RESUMO
PURPOSE: To investigate pharmacokinetics (PK) of encapsulated CPT-11, released CPT-11 and the active metabolite SN-38 following administration of IHL-305 and to identify factors that may influence IHL-305 PK. METHODS: Plasma samples from 39 patients with solid tumors were collected in a phase I study. IHL-305 was administered as a 1 h IV infusion with doses ranging from 3.5 to 210 mg/m(2). Plasma concentrations of encapsulated CPT-11, released CPT-11 and SN-38 were used to develop a population PK model using NONMEM®. RESULTS: PK of encapsulated CPT-11 was described by 1-compartment model with nonlinear clearance and PK of released CPT-11 was described by a 1-compartment model with linear clearance for all patients. PK of the active metabolite SN-38 was described by a 2-compartment model with linear clearance for all patients. Covariate analysis revealed that gender was a significant covariate for volume of distribution of encapsulated CPT-11. Vencap in male patients is 1.5-fold higher compared with female patients. CONCLUSIONS: The developed population PK modeling approach is useful to predict PK exposures of encapsulated and released drug and can be applied to the more than 300 other nanoparticle formulations of anticancer agents that are currently in development. The effect of gender on PK of IHL-305 needs to be further evaluated.
Assuntos
Antineoplásicos Fitogênicos/farmacocinética , Camptotecina/análogos & derivados , Modelos Biológicos , Neoplasias/sangue , Adulto , Idoso , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/sangue , Camptotecina/administração & dosagem , Camptotecina/sangue , Camptotecina/farmacocinética , Feminino , Humanos , Infusões Intravenosas , Irinotecano , Lipossomos , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Polietilenoglicóis/químicaRESUMO
PURPOSE: In this study, to optimize the polymeric drug delivery system for cancer chemotherapy, we developed a new pH-sensitive polymeric carrier, poly(vinylpyrrolidone-co-dimethylmaleic anhydride) [PVD], that could gradually release native form of drugs with full activity, from the conjugates in response to changes in pH. We examined the usefulness of PVD as a polymeric drug carrier. EXPERIMENTAL DESIGN: PVD was radically synthesized with vinylpyrrolidone and 2,3-dimethylmaleic anhydride, which is known to be a pH-reversible amino-protecting reagent. Conjugates between PVD and other drugs, such as Adriamycin (ADR), were prepared under the slightly basic conditions (pH 8.5). The drug-release pattern and the antitumor activity of PVD were examined. RESULTS: At pH 8.5, the release of the drugs from the conjugate was not observed. In contrast, PVD could release fully active drugs in the native form in response to the change in pH near neutrality, and gradually released drugs at neutral pH (7.0) and slightly acidic pH (6.0). The drug-release pattern in serum was almost similar to that observed during these physiological conditions. The PVD-conjugated ADR showed superior antitumor activity against sarcoma-180 solid tumor in mice, and it had less toxic side effects than free ADR. This enhancement in the antitumor therapeutic window may be due to not only the improvement of plasma half-lives and tumor accumulation of ADR, but also its controlled and sustained release from the conjugates in vivo. CONCLUSIONS: These results indicate that PVD is an effective polymeric carrier for optimizing cancer therapy.
Assuntos
Portadores de Fármacos , Neoplasias/tratamento farmacológico , Polímeros/química , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Corantes Fluorescentes/farmacologia , Concentração de Íons de Hidrogênio , Isoquinolinas/farmacologia , Camundongos , Modelos Químicos , Transplante de Neoplasias , Neoplasias Experimentais/tratamento farmacológico , Pirrolidinas/farmacologia , Fatores de Tempo , Compostos de Vinila/farmacologiaRESUMO
IHL-305 is a PEGylated liposomal formulation of irinotecan (CPT-11). The objective of this study was to evaluate the factors associated with interpatient variability in the pharmacokinetics and pharmacodynamics of IHL-305 in patients with advanced solid tumors. IHL-305 was administered intravenously once every 4 weeks as part of a Phase I study. Pharmacokinetic studies of the liposomal sum total CPT-11, released CPT-11, SN-38, SN-38G, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin, and 7-ethyl-10-[4-amino-1-piperidino]-carbonyloxycamptothecin in plasma were performed. Noncompartmental and compartmental pharmacokinetic analyses were conducted using pharmacokinetic data for sum total CPT-11. The pharmacokinetic variability of IHL-305 is associated with linear and nonlinear clearance. Patients whose age and body composition (ratio of total body weight to ideal body weight [TBW/IBW]) were greater than the median age and TBW/IBW of the study had a 1.7-fold to 2.6-fold higher ratio of released CPT-11 area under the concentration versus time curve (AUC) to sum total CPT-11 AUC. Patients aged <60 years had a 1.3-fold higher ratio of percent decrease in monocytes at nadir to percent decrease in absolute neutrophil count at nadir as compared with patients aged ≥60 years. There was an inverse relationship between patient age and percent decrease in monocytes at nadir, ie, younger patients have a higher percent decrease in monocytes. Patients with a higher percent decrease in monocytes at nadir have a decreased plasma exposure of sum total CPT-11. The pharmacokinetics and pharmacodynamics of IHL-305 are consistent with those of other PEGylated liposomal carriers. Interpatient variability in the pharmacokinetics and pharmacodynamics of IHL-305 was associated with age, body composition, and monocytes.
Assuntos
Antineoplásicos , Camptotecina/análogos & derivados , Lipossomos , Neoplasias/tratamento farmacológico , Polietilenoglicóis , Adulto , Idoso , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Camptotecina/sangue , Camptotecina/farmacocinética , Camptotecina/farmacologia , Camptotecina/uso terapêutico , Feminino , Humanos , Irinotecano , Lipossomos/sangue , Lipossomos/farmacocinética , Lipossomos/farmacologia , Lipossomos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/análise , Polietilenoglicóis/farmacocinética , Polietilenoglicóis/farmacologia , Polietilenoglicóis/uso terapêuticoRESUMO
We reported that the co-polymer composed of vinylpyrrolidone and maleic acid selectively distributed into the kidneys after i.v. injection. To further optimize the renal drug delivery system, we assessed the renal targeting capability of anionized polyvinylpyrrolidone (PVP) derivatives after intravenous administration in mice. The elimination of anionized PVP derivatives from the blood decreased with increasing anionic groups, and the clearance of carboxylated PVP and sulfonated PVP from the blood was almost similar. But carboxylated PVP efficiently accumulated in the kidney, whereas sulfonated PVP was rapidly excreted in the urine. The renal levels of carboxylated PVP were about five-fold higher than sulfonated PVP. Additionally, carboxylated PVP was effectively taken up by the renal proximal tubular epithelial cells in vivo after i.v. injection. These anionized PVP derivatives did not show any cytotoxicity against renal tubular cells and endothelial cells in vitro. Thus, these carboxylated and sulfonated PVPs may be useful polymeric carriers for drug delivery to the kidney and bladder, respectively.
Assuntos
Sistemas de Liberação de Medicamentos/métodos , Células Endoteliais/efeitos dos fármacos , Túbulos Renais/efeitos dos fármacos , Rim/metabolismo , Povidona/administração & dosagem , Povidona/farmacocinética , Sarcoma/patologia , Animais , Ânions , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/farmacocinética , Avaliação Pré-Clínica de Medicamentos/métodos , Células Endoteliais/patologia , Humanos , Injeções Intravenosas , Túbulos Renais/patologia , Masculino , Taxa de Depuração Metabólica , Camundongos , Camundongos Endogâmicos A , Especificidade de Órgãos , Povidona/toxicidadeRESUMO
To achieve an optimum drug delivery such as targeting or controlled release utilizing bioconjugation with polymeric modifier, the conjugate between drugs and polymeric modifiers must be designed to show desirable pharmacokinetic characteristics in vivo. In this study, we assessed the biopharmaceutical properties of various nonionic water-soluble polymers as polymeric drug carriers. Polyvinylpyrrolidone (PVP) showed the longest mean resident time (MRT) after i.v. injection of all nonionic polymers with the same molecular size. In fact, tumor necrosis factor-alpha (TNF-alpha) bioconjugated with PVP (PVP-TNF-alpha) circulated longer than TNF-alpha bioconjugated with polyethylene glycol (PEG-TNF-alpha) with the same molecular size. Each nonionic polymeric modifier showed a different tissue distribution. Dextran was accumulated in the spleen and liver. Polydimethylacrylamide (PDAAm) tended to distribute in the kidney. However, PVP showed the minimum volume of tissue distribution. These results suggested that PVP is the most suitable polymeric modifier for prolonging the circulation lifetime of a drug and localizing the conjugated drug in blood.
Assuntos
Portadores de Fármacos/farmacocinética , Fibrossarcoma/metabolismo , Povidona/farmacocinética , Fator de Necrose Tumoral alfa/administração & dosagem , Fator de Necrose Tumoral alfa/análise , Animais , Linhagem Celular Tumoral , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Avaliação de Medicamentos/métodos , Estabilidade de Medicamentos , Feminino , Meia-Vida , Masculino , Taxa de Depuração Metabólica , Camundongos , Camundongos Endogâmicos BALB C , Especificidade de Órgãos , Polímeros/administração & dosagem , Polímeros/química , Polímeros/farmacocinética , Povidona/administração & dosagem , Povidona/química , Distribuição Tecidual , Fator de Necrose Tumoral alfa/química , Fator de Necrose Tumoral alfa/metabolismoRESUMO
To optimize polymer-conjugated drugs as a polymeric drug delivery system, it is essential to design polymeric carriers with tissue-specific targeting capacity. Previously, we showed that polyvinylpyrrolidone (PVP) was the most suitable polymeric carrier for prolonging the blood-residency of drugs, and was one of the best parent polymers to design the polymeric carriers with targeting capacity. In this study, we synthesized some hydrophobic PVP derivatives, poly(vinylpyrrolidone-co-styrene) [poly(VP-co-S)] and poly(vinylpyrrolidone-co-vinyl laurate) [poly(VP-co-VL)], and assessed their biopharmaceutical properties after intravenous administration in mice. The elimination of hydrophobic PVP derivatives from blood was the same as PVP, and the plasma half-lives of poly(VP-co-S) were almost similar to that of poly(VP-co-VL). Poly(VP-co-VL) efficiently accumulated in the spleen, whereas poly(VP-co-S) effectively accumulated in the liver. The level of poly(VP-co-VL) in the spleen was about 20 times higher than PVP and poly(VP-co-S). These hydrophobic PVP derivatives did not show any cytotoxicity against endothelial cells in vitro. Thus, poly(VP-co-VL) may be a useful polymeric carrier for drug delivery to the spleen. This study will provide useful information to design optimal polymeric carriers with targeting capacity to the spleen and liver.
Assuntos
Materiais Biocompatíveis/farmacocinética , Povidona/farmacocinética , Baço/metabolismo , Animais , Materiais Biocompatíveis/síntese química , Materiais Biocompatíveis/química , Portadores de Fármacos/síntese química , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Sistemas de Liberação de Medicamentos , Fluorescência , Interações Hidrofóbicas e Hidrofílicas , Masculino , Teste de Materiais , Camundongos , Conformação Molecular , Povidona/síntese química , Povidona/química , Distribuição TecidualRESUMO
The antitumor effect of IHL-305, a novel pegylated liposome containing irinotecan, was investigated in human xenograft models. After subcutaneous transplantation of several human cancer cell lines (colorectal, non-small cell lung, small cell lung, prostate, ovarian and gastric cancer cells) to nude mice, IHL-305 or CPT-11 was administered intravenously 3 times at 4-day intervals. In all xenograft models tested, IHL-305 showed superior antitumor activity to that of CPT11 and a comparable tumor-growth-inhibitory effect at one-eighth or less of the dose of CPT-11, even against HT-29 colorectal and NCI-H460 non-small cell lung cancer cell lines, which show intrinsic resistance to CPT-11. A single injection or 2 injections of IHL-305 on several dosing schedules also resulted in a significant antitumor effect compared to that of vehicle control in a dose-dependent manner and showed comparable antitumor activity at about one-fifth the dose of the maximum tolerated dose of CPT-11. The analysis of the concentrations of irinotecan and SN-38, an active metabolite of CPT-11, in plasma and tumors revealed that irinotecan was maintained at high concentrations, and the prolonged presence of SN-38 in plasma and tumors in IHL-305 treated mice compared with CPT-11-treated mice. Therefore, the stronger tumor inhibitory effect of IHL-305, as compared to CPT-11, was associated with the difference in the concentration of irinotecan in plasma or tumors after each agent was administered and with the maintainance of a higher concentration of SN-38. These results indicate that IHL-305 demonstrated superior antitumor activity against a wide range of tumors at lower doses than CPT-11.
Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Camptotecina/análogos & derivados , Neoplasias Experimentais/tratamento farmacológico , Animais , Camptotecina/administração & dosagem , Camptotecina/farmacocinética , Linhagem Celular Tumoral , Humanos , Irinotecano , Lipossomos , Masculino , Camundongos , Camundongos Nus , Polietilenoglicóis , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PURPOSE: IHL-305 is a novel PEGylated liposome containing irinotecan. This study examined the safety profile and pharmacokinetics of IHL-305 and established the maximum tolerated dose and recommended phase II dose (RP2D). PATIENTS AND METHODS: In a standard 3 + 3 design, IHL-305 was administered IV on day 1 of a 28-day treatment schedule. Subsequently, a 14-day treatment schedule was also explored. Two patient populations were evaluated separately: Patients with at least one wild-type (wt) allele of UGT1A1 (UDP glucoronosyltransferase 1A1) wt/wt or wt/*28 as one group (referred to as UGT1A1 wt group) and patients with UGT1A1*28 homozygous variant (*28/*28) as another group. RESULTS: Sixty patients were treated: 42 on the 28-day schedule and 18 on the 14-day schedule. Seven patients were homozygous variant (*28/*28). In the UGT1A1 wt group, the MTD and RP2D of IHL-305 was 160 mg/m(2) every 28 days and 80 mg/m(2) every 14 days. DLTs included nausea, vomiting, diarrhea, and neutropenia. The most common adverse events were nausea (75 %), vomiting (52 %), diarrhea (62 %), anorexia (57 %), and fatigue (57 %). At the MTD for both schedules, IHL-305 administration resulted in a high and prolonged exposure of sum total irinotecan, released irinotecan, and SN-38 in plasma. One partial response was observed in a patient with breast cancer and eight patients had stable disease for >6 months. CONCLUSIONS: IHL-305, a novel preparation of irinotecan encapsulated in liposomes, can be safely given to patients in a repeated fashion on a 4- or 2-week dosing schedule.