Comparison of systemic pharmacodynamic effects of two combination pressurized metered dose inhalers that deliver salmeterol and fluticasone propionate.

AIM: The aim of this study was to test the systemic pharmacodynamic effects of the salmeterol component of two pressurized metered dose inhalers that delivered a combination of salmeterol and fluticasone propionate (SM/FP). METHODS: This was a six-way crossover study in 43 adult subjects, using a single blind design (subject blinded to product and clinical assessor blinded for all measurements). Each subject received single doses of two, six, and twelve inhalations from test and reference products that delivered SM/FP as 25/125 mcg per inhalation. Heart rate, QTcB, and plasma potassium and glucose were monitored over 6 h. RESULTS: Safety equivalence was shown by relative potency analysis for primary endpoints of maximum heart rate and maximum QTcB, since the 90% confidence intervals for both endpoints were within the acceptance limit of (0.67, 1.50). There were six secondary analyses for relative potency and equivalence was met for five of these endpoints. There were also 18 pairwise comparisons performed at each dose level. No statistical differences (95% confidence intervals included zero) among these pairwise comparisons were seen at the two-inhalation dose (therapeutic dose) or the six-inhalation dose. At the supratherapeutic dose of twelve inhalations, the test product was either comparable to or statistically less than that of the reference product for all comparisons. Overall, the results demonstrated comparable systemic safety. No differences were seen between the products in reported adverse events. CONCLUSION: The safety equivalence of the systemic pharmacodynamic effects of the SM component of the test and reference SM/FP products was demonstrated.

Pharmacokinetics of continuous once-a-week combination 17ß-Estradiol/Low- or high-dose levonorgestrel transdermal delivery systems in postmenopausal women.

Two open-label, randomized, two-period, crossover studies were performed to determine the safety, delivery rates, and pharmacokinetic properties of a combination estradiol (E2)/levonorgestrel (LNG) transdermal delivery system (TDS). Study 1 enrolled 24 postmenopausal women who received a single TDS containing 4.4 mg E2 and 1.39 mg of LNG (E2/LNG Low) or E2 0.050 mg/24 hours TDS and 0.090 mg LNG oral tablet. Study 2 enrolled 44 postmenopausal women who received either E2/LNG Low or TDS containing 4.4 mg E2 and 2.75 mg LNG (E2/LNG High) weekly for a period of 4 weeks. E2, estrone (E1), LNG, and sex hormone-binding globulin (SHBG) serum concentrations were determined. Overall, both E2/LNG TDS were well tolerated and had excellent adhesion properties. The average daily delivery for E2/LNG Low was 0.045 mg for E2 and 0.0132 mg for LNG. Following weekly delivery of E2/LNG Low or High for 4 weeks, the combination of E2 with two different strengths of LNG did not alter the pharmacokinetic profile of E2. SHBG, total cholesterol, and triglycerides concentrations significantly decreased compared to baseline. Both E2/LNG Low and High TDSs were well tolerated and provided continuous drug delivery over 7 days supporting the benefits of the transdermal route of administration in optimally delivering hormonal therapy.

Comparative pulmonary function and pharmacokinetics of fluticasone propionate and salmeterol xinafoate delivered by two dry powder inhalers to patients with asthma.

BACKGROUND: This report presents results of the first human study of a new dry powder inhaler (DPI-C). DPI-C uses reverse flow cyclone technology to retain larger particles in the device and to increase efficiency of respirable drug release. The study was conducted to determine comparative pharmacokinetics (not bioequivalence) of DPI-C and DPI-A (Advair Diskus®, GlaxoSmithKline) and to establish preliminary efficacy and safety of DPI-C. METHODS: Nineteen patients with mild-moderate asthma received two treatments (randomized crossover design). Treatments were one inhalation from DPI-A labeled to deliver 100 µg fluticasone propionate and 50 µg salmeterol, or one inhalation from DPI-C which contained ∼10% less of each drug per metered dose. Prior to dosing, 10 g of charcoal was administered. FEV1 increase over baseline (measured over 12 h), plasma concentrations of fluticasone and salmeterol (measured over 12.5 h), and occurrence of adverse events were the primary measures of device performance and safety. RESULTS: Seventeen patients were evaluable. Response profiles of percent increase in FEV1 over baseline showed no statistically significant differences between devices. Peak plasma concentrations of both fluticasone (p=0.003) and salmeterol (p=0.084) were higher from DPI-C. Mean extent of absorption [area under the curve (AUC)] of fluticasone was approximately 30% greater with DPI-C, whereas AUC of salmeterol was approximately 40% greater with DPI-A. CONCLUSIONS: DPI-C provided similar improvement in pulmonary function compared with DPI-A. Pharmacokinetic results showed a greater initial absorption of salmeterol with DPI-C but greater continued absorption and a 40% greater AUC with DPI-A, which we attribute to slower but more extensive oral absorption because of the greater mass of swallowed large particles of salmeterol generated by DPI-A. No patient reported any treatment-related adverse event or use of rescue medication during this study. Determination of the significance of the observed differences in pharmacokinetics from this single-dose study requires further exploration in studies using clinically relevant dosing regimens.

A pharmaceutical comparison of different commercially available imiquimod 5% cream products.

BACKGROUND: Alternatives to the innovator product for imiquimod 5% cream are currently marketed in South America and the People's Republic of China. METHODS: Seven alternative imiquimod 5% cream products were compared with the innovator product using physiochemical tests for cream appearance, pH, drug content and presence of crystals, as well as in vitro release testing of drug using Franz diffusion cells. RESULTS: In contrast to the innovator product, which had no crystalline imiquimod, significant amounts of suspended crystalline imiquimod were found in six of the seven alternative products. In vitro release rates of imiquimod were significantly slower in these six products compared with the innovator (p<0.001). In vitro release rates of imiquimod were significantly faster than the innovator (p<0.05) for the one alternative product without crystals. CONCLUSIONS: The clinical relevance of the differences observed is unknown; however, they raise concerns about whether these alternatives are therapeutically equivalent. While a generic topical imiquimod would almost certainly require clinical studies of therapeutic equivalence for approval in countries with more stringent regulatory environment, vigilance is warranted regarding importation of pharmaceutical products labeled as 'identical' in the absence of adequate evaluations.

Cutaneous pharmacodynamics of a toll-like receptor 7 agonist, 852A, in humans.

852A is a specific toll-like receptor 7 (TLR7) agonist. Thirty-two healthy adults (8 subjects per group) received two 1-g topical applications over 400 cm(2), separated by >or= 5 days, of 852A 0.01% followed by vehicle, vehicle followed by 852A 0.1%, 852A 0.3% followed by vehicle, or vehicle followed by 852A 1.0%. Systemic absorption was minimal as 852A was not quantifiable in any serum sample up to 24 hours postadministration and was only quantifiable at 24 hours in the urine of 4 of 8 subjects after application of 852A 1.0%. No systemic adverse events were associated with drug treatment. Gene expression analysis from application site biopsies showed a >or=2-fold increase in expression for 40 genes in at least 2 subjects. CXCL9/MIG (8/32 subjects), CCL2/MCP1 (7/32), and OAS3 (5/32) were most frequently increased, followed by other type I interferon-inducible genes. Cluster analysis of the genes with a >or=2-fold increase did not reveal a definitive pattern with respect to 852A concentration or time of biopsy. Overall, single topical application of 852A up to 1.0% was well tolerated. Data gathered from these subjects are suggestive that 852A can produce increases in local gene expression consistent with TLR7 stimulation.

First in human phase I trial of 852A, a novel systemic toll-like receptor 7 agonist, to activate innate immune responses in patients with advanced cancer.

PURPOSE: Recent advances in the understanding of innate immunity suggest that an orchestrated sequence of events is required to elicit a productive immune response against cancer. We studied the systemic administration of the Toll-like receptor 7 agonist 852A, a small-molecule imidazoquinoline, in patients with advanced cancer. Preclinical studies showed that 852A stimulates plasmacytoid dendritic cells to produce multiple cytokines, such as IFN-alpha, interleukin-1 receptor antagonist, and IFN-inducible protein-10. Our goal was to define the tolerated dose, pharmacokinetics, pharmacodynamics, and immunologic effects of 852A in humans. EXPERIMENTAL DESIGN: Eligible adult patients with refractory solid organ tumors received i.v. 852A thrice weekly for 2 weeks. Patients who had responses or stable disease were eligible for additional cycles. RESULTS: Twenty-five patients (median age, 55.0 years; 72% male) were enrolled in six cohorts at dose levels of 0.15 to 2.0 mg/m(2). Serum drug levels showed dose proportionality and no evidence of drug accumulation. The maximum tolerated dose was 1.2 mg/m(2); higher doses were limited by fatigue and constitutional symptoms. Increases in IFN-alpha, interleukin-1 receptor antagonist, and IFN-inducible protein-10, immunologic activity, and clinical symptoms were observed in all patients receiving dose levels > or =0.6 mg/m(2). Significant correlations were found between pharmacodynamic biomarkers and pharmacokinetic variables, and an objective clinical response was seen. CONCLUSIONS: 852A was safely administered i.v. at doses up to 1.2 mg/m(2) thrice weekly for 2 weeks with transient or reversible adverse effects. This novel Toll-like receptor 7 agonist is biologically active and holds promise for stimulating innate immune responses. Future trials are warranted to assess its therapeutic role in patients with cancer.

Pharmacokinetics of 852A, an imidazoquinoline Toll-like receptor 7-specific agonist, following intravenous, subcutaneous, and oral administrations in humans.

852A is an imidazoquinoline Toll-like receptor 7 agonist undergoing evaluation for the systemic treatment of cancer. 852A was administered to 6 healthy subjects as 3 rising subcutaneous doses (0.5 to 1.0 to 2.0 mg), to 6 subjects as 3 oral doses (10.0 to 20.0 to 15.0 mg, the third dose being a de-escalation), and to 6 subjects as a 2.0-mg dose by the subcutaneous, intravenous, and oral routes in crossover fashion. The subcutaneous and intravenous doses were well tolerated. One subject withdrew following the 20.0-mg oral dose because of hypotension. The 2.0-mg subcutaneous dose had 80.5% +/- 12.8% (mean +/- SD) bioavailability and gave serum concentrations comparable to intravenous administration by 30 minutes. Linear kinetics and an interferon-alpha dose response were observed for the 3 subcutaneous doses. Serum concentrations following the 2.0-mg oral dose were always lower than those following the same intravenous dose, and the oral route had a bioavailability of 26.5% +/- 7.84%. Concentrations appeared to increase with oral dose; however, large variabilities in both the rate and extent of absorption were seen between individuals. Approximately 40% of an absorbed dose was excreted unchanged in the urine. Overall, the study suggests that subcutaneous administration may be an acceptable method to deliver 852A for systemic applications.

Simultaneous estradiol and levonorgestrel transdermal delivery from a 7-day patch: in vitro and in vivo drug deliveries of three formulations.

A new drug-in-adhesive transdermal patch was developed to deliver both estradiol and levonorgestrel through the skin over a 7-day period, but at different rates. This report elucidates the in vitro and in vivo biopharmaceutical studies that were necessary during the development of this product. Three test patches had to be manufactured, all delivering estradiol at the same rate, but delivering levonorgestrel at three different rates so that a levonorgestrel dose response could be studied in the clinic. An in vitro hairless mouse skin model (HMS) using modified Franz diffusion cells was used to select the test products delivering levonorgestrel in the order of 1:2:3. HMS experiments also demonstrated that the presence of estradiol did not affect the flux of levonorgestrel. Two in vivo studies in postmenopausal women showed that at steady state (four weeks of once-weekly dosing) the three test products all delivered estradiol at comparable rates. Similarly, the levonorgestrel deliveries for the three test products were in the order expected. The target fluxes of both drugs were achieved in these three test products by varying the drug loads and patch size. That this approach was successful is evidence of the value of using the HMS penetration experiments in transdermal product development and should provide useful insights for other formulations having to develop complex systems. One of the test products is now marketed as Climara Pro.

Pharmacokinetics and safety of imiquimod 5% cream in the treatment of actinic keratoses of the face, scalp, or hands and arms.

The safety and efficacy of imiquimod 5% cream is being evaluated for the treatment of dysplastic lesions of the epidermis (actinic keratoses, AK). The objective of this clinical study was to describe the pharmacokinetics and safety of topical imiquimod during multiple dosing of AK subjects. A total of 58 adult subjects with 5 to 20 AK lesions at the treatment site applied imiquimod cream three times per week for up to 16 weeks as follows: 12 males and 11 females applied 12.5 mg imiquimod to the face; 11 males applied 25 mg to the entire balding area of the scalp; and 12 males and 12 females applied 75 mg to both hands and forearms. Pharmacokinetics and safety were assessed after the first and last doses, as well as biweekly. Imiquimod and its metabolites were measured in the serum and urine using sensitive liquid chromatography/mass spectrometry methods. Less than 0.6% of the applied doses was recovered in the urine of all subjects. Serum imiquimod levels were low, reflecting minimal dermal absorption, and increased with dose, although not proportionally. Peak levels at the end of dosing were 0.1, 0.2, and 1.6 ng/ml for the face, scalp, and hands/arms groups, respectively. A two- to fourfold accumulation was seen at the end of dosing. Local application site reactions were the most common adverse event, reported by approximately 50% of the subjects in each treatment group. The small number of systemic adverse events, including 'flu-like symptoms, were mostly mild and did not show a dose response. Thus, minimal systemic absorption and good safety margins for topical imiquimod were seen in AK subjects with doses as high as 75 mg three times per week for 16 weeks.

Pharmacokinetic comparison of beclomethasone dipropionate extrafine aerosol from two inhaler devices in children with asthma.

OBJECTIVE: The primary objective was to test the comparability of the pharmacokinetics of beclomethasone dipropionate (BDP) delivered from a pressurized extrafine solution formulation in two inhalation devices in children with asthma. One inhaler was actuated using the press and breathe (P&B) technique and the other was breath-actuated (AH); both inhalers used HFA-134a as propellant. METHODS: Eighteen children aged between 9 years and 12 years entered and completed the study; written informed consent was obtained from all patients and their legal guardians. Each patient received, according to a randomized three-period crossover design, 200 microg BDP as four inhalations from 50 microg/actuation P&B, 200 microg BDP as four inhalations from 50 microg/actuation AH, and 400 microg BDP as four inhalations from 100 microg/actuation AH. Each patient was instructed on the proper use of each device once, at the screening visit. Patients self-administered all inhalations at the same time of day during the study without further coaching. Blood samples were collected for 24 h during each period to assay for the presence of BDP and metabolites. The log-transformed pharmacokinetic data were compared using a confidence-interval approach. RESULTS: Almost all the BDP-derived material in the plasma was the active metabolite beclomethasone 17-monopropionate; pharmacokinetic analyses were only performed for this metabolite. The ratios each of the pharmacokinetic parameters maximum plasma concentration (C(max)) and area under the plasma concentration-time curve (AUC), between the AH and P&B inhaler devices, were 0.94 and 1.1, respectively, and the corresponding 95% confidence intervals demonstrated comparability of the devices. Dose proportionality of C(max) and AUC between the 200-microg and 400-microg doses was similarly shown. About twice as many inhalation errors occurred during the P&B administration as during the AH periods, but the incidence was still low and did not result in any change in pharmacokinetics. CONCLUSION: The rate and extent of drug absorption was comparable from the P&B and AH inhaler devices in children with asthma. Dose proportionality was also observed.

Pharmacokinetics of beclomethasone 17-monopropionate from a beclomethasone dipropionate extrafine aerosol in adults with asthma.

OBJECTIVE: The objectives of this study were to test the dose and strength proportionalities of beclomethasone dipropionate (BDP) delivered from two strengths of a pressurized extrafine solution formulation. METHODS: Thirty adults with mild, stable asthma, aged between 18 years and 70 years, completed the study; written informed consent was obtained from all patients. Each patient received, according to a randomized four-period crossover design, 100 microg BDP as two inhalations from 50-microg/actuation strength, 100 microg BDP as one inhalation from 100-microg/actuation strength, 400 microg BDP as eight inhalations from the 50-microg/actuation strength, and 400 microg BDP as four inhalations from the 100-microg/actuation strength. Patients self-administered all inhalations at the same time of day during the study. Blood samples were collected for 12 h during each period to assay for the presence of BDP and metabolites. The log-transformed pharmacokinetic data were compared for proportionality equivalence using a confidence-interval approach. RESULTS: Almost all the BDP-derived material in the plasma was the active metabolite beclomethasone 17-monopropionate (17-BMP). Due to low levels, neither elimination half-life ( t(1/2)) nor the area under the plasma concentration-time curve (AUC) for 17-BMP could be calculated for the 100-microg BDP doses. Dose proportionality of the 100-microg and 400-microg BDP doses, using 17-BMP maximum plasma concentration (C(max)) was demonstrated for each strength. Strength proportionality of the 50-microg and 100-microg/actuation strengths was observed for C(max) at both dose levels and for AUC at the higher dose level. The t(1/2) of 17-BMP was found to be approximately 2.8 h. CONCLUSION: This study demonstrated both the strength and dose proportionalities of the BDP extrafine aerosol. This important information will allow physicians maximum flexibility in prescribing this aerosol product.

Local versus total systemic bioavailability of beclomethasone dipropionate CFC and HFA metered dose inhaler formulations.

For inhaled formulations, the balance between desired local effects and undesired systemic activity can be expressed by L/T, where L represents bioavailability of drug from the lungs and T represents total systemic bioavailability. L/T is most useful when comparing formulations of the same inhaled substance. A high L/T is desirable as this implies efficient drug delivery to the target site, and minimization of unwanted activity from non-targeted drug delivery. The objective of this publication is to compare L/T for CFC and HFA inhaler formulations of beclomethasone dipropionate (BDP). Predictions of the L/T comparison were tested with clinical trials. From five deposition and pharmacokinetic studies, L/T ratios for CFC-BDP and HFA-BDP were calculated as 0.21 and 0.92, respectively. These ratios predicted two differences for the therapeutic use of these products: (1) a smaller dose of HFA-BDP than CFC-BDP may be required for efficacy; and (2) a smaller number of adverse events may be observed for the HFA-BDP product, when delivered at the equivalent dose, compared to the CFC comparitor. A dose-response study confirmed that less than half the dose of HFA-BDP is needed to give the same efficacy as CFC-BDP. Two safety studies that measured adrenal suppression demonstrated less suppression with HFA-BDP than with a comparable efficacious dose of CFC-BDP. It is concluded that L/T is a useful parameter that incorporates the systemic contributions of lung deposition and pharmacokinetics. It is recommended that this parameter be considered whenever deposition and pharmacokinetic data for two formulations of the same inhaled substance are compared.

Pharmacokinetics of HFA-134a: A Preliminary Report.

HFA-134a blood levels from four clinical studies were combined to give a preliminary description of its population pharmacokinetics. HFA-134a was absorbed promptly and was eliminated with a half-life of 5.1 min.

Serum Estradiol and Estrone Levels During 3 Weeks of Alternate-Site and Same-Site Applications of a Once-A-Week Drug-in-Adhesive Transdermal Estradiol Patch.

This open-label, randomized crossover trial was conducted in healthy postmenopausal women to characterize the serum estradiol and estrone profiles from a once-a-week transdermal estradiol patch applied repeatedly to the same site or to alternate sites on the abdomen over a 3-week period. Similar mean serum estradiol and estrone profiles and circulating estradiol:estrone ratios of approximately 1.0 were observed for both patch application regimes. Repeated application to the same or alternate sites did not result in an accumulation of exogenous estradiol or in a statistically significant increase in application-site reactions. Although the once-a-week transdermal estradiol patch should be applied to alternate sites to reduce the likelihood of dermatologic reactions, accidental application site overlap should not result in an increase in serum estradiol and estrone concentrations.

Bioequivalence Comparison of Two Drug-in-Adhesive Transdermal Nitroglycerin Patches.

Plasma concentrations of nitroglycerin, 1,2-dinitroglycerin and 1,3-dinitroglycerin in 50 healthy male subjects who received single 24-h applications of two 0.6 mg/h drug-in-adhesive transdermal nitroglycerin patch formulations were compared for the purpose of establishing bioequivalence. The rates of appearance and elimination of nitroglycerin and both dinitro metabolites were the same for both patch treatments. The pharmacokinetic and statistical analyses indicated that the 20-cm(2) test patch met the current two one-sided t-test criteria for bioequivalence with the 30-cm(2) reference patch for nitroglycerin and both dinitro metabolites, even though the reference patch was 50% larger in size and contained 120% more nitroglycerin than the test patch. A likely explanation for the equivalence in drug delivery with a smaller patch is that the test patch maintained more intimate skin contact than did the reference patch. This study shows that strict bioequivalence criteria can be met with a highly variable drug such as nitroglycerin.