Metabolism and disposition of eltrombopag, an oral, nonpeptide thrombopoietin receptor agonist, in healthy human subjects.

The metabolism and disposition of eltrombopag, the first-in-class small molecule human thrombopoietin receptor agonist, were studied in six healthy men after a single oral administration of a solution dose of [(14)C]eltrombopag (75 mg, 100 μCi). Eltrombopag was well tolerated. The drug was quickly absorbed and was the predominant circulating component in plasma (accounting for 63% of the total plasma radioactivity).

A phase I study of capecitabine, oxaliplatin, and lapatinib in metastatic or advanced solid tumors.

Background: Metastatic colorectal cancer (mCRC) is a leading cause of cancer-related mortality in the United States, and new treatment options are needed. This phase I study investigated a novel regimen combining 2 chemotherapy drugs with proven efficacy in mCRC (capecitabine and oxaliplatin) with a tyrosine kinase inhibitor (lapatinib). Lapatinib has already been approved by the US Food and Drug Administration for treatment of selected cases of breast cancer.

Eltrombopag increases plasma rosuvastatin exposure in healthy volunteers.

What Is Already Known About This Subject: OATP1B1 is important for hepatic uptake of rosuvastatin and BCRP is important for rosuvastatin absorption and elimination. Eltrombopag inhibits OATP1B1 and BCRP in vitro at clinically relevant concentrations. Inhibition of these transporters could change cholesterol-lowering efficacy and increase the risk of exposure-dependent toxicities.

Eltrombopag (75 mg) does not induce photosensitivity: results of a clinical pharmacology trial.

Background/purpose: Eltrombopag is an oral, small molecule, thrombopoietin receptor agonist approved in the United States for the treatment of chronic immune thrombocytopenic purpura and under investigation for treatment of thrombocytopenia due to other etiologies. In vitro studies identified a phototoxic potential for eltrombopag that was not confirmed in subsequent animal studies at exposures up to 11 times the human clinical exposure. A randomized study in healthy men and women was conducted to more fully characterize the photosensitizing potential of a therapeutic dose of eltrombopag (75 mg q.

Eltrombopag does not affect cardiac repolarization: results from a definitive QTc study in healthy subjects.

What Is Already Known About This Subject: Some non-anti-arrhythmic drugs delay cardiac repolarization, which can be measured as an increase in the QT interval. Delays in cardiac repolarization create an electrophysiological environment that favours the development of cardiac arrhythmias, which may lead to torsade de pointes, which can be fatal. As part of the clinical development of eltrombopag, a thorough QT(c) study was conducted to evaluate the effects of eltrombopag on cardiac repolarization at both therapeutic and supratherapeutic doses and to characterize the relationship between plasma eltrombopag concentrations and change in QT(c).

A first in human study of SB-743921, a kinesin spindle protein inhibitor, to determine pharmacokinetics, biologic effects and establish a recommended phase II dose.

Purpose: To determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), safety, pharmacokinetics, and pharmacodynamics of SB-743921 when administered as a 1-h infusion every 21 days to patients with advanced solid tumors or relapsed/refractory lymphoma.

Methods: Patients who failed prior standard therapy or those without any standard options were eligible. Forty-four patients were enrolled using an initial accelerated dose-escalation phase followed by a standard dose-escalation phase.

Clinical pharmacokinetics, platelet response, and safety of eltrombopag at supratherapeutic doses of up to 200 mg once daily in healthy volunteers.

This was a double-blind, placebo-controlled, randomized, parallel, dose-escalation study to assess the pharmacokinetics, platelet response, safety, and tolerability of supratherapeutic doses of eltrombopag (100 mg, 150 mg, and 200 mg once daily) administered for 5 days to 33 healthy adult volunteers. Plasma eltrombopag concentrations accumulated between days 1 and 5, with average increases of 66% to 81% for area under the plasma concentration-time curve from time zero to the end of the 24-hour dosing interval (AUC(0-τ)) and 32% to 45% for maximum observed plasma concentration (C(max)) across doses. After 5 days of dosing, AUC(0-τ) was dose-proportional and C(max) was less than dose-proportional over eltrombopag 100 to 200 mg with slope estimates (90% confidence intervals) of 0.

Effects of ketoconazole and carbamazepine on lapatinib pharmacokinetics in healthy subjects.

Aims: To characterize the impact of potent CYP3A4 inhibition and induction on lapatinib pharmacokinetics.

Methods: Two studies were conducted in healthy subjects. One study examined the effect of ketoconazole 200 mg b.

Phase I pharmacokinetic studies evaluating single and multiple doses of oral GW572016, a dual EGFR-ErbB2 inhibitor, in healthy subjects.

GW572016 is a dual EGFR-ErbB2 inhibitor that has promise as an anticancer agent. Two phase I studies were conducted to determine the safety, tolerability and pharmacokinetics of single and multiple doses given to healthy subjects. The single dose study evaluated two groups of eight subjects in an ascending dose, 4-way cross-over, while the multiple dose study evaluated twenty-seven healthy volunteers in an ascending dose, double-blind, randomized, placebo-controlled, staggered parallel design.