register-based cohort study

Observational studies have shown conflicting results on the potential protecting effect of biguanide use with the risk of colorectal neoplasms. In addition, the cellular mechanism can either support or oppose biguanides influence on colorectal carcinoma. Our objective was to evaluate the association between biguanide use and colorectal carcinoma. A population-based cohort study using healthcare data from the Danish National database (1996-2007), was conducted. Oral antidiabetic drug users (n = 177,281) were matched 1:3 with a population-based reference group. Cox proportional hazard models estimated hazard ratios (HRs) of colorectal carcinoma. Stratification was performed to analyse the risk of colorectal cancer in current biguanide users. Two sub-analyses were performed, to investigate the risk of colorectal cancer associated with discontinuous and prolonged use of biguanides. Instead of a protective effect, we found that current biguanide users had a 1.2-fold increased risk of colorectal cancer (HR = 1.19, 95% CI = 1.08-1.30) as compared with the non-diabetes reference group. Prolonged use was not inversely associated with colorectal cancer either. When studying colorectal risk with biguanides, the underlying T2DM should be taken into account since a 1.3-1.6-fold increased risk was found in oral antidiabetic drug users compared to controls unexposed to diabetic medication. This study could not detect a protective effect of biguanide use with colorectal cancer. Therefore, this study does not support a further investigation of the effectiveness of biguanides to prevent colorectal carcinoma in clinical studies