Population pharmacokinetics of doxorubicin and doxorubicinol in patients diagnosed with non-Hodgkin's lymphoma.

AIMS: The aims of the study were: (i) to characterize the pharmacokinetics (PK) of doxorubicin (DOX) and doxorubicinol (DOXol) in patients diagnosed with non-Hodgkin's lymphoma (NHL) using a population approach; (ii) to evaluate the influence of various covariates on the PK of DOX; and (iii) to evaluate the role of DOX and DOXol exposure in haematological toxicity. METHODS: Population PK modelling (using NONMEM) was performed using DOX and DOXol plasma concentration-time data from 45 NHL patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone). The influence of drug exposure on haematological toxicity was analysed using the Mann-Whitney-Wilcoxon test. RESULTS: A five-compartment model, three for DOX and two for DOXol, with first-order distribution and elimination for both entities best described the data. Population estimates for parent drug (CL) and metabolite (CLm ) clearance were 62 l h-1 and 27 l h-1 , respectively. The fraction metabolized to DOXol (Fm ) was estimated at 0.22. While bilirubin and aspartate aminotransferase showed an influence on the CL and CLm , the objective function value decrease was not statistically significant. A trend towards an association between the total area under the concentration-time curve (AUCtotal ), the area under the concentration-time curve for DOX (AUC) plus the area under the concentration-time curve for DOXol (AUCm ), and the neutropenia grade (P = 0.068) and the neutrophil counts (P = 0.089) was observed, according to an exponential relationship. CONCLUSIONS: The PK of DOX and DOXol were well characterized by the model developed, which could be used as a helpful tool to optimize the dosage of this drug. The results suggest that the main active metabolite of DOX, DOXol, is involved in the haematological toxicity of the parent drug.

Validation and clinical evaluation of a UHPLC method with fluorescence detector for plasma quantification of doxorubicin and doxorubicinol in haematological patients.

A rapid and simple UHPLC-fluorescence detection method for the quantification of doxorubicin and its main metabolite, doxorubicinol, in human plasma has been developed. The method was also validated for its application in therapeutic drug monitoring, a clinical approach used in the optimization of oncologic treatments. Following a single protein precipitation step, chromatographic separation was achieved using a C18 column (50mm×2.10mm, particle size 1.7µm) at 50°C with a mobile phase consisting of water (containing 0.4% triethylamine and 0.4% orthophosphoric acid)/acetonitrile (77:23, v/v). Flow rate was 0.50mL/min and fluorescence detection with an excitation wavelength of 470nm and an emission wavelength of 548nm was used. The method met the specifications of linearity, selectivity, sensitivity, accuracy, precision and stability of the FDA and EMA guidelines for the validation of bioanalytical methods. Linearity for the drug (8-3000ng/mL) and the metabolite (3-150ng/mL) was observed (R(2)>0.992) and the maximum intra-day and inter-day precision coefficients of variation were less than 14% for both. The lower limits of quantification were 8 and 3ng/mL for doxorubicin and doxorubicinol, respectively. The method was successfully applied to the quantify plasma concentrations of doxorubicin and doxorubicinol in 33 patients diagnosed with haematological malignancies in which broad ranges for drug (8.3-2766.0ng/mL) and metabolite (4.8-104.9ng/mL) levels were measured adequately.

Vancomycin dosing assessment in intensive care unit patients based on a population pharmacokinetic/pharmacodynamic simulation.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT * Despite the frequent use of vancomycin in intensive care unit (ICU) patients, few studies aimed at characterizing vancomycin population pharmacokinetics have been performed in this critical population. * Population pharmacokinetics coupled with pharmacodynamic analysis, in order to optimize drug exposure and hence antibacterial effectiveness, has been little applied in these specific patients. WHAT THIS STUDY ADDS * Our population model characterized the pharmacokinetic profile of vancomycin in adult ICU patients, higher distribution volume values (V) being observed when the patient's serum creatinine (Cr(Se)) was greater than 1 mg dl(-1). * Age and creatinine clearance (CL(cr)) were identified as the main covariates explaining the pharmacokinetic variability in vancomycin CL. * Our pharmacokinetic/pharmacodynamic (PK/PD) simulation should aid clinicians to select initial vancomycin doses that will maximize the rate of response in the ICU setting, taking into account the patient's age and renal function as well as the susceptibility of Staphylococcus aureus. AIM To estimate the vancomycin pharmacokinetic profile in adult ICU patients and to assess vancomycin dosages for increasing the likelihood of optimal exposure. METHODS Five hundred and sixty-nine concentration-time data from 191 patients were analysed using a population pharmacokinetic approach (NONMEN). External model evaluation was made in 46 additional patients. The 24 h area under the concentration-time curve (AUC(0,24 h)) was derived from the final model. Minimum inhibitory concentration (MIC) values for S. aureus were obtained from the EUCAST database. AUC(0,24 h) : MIC >/= 400 was considered as PK/PD efficacy index. The probability of different dosages attaining the target considering different strains of S. aureus and patient subgroups was estimated with Monte Carlo simulation. RESULTS Vancomycin CL showed a significant dependence on patient age and renal function whereas Cr(Se) > 1 mg dl(-1) increased V more than twofold. For our representative ICU patient, 61 years, 73 kg, Cr(Se)= 1.4 mg dl(-1), measured CL(Cr)= 74.7 ml min(-1), the estimated values were CL = 1.06 ml min(-1) kg(-1) and V= 2.04 l kg(-1). The cumulative fraction of response for a standard vancomycin dose (2 g day(-1)) was less than 25% for VISA strains, and 33% to 95% for susceptible S. aureus, depending on patient characteristics. CONCLUSIONS Simulations provide useful information regarding the initial assessment of vancomycin dosing, the conventional dosing regimen probably being suboptimal in adult ICU patients. A graphic approach provides the recommended dose for any selected probability of attaining the PK/PD efficacy target or to evaluate the cumulative fraction of response for any dosing regimen in this population.

Vancomycin dosage optimization in patients with malignant haematological disease by pharmacokinetic/pharmacodynamic analysis.

BACKGROUND: The use of vancomycin against Staphylococcus aureus is currently debated because of the increasing resistance developed by this pathogen. Nevertheless, antibacterial effectiveness is a limited resource that must be protected and restored. Novel dosage strategies based on pharmacokinetic/pharmacodynamic analyses are needed to retain effectiveness that could improve drug exposure in patients infected with such pathogens. OBJECTIVE: The aim of this study was to assess whether standard or higher vancomycin dosages are required to increase the probability of attaining a target pharmacokinetic/pharmacodynamic index for several staphylococcal strains and thus to estimate the minimum vancomycin daily dose related to a high probability of effective treatment in patients with malignant haematological disease. METHODS: Monte Carlo simulation was performed to calculate the cumulative fraction of response (CFR) for different vancomycin daily dosages, using a population pharmacokinetic model previously defined in patients with malignant haematological disease and the minimum inhibitory concentration (MIC) distribution for vancomycin against several staphylococcal species (vancomycin-susceptible S. aureus and vancomycin-intermediate S. aureus [VISA], S. epidermidis, S. haemolyticus and coagulase-negative Staphylococcus [CNS] species) obtained from the European Committee on Antimicrobial Susceptibility Testing (EUCAST) in order to predict the dose that would achieve the pharmacokinetic/pharmacodynamic index value associated with efficacy (the area under the concentration-time curve from 0 to 24 hours divided by the MIC [AUC(24)/MIC >/=400]). RESULTS: CFR values showed dependence on the renal function of the patient and the causative pathogen. Only in patients with a creatinine clearance (CL(CR)) <60 mL/min did the standard vancomycin dosage (2000 mg/day) induce CFRs >60% for all staphylococci, except the VISA strains. CFRs for S. aureus of 90.6%, 47.3% and 31.2% for CL(CR) values of <60, 60-120 and >120 mL/min, respectively, were obtained, whereas for the VISA strains, the corresponding values were only 14.0%, 0.3% and 0%. The impact of potential pathogens on CFRs is also significant. According to our pharmacokinetic/pharmacodynamic analysis, in patients with normal renal function (CL(CR) between 60 and 120 mL/min) vancomycin 2000 mg/day leads to a risk of not achieving the recommended AUC(24)/MIC breakpoint of 52.7%, 70.4%, 74.9% and 80.3% for S. aureus, S. haemolyticus, CNS and S. epidermidis, respectively. Application of our results to clinical practice graphically allows us to obtain the recommended dose for any a priori-selected probability of attaining the AUC(24)/MIC ratio of >/=400 and to evaluate the CFRs for any dosing regimen used in this population group, depending on the patients' renal function. CONCLUSIONS: Application of pharmacokinetic/pharmacodynamic analysis based on Monte Carlo simulation offers an excellent tool for selecting the therapeutic option with the highest probability of clinical success in patients with malignant haematological disease. Thus, for vancomycin-susceptible S. aureus, if a CFR >/=80 is assumed as clinically acceptable, vancomycin doses of 1500, 3000 and 4000 mg/day for a CL(CR) of <60, 60-120 and >120 mL/min, respectively, will be required.