Population pharmacokinetics of total and unbound teicoplanin concentrations and dosing simulations in patients with haematological malignancy.

Objectives: To develop a pharmacokinetic model describing total and unbound teicoplanin concentrations in patients with haematological malignancy and to perform Monte Carlo simulations to evaluate target attainment of unbound trough concentrations with various dose regimens. Methods: This was a hospital-based clinical trial (EudraCT 2013-004535-72). The dosing regimen was 600/800 mg q12h for three doses then 600/800 mg daily. Serial total and unbound teicoplanin concentrations were collected. Maximum protein binding was estimated from serum albumin concentration. Population pharmacokinetic analyses and Monte Carlo simulations were conducted using Pmetrics®. Target total and unbound trough concentrations were ≥20 and ≥1.5 mg/L, respectively. Results: Thirty adult patients were recruited with a mean (SD) bodyweight of 69.1 (15.8) kg, a mean (SD) CLCR of 72 (41) mL/min and a median (IQR) serum albumin concentration of 29 (4) g/L. A three-compartment complex binding pharmacokinetic model best described the concentration-time data. Total and unbound teicoplanin concentrations were related by serum albumin concentration and a dissociation constant. CLCR and bodyweight were supported as covariates for CL and volume of the central compartment, respectively. Dosing simulations showed that high CLCR was associated with reduced probability of achieving target total and unbound trough concentrations. Low serum albumin concentration was associated with a reduced probability of attaining target total but not unbound trough concentrations. A method to estimate the unbound teicoplanin concentration from the measured total concentration at different serum albumin concentration was demonstrated. Conclusions: Standard teicoplanin dosing regimens should be used with caution in patients with haematological malignancy. Bodyweight, CLCR and serum albumin concentration are important considerations for appropriate dosing.

Clinical outcomes and a high prevalence of abnormalities on comprehensive arterial and venous thrombophilia screening in TIA or ischaemic stroke patients with a patent foramen ovale, an inter-atrial septal aneurysm or both.

INTRODUCTION: Data are limited on the optimal management of cryptogenic TIA/stroke patients with a patent foramen ovale (PFO)±inter-atrial septal aneurysm (IASA), especially with an inherited thrombophilia. METHODS: Prospectively-collected data on TIA/ischaemic stroke patients with PFO, IASA or both who received 'goal-directed secondary-prevention medical treatment' were analysed. All patients had trans-oesophageal echocardiography, anti-nuclear, anti-cardiolipin, anti-beta 2 glycoprotein I antibodies, rheumatoid factor, lupus anticoagulant, protein C&S, anti-thrombin, factor VIII activity, activated protein C resistance, Factor V Leiden, prothrombin gene and MTHFR-c.677C>T mutation screening. ENA and homocysteine were assessed in the latter study period. RESULTS: Eighty-three patients were recruited. Mean follow-up: 48.1months. Forty-seven patients (56.6%) had an isolated PFO, 32 (38.6%) a PFO and an IASA, and 4 (4.8%) an IASA alone. Eighteen (21.7%) had ≥1 abnormality on thrombophilia screening. The most important abnormalities which lead to treatment changes in 11 patients (13.3%) were primary anti-phospholipid syndrome (N=3; 3.6%), protein S deficiency (N=2; 2.4%) hyper-homocysteinaemia (N=6/72 screened, 8.3%). Four patients (4.8%) opted for PFO closure: two with protein S deficiency, and two with no identified thrombophilia. Seven (8.4%) had recurrent TIA/ischaemic stroke during follow-up (overall annualised incidence: 2.1%), of whom five had a PFO alone and two a PFO and IASA. DISCUSSION: Comprehensive arterial and venous thrombophilia screening is warranted in TIA/ischaemic stroke patients with a PFO±IASA, is conclusively abnormal in over a fifth, and informed important decision-making regarding individualised therapy in 13.3% of patients. The incidence of recurrent vascular events in this population is low on optimal, personalised secondary-prevention treatment, even with an underlying thrombophilia.

Variability in Trough Total and Unbound Teicoplanin Concentrations and Achievement of Therapeutic Drug Monitoring Targets in Adult Patients with Hematological Malignancy.

The objective of this study was to explore the following aspects of teicoplanin use in patients with hematological malignancy: early attainment of target trough concentrations with current high-dose teicoplanin regimens, variability in unbound teicoplanin fractions, factors associated with observed total and unbound trough concentrations, efficacy and toxicity, and renal function estimation. This was a single-center, prospective study. Samples for determination of trough concentrations were taken on days 3, 4, 7, and 10. Total and unbound teicoplanin concentrations were determined using validated high-performance liquid chromatography methods. Regression analyses were used to identify the factors associated with the trough concentration. Thirty teicoplanin-treated adults with hematological malignancy were recruited. Despite the use of dosages higher than the conventional dosages, the proportions of patients with a trough concentration of ≥20 mg/liter at 48 h and at 72 h were 16.7% and 37.9%, respectively. Renal function was significantly negatively associated with total trough concentrations at 48 h and 72 h (P < 0.05). For an average hematological malignancy patient (creatinine clearance = 70 ml/min), sequential loading doses of at least 12 mg/kg of body weight may be needed to achieve early adequate exposure. In the absence of measured creatinine clearance, estimates obtained using the Cockcroft-Gault (total body weight) equation could prove to be an acceptable surrogate. The unbound fractions of teicoplanin were highly variable (3.4 to 18.8%). Higher unbound fractions were observed in patients with low serum albumin concentrations. Teicoplanin was well tolerated. Teicoplanin loading doses higher than those in current use appear to be necessary. Increased dosing is needed in patients with increased renal function. The high variability in protein binding supports the contention for therapeutic drug monitoring of unbound teicoplanin concentrations. (This study has been registered with EudraCT under registration no. 2013-004535-72.).

A review of therapy-related myelodysplastic syndromes and acute myeloid leukaemia (t-MDS/AML) in Irish patients: a single centre experience.

OBJECTIVES: To demonstrate the incidence, characteristics, treatment and outcomes of patients with therapy-related myelodysplastic syndromes and therapy-related acute myeloid leukaemia (t-MDS/AML) in a tertiary referral centre. METHODS: Patients meeting the diagnostic criteria for t-MDS/AML from 2003 to 2014 were reviewed to analyse their diagnostic features, details of antecedent disorder and treatment, approach to management and survival. RESULTS: 39 patients who developed t-MDS/AML were identified with incidence of 8.7%. Median age and gender distribution were similar to de novo MDS but t-MDS/AML patients had greater degree of cytopenia and adverse karyotypes. Time to development of t-MDS/AML was shortest for patients with antecedent haematological malignancy compared to solid tumours and autoimmune disorders (46, 85 and 109 months). Patients with prior acute leukaemia had the shortest latency and poor overall survival. Treatment options included best supportive care (56%), Azacitidine (31%) or intensive chemotherapy/allogeneic transplant (13%). Median OS of all patients was 14 months. Survival declined markedly after two years and 5-year OS was 13.8%. Longer survival was associated with blast count <5% at diagnosis, previous haematological disorder, lower risk IPSS-R and a normal karyotype. Four out of five patients who received intensive therapy/transplant remain alive with median OS of 14 months. Median OS of Azacitidine-treated group was 11 months. DISCUSSION: t-MDS/AML patients showed unique characteristics which influenced their treatment and outcomes. IPSS-R may be useful in risk-adapted treatment approaches and can predict outcomes. Survival remains poor but improved outcomes were seen with allogeneic transplantation. Azacitidine may be effective in patients unfit for intensive therapies.

Teicoplanin use in adult patients with haematological malignancy: Exploring relationships between dose, trough concentrations, efficacy and nephrotoxicity.

In 2010, our hospital introduced a higher target teicoplanin trough concentration of ≥20 mg/L by Day 3 for haematological malignancy patients. This study aimed to explore whether target trough concentrations were achieved, to identify factors associated with trough concentrations attained, and to assess clinical efficacy with teicoplanin treatments and nephrotoxicity. This was a retrospective, single-centre, cohort study of 172 teicoplanin treatments in 104 adults with haematological malignancy. Mixed-effects regression was used to evaluate factors affecting trough concentrations, and logistic regression was used to assess the relationship between trough concentrations and treatment outcomes. Nephrotoxicity was assessed using the RIFLE criteria. Considerable variability in trough concentrations was observed, with trough concentrations ≥20 mg/L rarely achieved early in therapy. A mixed-effects regression model explaining 52% of the variation in trough concentrations was developed. Dose and day of therapy were positively associated with trough concentration, whilst estimated renal function and, interestingly, acute myeloid leukaemia diagnosis were negatively associated (P<0.05). Results suggested a positive relationship between trough concentration and the likelihood of a favourable outcome for coagulase-negative staphylococcal central line-associated bloodstream infections. Elucidation of a specific target concentration requires further investigation. Teicoplanin was well tolerated renally. Findings suggest a risk of underexposure if conventional teicoplanin doses are used in haematological malignancy patients. Given the variability in trough concentrations observed, the identified factors affecting trough concentrations attained and the suggested link with clinical outcome, individualised initial dosing followed by therapeutic drug monitoring is recommended to ensure early adequate exposure in this vulnerable patient group.

A multi-centre retrospective study of rituximab use in the treatment of relapsed or resistant warm autoimmune haemolytic anaemia.

This retrospective analysis assessed the response, safety and duration of response to standard dose rituximab 375 mg/m(2) weekly for four weeks as therapy for patients with primary or secondary warm autoimmune haemolytic anaemia (WAIHA), who had failed initial treatment. Thirty-four patients received rituximab for WAIHA in seven centres in the Republic of Ireland. The overall response rate was 70·6% (24/34) with 26·5% (9/34) achieving a complete response (CR). The time to response was 1 month post-initiation of rituximab in 87·5% (21/24) and 3 months in 12·5% (3/24) of patients. The median duration of follow-up was 36 months (range 6-90 months). Of the patients who responded, 50% (12/24) relapsed during follow up with a median time to next treatment of 16·5 months (range 6-60 months). Three patients were re-treated with rituximab 375 mg/m2 weekly for four weeks at relapse and responded. There was a single episode of neutropenic sepsis. Rituximab is an effective and safe treatment for WAIHA but a significant number of patients will relapse in the first two years post treatment. Re-treatment was effective in a small number of patients, suggesting that intermittent pulse treatment or maintenance treatment may improve long-term response.

An assessment of the utility of unselected coagulation screening in general hospital practice.

Coagulation screening using prothrombin time (PT) and activated partial thromboplastin time (APTT) is widely used. We performed an audit of coagulation screening in an Irish teaching hospital. We analysed PT and/or APTT results received during normal working hours during a 1-week period in our hospital. Abnormal results due to anticoagulants were excluded from further study. In samples with PT longer than 15.5 s and/or APTT longer than 42 s, we proceeded to 1: 1 mixing studies if the PT was prolonged and 1: 1 mixing studies, factor XII assay and lupus screen if the APTT was prolonged. We also obtained referral source for all samples and clinical details for abnormal samples. Six hundred and seventy-one coagulation requests were received during the study period. Three hundred and eighteen of 671 (47.4%) coagulation requests were for monitoring of anticoagulation. Three hundred and fifty-three of 671 (52.6%) requests were for coagulation screening rather than anticoagulant monitoring. In the coagulation screens received, PT was prolonged in 19 of 353 (5.4%). PT was longer than 20 s in four of 353 cases (1.1%). APTT was prolonged in 19 of 353 (5.4%). APTT was longer than 50 s in four of 353 (1.1%). No patients with abnormal PT or APTT had any bleeding sequelae during the study period. Unregulated coagulation screening has a low yield of abnormal results; the majority of these abnormal results show mild prolongation of PT or APTT with no evidence that they are associated with an increased bleeding risk.