Ingrid Mai

Modulation of steady‐state kinetics of digoxin by haplotypes of the P‐glycoprotein MDR1 gene

We investigated the effect of polymorphisms in the P‐glycoprotein (P‐gp) MDR1 gene on steady‐state pharmacokinetics of digoxin in Caucasians. According to earlier data, homozygous TT of the exon 26 complementary deoxyribonucleic acid (cDNA) 3435C>T polymorphism was associated with low P‐gp expression in the human intestine.

Increase in cerivastatin systemic exposure after single and multiple dosing in cyclosporine‐treated kidney transplant recipients

The mutual drug‐drug interaction potential of the 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase inhibitor cerivastatin and cyclosporine (INN, ciclosporin) in kidney transplant recipients receiving individual immunosuppressive treatment was evaluated with respect to pharmacokinetic behavior of either drug and tolerability of concomitant use.

Pharmacodynamic monitoring of mycophenolate mofetil.

Abstract The immunosuppressive activity of Mycophenolate Mofetil (MMF) is based on the reversible inhibition of inosine-5′-monophosphate dehydrogenase (IMPDH) by mycophenolic acid. Pharmacodynamic monitoring by measurement of IMPDH activity reflects directly the biological response to MMF. For measurement of IMPDH activity in peripheral mononuclear cells we established a modified non-radioactive procedure, based on the incubation of cell lysates with inosine-5′-monophosphate and the chromatographic quantification of produced xanthosine-5′-monophosphate by isocratic ion-pair reversed phase HPLC. The between-run precision and within-run precision were 7% and 5%, respectively. We determined the time course of IMPDH activity in five patients after 1g MMF and in five healthy subjects without administration of MMF. Additionally, IMPDH activity was determined in a population study of 40 healthy volunteers. In healthy volunteers, we observed a wide range of IMPDH activity (4.7–32.9 nmol/h/mg) with only weak diurnal variation. All patients receiving MMF had a significant reduction of IMPDH activity (65–100%) after administration of the drug. Inhibition persisted for up to 6 hours, and after 11 hours IMPDH activity returned to predose activities. The interindividual variability of IMPDH activity may account for pharmacodynamic differences in MMF-treated patients. Based on pharmacodynamic monitoring better dosing strategies for MMF-treated patients may evolve.

Moxifloxacin does not alter ciclosporin pharmacokinetics in transplant patients: a multiple-dose, uncontrolled, single-centre study.

BACKGROUND Moxifloxacin has a broad antibacterial spectrum and rapid bactericidal activity, and is thus a good option for the treatment of bacterial infections in patients who have undergone organ or bone marrow transplantation. Transplant patients also receive immunosuppressant therapy such as ciclosporin. OBJECTIVE The primary objective of this study was to assess the steady-state pharmacokinetics of ciclosporin with and without concomitant treatment with moxifloxacin in transplant recipients. A secondary objective was to determine the safety and tolerability of the combined treatment. METHODS Patients (n = 9) with stable graft function after bone marrow or renal transplantation and who were already receiving ciclosporin therapy were enrolled into the study. The patients were given ciclosporin (Sandimmun Optoral) capsules twice daily (total daily dosage 150-380 mg/day) throughout the study period. Moxifloxacin (Avolox) tablets 400 mg once daily were given on days 2-8 inclusive. The primary outcome measure was the change in ciclosporin pharmacokinetics on coadministration with moxifloxacin. Secondary outcomes were the steady-state pharmacokinetics of moxifloxacin and ciclosporin plus its metabolites in patients receiving moxifloxacin and ciclosporin concomitantly. Moxifloxacin pharmacokinetic parameters in the presence of ciclosporin were compared with previously published pharmacokinetic data for moxifloxacin in healthy individuals. RESULTS No significant changes occurred in the concentration-time curves of ciclosporin and its metabolites following combination therapy with moxifloxacin. The geometric means of whole blood concentrations of ciclosporin and ciclosporin plus its metabolites on day 1 were similar to those on day 8 following combined administration of ciclosporin and moxifloxacin for 7 days. The ratio of combination treatment to monotherapy for ciclosporin was 1.01 (90% CI 0.91, 1.11) for the area under the blood concentration-time curve from time zero to 12 hours at steady state (AUC(12,ss)) and 0.96 (90% CI 0.88, 1.04) for the maximum steady-state blood drug concentration (C(max,ss)). For ciclosporin plus its metabolites the ratio was 1.07 (90% CI 0.99, 1.17) for AUC(12,ss) and 1.03 (90% CI 0.98, 1.09) for C(max,ss). The pharmacokinetic parameters for moxifloxacin were unaffected by the presence of ciclosporin. CONCLUSIONS Concomitant administration of moxifloxacin does not alter the pharmacokinetic parameters of ciclosporin or ciclosporin plus its metabolites in immunosuppressed patients. Therefore, no dose adjustments or additional drug monitoring are required when ciclosporin is coadministered with moxifloxacin.

PROBLEMS OF CYCLOSPORINE ABSORPTION PROFILING USING C2-MONITORING

UNLABELLED The present study sought to validate the concept of C2 monitoring in 41 de-novo transplant patients treated with microemulsion of cyclosporine, mycophenolatesodium, steroids and basiliximab. RESULTS After 6 months patient and graft survival was 98%, rejection rate was 19%. In the first week only a few patients achieved the suggested C2 levels (19% > 1500, 50% > 1200 ng/ml) despite an increased cyclosporine (CsA) dose. After 14 days 63% of patients reached C2 > 1500 ng/ml (83% C2 > 1200) despite decreased CsA dose. 35% of patients had intermittent high C0 (> 300) and low C2 (< 800), suggesting poor and/or slow absorption. Most of them suffered from CsA toxicity. There was a significant (p < 0.05) change of absorption as measured by C2/C0 leading to an increase of C2/dose. CONCLUSIONS C2 monitoring may be useful to better estimate the CsA exposure in individual patients; however our results indicate some limitations of the current concept of C2 monitoring. Despite increase of dosage many patients do not reach the proposed levels. A significant proportion of patients are poor and/or slow absorbers. CsA toxicity may not be detected by C2 monitoring alone. With the use of basiliximab and mycophenolatesodium lower target levels seem to be sufficient.