Population pharmacokinetic analysis of vancomycin in patients with hematological malignancies.

This study determines vancomycin (VAN) population pharmacokinetics (PK) in adult patients with hematological malignancies. VAN serum concentration data (n = 1,004) from therapeutic drug monitoring were collected retrospectively from 215 patients. A one-compartment PK model was selected. VAN pharmacokinetics population parameters were generated using the NONMEM program. A graphic approach and stepwise generalized additive modeling were used to elucidate the preliminary relationships between PK parameters and clinical covariates analyzed. Covariate selection revealed that total body weight (TBW) affected V, whereas renal function, estimated by creatinine clearance, and a diagnosis of acute myeloblastic leukemia (AML) influenced VAN clearance. We propose one general and two AML-specific models. The former was defined by CL (liters/h) = 1.08 x CL(CR(Cockcroft and Gault)) (liters/h); CV(CL) = 28.16% and V (liters) = 0.98 x TBW; CV(V) =37.15%. AML models confirmed this structure but with a higher clearance coefficient (1.17). The a priori performance of the models was evaluated in another 59 patients, and clinical suitability was confirmed. The models were fairly accurate, with more than 33% of the measured concentrations being within +/-20% of the predicted value. This therapeutic precision is twofold higher than that of a non-customized population model (16.1%). The corresponding standardized prediction errors included zero and a standard deviation close to unity. The models could be used to estimate appropriate VAN dosage guidelines, which are not clearly defined for this high-risk population. Their simple structure should allow easy implementation in clinical software and application in dosage individualization using the Bayesian approach.

Immunosuppressive therapy for paediatric transplant patients: pharmacokinetic considerations.

Immunosuppressive therapy in paediatric transplant recipients is changing as a consequence of the increasing number of available immunosuppressive agents. Generic and other new formulations are now emerging onto the market, clinical experience is growing, and it is expected that clinicians should tailor immunosuppressive protocols to individual patients by optimising dosages and drugs according to the maturation and clinical status of the child. Most information about the clinical pharmacokinetics of immunosuppressive drugs in paediatrics is centred on cyclosporin, tacrolimus and mycophenolate mofetil in renal and liver transplant recipients; data regarding other immunosuppressants and transplant types are limited. Although the clinical pharmacokinetics of these drugs in paediatric transplant recipients are still under investigation, it is evident that the pharmacokinetic parameters observed in adults may not be applicable to children, especially in younger age groups. In general, patients younger than 5 years old show higher clearance rates irrespective of the organ transplanted or drug used. Another important factor that frequently affects clearance in this patient population is the post-transplant time. In accordance with these findings, and in contrast with the usual under-dosage in children, the need for higher dosages in younger recipients and during the early post-transplant period seems evident. To achieve the best compromise between prevention of rejection and toxicity, dosage individualisation is required and this can be achieved through therapeutic drug monitoring (TDM). This approach is particularly useful to ensure the cost-effective management of paediatric transplant recipients in whom the pharmacokinetic behaviour, target concentrations for clinical use and optimal dosage strategies of a particular drug may not yet be well defined. Although TDM may be a tool for improving immunosuppressive therapy, there is little information concerning its positive contribution to clinical events, including outcomes, for paediatric patients. Substantial information to support the use of TDM exists for cyclosporin and, to a lesser extent, for tacrolimus, but a diversity of options affects their implementation in the clinical setting. The role of TDM in therapy with mycophenolate mofetil and sirolimus has yet to be defined regarding both methods and clinical indications. Pharmacodynamic monitoring appears more suited to other immunosuppressants such as azathioprine, corticosteroids and monoclonal or polyclonal antibodies. If coupled with pharmacokinetic measurements, such monitoring would allow earlier and more precise optimisation of therapy. Very few population pharmacokinetic studies have been carried out in paediatric transplant patients. This type of study is needed so that techniques such as Bayesian forecasting can be applied to optimise immunosuppressive therapy in paediatric transplant patients.