RESUMEN
AIMS: Plasma pharmacokinetics permit the assessment of efficacy and safety of inhaled drugs, and possibly their bioequivalence to other inhaled products. Correlating drug product attributes to lung deposited dose is important to achieving equivalence. PUR0200 is a spray-dried formulation of tiotropium that enables more efficient lung delivery than Spiriva® HandiHaler® (HH). The ratio of tiotropium lung-to-oral deposition in PUR0200 was varied to investigate the impact of particle size on tiotropium pharmacokinetics, and the contribution of oral absorption to tiotropium exposure was assessed using charcoal block. METHODS: A seven-period, single-dose, crossover study was performed in healthy subjects. PUR0200 formulations differing in dose and aerodynamic particle size were administered in five periods and Spiriva HH in two periods. In one period, Spiriva HH gastrointestinal absorption was blocked with oral charcoal. Tiotropium plasma concentrations were assessed over 8 h after inhalation. RESULTS: PUR0200 pharmacokinetics were influenced by aerodynamic particle size and the ratio of lung-to-oral deposition, with impactor sized mass (ISM) correlating most strongly with exposure. Formulation PUR0217a (3 µg tiotropium) lung deposition was similar to Spiriva HH (18 µg) with and without charcoal block, but total PUR0200 exposure was lower without charcoal. The Cmax and AUC0-0.5h of Spiriva HH with and without charcoal block were bioequivalent; however, Spiriva HH AUC0-8h was lower when gastrointestinal absorption was inhibited with oral charcoal administration. CONCLUSIONS: Pharmacokinetic bioequivalence indicative of lung deposition and efficacy can be achieved by matching the reference product ISM. Due to reduced oral deposition and more efficient lung delivery, PUR0200 results in a lower AUC0-t than Spiriva HH due to reduced absorption of drug from the gastrointestinal tract.
Asunto(s)
Broncodilatadores/farmacocinética , Absorción Gastrointestinal , Mucosa Bucal/metabolismo , Bromuro de Tiotropio/farmacocinética , Administración por Inhalación , Adulto , Área Bajo la Curva , Broncodilatadores/administración & dosificación , Broncodilatadores/química , Estudios Cruzados , Inhaladores de Polvo Seco , Femenino , Voluntarios Sanos , Humanos , Masculino , Tamaño de la Partícula , Proyectos Piloto , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Equivalencia Terapéutica , Bromuro de Tiotropio/administración & dosificación , Bromuro de Tiotropio/química , Adulto JovenRESUMEN
BACKGROUND AND OBJECTIVE: A novel tiotropium bromide monodose capsule dry powder inhaler (DPI) formulation and device have been developed. The formulation was based on a spray-dried matrix that enhances the aerosolizaton properties, allowing a less active tiotropium metered dose (13 µg/capsule) while maintaining the same delivered dose (10 µg/actuation). This study describes the pharmacokinetic bioequivalence to the reference product. METHODS: This randomized, two-stage, crossover, semi-replicate (three-way) study was performed in healthy volunteers. In each study period, subjects received a single dose of two capsules (20 µg delivered dose) of the study medication, separated by a 14-day washout period: tiotropium 10 µg delivered dose (Laboratorios Liconsa, Spain) and Spiriva HandiHaler(®) (Boehringer Ingelheim Pharma GmbH & Co KG, Germany). Blood samples were obtained up to 48 h post-dose to evaluate the comparative bioavailability. Tiotropium was measured in plasma by means of dual stage liquid-liquid extraction followed by the two-dimensional ultra-high performance liquid chromatography sensitive sub-pg/mL bioanalytical method. The main pharmacokinetic parameters were maximum plasma concentration (C max), area under the concentration-time curve (AUC) from time zero hours to the last observed concentration at time t (AUC t ), and AUC from time zero hours to 30 min (AUC0.5). Bioequivalence was accepted if the 90.20 % confidence interval (CI) for the ratio test/reference of the primary pharmacokinetic parameters lay within the acceptance range of 80-125 %. Safety assessment was a secondary endpoint. RESULTS: A total of 30 subjects were randomized and bioequivalence was demonstrated for all primary pharmacokinetic parameters: C max (CI 87.26-106.60 %), AUC t (CI 101.33-111.64 %), and AUC0.5 (CI 97.95-113.49 %). Both study treatments were well tolerated (four non-serious adverse events [AEs] were reported in four subjects: one AE before any product administration, two AEs after test product administration; and one AE after reference product administration). CONCLUSIONS: Both products containing tiotropium 10 µg delivered-dose DPI were bioequivalent and showed good tolerability and a similar safety profile.
Asunto(s)
Bromuro de Tiotropio/farmacocinética , Administración por Inhalación , Adolescente , Adulto , Área Bajo la Curva , Cápsulas , Cromatografía Líquida de Alta Presión , Estudios Cruzados , Composición de Medicamentos , Inhaladores de Polvo Seco , Femenino , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Equivalencia Terapéutica , Bromuro de Tiotropio/administración & dosificación , Bromuro de Tiotropio/efectos adversos , Adulto JovenRESUMEN
A monocentric, open, randomised, single-dose, six-period crossover trial was carried out in healthy volunteers under fasting conditions to establish the most appropriate study design for a pivotal bioequivalence trial with acarbose (CAS 56180-94-0) regarding a) dosage of the drug, b) type of carbohydrate load, c) type of primary endpoint, and d) sample size. 50 g sucrose or 50 g starch were used as carbohydrate load. Acarbose was administered in doses of 50 and 200 mg. Blood glucose and breath hydrogen were evaluated as endpoints. Both acarbose doses reduced the effect of carbohydrate load. Blood glucose: no statistically significant difference could be noted between the overall effect of 50 mg and that of 200 mg acarbose irrespective of the type of carbohydrate load. Breath hydrogen: an influence could be shown only for sucrose as carbohydrate load. Practically no effect was observed with starch. The overall increase of effect is by more than 200% with sucrose when the dose of acarbose increases from 50 to 200 mg. This difference between the effects of both doses of acarbose on breath hydrogen is statistically significant. For a pivotal trial, sucrose is the most appropriate type of carbohydrate load, baseline adjusted area under the breath hydrogen response is the most appropriate primary endpoint, and a dose of 100 mg acarbose is the most appropriate dosage. A total number of 100 subjects will be needed for proving pharmacodynamic equivalence between two acarbose products in a pivotal trial.
Asunto(s)
Acarbosa/farmacología , Glucemia/metabolismo , Carbohidratos de la Dieta/farmacología , Hidrógeno/metabolismo , Hipoglucemiantes/farmacología , Almidón/farmacología , Sacarosa/farmacología , Adolescente , Área Bajo la Curva , Pruebas Respiratorias , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Inhibidores de Glicósido Hidrolasas , Humanos , Masculino , Adulto JovenRESUMEN
The pharmacokinetic properties of a new recombinant erythropoietin preparation (epoetin zeta, CAS 604802-70-2) compared to a reference product (epoetin alfa, CAS 113427-24-0) were analyzed after a single intravenous bolus injection of 10,000 IU in a two-period crossover design in 24 healthy volunteers. Peripheral venous blood samples were obtained pre-dose, and 0:05, 0:20, 0:40, 1:00, 1:20, 1:40, 2:00, 3:00, 4:00, 6:00, 8:00, 12:00, 24:00, 36:00, 48:00, and 72:00 hours post dosing. Samples of 24 volunteers were analyzed by means of a specific immunoassay (ELISA). Three volunteers were excluded from statistical analysis due to a paravasal injection in one of both study periods with resulting low plasma levels of epoetin. Comparison of both preparations showed nearly identical pharmacokinetic properties after intravenous administration. The usual bioequivalence limits were fulfilled for all relevant pharmacokinetic parameters.
Asunto(s)
Eritropoyetina/farmacocinética , Hematínicos/farmacocinética , Adolescente , Adulto , Área Bajo la Curva , Química Farmacéutica , Estudios Cruzados , Ensayo de Inmunoadsorción Enzimática , Epoetina alfa , Femenino , Humanos , Inyecciones Intravenosas , Masculino , Persona de Mediana Edad , Proteínas RecombinantesRESUMEN
The subcutaneous bioavailability of a new recombinant erythropoietin preparation (epoetin zeta, CAS 604802-70-2) and the pharmacokinetic properties of this drug compared to a reference product (epoetin alfa, CAS 113427-24-0) were analyzed after a single intravenous bolus injection or subcutaneous injection of 10,000 IU in a three-period crossover design in 48 healthy volunteers. Peripheral venous blood samples were obtained pre-dose, and 0:05, 0:20, 0:40, 1:00, 1:20, 1:40, 2:00, 3:00, 4:00, 6:00, 8:00, 12:00, 24:00, 36:00, 48:00, and 72:00 h post dosing. Samples from 48 volunteers were analyzed by means of a specific immunoassay (ELISA). The systemic bioavailability of epoetin zeta after subcutaneous administration is approximately 24%. Comparison of both preparations showed nearly identical pharmacokinetic properties after subcutaneous administration. The usual bioequivalence limits were fulfilled for all relevant pharmacokinetic parameters.
Asunto(s)
Eritropoyetina/farmacocinética , Hematínicos/farmacocinética , Adolescente , Adulto , Área Bajo la Curva , Química Farmacéutica , Estudios Cruzados , Método Doble Ciego , Ensayo de Inmunoadsorción Enzimática , Epoetina alfa , Femenino , Semivida , Humanos , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , Proteínas RecombinantesRESUMEN
The results of pooled plasma analysis in a bioequivalence trial provide information comparable with that of the mean concentration vs. time curves for each formulation. Although it seems feasible that pool plasma analysis will have similar or even greater advantages in cases of bioequivalence trials with a parallel-group design, no such data has been published in the literature probably due to the limited number of such trials. The present study was designed with the aim to investigate the prediction value of pool plasma analysis in a bioequivalence trial with phenprocoumon (CAS 435-972). The study was performed as a monocentric, randomized, open clinical trial in two parallel groups of healthy male volunteers (31 per group), all of which received a single oral dose of 3 mg phenprocoumon. Serial blood samples were drawn for the pharmacokinetic analysis pre-dose, and 0.33, 0.67, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 12, 24, 48, 96, 144, 192, and 240 h after drug administration. Pool plasma was prepared for each sampling point and each formulation. Drug concentrations were measured by means of an HPLC method. A comparison between the pool plasma results and the results of individual analysis revealed a very good correspondence regarding the parameters AUC, Cmax and t(max). The present trial demonstrates that the method of time-wise pooling provides reliable information not only in cross-over trials but also in trials with parallel groups of volunteers.