Vincristine Sulfate Liposome Injection Research Articles

A phase II study of the tolerability and activity of weekly vincristine sulfate liposomes injection (VSLI) in adults with Philadelphia chromosome-negative (Ph-) acute lymphoblastic leukemia (ALL) in second relapse or progressing following two antileukemia treatment lines

7046 Background: VSLI (Marqibo) is a nanoparticle formulation of vincristine sulfate (VCR) encapsulated in sphingomyelin/cholesterol liposomes called Optisomes. The optisomal formulation lends itself to an improved pharmacokinetic profile and enhanced tumor penetration and concentration. Preclinical studies of VSLI showed enhanced efficacy versus standard VCR in a variety of solid and hematologic malignancies. VSLI has a maximum tolerated dose of 2.25 mg/m2 with no dose cap, while conventional VCR is dosed at 1.4 mg/m2 with a 2 mg dose cap. A previous study in relapsed ALL showed a complete response rate of 19%, warranting further study. Methods: Eligible adult subjects received single agent intravenous VSLI at a dose of 2.25 mg/m2 weekly with no dose cap. This international, multicenter, single-arm study will enroll approximately 56 subjects. Major endpoints include response rate and overall survival (OS). An interim analysis was planned following enrollment of 29 evaluable subjects. Results: 29 heavily pretreated subjects received ≥ 1 dose of VSLI. To date, at least 9 of 29 subjects had clearing of leukemic blasts and achievement of an M1 bone marrow. Based on preliminary data, the median OS is estimated to be 7.5 months (95% CI: 4.7–10.5) using the Kaplan-Meier method. The most frequent related adverse event (AE) was peripheral neuropathy (PN) (48%), half of which was grade 3. No grade 4 PN was reported. Six subjects had 8 treatment-associated grade 4 AEs of neutropenia (4), thrombocytopenia (2), anemia (1), and inappropriate antidiuretic hormone secretion (1). Conclusions: These results are encouraging, as VSLI was given as a single agent to a heavily pretreated patient population who nearly universally received prior VCR. This population typically has a very low response rate to anti-leukemia therapies. Early OS data compares favorably to an historical median OS of ∼ 2 months (8.7 weeks) in a second salvage population (data on file, M. D. Anderson). VSLI was well tolerated in these patients in the context of universal prior vincristine treatment. [Table: see text]

Phase 1 Study of Weekly Vincristine Sulfate (VCR) Liposomes Injection (VSLI, Marqibo™) Plus Dexamethasone in Adults with Relapsed or Refractory Acute Lymphoblastic Leukemia (ALL)

Novel formulations of standard chemotherapy allowing increased drug delivery without additional toxicity may improve outcomes for patients with relapsed or refractory acute lymphoblastic leukemia (ALL). Vincristine sulfate liposomes injection (VSLI, Marqibo®) is VCR encapsulated in sphingomyelin (55%)/cholesterol (45%) nanoparticle liposomes called Optisomes™. Pharmacokinetic studies have shown that the altered distribution and elimination phases of VSLI may lead to increased VCR exposure compared to traditional VCR, and may account for the increased efficacy observed in preclinical models. Activity of VCR is dose and time-dependent, but neurotoxicity limits dosing to 1.4 mg/m2 (capped at 2.0 mg). VSLI, however, may be given without dose capping. We conducted a phase 1, open-label, dose-escalation study of VSLI in adults with relapsed or refractory ALL to determine the safety, maximum tolerated dose (MTD), and activity of this formulation. Subjects received VSLI intravenously weekly at doses of 1.5, 1.825, 2.0, 2.25 or 2.4 mg/m2. Dexamethasone 40 mg was given days 1–4 and 11–14 of each 4 week cycle. Thirtysix eligible subjects, all of whom had been previously treated with VCR, received at least 1 dose of VSLI. All were Philadelphia chromosome negative except for one. Median number of doses received for all subjects was 4; total medium cumulative dose was 9.09 mg/m2 (19.20 mg). MTD of VSLI was 2.25 mg/m2 based on dose-limiting toxicities of grade 3 motor neuropathy, grade 4 seizure and grade 4 hepatotoxicity observed in 1 subject each at the 2.4 mg/m2 dose level. The most common toxicities (constipation [67%], fatigue [61%], pyrexia [50%], anemia [50%], peripheral neuropathy [50%; mostly grade 1–2]) were as expected. Complete response (CR) was achieved in 7 of 36 (19%) subjects based on intent to treat analysis (Table). Overall response rate (including 1 PR) was 22%. Four subjects (11%) achieved hematologic improvement, 13 (36%) had stable disease, and 9 (25%) progressed. CR rate was 29% for the 7 subjects treated with VSLI as second salvage. Five of 7 subjects who achieved CR were able to undergo allogeneic stem cell transplant (SCT). In conclusion, VSLI appears to be an effective therapeutic option which may permit potentially curative SCT. A phase 2 international multi-center trial of single agent VSLI in subjects with relapsed ALL is currently accruing.Table. VSLI Clinical Activity (CR) by Dose Level and Salvage Status1.5 mg/m2 n = 51.825 mg/m2 n = 32 mg/m2 n = 32.25 mg/m2 n = 182.4 mg/m2 n = 7Total n = 361st salvage1/10/1–2/71/44/13 (31)2nd or later salvage1/41/20/31/110/33/23 (13)

In Vivo Anti-Tumor Efficacy of Vincristine Sulfate Liposomes Injection (VSLI, Marqibo®) in Multiple Myeloma

Multiple myeloma (MM) is a bone marrow-based malignancy characterized by expansion of plasma cells that produce monoclonal immunoglobulin. Although many new options are available to treat MM, patients develop resistance to these agents. Thus, new therapeutic options are necessary for patients. Vincristine has been used to treat MM but its neurotoxic side effects and low level of anti-MM activity have limited its clinical use. Pharmacokinetic studies on a different formulation of this vinca alkaloid, vincristine sulfate liposomes injection (VSLI, Marqibo®), have shown that the altered distribution and elimination phases with this drug may lead to increased exposure within the tumor versus traditional vincristine. Thus, this new agent offers the potential to both reduce the neurotoxicity and increase the anti-MM effects compared to standard vincristine. In the present study, we evaluated the anti-MM effects of Marqibo and vincristine using two severe combined immunodeficiency (SCID) murine models of human MM. These models were developed from intramuscular (i.m.) implantation of bone marrow biopsies from a MM patient before (LAGκ-1A) and following (LAGκ-1B) the development of both melphalan and bortezomib resistance clinically and have been successfully passaged. One week following implantation i.m., mice were treated with Marqibo, vincristine or vehicle alone. Marqibo was administered intravenously (i.v.) once weekly for three weeks at 0.5, 1, and 2.5 mg/kg and vincristine was given three times per week (M, W, F) i.v. at 0.3 mg/kg. Mice were bled in order to obtain sera to measure human immunoglobulin (Ig) G levels and tumor volume measured weekly. hIgG levels were measured by ELISA and tumor volume using standard calipers. Treatment of LAGk-1A–bearing mice with Marqibo at 0.5, 1 and 2.5 mg/kg inhibited paraprotein secretion as determined by hIgG levels (P = 0.0001; P = 0.0002; P = 0.0055, respectively) compared to mice receiving vehicle. A reduction in tumor volume, compared to control mice, was also observed in mice treated with Marqibo at the specified doses (P = 0.0001; P = 0.0001; P = 0.0001, respectively) and also when compared to vincristine (P = 0.0006; P = 0.0003; P = 0.0001, respectively). In fact, mice treated with vincristine showed no reduction in tumor volume compared to vehicle alone-treated mice. Marqibo at 0.5 mg/kg contained almost half the quantity of free vincristine compared to vincristine administered at 0.3 mg/kg, yet a significant inhibition of both human paraprotein secretion and reduction of tumor volume was observed in LAGκ-1A-bearing mice treated with this dose of Marqibo. The vincristine dose was administered three times more often than Marqibo, contained almost 100% more free vincristine compared to Marqibo at 0.5 mg/kg and most importantly was less effective. Mice bearing a slower growing MM tumor, LAGκ-1B, have recently begun treatment using the same doses and schedules as the LAGκ-1A study. This study is currently ongoing but preliminary data show inhibition of tumor volume growth and inhibition of IgG levels using Marqibo at 0.5, 1 and 2.5 mg/kg (hIgG; P = 0.011, P = 0.0045 and P = 0.0060, respectively). The results of this study show that Marqibo, a novel liposomal formulation of vincristine, produces anti-MM effects in this SCID-hu model of human MM whereas vincristine showed no anti-MM tumor volume growth activity. Further studies are currently being conducted to explore the optimal schedule and effects of this new agent in combination with other active MM agents. These studies should provide the rationale for further clinical development of Marqibo for the treatment of MM patients.

Peripheral Neuropathy Profile of Vincristine Sulfate Liposomes Injection (VSLI, Marqibo®), a Nanoparticle Vincristine Formulation, in Adult Subjects with Relapsed/Refractory Acute Lymphoblastic Leukemia (ALL) and Non-Hodgkin's Lymphoma (NHL)

VSLI is a nanoparticle formulation of vincristine sulfate (VCR) encapsulated in sphingomyelin/cholesterol (SM/Chol) liposomes called Optisomes™. In preclinical studies, VSLI has provided targeted, increased, and sustained delivery of VCR to tumor cells compared to administration of conventional or non-SM/Chol liposome-encapsulated VCR. VSLI is being developed to improve patient outcomes without increased VCR-related peripheral neuropathy (PN). We report an integrated analysis of the PN profile of VSLI from two distinct multi-center clinical studies: A Phase 1 dose-escalation study in adult subjects with relapsed/refractory ALL of weekly VSLI plus pulse dexamethasone at doses ranging from 1.8 to 2.4 mg/m2 without dose cappingA Phase 2 study in adult subjects with relapsed/refractory NHL of biweekly VSLI at a dose of 2.0 mg/m2 without dose cappingSubjects with prior history of Grade 3 or 4 PN related to chemotherapeutic agents were not eligible for either study. Subject characteristics, VSLI dosing details, and relevant clinical outcomes are provided in the Table. Results are presented as median (range) unless otherwise stated.ALL (N=36, 12F/24M)NHL (N=119, 55F/64M)Age (years)32 (19–2)60 (25–87)Body surface area (m2)2.1 (1.5–2.8)1.9 (1.3–2.6)Prior VCR exposure100%97%Total VSLI dose (mg)19 (10–8)14 (3–66)Objective Response rate22%25%VSLI dose to complete response (mg)12 (9–3)n/aVSLI dose to objective response (mg)n/a14 (8–9)Peripheral neuropathy (PN) rate, n (%)22 (61)50 (42)Grade 112 (33)24 (20)Grade 27 (19)18 (15)Grade 32 (6)8 (7)Grade 41 (3)0VSLI dose to PN onset (mg)14 (4–2)12 (3–4)VSLI dose to Grade 3/4 PN (mg)23 (20–3)19 (3–4)Discontinuations due to PN, n (%)3 (8)7 (6)The median cumulative VSLI doses (including pre- and post-PN onset) for ALL and NHL subjects who experienced PN were 24 mg (range: 10–38 mg) and 18 mg (range: 3–66 mg), respectively, compared to 12 mg (range: 11–28 mg) and 11 mg (range: 3–54 mg) in ALL and NHL subjects who did not experience PN. Six of the 22 ALL subjects (27%) who experienced PN achieved CR, compared to 1 of 14 (7%) subjects without PN (p>0.05). Nineteen of the 50 NHL subjects (38%) who experienced PN responded to VSLI, compared to 11 of 69 (16%) subjects without PN (p=0.01). In general, the PN observed in these lymphoid malignancy populations, with near universal prior VCR exposure, was primarily mild and moderate in grade and rarely required VSLI discontinuation. Despite prior VCR exposure, and residual PN in some, the amount of VCR delivered as VSLI in both ALL and NHL subjects prior to PN onset was greater than the PN trigger cumulative doses reported for conventional VCR (5 mg for PN; 15 mg for severe PN). In both studies, subjects who experienced PN received higher cumulative doses of VSLI and achieved more responses compared to subjects who had not experienced PN. The pharmacokinetic profile, targeted delivery, and VCR dose-intensification facilitated by VSLI have the potential to produce meaningful response rates without therapy-limiting PN.

Safety and Efficacy of Marqibo (Vincristine Sulfate Liposomes Injection, OPTISOME™) in for the Treatment of Adults with Relapsed or Refractory Acute Lymphoblastic Leukemia (ALL).

Introduction: Vincristine sulfate (VCR) is a lipophilic, cell-cycle specific, antineoplastic agent that inhibits cell division by specifically binding to tubulin in mitotic spindles. The activity of VCR is dose and time-dependent, but central and peripheral neuropthy prohibits its use beyond doses of 1.4 mg/m2 (capped at 2 mg). Marqibo is a formulation of VCR encapsulated in a sphingomyelin/cholesterol liposome (OPTISOME) with a longer half-life than VCR. In murine models using L1210 or P388 lymphoid leukemia cell lines, Marqibo demonstrated greater anti-tumor activity compared with VCR. Marqibo was therefore an appropriate agent to study in relapsed or refractory ALL.Methods: Two clinical trials have been completed. First, a phase II trial of single agent Marqibo given at 2 mg/m2 (no dose capping) every 2 weeks enrolled 16 patients (pts) [Thomas et al, Cancer 106:120, 2006]. A multicenter dose escalation phase I trial using weekly Marqibo (1.5, 1.825, 2.0, 2.25, 2.4 mg/m2) in combination with pulse dexamethasone followed. There were no restrictions on the number of prior therapies. Subjects with grade 2 or greater central or peripheral neuropathy were ineligible.Results: In total, 52 pts with relapsed or refractory ALL were treated in the two studies combined. Median age was 34 years (range, 19–77), 31 males/21 females, with a median number of prior salvage regimens of 2 (range, 1–3). Nine pts had confirmed Philadelphia positive disease (8 in the pre-imatinib era, 1 resistant to tyrosine kinase inhibitor therapy). All pts had previously received conventional VCR therapy. There were 8 complete remissions and 3 partial remissions for an overall response rate of 21% [95% CI, 11, 35]. An additional 12 pts (23%) achieved hematological improvements (e.g., clearance of marrow blasts, platelet transfusion independence). Five responders were able to undergo allogeneic stem cell transplantation following therapy with Marqibo. The maximum tolerated dose in the phase I trial was 2.25 mg/m2 owing to grade 3 motor neuropathy, grade 4 seizure, and grade 4 hepatotoxicity observed in 1 patient each at the 2.4 mg/m2 dose level. Grade 1–2 peripheral neuropathy was manageable with dose modifications and anti-neuralgia agents such as gabapentin. Commonly observed toxicities included febrile neutropenia, myelosuppression, abdominal pain, nausea, constipation, diarrhea, fatigue, and infusion-related pyrexia.Conclusions: In reviewing the clinical experience to date, Marqibo with or without pulse dexamethasone has provided clinically meaningful activity in heavily pre-treated adults with ALL. A multicenter trial of single agent Marqibo in the setting of second salvage therapy for adults with relapsed ALL is underway. A phase III multicenter trial of Marqibo in combination with standard chemotherapy for de novo elderly ALL is in the planning phase.

Marqibo (Vincristine Sulfate Liposomes Injection, OPTISOME™) Concentrates Vincristine in Tumor Tissue and Lymphoid Malignancy Oriented Tissues in Tumor-Bearing Mice.

Background: Vincristine sulfate (VCR) is a cell-cycle specific, lipophilic, anti-cancer drug that inhibits cell division by binding to tubulin in mitotic spindles. Marqibo is a proprietary sphingomyelin/cholesterol liposome (OPTISOME) encapsulated formulation of VCR with an extended circulating half-life and the potential for preferential malignancy targeting, exposure, and anti-cancer activity. This report evaluates the concentration and accumulation of VCR in solid tumor tissue as well as tissues frequently involved with lymphoid malignancies in tumor-bearing mice following equivalent doses of Marqibo or conventional VCR.Methods: Mice were implanted subcutaneously with MX-1 human breast tumor tissue. When the tumor volume reached 162–485 mm3, mice received a single intravenous dose of Marqibo, containing 1.5 mg/kg of [14C]-VCR, or 1.5 mg/kg of non-liposomal [14C]-VCR. The total radioactivity from parent compound and metabolites in tissue, VCReq, was analyzed by Quantitative Whole Body Autoradioluminography (QWBA) and tissue digestion (TD). QWBA analysis of bone marrow (BM), tumor tissue, lymph nodes, liver, and spleen required 1 flash-frozen mouse per group at various time intervals. Sagittal sections were examined histologically for radioactivity. For TD, all tissues except bone marrow were obtained from 3 mice per group prior to infusion and at selected time points. The samples were chemically digested and analyzed for radioactivity by liquid scintillation counting.Results: QWBA analysis revealed at least two-fold higher VCReq tissue concentrations in the Marqibo-injected mice compared to the conventional VCR-injected mice.VCReq Tissue Concentration (mcg/g) at 48 hours Post-InjectionBMTumorLymphLiverSpleenMarqibo0.991.351.980.476.08VCR0.360.31--0.130.76Marqibo/VCR ratio2.754.35--3.618The TD results are consistent with the QWBA results shown in the table. Marqibo-injected mice demonstrated a minimum 5-fold increase in VCR exposure over a 96 hour period (VCReq AUC analysis) compared to VCR-injected mice over a 48 hour period, as defined in the parameters of the study, in the implanted tumor (123 vs. 21 hr*μg/g), lymph nodes (121 vs. 16.5 hr*μg/g), liver (68.8 vs. 12 hr*μg/g), and spleen (512 vs. 68.9 hr*μg/g). Though the parameters for the AUC values may favor Marqibo, the Tmax of all specified tissues are at least 16 times greater in Marqibo-injected mice than in VCR-injected mice (16 hrs vs. 1hr in tumor, spleen, and lymph; 4 hrs vs. 15 min. in liver; 16 hrs. vs. 15 min. in the kidney). The greatest increase in VCR exposure produced by Marqibo was observed in the spleen and lymph nodes (7.4- and 7.3-fold).Conclusions: Marqibo resulted in targeted delivery of VCR; concentration of VCR in tumor tissue, BM, lymph nodes, liver, and spleen; and maintenance of significant tissue drug concentrations for an extended period of time compared to conventional VCR. The ability of Marqibo to target drug to these tissues and organs makes it particularly attractive as a treatment for hematologic malignancies like myeloma, lymphoma, and acute lymphoblastic leukemia (ALL). Late-stage clinical development of Marqibo in adult ALL is underway.

Marqibo (Vincristine Sulfate Liposomes Injection (OPTISOME™) Demonstrates Activity in Patients with Relapsed and Refractory Peripheral T-Cell Lymphoma.

Introduction: New and more effective agents are needed to improve treatment outcomes for patients with relapsed and refractory peripheral T-cell lymphoma (PTCL). Marqibo is a novel formulation of vincristine (VCR) encapsulated in sphingomyelin/cholesterol liposome called OPTISOME. In preclinical studies, OPTISOME technology has been shown to provide targeted, increased, and sustained delivery of VCR to tumor cells compared to non-encapsulated VCR or VCR encapsulated in conventional liposomes.Methods: PTCL patients from two multi-center phase 2 studies of Marqibo in relapsed and refractory lymphoid malignancies are integrated for safety and efficacy evaluation. In both studies, Marqibo (2.0 mg/m2 without dose capping IV over 60 minutes) was administered every 14 days for up to 12 cycles or until toxicity or progressive disease was observed. The primary efficacy endpoint of the 2 studies was the objective response rate (ORR) defined as the percentage of patients whose best response was complete response (CR), complete response unconfirmed, or partial response (PR). Best response was determined according to the International Workshop Response Criteria. Secondary endpoints included adverse event evaluation, time to progression (TTP) and overall survival (OS).Results: Six (3M/3F) patients diagnosed with PTCL received at least one dose of Marqibo. At baseline, the median age was 59 years (range, 34–86). All six patients had aggressive disease and most were heavily pretreated. The median number of prior lines of chemotherapy and immunotherapy regimens was 3 (range, 1–6) and four patients (66.7%) had received prior autologous bone marrow transplant. All patients had prior exposure to neurotoxic therapy: platinum compounds (33.3%), taxanes (16.7%) and VCR (100%). All patients had achieved a CR or PR to their frontline therapy and 50% (3/6) had achieved a CR or PR to their last line of therapy prior to receiving Marqibo. Patients received a median of 4 cycles of Marqibo (range, 1–9). Median cumulative dose of Marqibo was 7 mg/m2 (range, 2–17.4). The most commonly reported adverse event was peripheral sensory neuropathy (3 of 6 patients) and all of Grade 1 severity. Three patients had PR, 1 patient had stable disease, 1 patient experienced disease progression, and 1 patient was unevaluable. Median OS and TTP were 194 and 70 days, respectively.Conclusions: These preliminary results suggest encouraging activity and tolerability of Marqibo in heavily pre-treated relapsed and refractory PTCL patients. Given the high proportion of exposure to neurotoxic agents preceding Marqibo, the low grade neurotoxicity noted following Marqibo is a favorable finding.

A pharmacokinetic comparison of the Marqibo 3 and 5 vial injection kits in metatastic melanoma patients

8575 Background: In nonclinical and clinical studies, liposomal encapsulation of vincristine sulfate (VCR) increased the circulation time and accumulation of VCR at the tumor site, and thus improved antitumor efficacy in comparison to VCR. Marqibo (vincristine sulfate liposomes injection) may be administered safely at doses exceeding that typically employed by VCR, with a manageable pattern of clinical toxicities consistent with VCR. Methods: We conducted a phase I, single-center, open-label, randomized, 2-arm crossover study designed to compare the pharmacokinetics (PK) of Marqibo utilizing the 3- and 5-vial kits administered 2 mg/m2 IV infusion once every 2 weeks in histologically confirmed, surgically nonresectable Stage III or IV metastatic cutaneous, mucosal, or choroidal melanoma patients. Patients randomized to receive the 3-vial kit at Cycle 1 were crossed over to receive the 5-vial kit at Cycle 2 or vice versa. The 3-vial kit was used for all patients at all cycles from Cycle 3 to end of treatment. Antitumor activity was assessed by CT scan every 4 cycles. Blood samples for PK analysis was collected at pretreatment, during infusion, end of infusion, and at various time points within 96 hours post end of infusion at Cycles 1 and 2. Total VCR concentration and released vincristine concentration was measured using HPLC-MS/MS method. Results: Fifteen patients were enrolled and treated; 11 were evaluable for the PK analysis. Median number of cycles received was 4 (1- 24). Objective response was observed in 13% (1 CR, 1 PR) or stable disease (20%, 3 SD) as their best response. The 90% CI (0.83–1.12) on the ratio of the means of the AUC0-inf of the 3- and 5-vial kits was within the interval of 0.80–1.25 confirming the bioequivalence of the two kits. Seventy-three percent discontinued treatment due to disease progression and 13% discontinued due to adverse events. Adverse events included hypoesthesia or paresthesia, constipation, numbness, weakness, fatigue, nausea, vomiting. Conclusions: Single agent Marqibo demonstrated moderate activity in advanced Stage IV melanoma patients and was generally well tolerated with similar adverse event profile to VCR. The 3- and 5-vial kits produced similar bioequivalent PK profiles. No significant financial relationships to disclose.

Pharmacokinetics and Urinary Excretion of Vincristine Sulfate Liposomes Injection in Metastatic Melanoma Patients

Vincristine sulfate liposomes injection (VSLI) is a liposomal formulation of vincristine encapsulated in sphingosomes composed of sphinogomyelin and cholesterol (58/42; mol/mol). The pharmacokinetics and urinary excretion of VSLI were evaluated in 12 patients with metastatic melanoma after single-dose (2.0 mg/m2 every 2 weeks = 1 cycle) and multiple-dose (cycle 3, pharmacokinetics only) administrations (intravenous infusion over 1 hour). After VSLI infusion, total (released and encapsulated) vincristine concentrations in plasma remained relatively constant for 3 to 12 hours and thereafter declined, with interpatient variability seen in the rate of decline resulting in monoexponential or biexponential profiles. The area under the plasma concentration-time curve from time zero to infinity of total vincristine in plasma ranged from 4933 to 40495 h.ng/mL and total clearance ranged from 131 to 445 mL/h. The volume of distribution at steady state was 2650 +/- 731 mL, indicating VSLI was mainly confined within the plasma. The released vincristine concentrations in plasma were below the level of quantitation in 95% of samples. The pharmacokinetic parameters were similar between cycles 1 and 3, and trough plasma levels of total vincristine were below the level of quantitation of 1 ng/mL. Approximately 8% of the injected dose was excreted in the urine as unchanged vincristine (7%) or N-desformylvincristine (0.8%). Overall, VSLI exhibited a longer circulation half-life and higher area under the plasma concentration-time curve compared to conventional vincristine, whereas its route of elimination remained unchanged.

Hydromorphone Hydrochloride Extended-Release Capsules (C-II)

Each month, subscribers to The Formulary Monograph Service receive five to six well-documented monographs on drugs that are newly released or are in late Phase III trials. The monographs are targeted to your Pharmacy and Therapeutics Committee. Subscribers also receive monthly one-page summary monographs on the agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation (DUE) is also provided each month. With a subscription, the monographs are sent to you in print and CD ROM forms and are available online. Monographs can be customized to meet the needs of your facility. Subscribers to the The Formulary Monograph Service also receive access to a pharmacy bulletin board, The Formulary Information Exchange (The F.I.X.). All topics pertinent to clinical and hospital pharmacy are discussed on The F.I.X. Through the cooperation of The Formulary, Hospital Pharmacy publishes selected reviews in this column. If you would like information about The Formulary Monograph Service or The F.I.X., call The Formulary at 800-322-4349. The January 2005 monograph topics are natalizumab, solifenacin succinate, vincristine sulfate liposomes injection, sodium tetradecyl sulfate injection, and testosterone transdermal. The DUE is on natalizumab.

Validation of a high-performance liquid chromatographic assay method for quantification of total vincristine sulfate in human plasma following administration of vincristine sulfate liposome injection

The validation of a high performance liquid chromatographic (HPLC) assay method for quantitation of total vincristine sulfate (VINC) in human plasma is described. VINC was extracted from plasma using BondElut CBA solid phase cartridges with vinblastine as the internal standard. Chromatography was accomplished using a Waters Symmetry C8 (250 mm×4.6 mm i.d.) analytical column, a Waters Delta-Pak ODS guard column with a mobile phase of 34.9% water–0.1% diethylamine (pH 7.0)–40% acetonitrile–25% methanol pumped isocratically at 1.0 ml min −1 with ultraviolet detection at 297 nm. Above the limit of quantitation of 28.6 ng ml −1, the area ratio precision (R.S.D. range 3.33–11.6%) and accuracy of predicted values (R.S.D. range 8.56–23.8% with the limit of quantitation being the only value above 20%) were acceptable. The assay was linear from 28.6–2860 ng ml −1 VINC in plasma. Recovery of VINC from plasma and VINC from plasma spiked with vincristine sulfate liposome injection ranged from 74.9–87.1%. Stability of VINC in plasma stored at −20°C for at least 49 days and of extracted plasma samples was demonstrated. Potential interference in quantitation of VINC from commonly co-administered drugs was evaluated along with day-to-day variability. The assay procedure was found suitable for evaluation of VINC clinical pharmacokinetics in plasma following administration of vincristine sulfate liposome injection prepared using distearoylphosphatidylcholine (DSPC)/cholesterol liposomes for injection.