Appetite and food intake results from phase I studies of anamorelin.

Background: Loss of appetite and body weight are potentially devastating, highly prevalent cancer complications. The ghrelin receptor is a mediator of appetite and metabolism, and anamorelin is a novel, orally administered ghrelin receptor agonist. Effects on appetite and food intake may influence body-weight gain but can be difficult to measure in multi-site studies.

An open-label clinical trial of the effects of age and gender on the pharmacodynamics, pharmacokinetics and safety of the ghrelin receptor agonist anamorelin.

Purpose: To assess the effect of age and gender on the pharmacokinetics (PK) of the ghrelin receptor agonist anamorelin.

Methods: Three demographic cohorts of healthy subjects were enrolled in this single-center, open-label study. Subjects received a single oral dose (25 mg) of anamorelin HCl.

Influence of a variable overall diameter hydrophilic acrylic sharp-edged single-piece intra-ocular lens on capsule opacification one year after surgery.

Background: To investigate the influence of the overall intraocular lens (IOL) diameter on posterior capsule opacification (PCO) formation.

Methods: In this prospective randomized clinical trial, 124 eyes of 62 patients with bilateral age-related cataract were included. Each patient received a Corneal A501D IOL in one eye and a Corneal J501D IOL in the fellow eye.

A Single-Dose Bioequivalence and Food Effect Study With Aprepitant and Fosaprepitant Dimeglumine in Healthy Young Adult Subjects.

Fosaprepitant dimeglumine, a lyophilized prodrug, is rapidly converted to aprepitant, a substance P/neurokinin 1 (NK1 ) receptor antagonist. Intravenous (IV) fosaprepitant and oral aprepitant are used in combination with other antiemetics to prevent chemotherapy-induced nausea and vomiting. This randomized, phase 1 study was designed to assess the aprepitant area under the curve (AUC0-∞ ) equivalence of a single, oral 165-mg or 185-mg dose of aprepitant to a single 150-mg fosaprepitant IV dose infused over 20 minutes, and to evaluate the effect of food on the bioavailability of the oral 165-mg and 185-mg aprepitant doses.

Pharmacokinetic drug interactions between clobazam and drugs metabolized by cytochrome P450 isoenzymes.

Study Objective: To investigate potential drug-drug interactions between clobazam and cytochrome P450 (CYP) isoenzyme substrates, inhibitors, and inducers.

Design: Two, prospective, open-label, single-center, drug-drug interaction (DDI) studies and a population pharmacokinetics analysis of seven multicenter phase II-III trials.

Setting: Clinical research unit.

Diplopia following sub-tenon's anaesthesia: an unusual complication.

Diplopia is a rare but well recognised complication following retrobulbar and peribulbar local anaesthesia but it has not been widely reported following sub-tenon's local anaesthesia (STLA). We report on a 76-year-old woman who developed vertical diplopia after left phacoemulsification. She had received a STLA.

Relative Bioavailability of an Emulsion Formulation for Omega-3-Acid Ethyl Esters Compared to the Commercially Available Formulation: A Randomized, Parallel-Group, Single-Dose Study Followed by Repeat Dosing in Healthy Volunteers.

LOVAZA (omega-3-acid ethyl esters; eicosapentaenoic acid [EPA]/docosahexaenoic acid [DHA]), with diet, lowers very high triglycerides (≥500 mg/dL) in adults. This study evaluated whether an emulsion formulation (LEM) increases the bioavailability of EPA/DHA compared to the reference formulation (RF) in healthy volunteers. Following relative bioavailability assessment, LEM, RF, and placebo were dosed for 2 weeks.

Effect of casopitant, a novel NK-1 receptor antagonist, on the pharmacokinetics and pharmacodynamics of steady-state warfarin.

Casopitant, a novel NK-1 receptor antagonist under investigation for the prevention of postoperative and chemotherapy-induced nausea and vomiting, is a weak to moderate inhibitor of CYP3A and a moderate inducer of CYP2C9 in vitro. Furthermore, both CYP enzymes are involved in the metabolism of R- and S-warfarin, respectively. This clinical study was conducted to explore the potential drug-drug interaction between casopitant and warfarin.

Ketoconazole and rifampin significantly affect the pharmacokinetics, but not the safety or QTc interval, of casopitant, a neurokinin-1 receptor antagonist.

Casopitant, an antiemetic, is a neurokinin-1 receptor antagonist metabolized primarily by cytochrome P450 3A4 (CYP3A4). Three phase 1 studies with 131 healthy subjects examined the impact of a strong CYP3A inhibitor (ketoconazole) and inducer (rifampin) on the pharmacokinetics and safety of casopitant. Oral casopitant was administered alone (study 1, 100-mg single dose; study 2, 150 mg on day 1, 50 mg on days 2 and 3; study 3, 150-mg single dose) with either 400 mg daily of oral ketoconazole or 600 mg daily of oral rifampin.

Pharmacokinetic and pharmacodynamic modeling of a copper-selective chelator (TETA) in healthy adults.

The population pharmacokinetics (PK) and pharmacodynamics (PD) of triethylenetetramine (TETA) dihydrochloride (trientine, GC811007) administered orally as 100-, 300-, 600-, or 1800-mg twice-daily doses were assessed in healthy adult male and female volunteers. This study was a randomized, double-blind, placebo-controlled, group-sequential, dose-escalating design. Forty participants, 10 per dose level (8 receiving TETA, 2 receiving placebo), received twice-daily doses for 14 consecutive days.

Population pharmacokinetic/pharmacodynamic modeling of systemic corticosteroid inhibition of whole blood lymphocytes: modeling interoccasion pharmacodynamic variability.

Purpose: To develop a population pharmacokinetic/pharmacodynamic (PK/PD) model that characterizes the effects of major systemic corticosteroids on lymphocyte trafficking and responsiveness.

Materials And Methods: Single, presumably equivalent, doses of intravenous hydrocortisone (HC), dexamethasone (DEX), methylprednisolone (MPL), and oral prednisolone (PNL) were administered to five healthy male subjects in a five--way crossover, placebo--controlled study. Measurements included plasma drug and cortisol concentrations, total lymphocyte counts, and whole blood lymphocyte proliferation (WBLP).

Evaluation of methods for improving precision of blood pressure measurements in phase I clinical trials.

Small sample sizes are typically incorporated in early Phase I clinical studies, which may lead to insignificant changes in safety parameters such as blood pressure. Therefore, it is paramount to identify an optimal, noninvasive method of accurately measuring blood pressure and an appropriate analysis strategy yielding the smallest variability. The goals of this study were (1) to compare the variability between automated and manual blood pressure measurements, (2) to determine whether triplicate blood pressure measurements were independent of one another, and (3) to assess how the number of blood pressure readings affects variability and study sample size.

Evaluation of potential inductive effects of aprepitant on cytochrome P450 3A4 and 2C9 activity.

The NK(1) receptor antagonist aprepitant (EMEND(R)), developed for use in combination with a 5HT(3) receptor antagonist and a corticosteroid to prevent highly emetogenic chemotherapy-induced nausea and vomiting (CINV), has been shown to have a moderate inhibitory effect as well as a possible inductive effect on cytochrome P450 (CYP) 3A4. Aprepitant has been noted to produce modest decreases in plasma S(-)-warfarin concentrations, suggesting potential induction of CYP2C9. Because metabolism of some chemotherapeutic agents may involve CYP3A4, the potential inductive effect of the CINV dosing regimen of aprepitant on this metabolic pathway was evaluated using intravenous midazolam, a sensitive probe substrate of CYP3A4.

Dose equivalency evaluation of major corticosteroids: pharmacokinetics and cell trafficking and cortisol dynamics.

The integrity of current corticosteroid dose equivalency tables, as assessed by mechanistic models for cell trafficking and cortisol dynamics, was investigated in this study. Single, presumably equivalent, doses of intravenous hydrocortisone, methylprednisolone, dexamethasone, and oral prednisolone were given to 5 white men, according to total body weight, in a 5-way crossover, placebo-controlled study. Pharmacodynamic (PD) response-time profiles for T helper cells, T suppressor cells, neutrophils, and adrenal suppression were evaluated by extended indirect response models.

Effects of aprepitant on cytochrome P450 3A4 activity using midazolam as a probe.

Background: Aprepitant is a neurokinin(1) receptor antagonist that enhances prevention of chemotherapy-induced nausea and vomiting when added to conventional therapy with a corticosteroid and a 5-hydroxytryptamine(3) (5-HT(3)) antagonist. Because aprepitant may be used with a variety of chemotherapeutic agents and ancillary support drugs, which may be substrates of cytochrome P450 (CYP) 3A4, assessment of the potential of this drug to inhibit CYP3A4 activity in vivo is important. The effect of aprepitant on in vivo CYP3A4 activity in humans with oral midazolam used as a sensitive probe of CYP3A4 activity was evaluated in this study.

Effects of aprepitant on the pharmacokinetics of ondansetron and granisetron in healthy subjects.

Background: The neurokinin-1-receptor antagonist aprepitant, when given in combination with a corticosteroid and a 5-hydroxytryptamine type 3 (5-HT(3))-receptor antagonist, has been shown to be effective for the prevention of acute and delated chemotherapy-induced nausea and vomiting (CINV).

Objective: Two studies were conducted to determine whether concomitant administration of aprepitant altered the pharmacokinetic profiles of ondansetron and granisetron, two 5-HT(3)-receptor antagonists commonly used as antiemetic therapy for CINV.

Methods: The 2 studies were randomized, open-label, crossover trials conducted in healthy subjects aged between 18 and 46 years.

Effects of the neurokinin1 receptor antagonist aprepitant on the pharmacokinetics of dexamethasone and methylprednisolone.

Background: Aprepitant is a neurokinin(1) receptor antagonist that, in combination with a corticosteroid and a 5-hydroxytryptamine(3) receptor antagonist, has been shown to be very effective in the prevention of chemotherapy-induced nausea and vomiting. At doses used for the management of chemotherapy-induced nausea and vomiting, aprepitant is a moderate inhibitor of cytochrome P4503A4 and may be used in conjunction with corticosteroids such as dexamethasone and methylprednisolone, which are substrates of cytochrome P4503A4. The effects of aprepitant on the these 2 corticosteroids were evaluated.

Pharmacokinetics and pharmacodynamics of a novel nizatidine controlled-release formulation in healthy subjects.

The pharmacokinetics and intragastric pH effects of a novel nizatidine controlled-release (CR) formulation were compared to a currently marketed immediate-release (IR) nizatidine formulation (Axid). The bimodal pulsatile release characteristics of nizatidine CR decreased its Cmax by approximately 42% compared to nizatidine IR while maintaining 90% relative bioavailability; tmax was approximately 1.6 times longer with the CR formulation.

Pharmacokinetics and safety of a single oral dose of once-daily alfuzosin, 10 mg, in male subjects with mild to severe renal impairment.

The effect of renal impairment on the safety and pharmacokinetics of a once-daily formulation of alfuzosin, 10 mg, was evaluated. In an open, single-dose study, 26 volunteers, ages 18 to 65 years, were classified as having normal renal function (n = 8) or mild (n = 6), moderate (n = 6), or severe (n = 6) renal impairment. Mean Cmax values increased by a factor of 1.

Pharmacokinetic and pharmacodynamic interactions between diltiazem and methylprednisolone in healthy volunteers.

Objectives: The pharmacokinetics and pharmacodynamics after administration of methylprednisolone alone, diltiazem alone, and both drugs jointly were assessed in healthy volunteers.

Methods: An unblinded, controlled, fixed-sequence, 2-period study was carried out in 5 healthy white men who received a single dose of intravenous methylprednisolone, 0.3 mg/kg, on day 2, followed by diltiazem alone, 180 mg, on days 5, 6, and 7, with joint dosing of both drugs on day 8.

Pharmacokinetic/pharmacodynamic model for prednisolone inhibition of whole blood lymphocyte proliferation.

Aims: Mitogen-induced ex vivo whole blood lymphocyte proliferation (WBLP) is a widely used method to assess lymphocyte responsiveness to immunosuppressive therapy. A three-component complex model was developed to characterize effects of prednisolone on cell trafficking, transduction, and lymphocyte suppression.

Methods: An oral dose (0.