Evaluation of a closed-system cytotoxic transfer device in a pharmaceutical isolator.

PURPOSE: The occupational risk associated with handling of cytotoxic anticancer drugs is well documented and, in many countries, pharmaceutical isolators are used to contain cytotoxic residues during preparation of cytotoxic infusions. Isolators are difficult to clean leading to concerns that cytotoxic contamination from the work area could be transferred to surfaces of products leaving the isolator. This study investigated the surface contamination arising from the preparation of five anticancer drug infusions (Epirubicin, Fluorouracil, Cisplatin, Oxaliplatin and Carboplatin) in a pharmaceutical isolator and compared use of a conventional syringe and needle technique with a closed-system drug transfer device (CSDTD). METHODS: Wipe samples were taken over 1 week from pre-defined areas in the isolator, gloves, preparation mats, and also from the surfaces of prepared cytotoxic infusion bags and pre-filled syringes to obtain baseline surface contamination data. Following operator familiarisation, the CSDTD was then introduced and sampling repeated for a further week (intervention period). The samples obtained were analysed using validated HPLC-UV, HPLC-FL and ICP-MS techniques, as appropriate. RESULTS: All surfaces sampled during baseline, including external surfaces of infusions and syringes, were contaminated with each marker drug. During the intervention phase, isolator surfaces were free from detectable contamination and the contamination measured on gloves, preparation mats and surface of infusions was markedly reduced. The frequency of contamination on syringe and infusion surfaces was also lower. CONCLUSION: Surface contamination from cytotoxic infusion preparation in a pharmaceutical isolator was significant and could transmit cytotoxic residues to patient and public areas via infusion surfaces. The frequency and amount of contamination were reduced by the CSDTD.

A national survey investigating UK prescribers' opinions on chemotherapy dosing and 'dose-banding'.

AIMS: The primary purpose of dose-banding for cancer chemotherapy is to reduce patient waiting times, but dose-banding also has additional benefits, such as reduced drug wastage, reduced stress for staff, and prospective quality control of infusions. However, the uptake of dose-banding seems fairly low. Possible reasons for this are a reluctance to use dose-banding for clinical reasons or a lack of awareness. Despite the seemingly minor change from established practice of dose preparation, dose-banding has the potential to alter patient chemotherapy exposure. The aim of this study was to investigate prescribers' awareness of dose-banding and their opinions on the scope and limitations of dose-banding in the context of UK chemotherapy services. MATERIALS AND METHODS: This survey was performed throughout the UK by use of a postal questionnaire, which was validated before national distribution to 1104 oncologists and haematologists. The questionnaire contained both quantitative and qualitative elements. A database was created for data entry and analysis. RESULTS: The response from prescribers was encouraging for a postal questionnaire, with a 35% response rate (387 responses). Many were aware of the concept of dose-banding (>80%) and were also supportive of the system. The weakness around body surface area-based dosing was a commonly discussed topic. However, opinions on which is the maximum acceptable deviation from the prescribed dose with dose-banding were controversial, and there was a concern about the lack of evidence to support the use of dose-banding. The views on whether carboplatin and targeted therapies should be dose-banded were also divided. CONCLUSIONS: There was general support for dose-banding, but concerns about the lack of an evidence base could be a barrier to the wider introduction of the system. Consequently, more clinical studies are required to justify the safety and efficacy of dose-banding, and also to evaluate whether dose-banding is acceptable within clinical trials.

Chemotherapy dosing part II: alternative approaches and future prospects.

This overview follows on from part I, which described the current practices used in chemotherapy dosing and the paucity of scientific evidence to support them. In part II, alternative approaches are discussed, both in terms of scientific rationale and practical application. These include therapeutic drug monitoring, the use of pharmacokinetic-pharmacodynamic relationships, flat-fixed dosing, Bayesian modelling and dose banding.

Chemotherapy dosing part I: scientific basis for current practice and use of body surface area.

Cytotoxic chemotherapy is characterised by a low therapeutic index and significant variability in therapeutic and toxic effects. In an attempt to reduce this variability, most chemotherapy doses are individualised according to patient body surface area (BSA). This practice, which was introduced almost 50 years ago, clearly has practical and economic implications for the healthcare system. Furthermore, the clinical value of this approach has, in recent years, been questioned. Despite established practice, chemotherapy dose selection remains complicated, partly because treatment effects are difficult to measure, partly because drugs are used in combination with other treatment modalities, and also because the patient's condition may change with disease progression. Various patient-related factors can affect drug pharmacokinetics (PK) and pharmacodynamics (PD), for example organ function, expression and activity of metabolising enzymes, drug resistance, body size, gender, age, concomitant disease and co-administration of other drugs. These factors may be of clinical significance in chemotherapy dose determination and measures of PK, PD or both feature in attempts to devise more rigorous methods for chemotherapy dosing. Part I of this series of two reviews describes the history and clinical impact of BSA-based chemotherapy, and examines the scientific evidence to support BSA dosing. It evaluates the factors affecting PK and PD for specific drugs that could inform and refine dose determination.

Stability of intravesical epirubicin infusion: a sequential temperature study.

OBJECTIVE: To investigate the stability of epirubicin bladder instillation, prepared from two different epirubicin formulations, under refrigerated storage, transportation and clinical use conditions. METHOD: A sequential study design was used. Epirubicin instillation (1 mg/mL) in polypropylene syringes was sequential incubated for periods of 84 days at 8 degrees C followed by 2 h at 25 degrees C and 1 h at 37 degrees C, the latter two temperatures replicating transport and intravesical conditions, respectively. RESULTS: The instillation was both chemically and physically stable under those incubation conditions. The formulation of epirubicin used to prepare the instillation infusions did not affect stability.

Novel liquid chromatographic assay for the low-level determination of apomorphine in plasma.

A novel HPLC assay which is rapid, reproducible and sensitive has been developed for the analysis of apomorphine in plasma. The assay incorporates boldine as an internal standard, and uses solid-phase extraction on C18 mini-columns for sample clean-up and concentration, so enabling quantitation of apomorphine at 500 pg/ml using fluorescence detection (lambda(ex) 270 nm, lambda(em) 450 nm). The HPLC assay comprised a 25 cm-long Techopak C18 column and a mobile phase of (0.25 M sodium dihydrogen phosphate plus 0.25% heptane sulphonic acid, to pH 3.3 with orthophosphoric acid) containing 30% (v/v) methanol and 0.003% (w/v) EDTA, run at a flow-rate of 1.5 ml/min. Calibration plots prepared in plasma were linear over the range 1-30 ng/ml, (limit of quantitation (LOQ) = 490 pg/ml) with R.S.D. of 0.05% and R.E. of 5.0% at the level of 1 ng/ml. Preliminary pharmacokinetic data from two patients given apomorphine by 12 h subcutaneous infusion (patient A dose = 35 mg and patient B dose = 141 mg) showed apomorphine elimination from plasma to fit a two-compartment model, with initial half-lives of 8.2 and 46.6 min, elimination half-lives of 76.4 and 166.5 min and area under the plasma concentration-time curve (AUC) values of 236 and 405 ng h/ml, respectively.

Practical guides. II: Hospital pharmacy quality control services.

This article briefly reviews the evolution, scope and operation of hospital quality control (QC) services. Recent initiatives and developments are considered alongside the traditional 'core' QC/quality assurance (QA) work. Important new areas of work which could benefit from QC involvement are also discussed.

Improved LC assay for the determination of mitozantrone in plasma: analytical considerations.

Preliminary method development studies on mitozantrone (MTZ) revealed a number of characteristics which were found to be important in the analysis of patient samples for pharmacokinetic studies. MTZ rapidly bound to glass, particularly at low concentrations (< 10 ng ml-1), necessitating the use of silanized glassware or polypropylene tubes for the handling of all solutions containing MTZ. MTZ was also found to react with two commonly-used antioxidants; sodium metabisulphite and EDTA. However, solutions containing MTZ were found to be stabilized by the addition of ascorbic acid (0.5% w/v). In the absence of ascorbic acid, MTZ underwent rapid, biphasic degradation in plasma at 24 and 37 degrees C, with terminal half-lives of approximately 70 h. Ascorbic acid (0.5% 2/v) was found to stabilize plasma samples containing MTZ throughout work-up procedures and during frozen storage. The addition of ascorbic acid to the sample collection vial was also necessary to prevent MTZ degradation in the eluting solvent of the solid-phase extraction system. Another important consideration was the requirement for an equilibration period of > 5 min after the addition of ametantrone (AM) internal standard to plasma samples. This was essential, since the slope of the calibration plot obtained using non-equilibrated plasma was approximately 30% of that obtained for calibration plots using equilibrated plasma, and would result in erroneous determination of MTZ plasma concentrations. The fully developed assay was rapid, precise and sensitive (relative errors at 1 ng ml-1 = 2.3%). MTZ concentrations determined using the LC method described in this report correlated well with an independently developed ELISA technique (r = 0.995, n = 20).

Stability studies on admixtures of 5-fluorouracil with carboplatin and 5-fluorouracil with heparin for administration in continuous infusion regimens.

The therapeutic index of several anticancer agents may be improved by replacing rapid infusion/bolus injection schedules with prolonged continuous infusion regimens. Admixtures of 5-fluorouracil (5FU) with carboplatin and 5FU with heparin were subjected to stability studies to establish the feasibility of administering these infusions on an in-patient and out-patient basis, respectively. In the first study the stability of carboplatin was determined in an admixture of carboplatin and 5FU for neoadjuvant treatment of in-patients with oesophageal carcinoma by 5-day infusion. A previous study had reported significant carboplatin degradation in 5FU/carboplatin admixtures. Our results were consistent with this study and demonstrated that under ward conditions (25 degrees C) carboplatin also degraded (16% in 24 h) in dilute admixtures with 5FU. However, the addition of a citric acid buffer, which reduced infusion pH from 8.65 to 6.5, increased the stability of carboplatin (4.8% degradation in 24 h), without compromising 5FU solubility or stability. In a second study, the stability of an infusion containing 5FU and heparin was determined. Prolonged continuous infusion is routinely used for adjuvant treatment of colorectal carcinoma but episodes of thromboses and occlusion of the central venous catheter have been associated with this treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

The stability of carboplatin, diamorphine, 5-fluorouracil and mitozantrone infusions in an ambulatory pump under storage and prolonged 'in-use' conditions.

Drug infusions can be exposed for prolonged periods to 'in-use' conditions where the temperature of an infusion in a holster-worn infusion pump may reach 37 degrees C. In this study, the stability of three cytotoxic drug infusions (carboplatin, 5-fluorouracil and mitozantrone) and one analgesic infusion (diamorphine HCl) was determined in Parker Micropump medication reservoirs under refrigerated storage and prolonged in-use conditions. The stability of the three cytotoxic drug infusions was unaffected by 14 days storage at either 4 or 37 degrees C. The diamorphine HCl infusion was stable over 14 days storage at 4 degrees C but under in-use conditions at 37 degrees C, drug degradation became significant (greater than 5%) if storage exceeded 7 days.

General practice theophylline audit in the Exeter Health District.

The serum theophylline concentration was determined in 150 asthmatic patients who received treatment from General Practitioners in the Exeter Health District. The serum theophylline concentration was below the therapeutic range in 75% of the patients evaluated. There was no correlation between serum concentration and daily dose, even when the latter was calculated with respect to bodyweight or body surface area. It was concluded that a theophylline Therapeutic Drug Monitoring (TDM) service should be available for general practice patients.

Qualitative studies on alpha-interferon-2b in prolonged continuous infusion regimes using gradient elution high-performance liquid chromatography.

The treatment of home-based cancer patients with continuous infusion chemotherapy requires that complete courses of medication in pre-filled syringes are provided on an out-patient basis. The infusion must remain stable prior to use during refrigerated storage (up to 14 days) and during infusion from holster-worn ambulatory infusion pumps where the temperature of the infusion can reach 37 degrees C. In this study, polypropylene syringes containing interferon alpha-2b infusion (3 mega units in 6 ml) were stored at 4 degrees C. The infusion was analysed during storage by a qualitative gradient-elution high-performance liquid chromatography procedure. Over 14 days storage at 4 degrees C or 24 h storage at 37 degrees C, chromatographic changes occurred indicating interconversion between interferon monomers and possibly oligomer formation. Until further studies are completed we consider interferon alpha-2b unsuitable for inclusion in our home oncology programme.

The formulation and stability of a unit-dose oral vitamin K1 preparation.

A unit-dose oral vitamin K1 solution (1 mg ml-1) was developed for administration to neonates as prophylaxis against early haemorrhagic disease of the new-born. Previously, a multidose oral-drop solution was prepared from sterile ampoules of vitamin K1 injection (10 mg ml-1). The unit-dose preparation enabled accurate and convenient dose delivery and was more economical than the multidose solution. Furthermore, the preparation of sterile, single-dose units enabled the elimination of potentially harmful preservatives from the formulation. The unit-dose preparation was shown to be stable for 6 months under refrigerated storage conditions.

The stability of carboplatin in ambulatory continuous infusion regimes.

Several anti-cancer agents are administered by continuous infusion in an attempt to improve the therapeutic index obtained with solid tumours. In Exeter this approach, combined with the use of ambulatory infusion pumps, forms the basis of a home oncology programme in which a complete course of medication in pre-filled syringes is supplied on an out-patient basis. It is essential to ensure that the drug remains stable during storage prior to use and also during infusion where the temperature of the drug solution in a holster-worn ambulatory pump can reach 37 degrees C. In this study the stability of a carboplatin infusion (20 mg in 2 ml) in pre-filled syringes under storage and in-use conditions was determined using a stability-indicating HPLC assay. There was no loss of carboplatin from pre-filled syringes stored at 4 degrees C for 5 days. At 37 degrees C, the loss of carboplatin was 3.1% over 24 h.

Analysis of hospital-formulated oral liquid preparations by second derivative ultraviolet spectroscopy.

Second derivative ultraviolet spectrophotometric methods have been devised for the analysis of hospital-formulated oral liquid preparations. These rapid techniques are useful in the routine quality control of oral liquid formulations where direct spectrophotometric determination of the drug analyte is precluded by interference from formulation excipients and colouring agents. This report describes examples in which the active principles of a dipipanone mixture, a methadone mixture and an orphenadrine syrup were determined by derivative spectroscopy. In each case spectral interference from formulation excipients was abolished. The accuracy, precision and specificity of each method has been established.