maytansine and Body-Weight

Trastuzumab emtansine (T-DM1) is a HER2-targeted antibody-drug conjugate in development for treatment of HER2-positive cancers. T-DM1 has been tested as a single agent in a phase I and 2 phase II studies of patients with heavily pretreated metastatic breast cancer (MBC), with the maximum tolerated dose established at 3.6 mg/kg intravenously for every-3-week dosing. The authors present results from the population pharmacokinetics analysis for T-DM1. Population pharmacokinetics for T-DM1 were characterized using a clinical database of 273 patients from the 3 studies. Pharmacokinetics was best described by a linear 2-compartment model. Population estimates (interindividual variability [IIV]) for pharmacokinetic parameters were clearance, 0.7 L/d (21.0%); central compartment volume (V(c)), 3.33 L (13.2%); peripheral compartment volume (V(p)), 0.89 L (50.4%); and intercompartmental clearance, 0.78 L/d. Body weight, albumin, tumor burden, and aspartate aminotransferase levels were identified as statistically significant covariates accounting for interindividual variability in T-DM1 pharmacokinetics, with body weight having a greater effect on IIV of clearance and V(c) than other covariates. T-DM1 exposure was relatively consistent across the weight range following body weight-based dosing. This analysis suggests no further T-DM1 dose adjustments are necessary in heavily pretreated patients with MBC.

Topics: Ado-Trastuzumab Emtansine; Adult; Antibodies, Monoclonal, Humanized; Aspartate Aminotransferases; Biomarkers, Tumor; Body Weight; Breast Neoplasms; Drug Administration Schedule; Drug Dosage Calculations; Female; Humans; Immunotoxins; Infusions, Intravenous; Linear Models; Maximum Tolerated Dose; Maytansine; Middle Aged; Models, Biological; Protein Binding; Receptor, ErbB-2; Serum Albumin; Trastuzumab; Treatment Outcome; Tubulin Modulators; Tumor Burden

We here provide the first report on the construction of nanoparticles formulating highly potent cytotoxic therapeutics using albumin. Maytansinoid DM1 can be efficiently integrated into albumin nanoparticles, resulting in remarkable alleviation of in vivo drug toxicity and expanding the repertoire of albumin technology available for cancer therapy.

Topics: Albumins; Animals; Antineoplastic Agents, Phytogenic; Body Weight; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Humans; Injections, Intravenous; Maytansine; Mice; Mice, Inbred ICR; Models, Molecular; Molecular Conformation; Nanoparticles

The development of antibody-drug conjugates (ADC), a promising class of anticancer agents, has traditionally relied on the use of antibodies capable of selective internalization in tumor cells. We have recently shown that also noninternalizing antibodies, coupled to cytotoxic drugs by means of disulfide linkers that can be cleaved in the tumor extracellular environment, can display a potent therapeutic activity. Here, we have compared the tumor-targeting properties, drug release rates, and therapeutic performance of two ADCs, based on the maytansinoid DM1 thiol drug and on the F8 antibody, directed against the alternatively spliced Extra Domain A (EDA) domain of fibronectin. The antibody was used in IgG or in small immune protein (SIP) format. In both cases, DM1 was coupled to unpaired cysteine residues, resulting in a drug-antibody ratio of 2. In biodistribution studies, SIP(F8)-SS-DM1 accumulated in the tumor and cleared from circulation more rapidly than IgG(F8)-SS-DM1. However, the ADC based on the IgG format exhibited a higher tumor uptake at later time points (e.g., 33%IA/g against 8%IA/g at 24 hours after intravenous administration). In mouse plasma, surprisingly, the ADC products in IgG format were substantially more stable compared with the SIP format (half-lives >48 hours and <3 hours at 37°C, respectively), revealing a novel mechanism for the control of disulfide-based drug release rates. Therapy experiments in immunocompetent mice bearing murine F9 tumors revealed that SIP(F8)-SS-DM1 was more efficacious than IgG(F8)-SS-DM1 when the two products were compared either in an equimolar basis or at equal milligram doses.

Topics: Animals; Antibodies; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Body Weight; Cell Line, Tumor; CHO Cells; Chromatography, Liquid; Cricetinae; Cricetulus; Drug Liberation; Electrophoresis, Polyacrylamide Gel; Female; Immunoconjugates; Mass Spectrometry; Maytansine; Mice; Microscopy, Fluorescence; Neoplasms, Experimental; Tissue Distribution; Treatment Outcome; Tumor Burden

Trastuzumab emtansine (T-DM1) is the first antibody-drug conjugate (ADC) approved for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. The therapeutic premise of ADCs is based on the hypothesis that targeted delivery of potent cytotoxic drugs to tumors will provide better tolerability and efficacy compared with non-targeted delivery, where poor tolerability can limit efficacious doses. Here, we present results from preclinical studies characterizing the toxicity profile of T-DM1, including limited assessment of unconjugated DM1. T-DM1 binds primate ErbB2 and human HER2 but not the rodent homolog c-neu. Therefore, antigen-dependent and non-antigen-dependent toxicity was evaluated in monkeys and rats, respectively, in both single- and repeat-dose studies; toxicity of DM1 was assessed in rats only. T-DM1 was well tolerated at doses up to 40 mg/kg (~4400 μg DM1/m(2)) and 30 mg/kg (~ 6000 μg DM1/m(2)) in rats and monkeys, respectively. In contrast, DM1 was only tolerated up to 0.2mg/kg (1600 μg DM1/m(2)). This suggests that at least two-fold higher doses of the cytotoxic agent are tolerated in T-DM1, supporting the premise of ADCs to improve the therapeutic index. In addition, T-DM1 and DM1 safety profiles were similar and consistent with the mechanism of action of DM1 (i.e., microtubule disruption). Findings included hepatic, bone marrow/hematologic (primarily platelet), lymphoid organ, and neuronal toxicities, and increased numbers of cells of epithelial and phagocytic origin in metaphase arrest. These adverse effects did not worsen with chronic dosing in monkeys and are consistent with those reported in T-DM1-treated patients to date.

Topics: Ado-Trastuzumab Emtansine; Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Blood Platelets; Body Weight; Cytotoxins; Drug Evaluation, Preclinical; Female; Humans; Macaca fascicularis; Male; Maytansine; Random Allocation; Rats; Rats, Sprague-Dawley; Trastuzumab

The effects of the antineoplastic drugs vincristine, maytansine and cis-platinum were studied to determine the appropriateness of a behavioral and electrophysiological test battery for characterizing the neurotoxicity of such therapeutic compounds. Single- and repeated-dose studies in rats were performed initially, to establish doses for the subchronic neurobehavioral study. Measurements obtained in the subchronic study included body weight, rectal temperature, forelimb and hindlimb grip strengths; performance of a multisensory conditional avoidance response task and other behavioral tests; and a series of evoked responses (ventral caudal nerve action potential, brainstem auditory response and responses from other modalities). The drugs were injected intraperitoneally 5 days per week for 7 weeks. The rats were tested weekly during baseline, treatment and recovery phases. Each drug caused a different pattern of effects, but they all altered body weight, rectal temperature, peripheral nerve conduction velocity, the somatosensory evoked potential and undifferentiated motor activity. cis-Platinum was the most toxic, and maytansine was the least toxic. The results indicated that some elements of the test battery were useful for evaluating the neurotoxicity of anticancer drugs. However, other tests - notably, a test of negative geotaxis and the cortical auditory evoked response - were unreliable.

Topics: Action Potentials; Animals; Avoidance Learning; Behavior, Animal; Body Temperature; Body Weight; Cisplatin; Evoked Potentials, Auditory; Evoked Potentials, Somatosensory; Evoked Potentials, Visual; Male; Maytansine; Motor Activity; Nervous System; Oxazines; Rats; Rats, Inbred F344; Vincristine

The toxicity of maytansine given by sc administration was studied in 5-week-old mald F344 rats. The LD50 (14-day) was 0.48 mg/kg. A dose response to drug administration was indicated by body weight changes and diarrhea. A single, acutely toxic dose of maytansine was shown to possess marked activity against dividing cells which was regarded as an important factor in the pathogenesis of acute lesions in tissues with a normal high rate of cell division. Histologically, mitotic figues were observed in many tissues from 6 to 24 hours after drug administration. Subsequently, necrotizing lesions led to atrophic changes in gastrointestinal tract mucosa, thymus, spleen, bone marrow, and testis. Maytansine also induced hemorrhagic lesions in parenchymatous organs and brain and perivascular monomuclear infiltration in the meninges, and chromatolysis and vacuolation of dorsal root ganglion cells, accompanied by clinical signs of ataxia. Ulcerative skin lesions were observed at the sc site of drug administration.

Topics: Acute Disease; Animals; Atrophy; Body Weight; Bone Marrow; Cerebral Hemorrhage; Diarrhea; Dose-Response Relationship, Drug; Gastric Mucosa; Injections, Subcutaneous; Intestinal Mucosa; Male; Maytansine; Necrosis; Oxazines; Rats; Rats, Inbred F344; Spleen; Testis; Thymus Gland