Bioequivalence Evaluation Between Acarbose and Metformin Fixed-Dose Combination and Corresponding Individual Components in Healthy Chinese Male and Female Subjects.

Acarbose and metformin have been recommended both as monotherapy and add-on therapy in type 2 diabetes mellitus. A novel fixed-dose combination (FDC) of acarbose and metformin has been developed to improve compliance and patient adherence to therapy. The current study investigated the bioequivalence (BE) between acarbose/metformin FDC (50 mg/500 mg) with corresponding loose combination of individual components under fasting conditions in healthy Chinese male and female subjects, using a randomized, 2-period, 2-way crossover study design.

Phase 1 dose-escalation and pharmacokinetic study of regorafenib in paediatric patients with recurrent or refractory solid malignancies.

Background: This phase 1 study evaluated safety, pharmacokinetics (PK), maximum tolerated dose (MTD), and antitumour activity of regorafenib in paediatric patients with solid tumours.

Patients And Methods: Patients (aged 6 months to <18 years) with recurrent/refractory solid tumours received oral regorafenib once daily for 3 weeks on/1 week off. The starting dose (60 mg/m) was derived from an adult physiology-based PK model and scaled to children; dose escalation was followed by safety expansion of the MTD cohort.

Th-Labeled Anti-CD22 Antibody (BAY 1862864) in Relapsed/Refractory CD22-Positive Non-Hodgkin Lymphoma: A First-in-Human, Phase I Study.

BAY 1862864 is an α-particle emitting Th-labeled CD22-targeting antibody. This first-in-human dose-escalation phase I study evaluated BAY 1862864 in patients with CD22-positive relapsed/refractory B cell non-Hodgkin lymphoma (R/R-NHL). BAY 1862864 intravenous injections were administered at the starting Th radioactivity dose of 1.

Feasibility of Thorium-227/Radium-223 Gamma-Camera Imaging During Radionuclide Therapy.

Thorium-227 (Th) is a long-lived (T = 18.7 d) α-emitter that has emerged as candidate for radioimmunotherapy. Imaging of patients treated with thorium-227 conjugates is challenging due to the low activity administered and to photon emissions with low yields.

Quantitative Dual-Isotope Planar Imaging of Thorium-227 and Radium-223 Using Defined Energy Windows.

Thorium-227 is an alpha-emitting radioisotope with potential therapeutic applications in targeted alpha therapy. Thorium-227 decays to Radium-223, which may have an independent biodistribution to that of the parent Thorium-227 radiopharmaceutical. Quantitative imaging with sodium iodide (NaI) detectors is challenging due to cross-talk between neighboring γ-photopeaks as well as scattered γ-photons.

Population pharmacokinetics of regorafenib in solid tumours: Exposure in clinical practice considering enterohepatic circulation and food intake.

Aim: Regorafenib is an oral multikinase inhibitor with clinical efficacy in a range of advanced solid tumours. A population pharmacokinetic (PK) model was developed to evaluate the variability of the PK of regorafenib and its pharmacologically active metabolites M-2 and M-5 in solid tumours.

Methods: The model was initially developed using densely sampled phase 1 data and information on food intake to incorporate enterohepatic circulation (EHC) that was identified to considerably contribute to the PK of regorafenib.

Prolonged Response to Regorafenib in a Patient with Iodine Refractory Thyroid Cancer.

Thyroid cancer is the most common type of endocrine malignancy. Cornerstones of thyroid cancer treatment include surgery, radioactive iodine ablation, and thyroid stimulating hormone suppression. The National Comprehensive Cancer Network guidelines recommend two tyrosine kinase inhibitors for thyroid cancer patients who are non-responsive to iodine: sorafenib and lenvatinib.

The effect of gastrectomy on regorafenib exposure and progression-free survival in patients with advanced gastrointestinal stromal tumours.

Aims: We investigated whether major gastrectomy influences the plasma exposure of regorafenib and treatment outcome.

Methods: Efficacy and pharmacokinetic data from 133 gastrointestinal stromal tumour patients included in a phase III trial were analysed. Patients were subdivided into 2 groups according to the extent of the gastrectomy (no/nonsignificant gastrectomy and major gastrectomy).

A phase 1b study evaluating the safety and pharmacokinetics of regorafenib in combination with cetuximab in patients with advanced solid tumors.

Regorafenib 160 mg orally once daily (QD) 3 weeks on/1 week off is approved in colorectal cancer, gastrointestinal stromal tumors and hepatocellular carcinoma. We established the safety and pharmacokinetics (PK) of regorafenib combined with cetuximab in advanced refractory solid tumors. This was a phase 1, open-label, dose-escalation study (NCT01973868) in patients with advanced/metastatic solid tumors who progressed after standard therapy.

Mass balance, metabolic disposition, and pharmacokinetics of a single oral dose of regorafenib in healthy human subjects.

Purpose: To evaluate the mass balance, metabolic disposition, and pharmacokinetics of a single dose of regorafenib in healthy volunteers. In addition, in vitro metabolism of regorafenib in human hepatocytes was investigated.

Methods: Four healthy male subjects received one 120 mg oral dose of regorafenib containing approximately 100 µCi (3.

Exposure-response relationship of regorafenib efficacy in patients with hepatocellular carcinoma.

Purpose: To explore the relationship between regorafenib exposure and efficacy in patients with hepatocellular carcinoma (HCC) who had disease progression during sorafenib treatment (RESORCE).

Methods: Exposure-response (ER) analyses for regorafenib were performed using data from a phase 3, randomized, placebo-controlled trial (RESORCE). Patients received 160mg regorafenib or placebo once daily (3weeks on/1week off in a 4-week cycle) with best supportive care until disease progression, death, or unacceptable toxicity.

Pharmacokinetics of the Inhaled Selective Glucocorticoid Receptor Modulator AZD5423 Following Inhalation Using Different Devices.

AZD5423 is a non-steroidal glucocorticoid receptor modulator, with low aqueous solubility, developed for treatment of asthma and COPD. In this work, we aim to evaluate and compare the absorption pharmacokinetics (PK) of AZD5423 after inhalation via four devices, (Spira®, I-neb®, Turbuhaler® and a new dry powder inhaler (new DPI)) with two formulations using differently sized primary particles, and to compare the pulmonary bioavailability with the predicted lung deposited dose. Plasma concentration-time data after intravenous, oral and inhaled administration via four devices were available from two clinical studies in healthy and asthmatic subjects.

Pharmacokinetic profile after multiple deltoid or gluteal intramuscular injections of paliperidone palmitate in patients with schizophrenia.

Paliperidone palmitate (PP) is a once-monthly long-acting injectable antipsychotic approved for the treatment of schizophrenia in many countries. To evaluate the different injection-site options, we compared the pharmacokinetic profile of paliperidone after multiple injections of PP 100 mg eq. (156 mg of PP, equivalent to 100 mg of paliperidone) on days 1, 8, 36, and 64 into the deltoid (n = 24) or gluteal muscle (n = 25) in patients with schizophrenia.

Effect of carbamazepine on the pharmacokinetics of paliperidone extended-release tablets at steady-state.

Given the potential concomitant use of carbamazepine and paliperidone extended-release (ER) in the treatment of schizophrenia or schizoaffective disorder, this open-label, two-treatment sequential study investigated the effect of repeated administration of carbamazepine on the steady-state pharmacokinetics of paliperidone. Sixty-four patients with a diagnosis of schizophrenia or bipolar-I disorder received the following treatments in a fixed sequential order, without washout between treatments: (i) paliperidone ER 6 mg tablet once daily for 7 days, and (ii) paliperidone ER 6 mg once daily concomitantly with carbamazepine 200 mg twice daily for the subsequent 21 days. Upon coadministration with carbamazepine, paliperidone steady-state total exposure (AUC24 h ) and peak plasma concentrations (Cmax ) decreased by approximately 37% [LSM ratio-AUC24 h : 63.

A single-dose, open-label, parallel, randomized, dose-proportionality study of paliperidone after intramuscular injections of paliperidone palmitate in the deltoid or gluteal muscle in patients with schizophrenia.

Paliperidone palmitate (PP) is a long-acting injectable (LAI) antipsychotic, developed for monthly intramuscular (i.m.) administration into deltoid/gluteal muscle, approved for the treatment of schizophrenia in many countries.

Characterizing systemic exposure of inhaled drugs: application to the long-acting β2-agonist PF-00610355.

Background And Objectives: PF-00610355 is an orally inhaled long-acting β2-adrenoreceptor agonist that is being developed for the once-daily treatment of chronic obstructive pulmonary disease (COPD). The pharmacological effect is exerted in the lungs. However, systemic exposure of PF-00610355 is expected to be responsible for certain drug-related adverse effects.

Predicted heart rate effect of inhaled PF-00610355, a long acting β-adrenoceptor agonist, in volunteers and patients with chronic obstructive pulmonary disease.

Aim: To assess the cardiovascular effects of a new inhaled long-acting β-adrenoceptor agonist PF-00610355 in COPD patients.

Methods: Thirteen thousand and sixty-two heart rate measurements collected in 10 clinical studies from 579 healthy volunteers, asthma and COPD patients were analyzed. The relationship between heart rate profiles and predicted plasma concentration profiles, patient status, demographics and concomitant medication was evaluated using non-linear mixed-effects models.

Sequential protein and peptide immunoaffinity capture for mass spectrometry-based quantification of total human β-nerve growth factor.

Nerve growth factor (NGF) is a neurotrophin that is implicated in the modulation of pain perception. Tanezumab, a humanized monoclonal antibody (mAb) specific for NGF, is highly potent in sequestering NGF and has demonstrated efficacy for treatment of chronic pain in clinical trials. We describe a novel, sensitive immunoaffinity liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for quantitative determination of human serum NGF levels at baseline and after tanezumab treatment.

Longitudinal FEV1 dose-response model for inhaled PF-00610355 and salmeterol in patients with chronic obstructive pulmonary disease.

The objective of this work was to characterize the dose-response relationship between two inhaled long-acting beta agonists (PF-00610355 and salmeterol) and the forced expiratory volume in one second (FEV1) in order to inform dosing recommendations for future clinical trials in patients with chronic obstructive pulmonary disease (COPD). This meta-analysis of four studies included 8,513 FEV1 measurements from 690 patients with moderate COPD. A longitudinal kinetic-pharmacodynamic (K-PD) model was developed and adequately described changes in FEV1 measurements over time, including circadian patterns within a day, as well as changes in FEV1 measurements elicited from administration of PF-00610355 or salmeterol.

A time scaling approach to develop an in vitro-in vivo correlation (IVIVC) model using a convolution-based technique.

In vitro-in vivo correlation (IVIVC) models prove very useful during drug formulation development, the setting of dissolution specifications and bio-waiver applications following post approval changes. A convolution-based population approach for developing an IVIVC has recently been proposed as an alternative to traditional deconvolution based methods, which pose some statistical concerns. Our aim in this study was to use a time-scaling approach using a convolution-based technique to successfully develop an IVIVC model for a drug with quite different in vitro and in vivo time scales.

A comparison of serum prolactin concentrations after administration of paliperidone extended-release and risperidone tablets in patients with schizophrenia.

Increases in serum prolactin concentrations after administration of risperidone have been attributed, by some, to the availability of paliperidone in plasma. This double-blind, randomized, parallel-group study in patients with schizophrenia compared serum prolactin concentrations following the administration of paliperidone extended-release and risperidone immediate-release tablets. At steady state, the doses administered resulted in a similar exposure to paliperidone and the pharmacologically active fraction of risperidone (i.

Single- and multiple-dose pharmacokinetics and dose proportionality of the psychotropic agent paliperidone extended release.

Paliperidone extended-release tablet (paliperidone ER) is a centrally active dopamine D(2)- and serotonergic 5-HT(2A)-receptor antagonist that is registered for the treatment of schizophrenia. The controlled rate of release of paliperidone from the ER formulation is designed to have a slower absorption rate, which results in gradual ascending plasma concentrations with observed maximum plasma concentrations occurring at 24 hours after dosing on the first dosing day. On subsequent treatment days, the ER formulation provides minimal fluctuations in plasma concentrations.

No pharmacokinetic interaction between paliperidone extended-release tablets and trimethoprim in healthy subjects.

Objective: The effect of trimethoprim, a potent organic cation transport inhibitor, on the pharmacokinetics (PK) of paliperidone extended-release tablets (paliperidone ER), an organic cation mainly eliminated via renal excretion, was assessed.

Methods: Open-label, two-period, randomized, crossover study in 30 healthy males. Single dose of paliperidone ER 6 mg was administered either alone on day 1 or day 5 during an 8-day treatment period of trimethoprim 200 mg twice daily.

Absorption, metabolism, and excretion of paliperidone, a new monoaminergic antagonist, in humans.

Absorption, metabolism, and excretion of paliperidone, an atypical antipsychotic, was studied in five healthy male subjects after a single dose of 1 mg of [(14)C]paliperidone oral solution ( approximately 16 microCi/subject). One week after dosing, 88.4 to 93.

A double-blind, placebo-controlled, randomized study evaluating the effect of paliperidone extended-release tablets on sleep architecture in patients with schizophrenia.

The effects of paliperidone extended-release on sleep architecture in patients with schizophrenia-related insomnia were evaluated in this multicenter, double-blind, randomized, placebo-controlled study. Patients received paliperidone extended-release 9 mg/day or matching placebo during the 14-day double-blind phase. Sleep architecture and sleep continuity were evaluated using polysomnograms.