Population pharmacokinetics of carboplatin, etoposide and melphalan in children: a re-evaluation of paediatric dosing formulas for carboplatin in patients with normal or mild impairment of renal function.

AIMS: Carboplatin dosage is calculated by using the estimated glomerular filtration rate (GFR) to achieve a target plasma area under the plasma concentration-time curve (AUC). The aims of the present study were to investigate factors that influence the pharmacokinetics of carboplatin in children with high-risk neuroblastoma, and whether target exposures for carboplatin were achieved using current treatment protocols. METHODS: Data on children receiving high-dose carboplatin, etoposide and melphalan for neuroblastoma were obtained from two study sites [European International Society for Paediatric Oncology (SIOP) Neuroblastoma study, Children's Hospital at Westmead; n = 51]. A population pharmacokinetic model was built for carboplatin to evaluate various dosing formulas. The pharmacokinetics of etoposide and melphalan was also investigated. The final model was used to simulate whether target carboplatin AUC (16.4 mg ml-1 ·min) would be achieved using the paediatric Newell formula, modified Calvert formula and weight-based dosing. RESULTS: Allometric weight was the only significant, independent covariate for the pharmacokinetic parameters of carboplatin, etoposide and melphalan. The paediatric Newell formula and modified Calvert formula were suitable for achieving the target AUC of carboplatin for children with a GFR <100 ml min-1 1.73 m-2 but not for those with a GFR ≥100 ml min-1 1.73 m-2 . A weight-based dosing regimen of 50 mg kg-1 achieved the target AUC more consistently than the other formulas, regardless of renal function. CONCLUSIONS: GFR did not appear to influence the pharmacokinetics of carboplatin after adjusting pharmacokinetic parameters for weight. This model-based approach validates the use of weight-based dosing as an appropriate alternative for carboplatin in children with either mild renal impairment or normal renal function.

Not too little, not too much-just right! (Better ways to give high dose melphalan).

Of the 13 286 autologous haematopoietic cell transplant procedures reported in the US in 2010-2012 for plasma cell disorders, 10 557 used single agent, high-dose melphalan. Despite 30 years of clinical and pharmacokinetic (PK) experience with high-dose melphalan, and its continuing central role as cytoreductive therapy for large numbers of patients with myeloma, the pharmacodynamics and pharmacogenomics of melphalan are still in their infancy. The addition of protectant agents such as amifostine and palifermin allows dose escalation to 280 mg/m(2), but at these doses it is cardiac, rather than gut, toxicity that is dose-limiting. Although combination with additional alkylating agents is feasible, the additional TRM may not be justified when so many post-consolidation therapies are available for myeloma patients. Current research should optimise the delivery of this single-agent chemotherapy. This includes the use of newer formulations and real-time PKs. These strategies may allow a safe and effective platform for adding synergistic novel therapies and provide a window of lymphodepletion for the addition of immunotherapies.

Population pharmacokinetics of acyclovir in children and young people with malignancy after administration of intravenous acyclovir or oral valacyclovir.

Acyclovir is effective in the prevention and treatment of herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections. The aim of this study was to characterize the population pharmacokinetics of acyclovir observed following treatment with intravenous acyclovir and oral valacyclovir (valaciclovir) in young people with malignancy. Plasma acyclovir concentration-time data were collected from 43 patients (age range, 9 months to 20 years) who had been given multiple doses of acyclovir (5 mg/kg of body weight) and/or valacyclovir (10 mg/kg). Nonlinear mixed-effect modeling was employed to analyze acyclovir population pharmacokinetics and identify influential covariates. Simulations (n = 1,000) were conducted to explore the ability of the current doses to maintain acyclovir concentrations above the recommended 50% inhibitory concentration for HSV or VZV (0.56 mg/liter or 1.125 mg/liter, respectively) for more than 12 h. A one-compartment pharmacokinetic model with first-order elimination best described the acyclovir concentration-time data. The population mean estimates for clearance (CL), volume of distribution (V), absorption rate (k(a)), and bioavailability (F) were 3.55 liters/h, 7.36 liters, 0.63 h(-1), and 0.60, respectively. Inclusion of body weight and estimated creatinine CL (CL(CR)) in the final model reduced the interindividual variabilities in CL and V from 61% to 24% and from 75% to 36%, respectively. Simulations revealed that with the use of the current doses, maximal efficacy can be achieved in over 45% of patients weighing 25 to 50 kg and with CL(CR) levels of 2.0 to 4.0 liters/h/m(2), but only in a much smaller proportion of patients, with low weights (10 kg) and high CL(CR)s (5.5 liters/h/m(2)), suggesting that higher doses are required for this subgroup. This validated population pharmacokinetic model for acyclovir may be used to develop dosing guidelines for safe and effective antiviral therapy in young people with malignancy.

HPLC-fluorescence assay for acyclovir in children.

A simple, accurate, reliable and sensitive HPLC method was developed and validated for quantitating acyclovir in human plasma. Sample (100 microL) preparation involved addition of guanosine (internal standard) and protein precipitation with 7% perchloric acid and centrifugation. Supernatant (20 microL) was injected onto a C18 HPLC column with a mobile phase of 0.05 m sodium phosphate buffer-acetonitrile (pH 2.35, 992:8, v/v) with 25 microL of 0.4 m tetrabutylammonium hydroxide titrant and fluorescence detection (excitation, 260 nm; emission, 375 nm). Analyte recovery was 101% and the assay response was linear over the acyclovir concentration range of 0.1-20 mg/L. Intra- and inter-day accuracy and precision were less than 7%. The limit of detection and limit of quantitation were 0.033 and 0.1 mg/L, respectively. In five paediatric oncology patients administered intravenous acyclovir, concentrations ranged from 0.24 to 43.65 mg/L. This method can be used to measure acyclovir concentrations in paediatric patients.

Population pharmacokinetics of amphotericin B in children with malignant diseases.

AIMS: To construct a population pharmacokinetic model for the antifungal agent, amphotericin B (AmB), in children with malignant diseases. METHODS: A two compartment population pharmacokinetic model for AmB was developed using concentration-time data from 57 children aged between 9 months and 16 years who had received 1 mg kg(-1) day(-1) doses in either dextrose (doseform=1) or lipid emulsion (doseform=2). P-Pharm (version 1.5) was used to estimate the basic population parameters, to identify covariates with significant relationships with the pharmacokinetic parameters and to construct a Covariate model. The predictive performance of the Covariate model was assessed in an independent group of 26 children (the validation group). RESULTS: The Covariate model had population mean estimates for clearance (CL), volume of distribution into the central compartment (V) and the distributional rate constants (k12 and k21) of 0.88 l h(-1), 9.97 l, 0.27 h(-1) and 0.16 h(-1), respectively, and the intersubject variability of these parameters was 19%, 49%, 55% and 48%, respectively. The following covariate relationships were identified: CL (l h(-1)) = 0.053 + 0.0456 weight (0.75) (kg) + 0.242 doseform and V (l) = 7.11 + 0.107 weight (kg). Our Covariate model provided unbiased and precise predictions of AmB concentrations in the validation group of children: the mean prediction error was 0.0089 mg l(-1) (95% confidence interval: -0.0075, 0.0252 mg l(-1)) and the root mean square prediction error was 0.1245 mg l(-1) (95% confidence interval: 0.1131, 0.1349 mg l(-1)). CONCLUSIONS: A valid population pharmacokinetic model for AmB has been developed and may now be used in conjunction with AmB toxicity and efficacy data to develop dosing guidelines for safe and effective AmB therapy in children with malignancy.

Amphotericin B in children with malignant disease: a comparison of the toxicities and pharmacokinetics of amphotericin B administered in dextrose versus lipid emulsion.

In a prospective, randomized clinical trial, the toxicity of 1 mg of amphotericin B (AmB) per kg of body weight per day infused in 5% dextrose was compared with that of AmB infused in lipid emulsion in children with malignant disease. In an analysis of 82 children who received a full course of 6 days or more of AmB (117 courses), it was shown that there were significant increases in plasma urea and creatinine concentrations and in potassium requirement after 6 days of therapy with both AmB infused in dextrose and AmB infused in lipid emulsion, with there being no difference between the two methods of AmB administration. An intent-to-treat comparison of the numbers of courses affected by acute toxicity (fever, rigors) and chronic toxicity (nephrotoxicity) also indicated that there was no significant difference between AmB infused in dextrose (78 courses) and AmB infused in lipid emulsion (84 courses). The pharmacokinetics of AmB were investigated in 20 children who received AmB in dextrose and 15 children who received AmB in lipid emulsion. Blood samples were collected up to 24 h after administration of the first dose, and the concentration of AmB in plasma was analyzed by a high-performance liquid chromatography assay. The clearance (CL) of AmB in dextrose (0.039 +/- 0.016 liter. h-1. kg-1) was significantly lower (P < 0.005) than the CL of AmB in lipid emulsion (0.062 +/- 0. 024 liter. h-1. kg-1). The steady-state volume of distribution for AmB in dextrose (0.83 +/- 0.33 liter. kg-1) was also significantly lower (P < 0.005) than that for AmB in lipid emulsion (1.47 +/- 0.77 liter. kg-1). Although AmB in lipid emulsion is apparently cleared faster and distributes more widely than AmB in dextrose, this study did not reveal any significant advantage with respect to safety and tolerance in the administration of AmB in lipid emulsion compared to its administration in dextrose in children with malignant disease.