Andreas Jenke

Pharmacokinetics and cellular uptake of imatinib and its main metabolite CGP74588

Despite the remarkable clinical response rates to imatinib in the treatment of bcr-abl leukemic patients, pharmacokinetic data on this relatively novel substance are needed to improve our understanding of the emergence of resistance, the interindividual variations of clinical response and the clinical and biologic relevance of its main metabolite N-desmethyl-imatinib. We present here pharmacokinetic data obtained with a newly designed HPLC approach in 97 patients with chronic myeloid leukemia or acute lymphatic leukemia (ALL) under treatment with imatinib that allowed us to calculate the AUC (39.5xa0μg·h/ml for an oral dose of 400xa0mg daily), the t1/2 (18.2xa0h) and the peak concentration (1.92xa0μ/ml for an oral dose of 400xa0mg daily) of imatinib in plasma. In a subgroup of patients, the same parameters were analyzed for N-desmethyl-imatinib. We also provide data on the imatinib concentration in the cerebrospinal fluid (CSF) of ALL patients and demonstrate that oral administration of imatinib resulted only in a marginal flux across the blood-brain barrier. Finally, in an in vitro setting, we determined cellular concentrations of imatinib in HL-60 cells and showed an over-proportional uptake both in RPMI medium and in human plasma. Using an arithmetical approach combining all parameters obtained in imatinib-treated patients, we finally provide a conclusive approximation of basic pharmacokinetic data for both imatinib and its main metabolite N-desmethyl-imatinib.

CNS blast crisis of chronic myelogenous leukemia in a patient with a major cytogenetic response in bone marrow associated with low levels of imatinib mesylate and its N-desmethylated metabolite in cerebral spinal fluid

Imatinib mesylate (STI571) is a very effective treatment option for Ph+ chronic myeloid leukemia (CML) in chronic phase. Secondary treatment failures have mostly been observed in patients with advanced stages of disease. We report the case of a patient who unexpectedly experienced blast crisis of the central nervous system although having achieved complete cytogenetic remission in the bone marrow. The levels of STI571 and its metabolite N-desmethyl STI were 40-fold lower in the cerebral spine fluid than in plasma. The risk of CNS disease has to be kept in mind when patients with CML in chronic phase who are at an increased risk for blastic transformation are treated with imatinib mesylate.

Pharmacokinetics of intravenous mycophenolate mofetil after allogeneic blood stem cell transplantation

Background. Mycophenolate mofetil (MMF) has shown synergistic effects in combination with cyclosporin A (CsA) in prevention of acute graft versus host disease (GvHD) after allogeneic blood stem cell transplantation (BSCT) in preclinical animal models. After having measured low plasma levels of the active metabolite mycophenolic acid (MPA) in recipients of allogeneic blood stem cell transplants after oral administration of MMF, we initiated a phase I/II study evaluating different dose levels of the intravenous (i.v.) formulation together with standard dose CsA. u2028 Methods. A total of 15 patients received i.v. MMF in two split doses for 21 d after allogeneic BSCT from related (n=9) and unrelated (n=6) donors. Total daily doses of 25, 28, 31 and 34 mg/kg were investigated in 3–5 patients at each dose level. Plasma concentrations of MPA and its metabolite mycophenolic acid glucuronide (MPAG) were measured by high‐performance liquid chromatography (HPLC). u2028 Results. Mean trough blood levels of MPA ranged between 68.8 and 340 ng/mL with a median of 146.7 ng/mL. The mean MPA AUC0–12 h after first dose ranged between 19349±5087 ngu2003*u2003h/mL and 25705±3042 ngu2003*u2003h/mL and correlated with the dose level of MMF. The incidence of acute GvHD>grade I was 40%. No dose limiting toxicities were observed. u2028 Conclusions. The application of i.v. MMF is safe at a weight‐adjusted dose between 25 and 34 mg/kg after allogeneic BSCT. The measured trough blood levels of MPA in patients after BSCT were ten times lower than in healthy volunteers. The toxicity induced by the conditioning therapy seems to negatively influence the pharmacokinetic behavior of MMF, MPA and MPAG.

Intravenous busulphan for conditioning before autologous or allogeneic human blood stem cell transplantation

This study was undertaken to evaluate the toxicity and pharmacokinetics of a dimethyl sulphoxide (DMSO)‐based intravenous formulation of busulphan in the conditioning of 45 patients undergoing allogeneic or autologous stem cell transplantation (SCT). Busulphan was given as a single daily dose. In 15 patients a single dose of intravenous busulphan, given over 3u2003h in 1u2003d, was combined with additional oral (single daily) doses. Thirty patients received all four daily doses intravenously. Busulphan plasma levels were analysed using high performance liquid chromatography. There was no major acute toxicity with daily intravenous doses of 2·8–3·1u2003mg/kg infused over 3u2003h. No veno‐occlusive disease (VOD) was seen in 30 patients receiving busulphan as an intravenous formulation over 4u2003d. In the group of 15 patients receiving three oral doses and one intravenous single daily dose, one patient experienced mild VOD. Pharmacokinetic samples were taken over at least 2u2003d of treatment in 44 patients. The area under the concentration time curve (AUC) values normalized for a dose of 1u2003mg/kg were 7000u2003ng/mlu2003×u2003h on du20031 and 5890u2003ng/mlu2003×u2003h on du20034, thus showing a moderate decrease over time. This was accompanied by a moderate increase of the clearance from 2·6 to 3·0u2003ml/min/kg. Administration of busulphan as a DMSO‐based intravenous formulation was well tolerated. The total dose of busulphan can be given in four (rather than the typical 16) doses. With such a regimen, the intravenous administration becomes feasible on an outpatient basis.

Population pharmacokinetics of oral busulfan in children

PurposeTo characterize the population pharmacokinetics of oral busulfan in 48 children including pooled data from three transplantation centres with the aim of estimating the variability in the kinetics of busulfan and to identify covariates that could be used for dose calculation.MethodsA total of 508 plasma samples from 250 administrations (mean 9 samples per patient over 4xa0days of treatment) were collected from 48 children receiving busulfan orally every 6xa0h. The dosing varied between 13 and 20xa0mg/kg with seven patients receiving a dose of 600xa0mg/m2. The busulfan formulations administered varied considerably. They included 2-mg tablets (Myleran), gelatine capsules, crushed tablets suspended in water and suspension for administration via nasogastric tube. Samples were analysed for busulfan either by HPLC using postcolumn photolysis or by LC-MS. Plasma concentration-time data were analysed by population pharmacokinetic modelling using NONMEM.ResultsBusulfan kinetics were best described by a one-compartment model (subroutine ADVAN 2 TRANS 2). Residual variability was modelled using a combined additive and proportional error model. The influence of different covariates on the pharmacokinetic parameters was tested. The best results were obtained by inclusion of body surface area (BSA) as a covariate for clearance (Cl/F) and volume of distribution (V/F). The final population estimates were: Cl/F 4.13xa0l/h per m2 ±26%, V/F 21.3xa0l/m2 ±31% and ka 1.31xa0h−1 ±110% (population mean ± interindividual variability, IIV). Variability in one patient during the 4xa0days of treatment (interoccasion variability, IOV) for Cl/F (10%) and V/F (19%) were calculated to be less than interindividual variability, fulfilling the condition for individualization of busulfan dosage regimens.ConclusionsIn our paediatric population, BSA, not body weight, is the best predictor of Cl/F and V/F. Our final estimations reflect the wide interpatient variability after oral administration of busulfan with an IIV for ka of 110%.