Evaluation of Methods for Estimating Time to Steady State with Examples from Phase 1 Studies

An overview is provided of the methodologies used in determining the time to steady state for Phase 1 multiple dose studies. These methods include NOSTASOT (no-statistical-significance-of-trend), Helmert contrasts, spline (quadratic) regression, effective half life for accumulation, nonlinear mixed effects modeling, and Bayesian approach using Markov Chain Monte Carlo (MCMC) methods. For each methodology we describe its advantages and disadvantages. The first two methods do not require any distributional assumptions for the pharmacokinetic (PK) parameters and are limited to average assessment of steady state. Also spline regression which provides both average and individual assessment of time to steady state does not require any distributional assumptions for the PK parameters. On the other hand, nonlinear mixed effects modeling and Bayesian hierarchical modeling which allow for the estimation of both population and subject-specific estimates of time to steady state do require distributional assumptions on PK parameters. The current investigation presents eight case studies for which the time to steady state was assessed using the above mentioned methodologies. The time to steady state estimates obtained from nonlinear mixed effects modeling, Bayesian hierarchal approach, effective half life, and spline regression were generally similar

Search for eccentric black hole coalescences during the third observing run of LIGO and Virgo

Despite the growing number of confident binary black hole coalescences observed through gravitational waves so far, the astrophysical origin of these binaries remains uncertain. Orbital eccentricity is one of the clearest tracers of binary formation channels. Identifying binary eccentricity, however, remains challenging due to the limited availability of gravitational waveforms that include effects of eccentricity. Here, we present observational results for a waveform-independent search sensitive to eccentric black hole coalescences, covering the third observing run (O3) of the LIGO and Virgo detectors. We identified no new high-significance candidates beyond those that were already identified with searches focusing on quasi-circular binaries. We determine the sensitivity of our search to high-mass (total mass M>70 M⊙) binaries covering eccentricities up to 0.3 at 15 Hz orbital frequency, and use this to compare model predictions to search results. Assuming all detections are indeed quasi-circular, for our fiducial population model, we place an upper limit for the merger rate density of high-mass binaries with eccentricities 0<e≤0.3 at 0.33 Gpc−3 yr−1 at 90\% confidence level

Ultralight vector dark matter search using data from the KAGRA O3GK run

Among the various candidates for dark matter (DM), ultralight vector DM can be probed by laser interferometric gravitational wave detectors through the measurement of oscillating length changes in the arm cavities. In this context, KAGRA has a unique feature due to differing compositions of its mirrors, enhancing the signal of vector DM in the length change in the auxiliary channels. Here we present the result of a search for U(1)B−L gauge boson DM using the KAGRA data from auxiliary length channels during the first joint observation run together with GEO600. By applying our search pipeline, which takes into account the stochastic nature of ultralight DM, upper bounds on the coupling strength between the U(1)B−L gauge boson and ordinary matter are obtained for a range of DM masses. While our constraints are less stringent than those derived from previous experiments, this study demonstrates the applicability of our method to the lower-mass vector DM search, which is made difficult in this measurement by the short observation time compared to the auto-correlation time scale of DM

An Oral Contraceptive Drug Interaction Study

This article, created by Thomas E. Bradstreet and Deborah L. Panebianco of Merck Research Laboratories, describes data from a drug interaction study of a new drug and a standard oral contraceptive therapy. Both normal theory and distribution-free statistical analyzes are provided along with a notable amount of graphical insight into the dataset. The article itself contains sections such as: an introduction, bioavailability, bioequivalence, interaction studies, motivation for the study, an initial exploration of the data, the model with ANOVA, software employed and references. This is an excellent look at the procedures behind medical testing

Relative bioavailability of diazoxide, manufactured at two different international locations, in healthy participants under fasting conditions: an open-label, two-stage, adaptive, sequential two-period crossover study

Abstract Theoretically, calculating the sample size required for achieving the desired power is straightforward with true coefficient of variance (CV) estimates and true test/reference geometric mean ratios (GMRs) of selected parameters. However, true variance estimates are often not known and are, instead, based on published literature or pilot trials. An open-label, two-stage, adaptive, sequential two-period crossover study was used to determine relative bioavailability of a single 100 mg dose of diazoxide manufactured at two different international sites. This design was utilized due to the lack of intra-subject variance estimation data for diazoxide pharmacokinetic parameters. Second-stage sample size was estimated using intra-participant variance from the first stage. Thirty-six healthy adults (age, 18–55 years) were randomized (1:1) to receive a single dose of test/reference product, a single dose of diazoxide (100 mg capsule), under fasting conditions with crossover after 14 days. GMRs (90% confidence interval [CI]) of area under curve from time zero to infinity (AUC0-inf) and maximum plasma concentrations (Cmax) of test versus reference product were 1.06 (1.03–1.10) and 1.17 (1.14–1.20), respectively. Bioequivalence was declared at stage 1 because 90% CIs were between 0.80 and 1.25; stage 2 was not initiated since the estimated power was >99% for both AUC0-inf and Cmax. Results of this study demonstrate efficient use of an adaptive, two-stage sequential design to assess bioequivalence. Similar study design may be effectively used in other bioequivalence studies wherein CV and GMRs of relevant parameters are unknown and sample size estimation is difficult

Odanacatib, a selective cathepsin K inhibitor to treat osteoporosis: safety, tolerability, pharmacokinetics and pharmacodynamics: results from single oral dose studies in healthy volunteers

Aims: To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of odanacatib (ODN), a cathepsin K inhibitor, in humans. Methods: Two double-blind, randomized, placebo-controlled, single oral dose studies were performed with ODN (2600mg) in 44 healthy volunteers (36 men and eight postmenopausal women). Results: Adverse experiences (AEs) with single doses of ODN were transient and mild to moderate, with the exception of one severe AE of gastroenteritis. Headache was the most frequent AE. After absorption of ODN (initial peak concentrations 46h postdose), plasma concentrations exhibited a monophasic decline, with an apparent terminal half-life of approximate to 4080h. The area under the curve0-24 hours (AUC024h), concentration at 24 hours (C24h) and maximum concentration (Cmax,overal) increased in a less than dose-proportional manner from 2 to 600mg. Administration of ODN with a high-fat meal led to approximate to 100% increases in AUC024h, Cmax,day1, Cmax,overall and C24h relative to the fasted state, while administration with a low-fat meal led to a approximate to 30% increase in those parameters. Reduction of biomarkers of bone resorption, the C- and N-telopeptides of cross-links of type I collagen, (CTx and NTx, respectively), was noted at 24h for doses 5mg and at 168h postdose for 10mg. In postmenopausal women administered 50mg ODN, reductions in serum CTx of 66% and urine NTx/creatinine (uNTx/Cr) of 51% relative to placebo were observed at 24h. At 168h, reductions in serum CTx (70%) and uNTx/Cr (78%) were observed relative to baseline. Pharmacokinetic/pharmacodynamic modeling characterized the ODN concentration/uNTx/Cr relation, with a modeled EC50 value of 43.8nM and approximate to 80% maximal reduction. Conclusions: Odanacatib was well tolerated and has a pharmacokinetic and pharmacodynamic profile suitable for once weekly dosing