There are a number of effective but highly toxic drugs that exhibit a narrow therapeutic index and marked interpatient pharmacokinetic variability. Individualized therapy with such drugs requires therapeutic drug monitoring (TDM) to obtain the desired clinical effects safely. Cost-effectiveness analysis in health care is still at an early stage of development, especially for TDM. A systematic review was carried out to document studies that have addressed the cost-effectiveness of TDM. The Cochrane database and Medline were searched. References identified by this approach were then searched manually for relevant articles. Very few studies have been performed that document the cost-effectiveness of TDM, and TDM has been demonstrated to be cost-effective only for aminoglycosides. For the other classes of drugs that are monitored, the rationale for TDM has been supported, but appropriate cost-effectiveness analyses have not been performed. Because the use of many of these drugs without TDM would increase the risk of under- or overdosing, emphasis should not be placed solely on cost-effectiveness but rather on how such interventions can be applied in the most cost-effective and clinically useful manner.

The pharmacokinetics of tobramycin do not differ significantly in CF patients compared with patients without CF when subject age, fat-free mass, sex and renal function are taken into consideration. Variations in tobramycin dosing between CF and non-CF patients should therefore reflect target concentrations or exposures based on differences in expected pathogen sensitivity and not the presence of CF.

AIMSVancomycin is one of the most evaluated antibiotics in neonates using modeling and simulation approaches. However no clear consensus on optimal dosing has been achieved. The objective of the present study was to perform an external evaluation of published models, in order to test their predictive performances in an independent dataset and to identify the possible study-related factors influencing the transferability of pharmacokinetic models to different clinical settings. METHODPublished neonatal vancomycin pharmacokinetic models were screened from the literature. The predictive performance of six models was evaluated using an independent dataset (112 concentrations from 78 neonates). The evaluation procedures used simulation-based diagnostics [visual predictive check (VPC) and normalized prediction distribution errors (NPDE)]. RESULTSDifferences in predictive performances of models for vancomycin pharmacokinetics in neonates were found. The mean of NPDE for six evaluated models were 1.35, -0.22, -0.36, 0.24, 0.66 and 0.48, respectively. These differences were explained, at least partly, by taking into account the method used to measure serum creatinine concentrations. The adult conversion factor of 1.3 (enzymatic to Jaffé) was tested with an improvement in the VPC and NPDE, but it still needs to be evaluated and validated in neonates. Differences were also identified between analytical methods for vancomycin. CONCLUSIONThe importance of analytical techniques for serum creatinine concentrations and vancomycin as predictors of vancomycin concentrations in neonates have been confirmed. Dosage individualization of vancomycin in neonates should consider not only patients' characteristics and clinical conditions, but also the methods used to measure serum creatinine and vancomycin. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Population pharmacokinetics of vancomycin have been widely studied in neonates.• Many covariates including bodyweight, gestational age and post-natal age, renal function, co-administered drugs, etc. have been evaluated and some of them are associated with inter-individual pharmacokinetic variability. WHAT THIS STUDY ADDS• The analytical technique used for measuring serum creatinine concentrations has been confirmed as a study-related factor influencing the transferability of published models to different clinical settings.• Different predictive performances were demonstrated between analytical methods (FPIA and EMIT).• The neonatal conversion factor of serum creatinine concentrations between the Jaffé and enzymatic methods and the interferences/cross-reactivity of analytical methods need to be evaluated in neonates in future studies.

A meropenem dose of 1g iv every 12 hrs provides adequate serum concentrations in the majority of patients receiving continuous veno-venous hemofiltration or continuous venovenous hemofiltration with a 0.9-m2 polyacrylonitrile filter at combined ultrafiltrate/dialysate flow rates of up to 3 L/hr. A lower dose would not be sufficient for the empirical treatment of potentially life-threatening infections in all patients.

The development of new onset diabetes after transplantation (NODAT) is associated with increased cardiovascular morbidity and mortality. This study aimed at identifying risk factors for the development of NODAT. We performed a retrospective review of 787 renal transplants performed between 1994 and 2004 at a single centre. NODAT was diagnosed in patients who had two random plasma glucose concentrations >11.1 mmol/L after the first month post-transplant or patients who required treatment for hyperglycaemia within the first month and continued treatment thereafter. The incidence of NODAT was 7.7%. The incidence of NODAT requiring either insulin or oral hypoglycaemic agents was 4.5%. Risk factors for the development of NODAT were older age (HR 1.04, 95% CI: 1.01-1.07, p < 0.01), heavier weight at time of transplantation (HR 1.04, 95% CI: 1.02-1.07, p < 0.01), higher mean pre-transplant random plasma glucose concentrations (HR 1.54, 95% CI: 1.14-2.08, p < 0.01), higher plasma glucose within the first seven d post-transplant (HR 1.27, 95% CI: 1.09-1.47, p < 0.01) and use of tacrolimus (HR 3.70, 95% CI: 1.61-8.46, p < 0.01). Ten yr actuarial patient survival was 67.1% in patients with NODAT compared with 81.9% for those without diabetes and 65.3% in patients known to have diabetes pre-transplant. There was no difference in graft survival. We have identified a high-risk group in which attempts should be made to reduce the incidence of NODAT by tailoring immunosuppression, lifestyle modification and selecting non-diabetogenic medications. Improvements in management of patients at higher risk of NODAT may help reduce the incidence of deaths with a functioning graft.

The population pharmacokinetics of caffeine were investigated in 60 neonates and young infants using data collected during routine therapeutic drug monitoring. Clearance was influenced by body weight and postnatal age, and increased in the presence of dexamethasone. No clinical factors were identified that influenced volume of distribution. The population pharmacokinetic parameter estimates were then tested prospectively in a further 20 neonates. Although they produced unbiased results, the dexamethasone effect could not be identified. A final analysis using all 80 patients found clearance (L/day) = 0.14 x weight (kg) + 0.0024 x postnatal age (days) (+/- 20%) and volume of distribution = 0.82 L (+/- 24%). Simulations based on these results indicated that the current dosage guidelines of 20 mg/kg loading dose of caffeine citrate followed by a 5 mg/kg/day maintenance dose should achieve concentrations within the traditional target range in > 70% of neonates.

AimIf appropriately accounted for in a pharmacokinetic (PK)-pharmacodynamic (PD) model, time-varying covariates can provide additional information to that obtained from time-constant covariates. The aim was to present and apply two models applicable to time-varying covariates that capture such additional information. MethodsThe first model estimates different covariate-parameter relationships for within-and between-individual variation in covariate values, by splitting the standard covariate model into a baseline covariate (BCOV) effect and a difference from baseline covariate (DCOV) effect. The second model allows the magnitude of the covariate effect to vary between individuals, by inclusion of interindividual variability in the covariate effect. The models were applied to four previously analysed data sets. ResultsThe models were applied to 10 covariate-parameter relationships and for three of these the first extended model resulted in a significant improvement of the fit. Even when this model did not improve the fit significantly, it provided useful information because the standard covariate model, which assumes within-and between-patient covariate relationships of the same magnitude, was only suppor ted by the data in four cases. The inclusion of BCOV was not supported in two cases and DCOV was unnecessary in three cases. In one case, significantly different, nonzero, relationships were found for DCOV and BCOV. The second extended model was found to be significant for four of the 10 covariate-parameter relationships. ConclusionsOn the basis of the examples presented, traditionally made simplifications of covariate-parameter relationships are often inadequate. Extensions to the covariateparameter relationships that include time-varying covariates have been developed, and their appropriateness and benefits have been described. Correspondence

The wide interindividual variability in plasma and salivary profiles of cortisol following the administration of IV and oral hydrocortisone to patients with adrenal insufficiency and the poor correlation between salivary and plasma measurements suggest that salivary cortisol measurements cannot be used for individual hydrocortisone dosage adjustment.