Eberhard Schleyer

Pharmacokinetics of gemcitabine in a patient with end-stage renal disease: effective clearance of its main metabolite by standard hemodialysis treatment

PurposeGemcitabine (2′,2′-difluorodeoxycytidine) is a cytotoxic agent with a low toxicity profile and proven activity against a number of solid tumors. It is not known whether gemcitabine is safe to administer to patients with kidney failure, and if dose adjustment is necessary. We determined the tolerability and pharmacokinetics of gemcitabine and its noncytotoxic metabolite 2′,2′-difluorodeoxyuridine (dFdU) in a patient with end-stage renal disease on maintenance hemodialysis therapy.Patient and methodsA 64-year-old patient with pancreatic cancer and end-stage renal disease received two cycles of gemcitabine at a standard dose of 1000xa0mg/m2 given as a 30-min infusion on daysxa01 and 10. A regular 3.5-h hemodialysis treatment was performed 24xa0h after each infusion. Plasma and dialysate concentrations of gemcitabine and dFdU were determined by HPLC. The tolerability of gemcitabine treatment was assessed by clinical and laboratory parameters.ResultsFor gemcitabine, the maximal plasma concentration, terminal half-life (t1/2) and area under the concentration-time curve (AUC) were similar to those reported for patients with normal renal function. In contrast, end-stage renal disease resulted in a five- to tenfold prolongation of terminal half-life and a distinct increase in the AUC of plasma dFdU in this patient. Plasma dFdU was effectively eliminated by hemodialysis treatment. Both cycles of gemcitabine were tolerated well with no unexpected side effects observed.ConclusionsGemcitabine treatment in end-stage renal disease with intermittent standard hemodialysis treatment is safe and well tolerated. The pharmacokinetic data suggest that dose adjustment of gemcitabine should be avoided to ensure its full cytotoxic activity, and that hemodialysis treatment should be initiated 6–12xa0h after its administration to minimize the potential side effects of the metabolite dFdU.

Activity of sirolimus in patients with myelodysplastic syndrome – results of a pilot study

The pathophysiology of the myelodysplastic syndromes (MDS) involves disturbed regulation of angiogenesis, apoptosis, proliferation and differentiation as well as immune surveillance. Increasing data suggest that sirolimus might affect these pathways positively, thus being of possible therapeutic benefit in patients with this disease. Nineteen patients (nu2003=u200319) with a median age of 72u2003years (range 54–80u2003years) diagnosed with MDS received sirolimus orally with a target blood concentration of 3–12u2003ng/ml. Sirolimus was administered for a median of 3·7u2003months (range 0·3–11u2003months). Three patients [1u2003×u2003refractory anaemia with excess blasts (RAEB)‐2, 1u2003×u2003RAEB‐1, 1u2003×u2003refractory cytopenia with multilineage dysplasia] showed either a major (1u2003×u2003platelet, 1u2003×u2003neutrophil) or a minor (1u2003×u2003erythroid, 2u2003×u2003platelet) haematological response according to International Working Group criteria. Major side‐effects were hyperlipidaemia (nu2003=u20034), stomatitis (nu2003=u20033), thrombocytopenia (nu2003=u20032) and urinary tract infection (nu2003=u20031). These data suggest that sirolimus has activity in a subset of patients with more advanced MDS.

Glycoprotein IIb/IIIa inhibitor-induced thrombocytopenia : Diagnosis and treatment

SummaryThrombocyte glycoprotein IIb/IIIa inhibitors prevent fibrinogen binding and thereby thrombocyte aggregation. The inhibition of thrombocyte activation at the damaged coronary plaque is the target of the new therapeutic strategies in treating acute coronary syndrome. This reduces the ischemic complications associated with the non-STelevation myocardial infarction (NSTEMI) and percutaneous coronary intervention (PCI).Thrombocytopenia is a known complication of glycoprotein (GP) IIb/IIIa inhibitors. Although, in general, GP IIb/IIIa inhibitor-induced thrombocytopenia is a harmless side effect which responds readily to thrombocyte transfusion, it can occasionally be a very serious complication associated with serious bleeding. In addition patients developing thrombocytopenia have unfavorable outcome (e.g., death, myocardial infarction, bypass surgery or additional PCI) in comparison to patients without thrombocytopenia.Advanced age (> 65 years), low BMI and a low initial thrombocyte count (<180 000/µl) are independent risk factors of thrombocytopenia. The risk of bleeding is higher with this form of thrombocytopenia not only due to the low thrombocyte count but also to the impaired function of the remaining thrombocytes.It is important to closely monitor platelet count during GP IIb/IIIa antagonist treatment. Platelet count monitoring two, six, twelve and 24 hour after starting the treatment reveals most cases of acute thrombocytopenia. Side effects can be avoided by the early discontinuation of the GP IIb/IIIa antagonist treatment.This article reviews the diagnosis and treatment of glycoprotein IIb/IIIa inhibitor-induced thrombocytopenia and summarizes the differential diagnosis from heparin-induced thrombocytopenia and laboratory-related pseudothrombocytopenia.

Targeting mycophenolate mofetil for graft-versus-host disease prophylaxis after allogeneic blood stem cell transplantation.

As low trough levels of mycophenolic acid (MPA) have been measured in recipients of allo-SCTs, we performed a pilot study targeting mycophenolate mofetil (MMF) doses according to the MPA area under the concentration (AUC) levels. Twenty-nine patients were transplanted from matched sibling (n=7) and unrelated donors (n=22). Tacrolimus was given orally from day −1 to achieve trough blood levels of 5–10u2009ng/ml. MMF was started on day 0 at 1500u2009mg intravenously b.i.d. AUC measurements of MPA by HPLC were scheduled on days 3, 7 and 11 after transplantation. The MMF dose was modified to achieve an MPA AUC of 35–60u2009μg/ml/h. With the respective adjustments 66 and 75% surpassed the lower AUC target on days 7 and 11, respectively. The cumulative incidence of grade III–IV acute GVHD was 28% (8/29). Eight out of 24 evaluable patients (33%) suffer from limited (n=3) or extensive (n=5) chronic GVHD. Overall, the results of this study suggest that targeting of MPA exposure is feasible early after transplantation. A simplified MMF targeting strategy based on MPA Cmax or C2h levels seems to be warranted in future trials involving more patients at later time points in the outpatient setting.

Survey and analysis of the efficacy and prescription pattern of sorafenib in patients with acute myeloid leukemia

Sorafenib is a multi-kinase inhibitor with activity against several intracellular kinases which may play a role in the pathogenesis of acute myeloid leukemia (AML). In vitro data and results from early clinical trials suggest that sorafenib might be an effective drug for the treatment of AML. However, clinical data are still sparse, and there are only a few reported cases of monotherapy. The aim of the present research was to collect clinical data on efficacy and safety in a systematic way by conducting a survey on clinical experience with sorafenib. Thirty institutions were asked to document all patients treated with sorafenib diagnosed with AML. Of all 29 evaluable patients, six (21%) responded to sorafenib containing treatment by achieving a complete remission (CR, n = 2) or complete remission with incomplete platelet recovery (CRi, n = 4). In 23 patients receiving sorafenib as monotherapy, the CRi rate amounted to 13% and no CRs were documented. Of the 18 FLT-ITD positive patients with sorafenib monotherapy, two patients achieved a CRi (11%). In five FLT3-ITD negative cases, one CRi was documented (20%). Our results suggest the potential ability of the drug to induce remissions in refractory or relapsed AML even when given as monotherapy.

F-ara-A pharmacokinetics during reduced-intensity conditioning therapy with fludarabine and busulfan

Fludarabine is commonly used in combination with busulfan as part of conditioning regimens before allogeneic stem cell transplantation. So far, no data are available on busulfan–fludarabine drug interactions in transplant recipients. The pharmacokinetic (PK) properties of F-ara-A (9-β-D-arabinosyl-2-fluoradenine) before and after application of busulfan were prospectively investigated in 16 patients with hematological malignancies. The conditioning regimen consisted of intravenous fludarabine 30u2009mg/m2 over 30u2009min from day −6 to day −3, and oral busulfan given at 1u2009mg/kg every 6u2009h from day −5 to day −2. PK parameters of F-ara-A, derived from plasma and urine on day −6, −5, −4 and −3, were determined using high-performance liquid chromatography (HPLC). AUC, Cmax, t1/2, Cltotal and VSS were 21.9u2009μMh, 3.5u2009μM, 13.0u2009h, 4.3 l/h/m2, 60.0u2009l/m2 on day −6 and 22.4u2009μMh, 3.5u2009μM, 14.0u2009h, 4.7u2009l/h/m2, 69.0u2009l/m2 on day −5 to (−2), respectively. Clrenal and the urine-recovery were 4.8u2009l/h, 43.7% of the fludarabine dose on day −6 and 3.9u2009l/h, 44.2% of the fludarabine dose on day −5 to (−2), respectively. There were no changes in PK parameters of fludarabine given before and after intake of busulfan. This implies that a clinically relevant busulfan–fludarabine drug interaction is unlikely.

Accidental busulfan overdose during conditioning for stem cell transplantation.

Summary:High dose busulfan is widely used in preparative regimens for bone marrow transplantation. We describe three cases of accidental busulfan overdosing. Two adults received a single dose of 8 and 18 mg/kg busulfan, respectively. Doses of 9 × 4 mg/kg were ingested by a 14-year-old girl, who experienced seizures. In all cases, no severe liver toxicity including veno-occlusive disease was observed. Plasma samples were obtained from two patients. Busulfan plasma concentrations were far above published values after high-dose busulfan treatment. Busulfan was eliminated by a first-order process. All patients survived these high doses of busulfan and successful transplantation was possible. Two patients died from refractory GvHD on days 91 and 80 after transplantation. One patient is alive in remission after an observation time of 18 months. These cases show that busulfan overdosing may occur and pharmacokinetic evaluation is warranted to estimate risk of early and late toxicity.

Targeting once-daily intravenous busulfan in combination with fludarabine before allogeneic hematopoietic cell transplantation.

A recent report by de Lima and coworkers showed that intravenous busulfan administered once daily over 4 days together with fludarabine can be used successfully as the preparative regimen before allogeneic hematopoietic cell transplantation from matched sibling and unrelated donors.1 Besides the positive outcome of their study, they showed that the once-daily infusion of busulfan was associated with low interdose variation of busulfan plasma pharmacokinetics (PK) and no accumulation over the 4 days of administration. Although interdosing variability was minimal, the daily area under the concentration–time curve (AUC) ranged between 2931 and 8271 mol min. Targeting of oral busulfan has been associated with favorable clinical results and reduced toxicity in patients receiving allogeneic transplantation for CML and MDS.2, 3 We therefore performed a pilot study in 10 patients with hematological malignancies combining 30 mg/m2 fludarabine i.v. (day -9 to -6) over 4 days with single doses of intravenous busulfan infused over 2 h on four consecutive days (-5 to -2). The starting dose of busulfan administered was 3.3 mg/kg adjusted to ideal body weight. We used a DMSO-based formulation which has been described in previous dose-finding studies.4 Blood samples were drawn every day during busulfan administration at time-points 0, 1, 2 (end of infusion), 3, 4 and 6 h. The busulfan plasma concentration was determined by HPLC.5 The dose of busulfan was targeted to achieve a concentration at steady state (Css) of 800–1000 ng/ml on the subsequent day. This target corresponded to AUC values of 4677–5847 mol min/l after daily single doses of busulfan, and was equivalent to the Css target used in a recent clinical study with fludarabine and oral busulfan.6 Figure 1 summarizes the doses of busulfan administered on each day and the corresponding plasma levels achieved. Three patients had a coefficient of variation of >25%, requiring more rigorous dose modifications. One of these patients had an elevated creatinin which dropped after infusion therapy. Minor dose modifications were required on the third and fourth days of busulfan application in all cases. Table 1 shows the PK parameters achieved with our approach. After transplantation of G-CSF-mobilized blood, GvHD prophylaxis consisted of tacrolimus 0.03 mg/kg and mycophenolate mofetil 2 1.5 g. Primary graft failure occurred in one patient only. He died after a second transplant from a mismatched sibling donor. Grade 4 hyperbilirubinemia associated with sepsis from Escherichia coli was observed in one patient who subsequently succumbed with multiorgan failure. No additional case of grade 4 extramedullary toxicity was observed. Relapse of high-risk acute myeloid leukemia occurred in two cases. Six patients are alive between 120 and 380 days after transplantation without signs of active disease. Our preliminary findings suggest that targeting of single-dose intravenous busulfan using a limited sampling strategy might allow to achieve a lower interpatient variability than reported by de Lima and coworkers.1 Of course the ideal target dose in this setting has not been defined yet. Prospective studies are warranted to prove whether the target level of once-daily intravenous busulfan, as described here, offers a meaningful clinical benefit compared to the standard split-dose application.

Pharmacokinetic comparison of oral and intravenous etoposide in patients treated with the CHOEP-regimen for malignant lymphomas

BackgroundThe addition of etoposide to the CHOP protocol (CHOEP) has been shown to improve outcome in patients with aggressive non-Hodgkin’s lymphoma. The intravenous administration of etoposide on three consecutive days represents a logistic problem and needs resources particular in the outpatient setting. This could be avoided by using etoposide capsules on days 2 and 3. However, the oral administration of cytotoxic agents is often affected by variable absorption and drug interactions.Patients and methodsWe investigated the pharmacokinetic equivalency of oral and intravenous etoposide in ten patients (male, nxa0=xa07; female, nxa0=xa03; median age 56xa0years) with aggressive lymphomas. Treatment consisted of standard CHOP plus etoposide 100xa0mg/m2 given intravenously on day 1, and 200xa0mg/m2 orally on days 3 and 4. Samples from blood and urine were taken on days 1 (i.v. study) and 3 (p.o. study) before and after etoposide administration. Etoposide levels were determined by high-performance liquid chromatography (HPLC), and pharmacokinetic parameters were calculated with the TOPFIT computer program.ResultsMean peak plasma level after intravenous etoposide was significantly higher compared to oral administration (16.3xa0±xa03.7 vs. 12.0xa0±xa04.2xa0μg/ml; Pxa0=xa00.015). The mean bioavailability of oral etoposide was 58xa0±xa015% with an interpatient variability of 26%. Significant differences of bioavailability of oral etoposide between the used dose levels (350, 400 and 450xa0mg) were not observed. Mean AUC after a 100xa0mg/m2 intravenous and a 200xa0mg/m2 oral dose of etoposide were 74.0xa0±xa018.3 and 84.9xa0±xa029.6xa0μgxa0h/ml (Pxa0=xa00.481). Interpatient variability of AUC was 25% for the intravenous route and 35% after oral intake. Urinary etoposide excretion as percentage of administered dose was 39.4xa0±xa010.6% after intravenous infusion versus 35.4xa0±xa09.4% after oral intake (Pxa0=xa00.422). Renal clearance was also very similar with intravenous and oral route (18.5xa0±xa07.4 vs. 16.7xa0±xa06.6xa0ml/min; Pxa0=xa00.546).ConclusionThe equivalency of AUC after 200xa0mg/m2 of oral and 100xa0mg/m2 of intravenous etoposide support the use of the oral preparation in patients treated with the CHOEP regimen, which makes the chemotherapy more convenient for the patients and help to reduce costs.

Stable molecular remission induced by imatinib mesylate (STI571) in a patient with CML lymphoid blast crisis relapsing after allogeneic stem cell transplantation

Summary:We report the response to the ABL kinase inhibitor imatinib mesylate (STI571) in a patient with chronic myeloid leukemia (CML) who relapsed twice after dose-reduced allogeneic stem cell transplantation (alloSCT) for B lymphoid blast crisis (BC) and failed to develop an antileukemic response despite grade 3 graft-versus-host disease (GvHD). Complete hematologic, cytogenetic and molecular responses were achieved within 9 weeks of therapy and are maintained after 27 months. Extensive chronic skin GvHD necessitating immunosuppressive therapy developed after 14 months. This case illustrates the ability of imatinib to induce sustained hematologic and molecular remissions in some patients relapsing with advanced stage CML after alloSCT.