Comparative pharmacokinetic/pharmacodynamic characterisation of a new pegylated recombinant E. coli L-asparaginase preparation (MC0609) in Beagle dog.

PURPOSE: A new pegylated recombinant L-asparaginase (MC0609) was designed to improve pharmacokinetic characteristics and to further reduce immunogenicity in comparison with the currently marketed pegylated Escherichia coli L-asparaginase (pegaspargase, Oncaspar(®)). METHODS: Comparative pharmacokinetics (PK), bioavailability, pharmacodynamics and immunogenicity studies were performed in CD(®) rats and Beagle dogs after intravenous (i.v.) and intramuscular (i.m.) single-dose administration of MC0609 or Oncaspar(®). Bioanalytical data on enzymatic activity in serum of animals were used to develop a population pharmacokinetic (PopPK) model to simulate different dosages of MC0609 comparable to the activity time profile of Oncaspar(®). RESULTS: In contrast to Oncaspar(®), which showed an accelerated elimination over time, a constant serum elimination of enzymatic activity over time was seen for MC0609. Linear PK of MC0609 resulted in a prolonged and dose-dependent duration of enzymatic activity and longer depletion of L-asparagine in peripheral blood. The different PK characteristics of MC0609 and Oncaspar(®) were confirmed by PopPK analysis and model development. The PK parameters of Oncaspar(®) in dog scaled to body surface area were in the same range than the parameters determined in paediatric acute lymphoblastic leukaemia patients. Therefore, the dog is considered a clinically relevant model for PK evaluation of Oncaspar(®). Distinct differences in immunogenic potential of both preparations were detected after single-dose administration of a therapeutic dose to dogs. An absolute bioavailability of 66 % was calculated for the intramuscular administration of MC0609. CONCLUSIONS: The new pegylated recombinant L-asparaginase preparation MC0609 revealed striking differences in PK/PD properties compared with Oncaspar(®) in rat and dog.

Plasma concentrations of posaconazole administered via nasogastric tube in patients in a surgical intensive care unit.

Abdominal surgery may affect intestinal absorption and the resulting levels of posaconazole in the blood. We measured plasma posaconazole levels in surgical intensive care unit (SICU) patients and tried to develop a predictive population pharmacokinetics model. A total of 270 samples from 15 patients receiving posaconazole via nasogastric tube were measured by high-performance liquid chromatography (HPLC). SICU patients showed lower plasma drug concentrations, a higher apparent clearance, and a higher volume of distribution than those in hematology patients, possibly due to poor absorption.

Population pharmacokinetics of native Escherichia coli asparaginase.

The main aim of this analysis was to characterize the population pharmacokinetics of native Escherichia coli asparaginase (ASNase medac) in pediatric patients with previously untreated acute lymphoblastic leukemia. Secondary objective was to give further evidence for bioequivalence between ASNase medac and a new recombinant ASNase preparation. The authors reanalyzed 233 plasma samples from 16 children treated according to the DCOG-ALL 10 protocol (5000 U/m(2) ASNase medac) using NONMEM. Subsequently, assessment of bioequivalence was performed by including the preparation as a categorical covariate into the PopPK model when analyzing data of both preparations (480 samples, 32 children). A linear 2-compartment model with first-order elimination sufficiently described ASNase medac pharmacokinetics. The parameters found were as follows: total body clearance 0.13 L/h ± 12.4% per 1.73 m(2), volume of distribution in the central compartment 4.11 L ± 12.3% per 70 kg, volume of distribution in the peripheral compartment 1.63 L per 70 kg and intercompartmental clearance 0.106 L/h (mean ± interindividual variability). A visual predictive check procedure and simulation of different dosages ASNase medac administered in the ALL-BFM protocol indicated adequate model performance. Assessment of bioequivalence provided a difference of about 14% in clearance of both preparations being too small to be considered as clinically relevant. A population pharmacokinetic model of ASNase medac in pediatric patients with previously untreated acute lymphoblastic leukemia was established. The model was able to describe asparaginase activity of different dosages in the ALL-BFM protocol and provides further evidence for bioequivalence between ASNase medac and a new recombinant asparaginase preparation.

Therapeutic drug monitoring of asparaginase in the ALL-BFM 2000 protocol between 2000 and 2007.

BACKGROUND: On a voluntary basis therapeutic drug monitoring (TDM) was implemented in the ALL-BFM 2000 protocol for the three currently used asparaginase (ASNase) preparations (first line: native Escherichia coli ASNase; second line: pegylated ASNase and third line: Erwinia chrysanthemi ASNase). PROCEDURE: Between 2000 and 2007, 2,074 ASNase samples from 763 patients out of 114 hospitals were evaluated (5,000 U/m2 E. coli ASNase (n = 318), 1,000 U/m2 pegylated ASNase (n = 416) and 10,000 U/m2 Erwinia chrysanthemi ASNase (n = 29)). RESULTS: First-line therapy with 5,000 U/m2 E. coli ASNase resulted in an ASNase activity of <100 U/L in 10% of all samples from day +3 after administration. Second-line treatment with 1,000 U/m2 PEG ASNase led to activity values below 100 U/L in approximately 30% of all samples taken +7 days. Relating ASNase activity to route of administration, 10,000 U/m2 Erwinia ASNase IM compared to IV as third-line treatment, led to a higher median activity (IM: median 151.5 U/L, range (0-750 U/L); IV: median 115 U/L, range (0-884 U/L), P = 0.3) and fewer samples below 100 U/L (IM: 15% vs. IV: 45%) at day +2. CONCLUSION: The reduced dose of 5,000 U/m2 E. coli ASNase for induction treatment succeeded to achieve an activity level above 100 U/L in more than 90% of all samples. They confirm that dose reduction is reasonable and provide the basis for future treatment strategies employing ASNase.