Lopinavir/ritonavir reduces bupropion plasma concentrations in healthy subjects.

Limited data are available about the effect of steady-state lopinavir and ritonavir (LPV/r) on bupropion pharmacokinetics. As patients may benefit by using these two agents in combination, this study determined the extent and direction of this drug-drug interaction. Twelve healthy volunteers received a single 100 mg dose of sustained-release bupropion before and after 2 weeks of treatment with LPV/r 400 mg/100 mg twice daily. Pharmacokinetics profiles were determined on days 1 and 30 for bupropion and hydroxybupropion and days 29 and 30 for LPV/r. LPV/r administration significantly decreased bupropion maximum plasma concentration (C(max)) by 57% (90% confidence interval (CI), 38-76%; P<0.01) and area under the curve (AUC) infinity by 57% (90% CI, 32-83%; P<0.01). Hydroxybupropion C(max) and AUC infinity decreased by 31% (90% CI, 7-55%; P<0.01) and by 50% (90% CI, 34-65%; P<0.01), respectively. No significant changes in the pharmacokinetics of LPV/r were found following administration of a single dose of bupropion. Concurrent use of LPV/r and bupropion resulted in decreased exposure to bupropion and its active metabolite hydroxybupropion that may necessitate as much as a 100% dose increase of bupropion. A probable mechanism for this interaction is the concurrent induction of cytochrome P450 2B6 and UDP-glucuronosyltransferase enzymes. LPV/r exposure is unaffected by a single dose of bupropion.

Topotecan-filgrastim combination is an effective regimen for mobilizing peripheral blood stem cells.

We compared the efficacy, toxicity, and cost of topotecan-filgrastim and filgrastim alone for mobilizing peripheral blood stem cells (PBSCs) in 24 consecutive pediatric patients with newly diagnosed medulloblastoma. PBSCs were mobilized with an upfront window of topotecan-filgrastim for 11 high-risk patients (residual tumor > or =1.5 cm2 after resection; metastases limited to neuraxis) and with filgrastim alone for 13 average-risk patients. All patients subsequently underwent craniospinal irradiation and four courses of high-dose chemotherapy with stem cell rescue. Target yields of CD34+ cells (> or =8 x 10(6)/kg) were obtained with only one apheresis procedure for each of the 11 patients treated with topotecan-filgrastim, but with a mean of 2.3 apheresis procedures for only six (46%) of the 13 patients treated with filgrastim alone (P = 0.0059). The median peak and median total yield of CD34+ cells were six-fold higher for the topotecan-filgrastim group (328/microl and 21.5 x 10(6)/kg, respectively) than for the filgrastim group (54/microl and 3.7 x 10(6)/kg, respectively). Mean times to neutrophil and platelet engraftment were similar. Myelosuppression was the only grade 4 toxicity associated with topotecan-filgrastim mobilization and lasted a median of 5 days. Compared with filgrastim mobilization, topotecan-filgrastim mobilization resulted in a mean cost saving of $3966 per patient. Topotecan-filgrastim is an efficacious, minimally toxic, and cost-saving combination for PBSC mobilization.

Peripheral blood progenitor cell transplantation: economic issues.

High-dose chemotherapy with autologous hematopoietic stem cell rescue is an expensive procedure. It is associated with improved long-term survival in many patients with cancer, but concern is growing about its cost and cost-effectiveness. The cost-effectiveness of high-dose chemotherapy depends largely on the magnitude of the difference in survival between it and standard-dose chemotherapy. Several economic analyses reported that the cost-effectiveness ratio of high-dose chemotherapy in the treatment of breast cancer is in the range of or slightly higher than that reported for other widely accepted medical interventions. Most centers are evaluating new strategies to reduce the overall cost of this therapy, including using peripheral blood progenitor cells rather than bone marrow-derived stem cells, optimizing the collection of peripheral blood progenitor cells, and shifting care from the inpatient to the outpatient setting.

The true cost of bone marrow transplantation.

Bone marrow transplantation is an example of a highly technical therapy that offers hope to patients with bone marrow failure or various malignancies. Bone marrow transplantation is much more costly "up-front" but perhaps not more costly long-term than alternative therapies. Although economic analyses appear relatively simple, interpretation and use can be problematic. Several economic analyses have identified complications that occur frequently and affect the reported cost-effectiveness of high-dose chemotherapy. Efforts to reduce the cost of bone marrow transplantation have focused on new strategies to more effectively control these complications. The introduction of new technologies to speed engraftment, to improve patient selection methods, and the shifting of care to outpatient settings all have resulted in significant reductions in duration of hospital stay, treatment-related mortality, and costs. More studies of long-term outcomes are needed for transplant and nontransplant treatment options to guide present and future applications of this treatment option.

Cost-utility analysis of taxane therapy.

A cost-utility analysis of docetaxel versus paclitaxel in patients with anthracycline-resistant metastatic breast cancer was reviewed. Cost-utility analysis provides estimates of the additional cost of a new therapy per quality-adjusted life-year (QALY) saved or gained. Utility scores measure the strength of a patient's preference for a given health state or outcome. Few studies have evaluated preferences in patients receiving cancer treatment. Since docetaxel may represent an advance in the management of anthracycline-resistant recurrent metastatic breast cancer, a decision-analysis model was developed to evaluate the pharmacoeconomics of this drug versus those of paclitaxel. Although the overall treatment costs of docetaxel were slightly higher than those of paclitaxel, docetaxel was associated with a gain of 0.0905 QALY per patient. This gain in QALYs is equivalent to 33 days of perfect health, which represents a substantial proportion of the life expectancy of one of these patients (typically no longer than nine months). The incremental cost-utility ratio associated with docetaxel therapy was estimated to be $4011 per QALY. Compared with paclitaxel, docetaxel for anthracycline-resistant metastatic breast cancer is within the acceptable range of cost-effectiveness ratios for most medical interventions. Cost-utility analysis is a valuable technique for evaluating new antineoplastic regimens that offer some treatment benefit but do not prolong survival compared with other therapeutic options.

The future of cell therapy.

Peripheral blood has replaced bone marrow as a source of hematopoietic stem cells for autologous rescue after high-dose chemotherapy. Patients who receive peripheral blood stem cell (PBSC) transplants experience rapid and sustained hematopoietic reconstitution. As a result, transplant-related mortality is now less than 5% at many centers, and the cost of high-dose chemotherapy has decreased considerably. However, the relapse rate continues to be unacceptably high, and the collection of hematopoietic stem cells from peripheral blood is inconvenient, time consuming, and expensive. This article discusses the current status of novel technologies such as positive selection of hematopoietic stem cells, ex vivo expansion of hematopoietic progenitor cells, allogeneic PBSC transplants, and umbilical cord blood transplants. Several companies are actively developing devices that positively select hematopoietic stem cells. Because positive selection reduces the volume of infused cells, patients experience fewer adverse effects related to dimethylsulfoxide (DMSO) or lysed cells. These devices may also serve as an ex vivo method to remove ("purge") residual tumor cells. Positively selected hematopoietic stem cells may be expanded ex vivo to produce a large number of a specific population of hematopoietic cells. By adding cytokines that stimulate and activate lymphocytes, natural killer cells, and other immune effector cells, investigators could expand the number of immune effector cells with antitumor activity and then infuse them into patients as a form of adoptive immunotherapy. Finally, peripheral blood and umbilical cord blood are promising new sources of hematopoietic stem cells for allogeneic transplants.

Pharmacodynamic studies of cyclosporine in marrow transplant recipients. A comparison of three assay methods.

We investigated the correlation between trough cyclosporine concentration in plasma measured by polyclonal fluorescence polarization immunoassay (FPIA) and polyclonal radioimmunoassay (RIA) or in whole blood measured by high-performance liquid chromatography (HPLC) and the risk of renal dysfunction or acute graft-versus-host disease in 29 patients undergoing allogeneic bone marrow transplantation for leukemia. The FPIA and RIA values were highly correlated (r = 0.93) and on the average CsA concentrations measured by FPIA were 1.56 times higher than those measured by RIA. Ten patients developed renal dysfunction and 10 developed grades II-IV acute GVHD. Although univariate analysis showed that plasma CsA concentrations measured by either FPIA or RIA were significantly correlated with renal dysfunction, the association was stronger with FPIA. Plasma CsA concentrations measured by FPIA but not RIA remained a significant risk factor for renal dysfunction in a multivariate relative risk model. Amphotericin therapy was significantly associated with renal dysfunction in the univariate analysis but not in the multivariate analysis. No significant associations were found between whole blood CsA or CsA M1 concentration, patients' age, gender, or CsA dose and the risk of renal dysfunction. None of the covariates analyzed significantly correlated with the development of acute GVHD. These data suggest that plasma CsA concentrations measured by nonspecific assays may more accurately correlate with renal dysfunction than whole-blood CsA concentrations measured by HPLC in marrow transplant recipients.

Stability of cyclosporine in dextrose 5%, NaCl 0.9%, dextrose/amino acid solution, and lipid emulsion.

OBJECTIVE: Because of limited intravenous access in patients who have undergone bone marrow transplant (BMT), we undertook a study to determine the safety of mixing cyclosporine in intravenous preparations commonly administered to BMT patients. DESIGN: In a pilot study, we investigated the stability of intravenous cyclosporine (Sandimmune) in four types of intravenous fluids: dextrose 5%, NaCl 0.9%, dextrose/amino acid solutions, and lipid emulsion. Because the pilot study showed highly variable cyclosporine concentrations that suggested inadequate mixing, we undertook another study to determine the effect of the mixing method on cyclosporine concentrations. OUTCOME MEASURE: Cyclosporine was considered stable in the study solutions if concentrations remained above 90 percent of the initial concentrations. RESULTS: Substantial variation in cyclosporine concentrations was observed in lipid emulsion and dextrose/amino acid solutions and gentle swirling of the solutions was insufficient to adequately disperse the drug. The variation was eliminated by vigorous shaking either before each sampling or once after the initial addition of cyclosporine. We used vigorous shaking methods to establish that cyclosporine is stable for up to 72 hours at room temperature in dextrose 5%, 10% amino acid solution with dextrose 50%, and Liposyn 10%, and up to 8 hours in NaCl 0.9%. CONCLUSIONS: These data may be used to simplify cyclosporine administration in patients who have limited intravenous access.

Hematopoiesis.

Hematopoiesis begins with the pluripotent stem cell in the marrow and culminates in mature, functional red blood cells, white blood cells, and platelets in the circulation. The process consists of a complex and well-orchestrated sequence of cell proliferation, differentiation, and maturation, that is stimulated and regulated by a host of cytokines and hormones. The various growth factors act individually and in concert at different stages of hematopoiesis and have important effects on mature cell function.

Colony-stimulating factors and tomorrow's pharmacy: why we must be ready.

The characteristics and clinical uses of recombinant colony-stimulating factors (CSFs) are described, and the pharmacist's role as a consultant and educator on biotherapeutic substances is discussed. CSFs stimulate the formation and differentiation of the erythrocytes, neutrophils, eosinophils, basophils, monocytes, and platelets that compose the blood cell population. Recombinant CSFs represent a means by which the numbers of hematopoietic cells can be modulated, thus making these agents potentially useful in treating hematologic and immunologic deficiencies. CSFs also can increase the ability of neutrophils and monocyte-macrophages to protect the body against foreign invasion. Granulocyte macrophage colony-stimulating factor (GM-CSF) has increased host defenses in acquired immunodeficiency syndrome patients with Kaposi's sarcoma; increased neutrophil, platelet, and erythrocyte counts in preleukemic patients; and increased neutrophil counts in patients with aplastic anemia. GM-CSF and granulocyte colony-stimulating factor (G-CSF) have appeared to alleviate the drastic decrease in neutrophil counts associated with cytotoxic chemotherapy. G-CSF also has shown promise in stimulating neutrophil production in patients with transitional cell carcinoma, congenital agranulocytosis, and hairy-cell leukemia. Mild adverse effects such as fever, chills, rash, fatigue, myalgia, and bone pain are associated with GM-CSF therapy; G-CSF therapy is associated mostly with mild to moderate bone pain. Areas of education for pharmacists working with biotherapeutic substances include stability, storage temperature, drug interactions, novel drug-delivery systems such as monoclonal antibodies or liposomes, variations in biologic activity, and the evolving nature of the information about these investigational drugs. The pharmacist can anticipate an increasing role as a consultant on the use of CSFs and other biotherapeutic substances.(ABSTRACT TRUNCATED AT 250 WORDS)

Minimal risk of chronic renal dysfunction in marrow transplant recipients treated with cyclosporine for 6 months.

To determine whether 6 months of cyclosporine therapy is associated with chronic renal dysfunction, we evaluated serum creatinine concentrations 1 year post-transplant in 82 marrow transplant recipients randomized to receive either cyclosporine (n = 40) or methotrexate (n = 42) as graft-versus-host disease (GVHD) prophylaxis. Nine patients in the methotrexate group were later given cyclosporine as treatment for acute or chronic GVHD (methotrexate----cyclosporine). Cyclosporine prophylaxis was started on the day before marrow infusion, given at full doses until day 50, then gradually tapered and discontinued by day 180. Methotrexate prophylaxis was started on day 1 and given intermittently until day 102. Patients in the cyclosporine and methotrexate----cyclosporine groups had significantly higher mean serum creatinine values during the first 100 days post-transplant than methotrexate-treated patients, but by 1 year mean serum creatinine values were not significantly different between the three groups. Serum creatinine values at 1 year were also not significantly different from baseline values in each of the groups. None of the patients who had their cyclosporine discontinued by day 180 developed chronic renal dysfunction, defined as a doubling of the baseline serum creatinine at 1 year. We conclude that chronic renal dysfunction occurs rarely in marrow transplant recipients treated with 6 months of cyclosporine and when it does occur, it appears to have minimal clinical significance.

Blood cyclosporine pharmacokinetics in patients undergoing marrow transplantation. Influence of age, obesity, and hematocrit.

Blood cyclosporine pharmacokinetics were studied in 85 patients aged 1-52 (median: 22) years undergoing allogeneic bone marrow transplantation for the treatment of hematologic disease. Pharmacokinetic studies were carried out during the first two weeks posttransplant after an intravenous dose of 2.1-4.4 mg/kg. Whole-blood cyclosporine concentrations were measured by high-performance liquid chromatography. Multiple stepwise regression analysis indicated that age (P less than 0.001) and hematocrit (P less than 0.05) correlated with cyclosporine clearance (CL) while steady-state volume of distribution (Vss) did not correlate with any of the factors studied. Cyclosporine CL significantly differed among nonobese patients in different age groups; patients less than or equal to 10 years old had a higher mean CL (13.1 ml/min/kg) than patients 11-20, 21-30, 31-40, or greater than 40 years old (mean CL: 8.5-10.3 ml/min/kg) (P less than 0.05). No significant differences in cyclosporine CL and Vss were observed between obese (greater than 125% ideal body weight) patients and age-matched nonobese patients. Hematocrit values (range: 24-39) were inversely correlated with cyclosporine CL, which suggests that red blood cells function as important ligands in cyclosporine binding. These results show that blood cyclosporine CL is higher in marrow transplant recipients than in solid organ transplant recipients and that these differences may be related to lower hematocrits in marrow transplant recipients compared with solid organ transplant recipients. When compared with previously published serum cyclosporine CL data, our findings suggest that age-related changes in CL are primarily related to changes in plasma protein binding and that obesity does not significantly alter cyclosporine CL and Vss.

Serum cyclosporine concentration and risk of acute graft-versus-host disease after allogeneic marrow transplantation.

To determine the relation between the serum cyclosporine concentration and the risk of acute graft-versus-host disease (GVHD), we studied 179 recipients of bone marrow grafts from HLA-identical sibling donors who received prophylaxis with cyclosporine, either by itself or combined with methotrexate. Cyclosporine was given either orally or intravenously at full doses from the day before transplantation until day 50; it was then tapered off and discontinued on day 180. Trough concentrations of serum cyclosporine were measured by radioimmunoassay. The relation between patients' characteristics and the risk of acute GVHD was analyzed with a relative-risk regression model. In 66 patients (37 percent), grades II to IV of acute GVHD developed 7 to 66 days (median, 13) after transplantation. The trough cyclosporine concentration for a given week was significantly associated with the risk that acute GVHD would develop during the following week. The relative risks were 0.7 (i.e., there was a 30 percent reduction in risk) for every increase of 100 ng per milliliter in cyclosporine concentration and 1.0, 0.60, and 0.20 for concentrations of less than 100, 100 to 199, and 200 or more ng per milliliter, respectively (P less than 0.01). A patient's age, prophylaxis regimen, and year of transplantation also influenced the risk of acute GVHD significantly. These data indicate that low cyclosporine concentrations can be a cause of treatment failure and that concentrations should be monitored in recipients of marrow transplants.