Author(s)

VERA DOMINGOS, VERA PIRES, SÍLVIA SANTOS, PATRÍCIA TRINDADE, ANA INÁCIO, ELZA CANDEIAS, SUSANA SIMÕES, PAULO PAIXÃO, NUNO MIRANDA, ANTÓNIO GOUVEIA

Why was it done?

Personalized BU dosing is considered because BU has a narrow therapeutic index and exposure have been associated with important clinical outcomes. High exposures have been associated with an increased risk of toxicities (acute graft-versus-host disease and veno-occlusive disease) and low exposures with graft rejection and relapse.
For this reason, in a multidisciplinary working group, we identified an opportunity to improve the treatment of your patients.

What was done?

Implementation of a TDM procedure for Busulfan (BU) in conditioning therapy for hematopoietic stem cell transplantation (HSCT). Study variability in PK parameters and evaluate TDM efficacy. From this initial period, we perform TDM on all patients under Bu conditioning.

How was it done?

The steps followed were:
1. Pre-implementation: bibliographic research, identify reference centers to perform BU plasma assay. Development and validation of a LC-MS / MS method by the National Institute of Forensic Medicine. PK analysis using ADAPT-5 software.
2. Pilot: Trial and assess the feasibility of the procedure. Cross-validation of the results with UMC Utrecht.
3. Implementation: clinical practice, doing the necessary dose adjustments. Prospective collection of clinical and PK data.

The main obstacle is the lack of analytical methodology in our center and the turnaround time.

What has been achieved?

We performed a preliminary analysis with 21 patients. Mean clearance (CL) was 0,19L/h*kg±0,05L/h*kg and volume of distribution 0,65L*kg±0,22L*kg. Body weight was the most predictive covariance.
CL was significantly different between patients 10 years old (p = 0,024) and over treatment (p=0,0191). The type of conditioning regimen didn’t show relation with the BU CL (p=0,0514).
TDM increased the number of patients with an optimal exposure (target AUC ±10%) from 42% to 83%.Dose was reduced in 10 patients (max 37%) and increased in 3 (max 19%). 1 patient maintained the prescribed dose.

What next?

TDM increased significantly the number of patients with optimal exposure to BU.
This procedure is pioneer at a national level and it relies on a strict protocol which includes collaboration with several hospital departments and other highly-specialized external centers. This can be used as a tool for other drugs and to empower the pharmacist as an active agent in the clinical setting.

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Why was it done?

Chemotherapies are generally prescribed and produced as a function of Body Surface Area (BSA). The most recent literature recommends that marketed drugs continue to use BSA-based dosing supported by clinical evidence. If not, it recommends DB with adjustments for other important parameters.

What was done?

Determine which of the drugs compounded in our centralised chemotherapy production unit were potential candidates for dose banding (DB) for adults, whilst guaranteeing patient safety and meeting the needs of physicians, pharmacists and nurses.

How was it done?

The database of chemotherapy doses produced between 2010 and 2013 was analysed to define a Top 10 chart of the most common protocols and compounds. Dosage patterns were analysed and new bands were modelled using exponential calculus in order to aid in DB decision-making. Discussions with interdisciplinary teams and senior physicians took place in order to promote acceptance of the project and its deployment.

What has been achieved?

Oncology professionals requested an integration of bands into the electronic prescription system, the possibility to prescribe doses above those suggested using BSA and a maximum 5% margin of difference to the usual prescribed dose. They highlighted the necessity of maintaining “ready for administration” doses. For example, in 2013, 613 infusion bags of gemcitabine were produced in 111 different doses, ranging from 266 to 2900 mg. Following the new specifications, just two bands (2000 mg and 1805 mg) already fulfil 50% of annual production needs; producing five band doses streamlines 90% of annual production needs.

What next?

Chemotherapeutic doses can now be prepared in bands and the pharmacy activity can be rationalised by producing doses in batches. The imminent introduction of automation should ensure accuracy of the doses delivered. Future studies should examine product stability so that chemotherapy production planning becomes highly efficient.

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