Busulfan exposure target attainment in adults undergoing allogeneic hematopoietic cell transplantation: a single day versus a multiple day therapeutic drug monitoring regimen.

BACKGROUND: Busulfan exposure has previously been linked to clinical outcomes, hence the need for therapeutic drug monitoring (TDM). OBJECTIVE: Study objective was to evaluate the effect of day 1 TDM-guided dosing (regimen d1) versus days 1 + 2 TDM-guided dosing (regimen d1 + 2) on attaining adequate busulfan exposure. STUDY: Design In this observational study, we included all adults who received an allogeneic HCT with intravenous once daily busulfan over 4 days as part of the conditioning regimen at the University Medical Centre Utrecht or between July 31th 2014 and November 12th 2021. The primary outcome was attainment of the therapeutic busulfan target (cumulative area under the curve [AUCcum] 80-100 mg*h/L). Dose adjustment was based on the estimated AUC of the preceding dosing day(s). Additional TDM was performed in the event of large dose adjustments (≥25%). The choice of TDM regimen was solely based on the first day the busulfan dose was administered (regimen d1+2 occurred when conditioning started on a Saturday). In all patients, blood sampling was performed on day 4 for evaluation. The AUCcum was estimated using a validated population pharmacokinetic model. Busulfan target exposure was compared between both TDM regimen groups using a propensity score adjusted logistic regression model. The variance in the AUCcum between the TDM regimens was compared using the F-test. Patients were stratified for age (categorical). RESULTS: In regimen d1, 87.6% (n = 113/129) attained a therapeutic busulfan exposure, while in regimen d1 + 2 a proportion of 97.4% was found (n = 74/76, adjusted odds ratio for non-therapeutic AUC = 0.19, 95% confidence interval 0.04-0.89). Variance of busulfan exposure in the regimen d1 group (SD = 6.8 mg*h/L) differed significantly from the variance in the regimen d1 + 2 group (SD = 3.6 mg*h/L, F-test, p < 0.001). CONCLUSION: Performing busulfan TDM on both day 1 and day 2, rather than only on day 1, improves busulfan target exposure attainment in adults undergoing HCT, provided that subsequent TDM is carried out if required.

Busulfan target exposure attainment in children undergoing allogeneic hematopoietic cell transplantation: a single day versus a multiday therapeutic drug monitoring regimen.

Busulfan exposure has previously been linked to clinical outcomes, hence the need for therapeutic drug monitoring (TDM). Study objective was to evaluate the effect of day 1 TDM-guided dosing (regimen d1) versus days 1 + 2 TDM-guided dosing (regimen d1 + 2) on attaining adequate busulfan exposure. In this observational study, we included all children receiving busulfan-based allogeneic hematopoietic cell transplantation. Primary outcome was the percentage of patients achieving busulfan target attainment in both TDM regimens. Secondary outcomes were the variance in busulfan exposure and day-4 clearance (Clday4) estimates between both TDM regimens and dosing day 1 and 2. In regimen d1, 84.3% (n = 91/108) attained a therapeutic busulfan exposure, while in regimen d1 + 2 a proportion of 90.9% was found (n = 30/33, not-significant). Variance of Clday4 estimate based on busulfan day 2 concentrations was significantly smaller than the variance of Clday4 estimates based on day 1 concentrations (p < 0.001). Therefore, day 1-guided TDM (pharmacometric model-based) of busulfan may be sufficient for attaining optimal target exposure, provided that subsequent TDM is carried out if required. However, performing TDM on subsequent days may be beneficial, as measurements on day 2 seemed to reduce the variance in the estimated clearance as compared to day 1 sampling.

Nature and frequency of prescription modifications in community pharmacies: A nationwide study in the Netherlands.

AIMS: To investigate the nature and frequency of prescription modifications in Dutch community pharmacies. METHODS: In this cross-sectional study, Dutch community pharmacists documented prescription modifications in their pharmacy during 1 predetermined day. Pharmacists from all Dutch community pharmacies were invited to participate. A prescription modification was defined as any modification in a prescription for a medicine or other healthcare product because of an administrative problem, logistic issue or potential drug-related problem (DRP). All documented modifications were assessed to establish the nature and frequency of prescription modifications. RESULTS: Pharmacists in 275 pharmacies completed the study. A modification was performed in 5.5% of all prescriptions. 1.3% of the prescriptions contained an administrative problem, of which insufficient specification of the dosing regimen was most common (63.1%). A modification was performed due to a logistic issue in 2.4% of the prescriptions. The most frequently recorded issues were unavailability of medication (40.9%) and obligatory product substitutions due to reimbursement policies (33.2%). A modification was performed in 1.8% of the prescriptions to solve or prevent potential DRPs. Of these, 69.2% was potentially clinically relevant according to the pharmacist concerned. The most frequently prevented potential DRP was an incorrect strength or dose (31.9%). CONCLUSION: Dutch community pharmacists modified almost 1 in 20 prescriptions per pharmacy. The nature of the modifications reflects current community pharmacy practice, in which pharmacists frequently deal with logistic issues and intervene to solve or prevent for DRPs several times a day. The majority of the DRPs were considered to be potentially clinically relevant.