Effects of Fostamatinib on the Pharmacokinetics of the CYP2C8 Substrate Pioglitazone: Results From In Vitro and Phase 1 Clinical Studies.

Fostamatinib is a prodrug that undergoes gastrointestinal tract dephosphorylation to form the active metabolite, R406. Here we report its cytochrome P450-inducing potential. In vitro, R406 3 and 10 μM induced CYP2C8 to levels representing 53% and 75%, respectively, of the level achieved by the positive control, rifampicin.

Osimertinib Western and Asian clinical pharmacokinetics in patients and healthy volunteers: implications for formulation, dose, and dosing frequency in pivotal clinical studies.

Purpose: Osimertinib (AZD9291) 80 mg once daily is approved by the US FDA for the treatment of patients with metastatic EGFR T790M-positive NSCLC whose disease has previously progressed on EGFR-TKI therapy. Osimertinib PK was evaluated to define the dose and dosing interval, whether a fixed-dosing approach can be used globally, and the impact of formulation and food on exposure.

Methods: AURA (NCT01802632): single- and multiple-dose PK of osimertinib (20-240 mg daily) was determined in patients with advanced NSCLC.

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.

Pharmacokinetic evaluations of the co-administrations of vandetanib and metformin, digoxin, midazolam, omeprazole or ranitidine.

Background And Objective: Vandetanib is a selective inhibitor of vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR) and rearranged during transfection (RET) signalling, indicated for the treatment of medullary thyroid cancer. We investigated potential drug-drug interactions between vandetanib and metformin [organic cation transporter 2 (OCT2) substrate; NCT01551615]; digoxin [P-glycoprotein (P-gp) substrate; NCT01561781]; midazolam [cytochrome P450 (CYP) 3A4 substrate; NCT01544140]; omeprazole (proton pump inhibitor) or ranitidine (histamine H2-receptor antagonist; both NCT01539655).

Methods: Four open-label, phase I studies were conducted in healthy volunteers: n = 14 (metformin), n = 14 (digoxin), n = 17 (midazolam), n = 16 (omeprazole), n = 18 (ranitidine).

Neurocognitive effects of brivaracetam, levetiracetam, and lorazepam.

Purpose: Brivaracetam (BRV) is a new anticonvulsant under development. Although BRV is an analog of levetiracetam (LEV), in addition to being an SV2A ligand, it also inhibits sodium channels in a voltage-dependent manner. The cognitive effects of BRV are uncertain.

Population PK-PD model for Fc-osteoprotegerin in healthy postmenopausal women.

Osteoporosis is a metabolic bone disease resulting from increased bone resorption and characterized by low bone mass that leads to increased bone fragility and risk of fracture, particularly of the hip, spine and wrist. Bone resorption is dependent on receptor activator of NF-kappa B ligand (RANKL), which binds to RANK receptor on preosteoclasts to initiate osteoclastogenesis and maintains osteoclast function and survival. To neutralize the effects of RANKL, the body naturally produces the protein osteoprotegerin (OPG), which acts as a decoy receptor for RANKL and contributes to bone homeostasis.

Safety, pharmacokinetics and immune effects in normal volunteers of CPG 10101 (ACTILON), an investigational synthetic toll-like receptor 9 agonist.

Unlabelled: CPG 10101 (ACTILON) is a novel potent and selective unmethylated cytidine-phosphate-guanosine (CpG)-containing oligodeoxynucleotide agonist of Toll-like receptor 9 (TLR9) being developed for the treatment of chronic infections such as HCV.

Objectives And Methods: In this randomized, double-blind, placebo-controlled Phase I study in 48 normal volunteers, we investigated the safety, pharmacokinetic parameters and immune effects of subcutaneous administration of CPG 10101. Five sequential escalating doses from 0.

The effects of supratherapeutic doses of duloxetine on blood pressure and pulse rate.

The effects of supratherapeutic dosages of duloxetine, a serotonin and norepinephrine reuptake inhibitor, on blood pressure and pulse rate were assessed in a multicenter, double-blind, randomized, placebo-controlled, crossover study in 117 healthy women aged 19 to 74 years. Dosages were escalated from 60 mg twice daily (BID) to 200 mg BID over 16 days. Vital signs were monitored at baseline, before morning dosing, and sequentially at steady state.

Phase 1 study of two merozoite surface protein 1 (MSP1(42)) vaccines for Plasmodium falciparum malaria.

Objectives: To assess the safety and immunogenicity of two vaccines, MSP1(42)-FVO/Alhydrogel and MSP1(42)-3D7/Alhydrogel, targeting blood-stage Plasmodium falciparum parasites.

Design: A Phase 1 open-label, dose-escalating study.

Setting: Quintiles Phase 1 Services, Lenexa, Kansas between July 2004 and November 2005.

QT effects of duloxetine at supratherapeutic doses: a placebo and positive controlled study.

Background: The electrophysiological effects of duloxetine at supratherapeutic exposures were evaluated to ensure compliance with regulatory criteria and to assess the QT prolongation potential.

Methods: Electrocardiograms were collected in a multicenter, double-blind, randomized, placebo-controlled, crossover study that enrolled 117 healthy female subjects aged 19 to 74 years. Duloxetine dosages escalated from 60 mg twice daily to 200 mg twice daily; a single moxifloxacin 400 mg dose was used as a positive control.

Pharmacokinetics, pharmacodynamics, and safety assessment of palifermin (rHuKGF) in healthy volunteers.

Background: Palifermin is a recombinant human keratinocyte growth factor approved to decrease the incidence and duration of severe oral mucositis in patients with hematologic malignancies who received myelotoxic therapy requiring hematopoietic stem cell support.

Methods: This randomized, double-blind, placebo-controlled study investigated the pharmacokinetics, pharmacodynamics, and safety of palifermin in healthy volunteers after single, escalating doses (60 to 250 mug/kg). Pharmacodynamic measurements (Ki67 staining) assessing buccal mucosal epithelial proliferation were performed at baseline and at 48 or 72 hours after dosing.

Clinical safety and efficacy of a powdered Hepatitis B nucleic acid vaccine delivered to the epidermis by a commercial prototype device.

This clinical delivery system bridging study evaluated the performance of a single-use disposable, commercial prototype device (designated ND 5.5) for particle-mediated epidermal delivery (PMED) of a nucleic acid vaccine against Hepatitis B virus (HBV). Healthy adults, previously immunized with licensed HBV vaccine, received a single boost vaccination of HBV nucleic acid vaccine administered by ND 5.

Safety and pharmacokinetic evaluation of intravenous vaccinia immune globulin in healthy volunteers.

Background: Vaccinia immune globulin (VIG) administered via the intramuscular route has historically been used for the treatment of complications of smallpox vaccination. Intravenous formulations of VIG are required to improve tolerability and pharmacokinetic profile.

Methods: We conducted 2 separate studies to evaluate the feasibility of administration of an intravenous formulation of antivaccinia immune globulin (VIGIV).

A single-dose placebo-controlled study of AMG 162, a fully human monoclonal antibody to RANKL, in postmenopausal women.

Unlabelled: The safety and bone antiresorptive effect of a single subcutaneous dose of AMG 162, a human monoclonal antibody to RANKL, was investigated in 49 postmenopausal women. AMG 162 is a potent antiresorptive agent for diseases such as osteoporosis.

Introduction: RANKL is an essential osteoclastic differentiation and activation factor.

The COX-2 selective inhibitor, valdecoxib, does not impair platelet function in the elderly: results of a randomized controlled trial.

The effects of the new cyclooxygenase (COX)-2 selective inhibitor, valdecoxib (40 mg bid; n = 17), on platelet function were evaluated, along with ibuprofen (800 mg tid; n = 15) and placebo (n = 15), in healthy elderly subjects (65-85 years) in this 7.5-day, randomized, single-center, double-blind study. Platelet aggregation (to sodium arachidonate, collagen, and adenosine diphosphate), bleeding time, and serum thromboxane B2 (TxB2) concentrations were measured up to 8 hours postdose on Days 1 and 8.

Valdecoxib does not impair platelet function.

The platelet effects of a supratherapeutic dose of the new cyclooxygenase (COX)-2 specific inhibitor, valdecoxib (40 mg twice a day), naproxen 500 mg twice a day, diclofenac 75 mg twice a day, and placebo were compared in 62 healthy adult subjects in this 7(1/2) day single-center, randomized, placebo-controlled trial. Platelet aggregation responses (to arachidonate [AA], collagen, and adenosine diphosphate [ADP]), bleeding time, and serum thromboxane B(2) (TxB(2)) concentrations were measured at baseline and at regular intervals on days 1 and 8. Valdecoxib had no effect on platelet function.

Dosing in heavy-weight/obese patients with the LMWH, tinzaparin: a pharmacodynamic study.

This pharmacodynamic study examined weight-based dosing of the low molecular weight heparin (LMWH), tinzaparin, in heavyweight/obese subjects. Single doses (175 and 75 IU/kg) were administered subcutaneously (SC) to 37 healthy heavy-weight subjects (101-165 kg; 26-61 kg/m2). AUA and Amax values of anti-Xa and anti-IIa activities were consistent over these body weight and body mass index (BMI) ranges, indicating that tinzaparin pharmacodynamics are not influenced by body weight or BMI.

The pharmacokinetics of sumatriptan when administered with clarithromycin in healthy volunteers.

Background: Macrolide antibiotics such as clarithromycin are potent inhibitors of the cytochrome P450 (CYP)3A4 isozyme and have the potential to attenuate the metabolism and increase blood concentrations of drugs metabolized by this pathway. In vitro studies have suggested that sumatriptan is metabolized primarily by the monoamine oxidase-A isozyme and not by CYP3A4.

Objective: This study sought to determine the effect of coadministration of clarithromycin dosed to steady state on the pharmacokinetics of a single dose of sumatriptan.