P2X3 Receptor Antagonist Eliapixant in Phase I Clinical Trials: Safety and Inter-ethnic Comparison of Pharmacokinetics in Healthy Chinese and Japanese Participants.

Background: Afferent neuronal hypersensitization via P2X3 receptor signaling has been implicated as a driver of several disorders, including refractory chronic cough, endometriosis, diabetic neuropathic pain, and overactive bladder. Eliapixant, a selective P2X3 receptor antagonist, has been in clinical development for all four disorders.

Objective: This paper describes pharmacokinetic (PK) and safety data from two phase I studies of eliapixant in healthy Japanese and Chinese participants and compares those data within the two populations and with previous multiple dose data from Caucasian participants.

Mass Balance and Metabolic Pathways of Eliapixant, a P2X3 Receptor Antagonist, in Healthy Male Volunteers.

Background: Overactive adenosine triphosphate signaling via P2X3 homotrimeric receptors is implicated in multiple conditions. To fully understand the metabolism and elimination pathways of eliapixant, a study was conducted to assess the pharmacokinetics, mass balance, and routes of excretion of a single oral dose of the selective P2X3 receptor antagonist eliapixant, in addition to an in vitro characterization.

Methods: In this single-center open-label non-randomized non-placebo-controlled phase I study, healthy male subjects (n = 6) received a single dose of 50 mg eliapixant blended with 3.

Hepatotoxicity of AKR1C3 Inhibitor BAY1128688: Findings from an Early Terminated Phase IIa Trial for the Treatment of Endometriosis.

Introduction: BAY1128688 is a selective inhibitor of aldo-keto reductase family 1 member C3 (AKR1C3), an enzyme implicated in the pathology of endometriosis and other disorders. In vivo animal studies suggested a potential therapeutic application of BAY1128688 in treating endometriosis. Early clinical studies in healthy volunteers supported the start of phase IIa.

Novel aldo-keto reductase 1C3 inhibitor affects androgen metabolism but not ovarian function in healthy women: a phase 1 study.

Objective: Aldo-keto reductase 1C3 (AKR1C3) has been postulated to be involved in androgen, progesterone, and estrogen metabolism. Aldo-keto reductase 1C3 inhibition has been proposed for treatment of endometriosis and polycystic ovary syndrome. Clinical biomarkers of target engagement, which can greatly facilitate drug development, have not yet been described for AKR1C3 inhibitors.

Pharmacokinetics of intravenous pan-class I phosphatidylinositol 3-kinase (PI3K) inhibitor [C]copanlisib (BAY 80-6946) in a mass balance study in healthy male volunteers.

Purpose: To determine the pharmacokinetics of radiolabeled copanlisib (BAY 80-6946) in healthy male volunteers and to investigate the disposition and biotransformation of copanlisib.

Methods: A single dose of 12 mg copanlisib containing 2.76 MBq [C]copanlisib was administered as a 1-h intravenous infusion to 6 volunteers with subsequent sampling up to 34 days.

Characterisation of the pharmacokinetics of ethinylestradiol and drospirenone in extended-cycle regimens: population pharmacokinetic analysis from a randomised Phase III study.

Objectives: The primary objective of this analysis was to characterise the steady-state pharmacokinetics (PK) of ethinylestradiol (EE) and drospirenone (DRSP) in a randomised Phase III study that investigated the contraceptive efficacy and safety of three different regimens of EE 20 µg/DRSP 3 mg.

Methods: Non-linear mixed-effects modelling was used to develop population PK models for EE and DRSP. EE and DRSP serum concentrations were determined in blood samples obtained from approximately 1100 healthy young women on two occasions during the first cycle (Week 3) and after 6 months (Week 27) of EE 20 µg/DRSP 3 mg use.

Pharmacokinetics of drospirenone and ethinylestradiol in Caucasian and Japanese women.

Objective: To investigate the pharmacokinetics of drospirenone (DRSP) and ethinylestradiol (EE) in Caucasian and Japanese women.

Method: Three open-label, non-randomised studies were performed to assess the pharmacokinetics following single doses of EE 0.02 mg/DRSP 3 mg or DRSP monotherapy (1, 3 or 6 mg) in Caucasian (Study 1) and Japanese (Study 2) women, and daily doses with EE 0.

From adults to children: simulation-based choice of an appropriate sparse-sampling schedule.

Background: According to the International Conference on Harmonisation guideline E11, pharmacokinetic (PK) bridging studies can be applied to support pediatric drug development. However, for PK studies in infants and children the sampling schedule needs to be optimized to minimize the number of blood samples per individual.

Objective: The aim of this study was to describe how clinical trial simulations (CTS) based on adult data were used to select an appropriate sparse-sampling schedule for a future pediatric population PK (popPK) study.

Pharmacokinetics and safety of gadobutrol-enhanced magnetic resonance imaging in pediatric patients.

Objectives: This clinical study investigated the pharmacokinetics and safety of gadobutrol, a magnetic resonance (MR) imaging extracellular contrast agent, in pediatric patients aged 2 to 17 years.

Materials And Methods: In this open-label, multicenter study, patients scheduled for routine contrast-enhanced MR imaging of the brain, spine, liver or kidney, or MR angiography received a single intravenous injection of gadobutrol (0.1 mmol/kg/0.

Population pharmacokinetics of the BEACOPP polychemotherapy regimen in Hodgkin's lymphoma and its effect on myelotoxicity.

Background And Objective: The BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone) chemotherapy regimen for the treatment of advanced Hodgkin's lymphoma has a superior outcome, but its toxicity (mainly haematotoxicity) is pronounced and highly variable. The present study was conducted to address the role of pharmacokinetics in individual toxicity.

Study Design: Three plasma samples and a 24-hour urine collection for day 1 of the first three cycles of chemotherapy were analysed in 30 patients, and the pharmacokinetic parameters of the respective drugs were estimated by population pharmacokinetic methods (nonlinear mixed-effects model [NONMEM] software).

Effect of grapefruit juice intake on etoposide bioavailability.

Purpose: Oral administration of etoposide is limited by the high degree of unpredictable variation in systemic availability. This pilot study was conducted to evaluate the potential of pretreatment with grapefruit juice for improving the use of oral etoposide.

Methods: In a randomized crossover study, six patients were sequentially treated with 50 mg IV etoposide over 1 h, 50 mg orally, or 50 mg orally post grapefruit juice on day 1, day 4, and day 8.