The pharmacokinetics and pharmacodynamics of busulfan when combined with melphalan as conditioning in adult autologous stem cell transplant recipients.

Busulfan (Bu) is an alkylating agent widely used in conditioning regimes prior to stem cell transplantation (SCT), most commonly in combination with cyclophosphamide (Bu-cy) or fludarabine (Bu-flu) as myeloablative conditioning prior to allograft or with high-dose melphalan (Bu-mel) prior to autologous SCT. Despite many decades of Bu use, initially orally but now intravenously (IV), a paucity of pharmacokinetic (PK) and pharmacodynamic (PD) data exists to inform evidence-based guidelines as how best to balance the efficacy and toxicity of this agent. This is a non-randomized retrospective real-world study at three hospitals investigating the role of PK guidance in dosing Bu in the setting of IV Bu-mel autologous SCT. The primary intent was to examine how effectively PK assessment could be used to achieve a desirable drug exposure and to evaluate factors, particularly, age, sex, actual weight, body mass index (BMI), body surface area (BSA), disease, number of prior treatments, renal function, and the use of concomitant medications that may influence Bu exposure. All patients underwent PK analysis on a test dose of Bu (1.6 mg/kg, i.e., 50% of the first dose) on D-7 and subsequently received a second 1.6 mg/kg dose on D-6. Bu dose was calculated using actual body weight (ABW) if patients were less than ideal body weight (IBW), or adjusted ideal body weight (AIBW) if ABW was greater than IBW. Thereafter, at the discretion of the investigator, the group was divided into two; a weight-based cohort at two hospitals and a PK-guided cohort at the third hospital. Thirty-seven patients received PK-adjusted dosing guided by the results of the initial PK results, targeting a specific Bu exposure expressed as the area-under-the-concentration-versus-time curve (AUC) of between 4000 and 5000 µmol min/day (median 4800). The remaining 27 patients received unadjusted weight-based doses with a further three doses of 3.2 mg/kg of Bu infused over 180 min (D-5 to - 3) irrespective of their initial PK results. For the purposes of the analysis, we selected a target AUC of 4800 µmol min/day in this group, equivalent to the median targeted AUC in the PK-adjusted group. All patients subsequently had repeated PK analysis on D-5 after receiving their "therapeutic" Bu dose. Mel (140 mg/m2 or 100 mg/m2) IV was given on D-2. Sixty-four adult patients were enrolled. Patients who received PK-guided Bu dosing received a higher median Bu dose than the unadjusted weight-based cohort (3.5 mg/kg vs 3.2 mg/kg respectively, p = 0.007). Eighty-one percent (30/37) of patients in the PK-guided group achieved their target AUC (± 15%) compared with 56% (15/27) in the weight-based cohort (p = 0.027). The respective median AUCs of 5064 µmol min/day (range 3639-6157 µmol min/day) and 4854 µmol min/day (range 3251-6305 µmol min/day) were not significantly different (p = 0.16). Multivariate analysis identified ABW as the only independent variable that affected the relationship between Bu dosing and exposure (p = 0.02) with heavier patients achieving lower than anticipated AUCs for the dose they received. On D-5, within the weight-based cohort, the mean AUCs were 12% higher than anticipated based on initial D-7 PK. No correlation between AUC and grade 3-4 transplant-related toxicities were observed, although only three patients had AUCs > 6000 µmol min/day. These results suggest that PK-directed Bu dosing may be of benefit in achieving a target level of drug exposure, with larger studies needed to determine the clinical significance of this strategy.

Use of vemurafenib in a patient unable to swallow whole.

The treatment landscape for metastatic melanoma has increased dramatically in the past five years, with the pivotal discovery of activating BRAF mutations in half of all melanomas spurring the development for effective treatments that target mitogen-activated protein kinase (RAS/RAF/MEK/ERK) pathway. Vemurafenib, a selective mutant BRAF Val600 inhibitor, results in striking tumour responses and a survival advantage over conventional chemotherapy. We present here the case of a 38-year-old woman with metastatic BRAFV600E mutant melanoma and a severe tablet phobia, who was found to have been crushing and/or chewing her vemurafenib tablets. In this case, she attained a partial response and significant clinical benefit, albeit temporarily.

Dosing of antibiotics in obesity.

PURPOSE OF REVIEW: Obesity is becoming a major burden on healthcare systems worldwide. The management of infections is problematic due to both an increased risk of morbidity and mortality, as well as a lack of information about dosing of antibiotics in the obese population. Recommendations in this patient group are severely lacking, so clinicians need to consider pharmacokinetic/pharmacodynamic parameters and the relative risks of overdosing and underdosing. RECENT FINDINGS: Since 2011, articles on a number of antibiotics have been published, including cefazolin/cephazolin, cefepime, cefoxitin, clindamycin, cotrimoxazole, daptomycin, ertapenem, levofloxacin, linezolid, meropenem, moxifloxacin, piperacillin/tazobactam and vancomycin. SUMMARY: Obesity causes a number of changes, including an increase in volume of distribution and changes in hepatic metabolism and renal excretion. Several antibiotics have sufficient data to be able to make recommendations, whereas other antibiotics may need to make use of doses at the upper end of the recommended range, or utilize other dose modifications based on pharmacokinetic/pharmacodynamic parameters, in an attempt to reach adequate levels and achieve similar efficacy.

Carmustine infusion reactions are more common with rapid administration.

PURPOSE: Carmustine is a nitrosurea alkylating agent predominantly used at Peter MacCallum Cancer Centre as part of the autologous stem cell transplant induction regimens Stanford BCNU and BEAM. Acute infusion reactions were anecdotally reported to be higher than the reported rates of 10%, and it was suggested that the rate of infusion being employed was excessive. Some references suggest maximum infusion rates of 3 mg/m(2)/min for carmustine, a rate which is exceeded in the 2-h infusions used for Stanford BCNU, but not with BEAM. METHODS: A retrospective audit was conducted in 64 patients (57 Stanford BCNU, 7 BEAM) who had received these regimens between January 2009 and November 2010. RESULTS: Rates of infusion reaction to carmustine were higher than literature values, with reactions in Stanford BCNU (94.7%) being significantly higher than for BEAM (28.6%; P = 0.0003). These findings have resulted in a change of administration of carmustine in Stanford BCNU from 2 to 3 h. Further studies plan to compare the incidence of infusion reactions before and after the change in administration rates. CONCLUSION: Patients receiving rapid infusion of carmustine in the Stanford BCNU regimen for stem cell conditioning have a high rate of infusion reaction. A maximum rate of 3 mg/m(2)/min is recommended.