The Pharmacokinetics of Fluticasone Furoate Given Intranasally in Healthy Subjects Using an Ultra-Sensitive Analytical Assay.

PURPOSE: It has been previously shown that the complete pharmacokinetic profile, in particular the elimination phase, of intranasal fluticasone furoate has not been fully characterized due to the inability to quantify concentrations at low enough levels. This study was designed to evaluate the pharmacokinetic profile of intranasal FF using a validated, ultra-sensitive analytical method in healthy subjects. METHODS: This was an open-label, single-dose, two-period, one-treatment, crossover study. A dose of 880 µg fluticasone furoate was administered intra nasally. Blood samples for pharmacokinetic analysis were collected at 23 time points up to 36 h and analyzed for FF plasma levels using a lower limit of quantitation (LLOQ) of 0.1 pg/mL. Medical and adverse events (AE) were monitored throughout the study. RESULTS: Eighteen subjects were enrolled in and 17 completed the study. The results showed that all 17 subjects had measurable fluticasone furoate plasma concentrations at all time points with a clearly defined elimination phase, thus allowing estimation of AUCinf and t1/2. Median Tmax was 1.33 h (range=0.75-6.00), mean Cmax was 13.05±7.59 pg/mL, mean AUCt was 148.48±77.76 pg/mL*h, mean AUCinf was 279.07±187.81 pg/mL*h, and mean t1/2 was 31.67±29.23 h. In total 4 subjects (22.2%) experienced 4 AEs. CONCLUSION: Using a lower LLOQ than what has been previously reported, a complete characterization of intranasal fluticasone furoate pharmacokinetics, including a clearly defined terminal elimination phase, was achieved. This method will allow for further investigations into the pharmacokinetics of fluticasone furoate.

A Pharmacokinetic Evaluation of Dabigatran Etexilate, Total Dabigatran, and Unconjugated Dabigatran Following the Administration of Dabigatran Etexilate Mesylate Capsules in Healthy Male and Female Subjects.

PURPOSE: Due to bioanalytical limitations it was previously not possible to evaluate the pharmacokinetics of dabigatran etexilate. We have developed validated methods to assay dabigatran etexilate, unconjugated dabigatran, and total dabigatran that will allow for a complete investigation into the pharmacokinetics of dabigatran etexilate mesylate. This study was designed to evaluate the pharmacokinetics of these analytes in healthy subjects. METHODS: This was an open-label, single-dose, one-period, one-treatment study. A single oral dose of dabigatran etexilate mesylate capsule containing the equivalent of 150 mg dabigatran etexilate was administered to each subject. A total of 23 blood samples for pharmacokinetic analysis were collected and analyzed from each subject. Safety and tolerability were monitored throughout the study. RESULTS: Eighteen healthy subjects were enrolled, dosed, and completed the study. The dabigatran etexilate mean Cmax was 6.9±5.63 ng/mL, the median Tmax was 0.67 h (range=0.50-1.00 h), the mean AUCt was 5.32±4.82 ng/mL·h, the mean AUCinf was 5.36±4.83 pg/mL*h, and the mean t1/2 was 0.54±0.26 h. Only one subject experienced an adverse event. CONCLUSION: Using validated bioanalytical methods, a complete characterization of dabigatran etexilate, total dabigatran, and unconjugated dabigatran pharmacokinetics was achieved. Advancements in the development of new more accurate, specific, and sensitive validated bioanalytical methods such as these enable for a complete understanding of the drug's pharmacokinetics and this, in turn, can have an impact on both the drug development and the evaluation of generic formulations.

An evaluation of the pharmacokinetics of tiotropium following a single-dose inhalation in healthy subjects using an ultra-sensitive bioanalytical method.

Objective and significance: The systemic bioavailability of tiotropium following administration via inhalation is known to be very low. A validated ultra-sensitive bioanalytical method with the lowest lower limit of quantitation (LLOQ) was developed and used to evaluate the complete pharmacokinetic profile of tiotropium.Methods: This was a pharmacokinetic study performed in 18 healthy subjects. Each subject was administered a dose of 18 mcg of tiotropium from a dry powder inhaler (DPI). The subjects' plasma tiotropium concentrations were assayed with LLOQ of 0.1 pg/mL.Results: The results showed a mean Cmax of 4.98 ± 3.55 pg/mL, and a median (tmax) of 3.6 minutes (range: 1.8-12 minutes). The means for area under the concentration-time curve (AUC) from time zero hours to infinity (AUCinf) and AUC from time zero hours to the time of the last measurable tiotropium concentration (AUCt) were 51.11 ± 27.4 pg*h/mL and 37.37 ± 23.38 pg*h/mL, respectively. The mean apparent elimination half-life (t1/2) was 68.02 ± 24.55 hours. This calculated half-life is longer than what others have reported where a less sensitive LLOQ was used.Conclusion: The lower LLOQ enabled further insight into the pharmacokinetics of tiotropium that was not possible with other analytical methods. With this method, we were able to quantify tiotropium concentrations as early as one minute following drug administration and up to 144 hours after dosing. The application of this method will allow for studies to be designed properly and enable further investigations into the pharmacokinetics of tiotropium.

Evaluation of the Pharmacokinetics of Abiraterone Acetate and Abiraterone Following Single-Dose Administration of Abiraterone Acetate to Healthy Subjects.

BACKGROUND AND OBJECTIVE: Following oral administration of abiraterone acetate, the parent compound abiraterone acetate is rapidly metabolized to abiraterone. To our knowledge, bioanalytical methods to date have not been able to detect the parent compound in human plasma, and bioassay was only performed on the metabolite. A highly sensitive bioanalytical method was developed and validated to measure plasma concentrations of the parent compound. In this study, both analytes were assayed and used to evaluate the full pharmacokinetic profile of abiraterone acetate tablets. METHODS: This was an open-label, single-dose, one-period, one-treatment, pharmacokinetic study performed in 18 healthy subjects. Each subject was administered four tablets (corresponding to a total dose of 1000 mg) of abiraterone acetate. Blood samples for pharmacokinetic analysis were collected up to 60 h post-dose. Subjects' plasma concentrations for abiraterone acetate were assayed using highly sensitive validated bioanalytical methods with a lower limit of quantitation (LLOQ) of 0.5 pg/ml for abiraterone acetate and 0.1 ng/ml for abiraterone. Safety assessments were performed throughout the study. RESULTS: The pharmacokinetic results for abiraterone acetate showed a mean for the maximum plasma concentration (Cmax) of 54.67 ± 68.30 pg/ml, and a median time to maximum concentrations (tmax) of 5.53 h (range 2.67-35.00 h). The means for area under the concentration-time curve (AUC) from time 0 h to infinity (AUCinf) and AUC from time zero h to the time of the last measurable abiraterone acetate concentrations (AUCt) were 386.13 ± 266.80 pg·h/ml and 460.07 ± 378.78 pg·h/ml, respectively. The apparent elimination half-life (t1/2) showed a mean of 8.98 ± 3.92 h. None of the adverse events that affected three subjects (16.7%) were related to the study drug. CONCLUSION: The ability to detect the low plasma abiraterone acetate concentrations, in addition to abiraterone, resulted in a complete characterization of the pharmacokinetics of abiraterone acetate that was not possible with other analytical methods that only measured the metabolite. The development of new bioanalytical methods such as these will allow for a more thorough understanding of the pharmacokinetics of abiraterone acetate, and this, in turn, can have an impact on both future examinations into abiraterone acetate pharmacokinetic behaviour and the evaluation of its generic formulations.

Pharmacokinetic/pharmacodynamic evaluation of urinary cortisol suppression after inhalation of fluticasone propionate and mometasone furoate.

AIM: Fluticasone propionate (FP) and mometasone furoate (MF) are inhaled corticosteroids that possess a high ratio of topical to systemic activity. The systemic bioavailability of MF has been claimed to be minimal (1%). FP has been shown to exhibit the same degree of systemic effects, but its systemic availability is between 13 and 17%. We hypothesize that FP and MF have comparable systemic availabilities that can explain their potential to cause systemic effects. METHODS: Steady-state FP and MF trough plasma samples were determined from a clinical study by Fardon et al. in patients with persistent asthma (forced expiratory volume in 1 s = 91%). The percent plasma protein binding of FP and MF was measured using ultracentrifugation. Free FP plasma concentrations were normalized for their differences in receptor binding affinity compared with MF and linked to overnight urinary cortisol/creatinine with an inhibitory E(max). RESULTS: A plot of steady-state FP and MF total trough plasma concentrations vs. dose showed that both drugs exhibit dose linearity. MF has comparable bioavailability to FP based on the steady-state concentrations observed for the different doses. The free plasma concentration producing 50% of urinary cortisol suppression (IC(50)) for MF was not statistically different from the free, normalized IC(50) for FP. CONCLUSION: FP and MF have similar pulmonary deposition and the same potential to cause systemic side-effects due to their similar IC(50) values. The observed urinary cortisol suppression of FP and MF is in agreement with their systemic availability, their differences in plasma protein binding and receptor binding affinity.

Advances in single-entity inhaled corticosteroid therapy.

The aim of inhaled corticosteroid (ICS) therapy is to achieve optimal drug targeting by producing pulmonary effects with a minimum of systemic side effects. To achieve a favorable safety and efficacy profile, an ICS should possess the necessary pharmacokinetic and pharmacodynamic characteristics. Ideally, an ICS would have high pulmonary deposition efficiency, high systemic clearance, negligible oral bioavailability, sustained pulmonary residence time, selective binding to the corticosteroid receptor, and high plasma protein binding. Recent developments in ICS therapy have used these concepts in producing more effective compounds resulting in drugs with a very high therapeutic index. Additional developments may consider exploring improvements in delivery devices and drug formulations to improve pulmonary residence time.

Pharmacokinetic and pharmacodynamic effects of high-dose monoclonal antibody therapy in a rat model of immune thrombocytopenia.

Intravenous administration of pooled, polyvalent human immunoglobulin (IVIG) has been used for over 20 years as a therapy for immune thrombocytopenia (ITP). IVIG is available in limited quantities, and clinical preparations have been associated with the transfer of human pathogens. We have proposed that high-dose monoclonal antibody may be used in lieu of IVIG to achieve beneficial effects in the treatment of ITP. The current study investigates the effects of high-dose monoclonal antibody therapy in a rat model of ITP. Hybridoma cells secreting a murine monoclonal antiplatelet antibody (7E3) and murine monoclonal anti-methotrexate IgG (AMI) were grown in serum-free media. Next, 7E3, 8 mg kg(-1), was administered intravenously to rats following pretreatment with saline or AMI (1 g kg(-1) IV). AMI and 7E3 plasma concentrations were determined via enzyme-linked immunosorbent assay, and platelet count was determined with a Cell-Dyne hematology analyzer. Severe, transient thrombocytopenia was induced by 7E3. Platelet counts dropped to approximately 8% of initial values within 1 hour after 7E3 administration. AMI pretreatment dramatically affected 7E3-induced thrombocytopenia, significantly altering the time course of thrombocytopenia (P < .05) and significantly decreasing the severity of 7E3-induced thrombocytopenia (ie, following AMI pretreatment, nadir platelet count was greater than 8-fold that of the control group, P < .05). In addition, AMI pretreatment induced a 57% increase in 7E3 clearance (1.13 +/- 0.13 mL h(-1) kg(-1) vs 0.72 +/- 0.08 mL h(-1) kg(-1), P < .05). Consequently, high-dose monoclonal antibody therapy attenuated thrombocytopenia and produced a moderate increase in the clearance of antiplatelet antibodies in a rat model of ITP.

Pharmacokinetic/pharmacodynamic evaluation of inhalation drugs: application to targeted pulmonary delivery systems.

Inhaled therapy with either glucocorticoids and/or beta(2)-adrenergic drugs remains the mainstay of asthma treatment. In the last few years, a number of new products have been introduced into the market with the goal of improving efficacy and safety. This review article summarises the pharmacokinetic and pharmacodynamic properties of inhaled drugs for topical delivery necessary to achieve this goal. Pharmacokinetic properties include a high pulmonary deposition, low oral bioavailability, optimised pulmonary residence time and a very high systemic clearance. Optimisation of pharmacodynamic properties, such as receptor selectivity, may also yield drugs with improved pulmonary selectivity. As existing drugs also provide high efficacy and safety profiles, future developments will represent only slight improvements and quantum leap improvements are unlikely to occur.

Development and validation of enzyme-linked immunosorbent assays for quantification of anti-methotrexate IgG and Fab in mouse and rat plasma.

This laboratory is investigating the use of anti-methotrexate IgG (AMI) and anti-methotrexate Fab fragments (AMF) within an inverse targeting strategy that is designed to enhance the pharmacokinetic selectivity of intraperitoneal (i.p.) chemotherapy. The goal of this study was to develop enzyme-linked immunosorbent assays (ELISAs) to determine concentrations of AMI and AMF in mouse and rat plasma. An antigen-specific ELISA was developed for AMI and AMF in mouse and rat plasma. The assay was validated with respect to precision and accuracy by evaluating the recovery of AMI and AMF from mouse and rat plasma samples. Preliminary pharmacokinetic studies of AMI and AMF were performed in Sprague-Dawley rats and Swiss Webster mice. The animals were instrumented with a jugular vein cannula and administered AMI or AMF, 15 mg kg(-1) via the cannula. Plasma samples were taken at various time points and analyzed using the ELISA, and the observed concentration vs. time profiles were subjected to non-compartmental pharmacokinetic analyses. Standard curves for the ELISAs were found to be linear over concentration ranges of 0-250 and 0-350 ng mL(-1) for AMI and AMF, respectively. Intra-assay and inter-assay recovery of AMI and AMF from plasma samples were found to be within 15% of theoretical values. Preliminary pharmacokinetic investigations of AMI allowed estimation of AMI clearance to be 0.017 mL kg(-1) min(-1) in the rat and 0.043 mL kg(-1) min(-1) in the mouse. AMF clearance was estimated to be 0.038 and 1.93 mL kg(-1) min(-1) in the mouse and rat, respectively. In conclusion, ELISAs have been developed and validated for quantitation of AMI and AMF in rat and mouse plasma. The assays will allow further investigations of AMI and AMF pharmacokinetics.