RESUMEN
Indibulin (ZIO-301/D-24851) is an orally applied small molecule with antitumor activity based upon destabilization of microtubule polymerization. The purpose of this phase I study was to determine the maximum tolerated dose (MTD) as well as the dose limiting toxicity (DLT), the pharmacokinetics, safety and tolerability of orally administered indibulin as capsule formulation in patients with advanced solid tumors. Patients received a single dose of indibulin. Seven dose-levels were evaluated: 100 mg, 150 mg, 250 mg, 350 mg and 600 mg once daily (QD), 450 mg and 600 mg twice daily (BID). After a washout period, patients received indibulin at the pre-defined daily dose for 14 days every 3 weeks (multiple dose part). A total of 28 patients entered the study. Indibulin administered as capsules was generally well tolerated. The MTD was not reached. There was a disproportionate increase of the area under the plasma concentration-time curve (AUC) with dose, with declining AUC corrected for dose starting at the 250 mg dose-level. There was no significant difference in AUC of indibulin after multiple dosing (day 1-14) compared to single administration (day-4). Inter-patient variability in AUC (102% CV) was high. A plateau in drug exposure was observed prior to reaching the MTD. Continued dose-escalation was unlikely to yield any increase in exposure of indibulin. The formulation needs optimization to increase the systemic exposure upon oral administration.
Asunto(s)
Acetamidas/farmacocinética , Acetamidas/uso terapéutico , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Indoles/farmacocinética , Indoles/uso terapéutico , Neoplasias/tratamiento farmacológico , Acetamidas/administración & dosificación , Acetamidas/efectos adversos , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Área Bajo la Curva , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Indoles/administración & dosificación , Indoles/efectos adversos , Masculino , Persona de Mediana Edad , Neoplasias/patología , Factores de TiempoRESUMEN
PURPOSE: To explore the pharmacokinetics (PKs) of paclitaxel and two major metabolites after three single oral administrations of a novel drinking solution and two capsule formulations in combination with cyclosporin A (CsA) in patients with advanced cancer. Moreover, the tolerability and safety of the formulations was studied. In addition, single nucleotide polymorphisms in the multidrug resistance (MDR1) gene were determined. PATIENTS AND METHODS: Ten patients were enrolled and randomized to receive CsA 10 mg/kg followed by oral paclitaxel 180 mg given as (1) drinking solution (formulation 1), (2) capsule formulation 2B, and (3) capsule formulation 2C on day 1, 8, or 15. RESULTS: The median C (max) of paclitaxel was 0.42 (0.23-0.96), 0.48 (0.08-0.59), and 0.39 (0.11-1.03) microg/ml and the area under the plasma concentration-time curve was 2.83 (1.69-5.12), 2.01 (1.57-3.04), and 2.67 (1.05-3.61) mug h/ml following administration of formulations 1, 2B, and 2C, respectively. The novel formulations were tolerated after single oral dose without causing relevant gastrointestinal or haematological toxicity. CONCLUSIONS: The PK and metabolism of paclitaxel were comparable between the oral formulations co-administered with CsA.
Asunto(s)
Neoplasias/tratamiento farmacológico , Paclitaxel/administración & dosificación , Paclitaxel/farmacocinética , Administración Oral , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica , Cápsulas , Química Farmacéutica , Ciclosporina/administración & dosificación , Ingestión de Líquidos , Esquema de Medicación , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Paclitaxel/efectos adversos , Paclitaxel/químicaRESUMEN
To explore the parmacokinetics, safety and tolerability of paclitaxel after oral administration of SMEOF#3, a novel Self-Microemulsifying Oily Formulation, in combination with cyclosporin A (CsA) in patients with advanced cancer. Seven patients were enrolled and randomly assigned to receive oral paclitaxel (SMEOF#3) 160 mg+CsA 700 mg on day 1, followed by oral paclitaxel (Taxol) 160 mg+CsA 700 mg on day 8 (group I) or vice versa (group II). Patients received paclitaxel (Taxol) 160 mg as 3-h infusion on day 15. The median (range) area under the plasma concentration-time curve of paclitaxel was 2.06 (1.15-3.47) microg h ml(-1) and 1.97 (0.58-3.22) microg h ml(-1) after oral administration of SMEOF#3 and Taxol, respectively, and 4.69 (3.90-6.09) microg h ml(-1) after intravenous Taxol. Oral SMEOF#3 resulted in a lower median T(max) of 2.0 (0.5-2.0) h than orally applied Taxol (T(max)=4.0 (0.8-6.1) h, P=0.02). The median apparent bioavailability of paclitaxel was 40 (19-83)% and 55 (9-70)% for the oral SMEOF#3 and oral Taxol formulation, respectively. Oral paclitaxel administered as SMEOF#3 or Taxol was safe and well tolerated by the patients. Remarkably, the SMEOF#3 formulation resulted in a significantly lower T(max) than orally applied Taxol, probably due to the excipients in the SMEOF#3 formulation resulting in a higher absorption rate of paclitaxel.