Balakrishna Hosmane

ABT‐335, the Choline Salt of Fenofibric Acid, Does Not Have a Clinically Significant Pharmacokinetic Interaction With Rosuvastatin in Humans

ABT‐335 is the choline salt of fenofibric acid under clinical development as a combination therapy with rosuvastatin for the management of dyslipidemia. ABT‐335 and rosuvastatin have different mechanisms of actions and exert complementary pharmacodynamic effects on lipids. The current study assessed the pharmacokinetic interaction between the 2 drugs following a multiple‐dose, open‐label, 3‐period, randomized, crossover design. Eighteen healthy men and women received 40 mg rosuvastatin alone, 135 mg ABT‐335 alone, and the 2 drugs in combination once daily for 10 days. Blood samples were collected prior to dosing on multiple days and up to 120 hours after day 10 dosing for the measurements of fenofibric acid and rosuvastatin plasma concentrations. Coadministering 40 mg rosuvastatin had no significant effect on the steady‐state Cmax, Cmin, or AUC24 of fenofibric acid (P > .05). Coadministering ABT‐335 had no significant effect on the steady‐state Cmin or AUC24 of rosuvastatin (P > .05) but increased Cmax by 20% (90% confidence interval: 12%–28%). All 3 regimens were generally well tolerated with no clinically significant changes in clinical laboratory values, vital signs, or electrocardiograms during the study. Results from this study demonstrate no clinically significant pharmacokinetic interaction between ABT‐335 at the full clinical dose and rosuvastatin at the highest approved dose.

A Simulation Study of Power in Thorough QT/QTc Studies and a Normal Approximation for Planning Purposes

We report the results of a simulation study on power in a thorough QT/QTc study with a four-period crossover design in which the treatments are placebo, positive control, higher dose of investigational drug, and therapeutic dose of investigational drug. In the study, QTc interval values were obtained for several specified times during treatment. An assessment of noninferiority of the higher dose to placebo was performed by the intersection-union test within the framework of a linear mixed-effects analysis. With a noninferiority bound of 8 ms and a peak drug effect of 4 ms, it is found that 96 or more subjects would be required to have 80% power, but with a noninferiority bound of 10 ms, 48 subjects give more than an estimated 80% power if the number of times of measurement is 10 or fewer. For the purposes of planning such a study, a power approximation based on the multivariate normal distribution of the estimator of the difference in means of high dose of investigational drug and placebo is presented. The approximated power and the power estimate from the simulation study were quite close.

Randomized, Placebo-Controlled, Double-Blind, Parallel Design Trial of the Efficacy and Safety of Zestra® in Women With Mixed Desire/Interest/Arousal/Orgasm Disorders

Over 256 women, age 21 to 65, with acquired mixed female sexual disorders participated in a 16-week randomized, placebo-controlled, double-blind study of Zestra®, a topical botanical preparation. Routine outcome instruments measured efficacy and safety. Zestra® was well tolerated. The only significant safety finding was mild-to-moderate genital burning seen only in Zestra®-treated subjects (14.6%). Zestra® provided significant desire, arousal, and treatment satisfaction benefits for a broadly generalized group of women with sexual difficulties.

On shrinkage estimation of the exponential location parameter

Under the assumption that the exponential distribution is a reasonable model for a given population, some shrinkage estimators for the location parameter based on type 1 and type II censored samples have been derived. It is shown that these estimators dominate maximum likelihood estimators (MLEs) asymptotically under the mean squared error (MSE) criterion. A Monte Carlo study shows a significant improvement of our estimators over MLEs in terms of MSE for small samples.

An empirical investigation of chi-square tests for the hypothesis of no three-factor interaction in I × J×K contingency tables

This paper is concerned with comparison of chi-square tests for the hypothesis of no three-factor interaction in a I ×J×K contingency table. Monte Carlo techniques are used to study the behavior of the Pearson chi-square statixtic X 2,likelihood ratio statistic G 2, Freeman-Tukey statistic T 2,power divergence statistic I(2/3) suggested by Cressie and Read (1984) and the Wald statistic W for small and moderate sample sizes. Results suggest that in comparison to other test criteria, the Pearson chi-square statistic X 2 and the power divergence statistic I(2/3) attain levels that are quite close to the nominal values. Also, these statistics X 2 and I(2/3) have similar powers. HoweverX 2 has a slight edge over I(2/3).

The Relationship between Terazosin Dose and Blood Pressure Response in Hypertensive Patients

A double‐blind, randomized, placebo‐controlled, multicenter study was conducted to describe the dose‐response curve for terazosin on blood pressure. A total of 128 patients with mild to moderate essential hypertension (supine diastolic blood pressure, 100 to 114 mmHg) participated in the study. The study consisted of a 4‐week single‐blind placebo lead‐in period and a 14‐week double‐blind treatment period. Patients were randomized in equal numbers to four parallel treatment groups: terazosin 1, 2, and 5 mg; terazosin 2, 5, and 10 mg; terazosin 20, 40, and 80 mg; and placebo. The 24‐hour ambulatory blood pressure measurements were performed at the end of the placebo lead‐in period and at the end of each 4‐week fixed‐dose period. The nonlinear, mixed‐effect model computer program was used to analyze the dose‐response relationship. There was a strong dose‐response relationship between fall in blood pressure and the 1 to 10 mg terazosin dose, as well as a plateauing of response for terazosin doses above 10 mg. The maximum antihypertensive response (Emax) to terazosin was 10.7 mmHg for systolic blood pressure and 8.0 mmHg for diastolic blood pressure. The daily dose of terazosin, which produced 50% of the maximum response (ED50), was 3.0 mg for systolic blood pressure and 1.5 mg for diastolic blood pressure. The results of this study suggest that although some patients may benefit from terazosin doses of greater than 10 mg, doses up to 10 mg will maximize therapeutic benefit for most patients, with acceptable side effects.

Improved likelihood ratio tests and pearson chi-square tests for independence in two dimensional contingency tables

When an I×J contingency table has many cells having very small frequencies, the usual chi-square approximation to the upper tail of the likelihood ratio goodness-of-fit statistic, G2 and Pearson chi-square statistic, X2, for testing independence, are not satisfactory. In this paper we consider the problem of adjusting G2 and X2. Suitable adjustments are suggested on the basis of analytical investigation of asymptotic bias terms for G2 and X2. A Monte Carlo simulation is performed for several tables to assess the adjustments of G2 and X2 in order to obtain a closer approximation to the nominal level of significance.

Antihypertensive and Metabolic Effects of Concomitant Administration of Terazosin and Methyclothiazide for the Treatment of Essential Hypertension

The efficacy and safety of once‐daily 2.5‐ or 5.0‐mg methyclothiazide (MCTZ) added to once‐daily 5.0‐mg terazosin (TRZ) versus 5.0‐mg TRZ alone was evaluated in this double‐blind, multicenter study. All patients received TRZ during a 6‐week titration period. Hypertensive patients (222) (mean blood pressure of 159/104 mm Hg) were randomized to one of three treatment groups: TRZ alone (N = 76); TRZ + MCTZ‐2.5 mg (N = 74); and TRZ + MCTZ‐5.0 mg (N = 72) for the 8‐week double‐blind period. Changes in the supine and standing SBP/DBP from preTRZ period were: TRZ alone (−4.8/−8.1 and −2.0/−6.1 mm Hg); TRZ + MCTZ‐2.5 mg (−17.3/−12.4 and −16.0/−11.2 mm Hg); and TRZ + MCTZ‐5.0 mg (−20.6/−14.4 and −23.3/−14.6 mm Hg). Blood pressure changes in the combination groups were significantly greater than those in the TRZ alone group. However, there were no statistically significant differences between the TRZ + MCTZ‐2.5‐mg and TRZ + MCTZ‐5.0‐mg groups. The combination of TRZ and MCTZ tends to mitigate the adverse effects on serum glucose, uric, potassium and lipids usually associated with thiazide diuretics. Thus, combination treatment that begins with TRZ and adds MCTZ is effective in lowering blood pressure without any significant adverse metabolic effects.

Sample Size and Power Estimation in Thorough QT/QTc Studies with Parallel Group Design

We developed analytical results for computing the power in a thorough QT/QTc study with a four-group parallel design in which the treatments are placebo, positive control, supratherapeutic dose of investigational drug, and therapeutic dose of investigational drug. An assessment of non-inferiority of the supratherapeutic dose to placebo is performed by the intersection–union test within the framework of a linear mixed effects analysis with baseline covariate. The power estimates obtained using analytical results and from the simulation study were presented and they are quite close and hence the analytical results could be used for computing power and sample size in the planning stage of a thorough QT/QTc study.

On a generalized stein estimator of regression coefficients

This paper studies a generalized Stein estimator of regression coefficients. The small disturbance approximations for the bias and mean square error matrix of the estimator are derived and a necessary and sufficient condition is obtained for the estimator to dominate the ordinary least squares estimator under the mean square error criterion.