Particle size and gastrointestinal absorption influence tiotropium pharmacokinetics: a pilot bioequivalence study of PUR0200 and Spiriva HandiHaler.

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.

Safety, influence on the endometrium, sonographic changes and bleeding profile after 13 cycles with the new drospirenone only pill (DOP) for contraception.

BACKGROUND: The primary objective of the present trial was to assess the endometrial safety of a new oral contraceptive containing 4 mg drospirenone for a total duration of 13 cycles of 28 days each: 24 days of active treatment followed by 4 days placebo treatment per treatment cycle. MATERIALS AND METHODS: This was a single-center, open-label, multiple-dose study on healthy female subjects at risk of pregnancy. Twenty one (= safety population set) pre-menopausal female Caucasian subjects started treatment with the study medication. The mean age was 29.0 years (range 19.0-36.0 years). Four subjects terminated the trial prematurely for the following reasons: on the subject's request (n=2), due to an adverse event (n=1) and due to loss of contact (n=1). Seventeen subjects completed the planned duration of 13 cycles of open treatment with the test product (each cycle of 28 days). RESULTS: At visit 1 (pre-treatment), the biopsy result in the safety population set was proliferative in 14 cases and secretory in seven cases. At visit 7, four cases showed an inadequate result (insufficient tissue for diagnosis), 12 as proliferative and three as secretory. The number of biopsies with proliferative and secretory results reduced under treatment (safety population). The pre-post treatment changes in the endometrial biopsy results in the treatment completers set (n=17) showed almost no differences. At visit 1 (pre-treatment), the biopsy result was proliferative in 12 cases and secretory in five cases. At visit 7 (after 13 cycles of 28 days), four cases showed an inadequate result (insufficient tissue for diagnosis), 11 as proliferative, and two as secretory. The mean endometrial thickness in the safety population was reduced from 8.3 mm at visit 1 to 6.0 mm at visit 7. When comparing the endometrial thickness in the 21 subjects (safety population), the endometrial thickness showed a pre-post difference of 2.1 mm, whereas the endometrial thickness in the 17 study completers showed a pre-post difference of 2.5 mm (8.2 mm at visit 1-5.6 mm at visit 7). CONCLUSIONS: Drospirenone 4 mg film-coated tablet in a dosage regime of 24/4 days is, regarding endometrial histology, a safe drug. Trial registration: EudraCT Register number: 2013-002300-13.

Early pliocene hominid tooth from Galili, Somali Region, Ethiopia.

A fossil hominid tooth was discovered during survey at Galili, Somali region, Ethiopia. The geological and faunal context indicate an Early Pliocene age. The specimen (GLL 33) consists of an almost complete lower right third molar likely representing a male individual of advanced age-at-death. Its comparative metrical, morphological and (micro)structural analysis (supported by a microtomographic record) suggests a tentative taxonomic allocation to Australopithecus cf A. afarensis.

Pharmacodynamic equivalence study of two preparations of eye drops containing dorzolamide and timolol in healthy volunteers.

OBJECTIVE: The aim of the present study was to assess the pharmacodynamic equivalence (lowering of intraocular pressure) of two preparations of eye drops containing 20 mg dorzolamide (CAS 120279-96-1) and 5 mg timolol (CAS 26839-75-8). METHOD: The study was conducted as a monocentric, observer-blinded, randomized, single-dose, two-period crossover study in 38 healthy volunteers. Each volunteer received on day 1 in each period in a random way a single dose of 1 drop of the test or the reference formulation in the conjunctival sac of the right eye separated by a wash-out period of 7 days. Measurement of intraocular pressure (IOP) of the right eye (by a blinded observer) was performed on day 1 of each study period pre-dose and 2 h post dosing by means of Goldmann applanation tonometry. In order to investigate the pharmacodynamic equivalence of both products, the two-sided 95% confidence interval was calculated for the difference of the primary target parameter (absolute decrease in IOP 2 h post dose), by means of a parametric (ANOVA) statistical method. RESULTS: The results of the statistical evaluation of the primary target parameter "absolute decrease in IOP 2 h post dose" demonstrated a decrease in the IOP of 4.72 mmHg for the eye treated with the test formulation (dorzolamide 20 mg/ml + timolol 5 mg/ml eye drops) and 4.61 mmHg for the treated with the reference formulation. The mean difference was 0.11 mmHg. The 95% confidence interval was between -0.33 and 0.55 mmHg and thus entirely within the pre-defined equivalence range (+/- 1.5 mmHg). The results of the statistical evaluation of the secondary target parameter relative (as % of baseline) decrease in IOP 2 h post dose demonstrated essentially similar effectiveness in lowering the IOP by 27.63% (test formulation) and 27.12% (reference formulation), respectively. Both drug products were well tolerated. CONCLUSION: Both formulations showed comparable results obtained at a time probably equal to the maximum effect concerning the primary target parameter lowering of IOP 2 h post dose. The safety profile of both preparations showed no difference.

Bioequivalence study of two different clopidogrel bisulfate film-coated tablets.

OBJECTIVE: The aim of the present study was to evaluate the bioequivalence of two oral clopidogrel (CAS 113665-84-2) formulations. METHOD: The study was conducted as a monocentric, open, randomized, single-dose, two-period crossover trial in 48 healthy volunteers with a duration of hospitalization of approximately 24 h after dosing on day 1 and with a real wash-out period of 7 days. Blood samples were collected for 24 h post dosing in each period. The plasma was separated and the concentrations of clopidogrel were determined by a LC-MS/MS method. AUC(0-tlast), Cmax, tmax, AUC(0-inf), MRT and t1/2 were calculated for both formulations. RESULTS: The arithmetic means of AUC(0-tlast) and Cmax were 3,656.01 pg x h/ml and 1970.22 pg/ml for the test formulation and 3771.51 pg x h/ml and 1756.52 pg/ml, respectively, for the reference formulation. The mean tmax was 1.16 h for the test and 1.13 h for the reference formulation. The point estimators of the ratios of the test and reference formulations for AUC(0-tlast) and Cmax were 1.042 and 1.115, respectively. Furthermore, the 90% confidence intervals calculated by means of ANOVA-log for the first primary endpoint of the trial, the intra-individual ratio (T/R) of AUC(0-tlast) of clopidogrel was between 0.932 and 1.165. The 90% confidence interval calculated by means of ANOVA-log for Cmax of clopidogrel was between 0.973 and 1.277. The 90% confidence intervals for both parameters were within the predefined acceptance ranges (0.80-1.25 for AUC(0-tlast) and 0.75-1.33 for Cmax). The intraindividual coefficients of variation determined by means of ANOVA-log were 33.51% for AUC(0-tlast) and 41.29% for Cmax. CONCLUSION: While both products were bioequivalent in terms of the rate and extent of absorption, the present study also confirmed a high variability for clopidogrel suggesting high volunteer numbers in bioequivalence trials.

Influence of acarbose on blood glucose and breath hydrogen after carbohydrate load with sucrose or starch.

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.

Evaluation of the pharmacokinetics of two recombinant human erythropoietin preparations: epoetin zeta and epoetin alfa. 1st Communication: A monocentric, open, randomized, single dose, two-period crossover trial in healthy volunteers.

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.

Evaluation of the pharmacokinetics of two recombinant human erythropoietin preparations: epoetin zeta and epoetin alfa. 2nd Communication: A monocentric, double-blind, randomized, single dose, three-period crossover trial in healthy volunteers.

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.