Methods of treatment using intravenous formulations comprising temozolomide

A technology for temozolomide and preparations, which is applied in the treatment field of using preparations for intravenous injection containing temozolomide, can solve the problems of reducing the bioavailability of drugs and the like

Inactive Publication Date: 2010-03-24
MERCK & CO INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

As the drug passes through the liver, it can be metabolized and a smaller portion of the absorbed drug will enter the systemic circulation, thereby reducing the bioavailability of the drug

Method used

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  • Methods of treatment using intravenous formulations comprising temozolomide
  • Methods of treatment using intravenous formulations comprising temozolomide
  • Methods of treatment using intravenous formulations comprising temozolomide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0152] A population pharmacokinetic model was developed to characterize the distribution of both TMZ and MTIC following PO administration. Pharmacokinetic parameters describing the absorption, distribution, metabolism and excretion of TMZ and MTIC were estimated using oral data obtained from a study (see Middleton, Journal of Clinical Oncology, 15(1): 158-166 (2000)). A PK model with first order absorption, unicompartmental distribution of TMZ, first order elimination of TMZ, unicompartmental distribution of MTIC and first order elimination of MTIC was used. Drugs and Pharmaceutical Sciences, Volume 15: Pharmacokinetics, Gibaldi and Perrier, Second Edition, 1982. The mathematical equations describing the model are shown in figure 1 middle.

[0153] In the equation shown in the figure, k a is the absorption rate constant, F is the bioavailability of TMZ following oral administration of the drug, k t To describe the rate constant for the conversion of TMZ to MTIC, V 1 is th...

Embodiment 2

[0174] Clinical trial simulations were performed using the IV PK model and the Pharsight trial simulator. Multiple simulation protocols were performed to evaluate different oral bioavailability and the total time that TMZ would need to be infused into the systemic blood circulation to match the Cmax and AUC obtained following oral administration. Each simulation was repeated 100 times and the probability of success was defined as the number of times the study passed the four bioequivalence criteria (Cmax TMZ, CmaxMTIC, AUC TMZ and AUC MTIC). Confidence intervals for Cmax and AUC for IV administration were within 80-125% of those for oral administration. Table 4 shows the results of these simulations.

[0175] Table 4

[0176]

[0177] * The four standards are: Cmax TMZ, Cmax MTIC, AUC TMZ and AUC MTIC.

[0178] Simulation results using an IV PK model show that if the total oral TMZ bioavailability (F) is greater than or equal to 90% (ie F = 0.9-1.0), no IV dose adjustme...

Embodiment 3

[0180] Formulations for intravenous injection according to the invention are provided in Table 5. The formulation was prepared according to the method of US Patent 6,987,108 and had a pH of about 4.

[0181] table 5

[0182] Component

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Abstract

This invention relates to methods and drug products for treating proliferative disorders using intravenous formulations comprising temozolomide over a specific infusion time. These methods and drug products are particularly well-suited for patients who cannot swallow oral formulations. These methods and drug products also afford an added convenience to patients who are already receiving other therapeutic treatments.

Description

technical field [0001] The present invention relates to methods and medicaments for the treatment of proliferative disorders using intravenous formulations containing temozolomide over specific infusion times. These methods and medicaments are especially useful for patients who cannot swallow oral formulations. These methods and medicaments also provide additional convenience for patients already undergoing other therapeutic treatments. Background technique [0002] Brain tumors account for approximately 2% of all malignancies. Stupp et al., J. Clin. Onc., 20(5):1375-1382 (2002). In the United States, more than 17,000 cases are diagnosed each year and there are about 13,000 related deaths. The standard regimen for the treatment of malignant gliomas involves cytoreduction by surgical resection when feasible, followed by radiation therapy (RT), with or without adjuvant chemotherapy. The paper by Stupp et al. mentioned above. [0003] Temozolomide or TMZ (supplied by Scher...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4188A61P35/00
CPCA61K31/4188A61K9/0019A61K9/19A61K31/495A61P35/00A61P35/02
Inventor M·亚布塔瑞夫P·史塔克基维契
Owner MERCK & CO INC
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