Background/Aims: Usually, the appropriate dosage of low-molecular-weight heparin during haemodialysis is empirically based on the clinical effect. We studied the pharmacokinetics of dalteparin during standard haemodialysis in different groups of patients to assess the added value of measuring the anti-Xa activity for dose monitoring and adjustments. Methods: The pharmacokinetics of intravenously administered dalteparin during haemodialysis was studied in 9 patients during 27 haemodialysis sessions. Six patients received a single bolus dose of dalteparin (group 1), and 3 patients received a higher initial bolus dose of dalteparin followed by a second bolus dose after 2 h (group 2). The clinical effect was evaluated by visual inspection for clot formation in the extracorporeal circuit. Results: The pharmacokinetic curve suggests a zero-order process of elimination. The mean decrease in anti-Xa activity (slope) was comparable in all patients. The mean anti-Xa activity at the end of haemodialysis (C_last) was 0.15 IU/ml in group 1 and 0.60 IU/ml in group 2. Conclusion: We conclude that measuring anti-Xa activity can be used to monitor the elimination of dalteparin during haemodialysis and is highly reproducible.

ObjectiveTo describe the pharmacodynamic monitoring of (immuno)proteasome inhibition following treatment with bortezomib in a therapy-refractory systemic lupus erythematosus (SLE) patient with life-threatening myocarditis and lupus nephritis.Patient and methodsInhibition of catalytic activities of the proteasome subunits β5 (constitutive proteasome), β5i and β1i (immunoproteasome) were measured in peripheral blood mononuclear cells using subunit-specific fluorogenic peptide substrates in a patient who received three cycles of bortezomib (1.3 mg/m2 subcutaneously, days 1, 4, 8 and 11; every three weeks) along with plasma exchange during the first two cycles.ResultsProteasome β5, β5i and β1i subunit activities were readily inhibited 1 h after bortezomib administration. Twenty-four hours post-bortezomib administration, β5 and β5i activities were largely restored, whereas inhibition of β1i activity was sustained. Clinically, after three cycles, cardiac function had improved, with concurrent improvement of haemodynamic stability during haemodialysis. Anti-ds-DNA dropped from >400 to 12 IU/mL along with normalisation of complement C3 and C4. Bortezomib therapy was well tolerated, and patient now has a sustained remission for >16 months.ConclusionsThis case illustrates the potential benefit of pharmacodynamic monitoring of (immune)proteasome subunit-specific activity after bortezomib dosing in patients with therapy refractory SLE. This tool may hold potential to guide personalised/precision dosing aiming to achieve maximal efficacy and minimal toxicity.

Background and objectives (Immuno) proteasomes play a crucial role in processing of key proteins involved in the functioning of immune effector cells implicated in the pathology of autoimmune diseases. To this end, proteasome inhibitors, e.g. bortezomib, have received considerable attention as experimental therapeutics of autoimmune diseases. Here, we report the clinical case of a 44-old male SLE patient following treatment with bortezomib, along with pharmacodynamic monitoring of the inhibition of (immuno) proteasome catalytic activity. The patient was previously treated with - and unresponsive - to hydroxychloroquine, high dose oral and iv corticosteroids, azathioprine, mycofenolate mofetil, rituximab, IVIG, and cyclophosphamide (cumulative 5100 mg). His manifestations of SLE were arthritis, pericarditis, lymphadenopathy, class IV lupus nephritis (WHO classification), with the following antibody profile: ANA-, anti-Sm-, anti-U1RNP-, and anti-dsDNA antibodies. At the time of bortezomib administration, he was critically ill, suffering from renal and cardiac failure, most likely due to lupus myocarditis. Materials and methods Patient received 3 cycles of bortezomib (1.3 mg/m2) with 1 month interval. During the first two cycles plasma filtration was also initiated: three times weekly after the first cycle and twice weekly after the second. Two weeks after the start of bortezomib, hemodialysis was necessary due to renal failure. Pharmacodynamically, inhibition of catalytic activity (mean of 3 cycles) of constitutive proteasome subunit β5 and immunoproteasome subunits β5i and β1i was examined in cell extracts of peripheral blood mononuclear cells (collected prior to therapy, 1hr and 24 h after bortezomib administration) using subunit-specific fluorogenic peptide substrates. Results One hour after bortezomib administration, β5-associated catalytic activity was 45% inhibited compared to pretreatment control, and after 24 h, this activity was largely recovered (11% inhibition). Immunoproteasome β5i-catalytic activity was more potently inhibited after 1 h bortezomib (73%) and partially recovery after 24 h (25% inhibition). β1i-associated catalytic activity was also potently inhibited 1 h after bortezomib administration (74%), and remarkably sustained after 24 h (65%). Clinically, after three months, cardiac function improved (ejection fraction 16% to 43%), with concurrent improvement of haemodynamic stability during hemodialysis. Anti-dsDNA (ELISA) dropped from >498 to 12 IU/ml. After two months the patient was dismissed from the hospital. Conclusions Bortezomib treatment in combination with plasma filtration proved useful in a complicated case of SLE. Pharmocodynamic monitoring of (immuno) proteasome catalytic activity with subunit-specific probes may be a potential tool to assess the potency and duration of bortezomib inhibition as parameter attributing to the therapeutic efficacy of bortezomib.