RESUMEN
OBJECTIVES: To evaluate the clinical PK/PD of PTH(1-34) delivered by a novel transdermal drug-coated microneedle patch system (ZP-PTH) for the treatment of osteoporosis. METHODS: Phase 1 PK studies evaluated the effect of site of administration, patch wear time and dose in normal volunteers, ages 40-85 yrs. Phase 2 was conducted in post-menopausal women with osteoporosis to determine the patch dose response compared to placebo patch and FORTEO® injection. RESULTS: Phase 1 ZP-PTH patch delivery demonstrated a rapid PTH plasma pulse profile with T(max) 3 times shorter and apparent T(1/2) 2 times shorter than FORTEO®. In Phase 2, ZP-PTH 20, 30 and 40 µg doses showed a proportional increase in plasma PTH AUC. Inter-subject and intra-subject AUC variability was similar for all patch doses and comparable to injection. All patch doses produced a significant increase in spine bone mineral density. Unexpectedly, ZP-PTH also produced an early increase in hip bone mineral density, an effect not observed with the injection. CONCLUSIONS: These studies suggest that this novel ZP-PTH patch system can deliver a consistent and therapeutically relevant PTH PK profile. Based on encouraging Phase 2 safety and efficacy data, the program is advancing into a pivotal Phase 3 clinical study.
Asunto(s)
Conservadores de la Densidad Ósea , Sistemas de Liberación de Medicamentos/métodos , Microinyecciones/métodos , Agujas , Osteoporosis Posmenopáusica/tratamiento farmacológico , Teriparatido , Adulto , Anciano , Anciano de 80 o más Años , Conservadores de la Densidad Ósea/administración & dosificación , Conservadores de la Densidad Ósea/farmacocinética , Conservadores de la Densidad Ósea/uso terapéutico , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Sistemas de Liberación de Medicamentos/efectos adversos , Sistemas de Liberación de Medicamentos/instrumentación , Diseño de Equipo , Femenino , Humanos , Inyecciones Intradérmicas , Microinyecciones/efectos adversos , Microinyecciones/instrumentación , Persona de Mediana Edad , Teriparatido/administración & dosificación , Teriparatido/farmacocinética , Teriparatido/uso terapéutico , Factores de Tiempo , Distribución Tisular , Resultado del TratamientoRESUMEN
CONTEXT: Treatment of osteoporosis with an anabolic agent, teriparatide [human PTH 1-34 (TPTD)], is effective in reducing incident fractures, but patient resistance to daily sc injections has limited its use. A novel transdermal patch, providing a rapid, pulse delivery of TPTD, may provide a desirable alternative. OBJECTIVE: The aim of the study was to determine the safety and efficacy of a novel transdermal TPTD patch compared to placebo patch and sc TPTD 20-microg injection in postmenopausal women with osteoporosis. DESIGN: Our study consisted of 6-month, randomized, placebo-controlled, positive control, multidose daily administration. PATIENTS: We enrolled 165 postmenopausal women (mean age, 64 yr) with osteoporosis. INTERVENTIONS: A TPTD patch with a 20-, 30-, or 40-microg dose or a placebo patch was self-administered daily for 30-min wear time, or 20 microg of TPTD was injected daily. OUTCOMES: The primary efficacy measure was mean percentage change in lumbar spine bone mineral density (BMD) from baseline at 6 months. RESULTS: TPTD delivered by transdermal patch significantly increased lumbar spine BMD vs. placebo patch in a dose-dependent manner at 6 months (P < 0.001). TPTD 40-microg patch increased total hip BMD compared to both placebo patch and TPTD injection (P < 0.05). Bone turnover markers (procollagen type I N-terminal propeptide and C-terminal cross-linked telopeptide of type I collagen) increased from baseline in a dose-dependent manner in all treatment groups and were all significantly different from placebo patch (P < 0.001). All treatments were well tolerated, and no prolonged hypercalcemia was observed. CONCLUSION: Transdermal patch delivery of TPTD in postmenopausal women with osteoporosis for 6 months is safe and effective in increasing lumbar spine and total hip BMD.
Asunto(s)
Densidad Ósea/efectos de los fármacos , Osteoporosis Posmenopáusica/tratamiento farmacológico , Teriparatido/administración & dosificación , Administración Cutánea , Anciano , Anciano de 80 o más Años , Algoritmos , Conservadores de la Densidad Ósea/administración & dosificación , Conservadores de la Densidad Ósea/efectos adversos , Conservadores de la Densidad Ósea/sangre , Conservadores de la Densidad Ósea/farmacocinética , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Persona de Mediana Edad , Osteoporosis Posmenopáusica/sangre , Osteoporosis Posmenopáusica/metabolismo , Placebos , Posmenopausia/efectos de los fármacos , Teriparatido/efectos adversos , Teriparatido/sangre , Teriparatido/farmacocinética , Resultado del TratamientoRESUMEN
Inducing apoptosis of activated lymphocytes via Fas ligand (FasL, CD95) may be a useful strategy for the treatment of autoimmune diseases mediated by pathogenic T cells. We propose that B cells may be ideal tools for effective delivery of a FasL-mediated apoptotic signal to pathogenic T cells for a variety of reasons, including their unique ability to efficiently take up and present antigen to T cells that share the same specificity. Here, we demonstrate that B cell clones engineered to express CD95 can effectively suppress a systemic primed antigen-specific T cell response in vivo. Intravenous injection of antigen-pulsed FasL-expressing B cells eliminated antigen-specific (TCR transgenic) T cells from the draining lymph nodes within 12-60 h, and suppressed a delayed-type hypersensitivity response in an antigen-specific manner. These results indicate that B cells can be engineered to express FasL, and used to impair T cell function in vivo, suggesting that FasL-expressing B cells may be an effective tool for the treatment of established T cell-mediated autoimmune and inflammatory diseases.
Asunto(s)
Antígenos/inmunología , Linfocitos B/fisiología , Glicoproteínas de Membrana/genética , Linfocitos T/inmunología , Transfección , Animales , Apoptosis , Enfermedades Autoinmunes/terapia , Proteína Ligando Fas , Femenino , Hipersensibilidad Tardía/prevención & control , Terapia de Inmunosupresión , Glicoproteínas de Membrana/fisiología , Ratones , Ratones Endogámicos BALB C , Células Tumorales CultivadasRESUMEN
PURPOSE: We evaluated the Macroflux microprojection array patch technology as a novel system for intracutaneous delivery of protein antigens. METHODS: Macroflux microprojection array systems (330-microm micro-projection length, 190 microprojections/cm2, 1- and 2-cm2 area) were coated with a model protein antigen, ovalbumin (OVA), to produce a dry-film coating. After system application, microprojection penetration depth, OVA delivery, and comparative immune responses were evaluated in a hairless guinea pig model. RESULTS: Macroflux microprojections penetrated into hairless guinea pig skin at an average depth of 100 microm with no projections deeper than 300 microm. Doses of I to 80 microg of OVA were delivered via 1- or 2-cm2 systems by varying the coating solution concentration and wearing time. Delivery rates were as high as 20 microg in 5 s. In a prime and boost dose immune response study, OVA-coated Macroflux was most comparable to equivalent doses injected intradermally. Higher antibody titers were observed when OVA was administered with the microprojection array or intradermally at low doses (1 and 5 microg). Macroflux administration at 1- and 5-microg doses gave immune responses up to 50-fold greater than that observed after the same subcutaneous or intramuscular dose. Dry coating an adjuvant, glucosaminyl muramyl dipeptide, with OVA on the Macroflux resulted in augmented antibody responses. CONCLUSIONS: Macroflux skin patch technology provides rapid and reproducible intracutaneous administration of dry-coated antigen. The depth of skin penetration targets skin immune cells; the quantity of antigen delivered can be controlled by formulation, patch wearing time, and system size. This novel needle-free patch technology may ultimately have broad applications for a wide variety of therapeutic vaccines to improve efficacy and convenience of use.