Joseph S. Bubalo

Safety and efficacy of a multicenter study using intraarterial chemotherapy in conjunction with osmotic opening of the blood-brain barrier for the treatment of patients with malignant brain tumors.

The aim of this study was to determine the safety and efficacy of intraarterial chemotherapy with osmotic opening of the blood‐brain barrier (BBB) for the treatment of malignant brain tumors when administered across multiple centers.

Daptomycin Pharmacokinetics in Adult Oncology Patients with Neutropenic Fever

ABSTRACT Daptomycin is the first antibacterial agent of the cyclic lipopeptides with in vitro bactericidal activity against gram-positive organisms, including vancomycin-resistant enterococci, methicillin-resistant staphylococci, and glycopeptide-resistant Staphylococcus aureus. The pharmacokinetics of daptomycin were determined in 29 adult oncology patients with neutropenic fever. Serial blood samples were drawn at 0, 0.5, 1, 2, 4, 8, 12, and 24 h after the initial intravenous infusion of 6 mg/kg of body weight daptomycin. Daptomycin total and free plasma concentrations were determined by high-pressure liquid chromatography. Concentration-time data were analyzed by noncompartmental methods. The results (presented as means ± standard deviations and ranges, unless indicated otherwise) were as follows: the maximum concentration of drug in plasma (Cmax) was 49.04 ± 12.42 μg/ml (range, 21.54 to 75.20 μg/ml), the 24-h plasma concentration was 6.48 ± 5.31 μg/ml (range, 1.48 to 29.26 μg/ml), the area under the concentration-time curve (AUC) from time zero to infinity was 521.37 ± 523.53 μg·h/ml (range, 164.64 to 3155.11 μg·h/ml), the volume of distribution at steady state was 0.18 ± 0.05 liters/kg (range, 0.13 to 0.36 liters/kg), the clearance was 15.04 ± 6.09 ml/h/kg (range, 1.90 to 34.76 ml/h/kg), the half-life was 11.34 ± 14.15 h (range, 5.17 to 83.92 h), the mean residence time was 15.67 ± 20.66 h (range, 7.00 to 121.73 h), and the median time to Cmax was 0.6 h (range, 0.5 to 2.5 h). The fraction unbound in the plasma was 0.06 ± 0.02. All patients achieved Cmax/MIC and AUC from time zero to 24 h (AUC0-24)/MIC ratios for a bacteriostatic effect against Streptococcus pneumoniae. Twenty-seven patients (93%) achieved a Cmax/MIC ratio for a bacteriostatic effect against S. aureus, and 28 patients (97%) achieved an AUC0-24/MIC ratio for a bacteriostatic effect against S. aureus. Free plasma daptomycin concentrations were above the MIC for 50 to 100% of the dosing interval in 100% of patients for S. pneumoniae and 90% of patients for S. aureus. The median time to defervescence was 3 days from the start of daptomycin therapy. In summary, a 6-mg/kg intravenous infusion of daptomycin every 24 h was effective and well tolerated in neutropenic cancer patients.

Optimal prevention of seizures induced by high-dose busulfan

High‐dose busulfan is frequently used in a variety of conditioning regimens for hematopoietic cell transplantation. In this setting, busulfan has marked neurotoxicity, specifically causing seizures that generally are tonic‐clonic in character. Phenytoin has been the preferred drug to treat busulfan‐induced seizures, but this practice should be reexamined in light of newer antiepileptic drugs being preferentially used by neurologists. Characteristics of ideal seizure prophylaxis include lack of overlapping toxicity with the conditioning regimen, lack of interference with engraftment of donor cells, and minimal potential for pharmacokinetic drug interactions. Based on these criteria, phenytoin is suboptimal due to possible toxicities and is especially ill suited because of its ability to induce busulfan metabolism. It is postulated that this induction adversely affects efforts to update methods for targeting busulfan doses to individual patients, based on recent developments in the understanding of the pharmacogenomics of busulfan metabolism. The existing clinical data support the use of benzodiazepines, most notably clonazepam and lorazepam, to prevent busulfan‐induced seizures. The second‐generation antiepileptic drug levetiracetam possesses the characteristics of optimal prophylaxis for busulfan‐induced seizures, and early data of its efficacy are promising, although further study is needed.

Aprepitant Pharmacokinetics and Assessing the Impact of Aprepitant on Cyclophosphamide Metabolism in Cancer Patients Undergoing Hematopoietic Stem Cell Transplantation

Aprepitant, a neurokinin antagonist, is an effective antiemetic agent in chemotherapy for delayed nausea and vomiting. The study objective was to evaluate the pharmacokinetics of aprepitant and concurrent cyclophosphamide (CY), often a component of hematopoietic stem cell transplant (HSCT) conditioning regimen, in cancer patients undergoing HSCT. Forty subjects were randomized to either aprepitant or placebo in addition to standard antiemetics. Aprepitant or placebo was started 1 hour before the first chemotherapy or radiation dose for HSCT conditioning and administered daily until 4 days after infusion of the hematopoietic cell graft (for a total of 10–12 days). Serial blood samples were collected for aprepitant and CY plus 2 important CY metabolites. The results indicate that aprepitant is well absorbed and does not auto‐induce its metabolism. No significant drug interaction was observed with CY or its metabolites. A significant portion of the patients had subtherapeutic aprepitant concentrations; however, chemotherapy‐induced nausea and vomiting were effectively managed. No dosage adjustment was necessary, and administration of aprepitant in HSCT at the prescribed dosage of 125 mg orally on day 1 and 80 mg orally on each consecutive day through day +4 after HSCT was well tolerated with no significant changes in CY pharmacokinetic parameters.

Conditioning Chemotherapy Dose Adjustment in Obese Patients: A Review and Position Statement by the American Society for Blood and Marrow Transplantation Practice Guideline Committee

Hematopoietic stem cell transplantation (HCT) is a potentially life-saving therapy for patients with malignant and nonmalignant disease states. This article reviews the current published literature on the dosing of pharmacologic agents used for HCT preparative regimens with specific focus on the obese patient population. The review found that dose adjustments for obesity have, to date, been based empirically or extrapolated from published data in the nontransplantation patient population. As a result, the Committee determined that clear standards or dosing guidelines are unable to be made for the obese population because Level I and II evidence are unavailable at this time. Instead, the Committee provides a current published literature review to serve as a platform for conditioning agent dose selection in the setting of obesity. A necessary goal should be to encourage future prospective trials in this patient population because further information is needed to enhance our knowledge of the pharmacokinetics and pharmacodynamics of conditioning agents in the setting of obesity.

N-Acetylcysteine Use to Prevent Contrast Medium–induced Nephropathy: Premature Phase III Trials

To date there has been no general consensus regarding the effectiveness of N-acetylcysteine as a protective therapy against contrast medium-induced nephropathy. Several phase III clinical trials have been conducted without a proper understanding of N-acetylcysteine pharmacology, particularly with regard to first-pass hepatic metabolism. A review was conducted of the literature concerning contrast medium-induced nephropathy and new studies of human N-acetylcysteine pharmacology were performed. After an analysis was performed, it was concluded that further phase I and phase II trials are needed. The efficacy of N-acetylcysteine in the prevention of contrast medium-induced nephropathy may be demonstrated with the use of higher doses than used in earlier studies, in combination with parenteral administration.

Clinical experience with a simple algorithm for plerixafor utilization in autologous stem cell mobilization

Plerixafor augments PBSC collection, but the optimal approach for incorporating it into mobilization is uncertain. Forty-nine consecutive patients mobilized with G-CSF alone were analyzed, and a day 4 peripheral blood CD34+ cell count of 0.015/ml was found to predict for a day 5 apheresis yield of 2 × 106 CD34+ progenitors/kg, our institutional minimum necessary for a single autologous transplant. On the basis of this relationship, a clinical guideline was developed which recommended pre-emptive use of plerixafor if the day 4 peripheral blood CD34+ cell count was between 0.005 and 0.015/ml. A total of 166 consecutive subjects with lymphoma or plasma cell dyscrasias underwent G-CSF mobilization after adoption of this care pathway, and the mobilization failure rate was only 7% in patients managed per guideline. The median PBSC yield was 6.3 × 106 CD34+ progenitors/kg with G-CSF (day 4 peripheral blood CD34+ cell>0.015/ml) and 4.9 × 106 CD34+ progenitors/kg with G-CSF+plerixafor (day 4 peripheral blood CD34+ cell 0.005–0.015/ml). The median number of days of apheresis was 2 in both groups. This clinical guideline is an effective mobilization algorithm that minimizes mobilization failures, reduces poor apheresis yields, does not require risk factor identification and is simple to implement.

Utilization of collaborative practice agreements between physicians and pharmacists as a mechanism to increase capacity to care for hematopoietic stem cell transplant recipients.

Survival after hematopoietic stem cell transplantation (HSCT) has improved and the number of allogeneic HSCTs performed annually in the United States is expected to reach 10,000 by 2015. The National Marrow Donor Program created the System Capacity Initiative to formulate mechanisms to care for the growing number of HSCT recipients. One proposed method to increase capacity is utilization of pharmacists to manage drug therapy via collaborative practice agreements (CPAs). Pharmacists have managed drug therapy in oncology patients with CPAs for decades; however, there are limited HSCT centers that employ this practice. Engaging in collaborative practice and billing agreements with credentialed pharmacists to manage therapeutic drug monitoring, chronic medical conditions, and supportive care in HSCT recipients may be cost-effective and enable physicians to spend more time on new or more complex patients. The goal of this paper is to provide a framework for implementation of a CPA and address how it may improve HSCT program capacity.

Comparison of posaconazole serum concentrations from haematological cancer patients on posaconazole tablet and oral suspension for treatment and prevention of invasive fungal infections

Posaconazole tablet formulation (PTF) was developed to optimise bioavailability. This study compared posaconazole levels between patients on the PTF and oral suspension formulation (OSF). We also examined factors that may impact posaconazole levels. The primary and secondary objectives were analysed by comparing trough levels and attainment of target level between the formulation groups. For the 86 patients on PTF and 176 on OSF, the mean first levels was 1.32 μg ml−1 (SD = 0.69) and 0.81 μg ml−1 (SD = 0.59), P < 0.0001 respectively. PTF group was more likely to achieve levels ≥0.7 μg ml−1 than OSF group (OR 7.97 [95 CI; 3.75–16.93], P < 0.0001). Levels from patients on PTF and with presence of acid suppression, GI GVHD, mucositis or diarrhoea were not statistically different from those without these factors. For PTF, no correlation was found between patients weight (kg) and levels (R2 = 0.0536, P = 0.035). The incidences of elevation in ALT/AST or Tbili were similar between the formulation groups. In conclusion, PTF should be considered the preferred formulation because it demonstrated better absorption than the OSF. Patients on PTF for prophylaxis are more likely to attain target level and may not routinely require therapeutic drug monitoring during prophylaxis.

Randomized open-label trial of dolasetron for the control of nausea and vomiting associated with high-dose chemotherapy with hematopoietic stem cell transplantation

A prospective open-label trial was performed to compare the efficacy of dolasetron with that of ondansetron or granisetron (standard therapy) for prevention of nausea and vomiting associated with high-dose chemotherapy with or without total body irradiation followed by hematopoietic stem cell transplantation (HSCT). In a university teaching hospital setting, 62 patients were randomized to receive either dolasetron 100 mg daily or standard doses of ondansetron or granisetron. In addition to objective data such as number of episodes of emesis and quantity of rescue antiemetics required, 100 mm visual analogue scales were used to rate nausea, appetite, and changes in taste. A post-hoc subgroup analysis was performed between groups of patients that were matched for conditioning regimens. Sixty-five percent of the dolasetron-treated patients and 87% of patients in the standard therapy group achieved a major or complete response (P < .05) based on emetic episodes and nausea score. Patients in the standard therapy group used fewer rescue antiemetics and also rated more favorably on selected questions of the visual analogue scale. No differences in safety parameters or adverse effects were reported. At doses prescribed in this study, dolasetron was less effective than granisetron or ondansetron in preventing nausea and vomiting associated with high-dose chemotherapy/total body irradiation followed by HSCT.