Extrapolation of pharmacokinetics and pharmacodynamics of sunitinib in children with gastrointestinal stromal tumors.

Purpose: The starting dose of sunitinib in children with gastrointestinal stromal tumors (GIST) was extrapolated based on data in adults with GIST or solid tumors and children with solid tumors.

Methods: Integrated population pharmacokinetics (PK), PK/pharmacodynamics (PD), and exposure-response analyses using nonlinear mixed-effects modeling approaches were performed to extrapolate PK and PD of sunitinib in children with GIST at projected dose(s) with plasma drug exposures comparable to 50-mg/day in adults with GIST. The analysis datasets included PK/PD data in adults with GIST and adults and children with solid tumors.

Development and validation of an LC-MS/MS method for the quantitative analysis of the adenosine A2a receptor antagonist NIR178 and its monohydroxy metabolite in human plasma: Application to clinical pharmacokinetics.

We report a selective LC-MS/MS method for the simultaneous quantitative determinations of the adenosine A2a receptor antagonist NIR178 (NIR178) and its major metabolite NJI765 in human plasma. Sample preparation steps involved protein precipitation, sample evaporation and reconstitution using a plasma sample volume of 0.1 ml plasma.

Population Pharmacokinetics of Sertraline in Healthy Subjects: a Model-Based Meta-analysis.

Sertraline pharmacokinetics is poorly understood and highly variable due to large between-subject variability with inconsistent reports for oral bioavailability. The study objective was to characterize sertraline pharmacokinetics by developing and validating a sertraline population pharmacokinetic (PK) model in healthy subjects using published clinical PK data. We carried a systematic literature search in PubMed in October 2015 and identified 27 pharmacokinetic studies of sertraline conducted in healthy adult subjects and reported in the English language.

Physiologically-Based Pharmacokinetic Model of Sertraline in Human to Predict Clinical Relevance of Concentrations at Target Tissues.

Significant in vitro and in vivo evidence supports the potential use of sertraline as an anticancer and antimicrobial agent. Yet, it is unknown whether effective sertraline concentrations are clinically achieved at therapeutic doses. The study objectives were to develop a physiologically-based pharmacokinetic (PBPK) model of sertraline and estimate the probability of achieving effective concentrations in various human tissues.

Pharmacokinetics-pharmacodynamics of sertraline as an antifungal in HIV-infected Ugandans with cryptococcal meningitis.

The ASTRO-CM dose-finding pilot study investigated the role of adjunctive sertraline for the treatment of HIV-associated cryptococcal meningitis in HIV-infected Ugandan patients. The present study is a post hoc pharmacokinetic-pharmacodynamic analysis of the ASTRO-CM pilot study to provide insight into sertraline exposure-response-outcome relationships. We performed a population pharmacokinetic analysis using sertraline plasma concentration data and correlated various predicted PK-PD indices with the percentage change in log CFU/mL from baseline.

Intracranial antitumor responses of nivolumab and ipilimumab: a pharmacodynamic and pharmacokinetic perspective, a scoping systematic review.

Background: Recently, two phase II trials showed intracranial activity of the immune checkpoint inhibitors nivolumab and ipilimumab in patients with melanoma brain metastases. However, it is generally assumed that large molecules like monoclonal antibodies nivolumab and ipilimumab cannot penetrate and pass an intact blood brain barrier (BBB). In this systematic review we provide a pharmacodynamic and pharmacokinetic consideration of the clinical activity of the immune checkpoint inhibitors nivolumab and ipilimumab in melanoma brain metastases.

Effect of cyclosporine coadministration on the pharmacokinetics of eltrombopag in healthy volunteers.

Purpose: Eltrombopag is indicated in patients with severe aplastic anemia (SAA) refractory to prior immunosuppressive therapy. The combination of eltrombopag and immunosuppressive therapy (such as cyclosporine) is currently being evaluated in patients with treatment-naive SAA. Cyclosporine is a human breast cancer resistance protein (BCRP) inhibitor, and can potentially alter plasma exposure to eltrombopag, a BCRP substrate.

EpCAM-based assays for epithelial tumor cell detection in cerebrospinal fluid.

The diagnosis of leptomeningeal metastases (LM) of solid tumors is complicated due to low sensitivities of both magnetic resonance imaging (MRI) and cytology. MRI has a sensitivity of 76% for the diagnosis of LM and cerebrospinal fluid (CSF) cytology has a sensitivity of 44-67% at first lumbar puncture which increases to 84-91% upon second CSF sampling. Epithelial cell adhesion molecule (EpCAM) is expressed by solid tumors of epithelial origin like non-small-cell lung cancer, breast cancer or ovarium cancer.

Population Pharmacokinetics of Subcutaneous Pasireotide in Healthy Volunteers and Cushing's Disease Patients.

Background And Objective: Pasireotide (SOM230, Signifor) is a somatostatin analog approved in a subcutaneous formulation for the treatment of Cushing's disease. This analysis characterizes the population pharmacokinetics (PopPK) of subcutaneous pasireotide jointly in healthy volunteers (HVs) and Cushing's disease patients (CDPs), evaluating the effects of age, body size, and population on pasireotide pharmacokinetics.

Methods: The analysis dataset included five phase I studies and one each from phase II and phase III.

A Physiologically-Based Pharmacokinetic Modeling Approach To Predict Drug-Drug Interactions of Sonidegib (LDE225) with Perpetrators of CYP3A in Cancer Patients.

Sonidegib (Odomzo) is an orally available Smoothened inhibitor for the treatment of advanced basal cell carcinoma. Sonidegib was found to be metabolized primarily by cytochrome P450 (CYP)3A in vitro. The effect of multiple doses of the strong CYP3A perpetrators, ketoconazole (KTZ) and rifampin (RIF), on sonidegib pharmacokinetics (PK) after a single 800 mg dose in healthy subjects was therefore assessed.

Phase I, multicenter, open-label, dose-escalation study of sonidegib in Asian patients with advanced solid tumors.

Sonidegib is a selective inhibitor of Smoothened receptor, which is a key regulator of the Hedgehog signaling pathway. The purpose of this study was to determine the maximum tolerated dose based on dose-limiting toxicity (DLT) and the recommended dose (RD) of sonidegib in Asian patients with advanced solid tumors. This was an open-label, single-arm, multicenter, two-group, parallel, dose-escalation, phase I study undertaken in Asian patients; group 1 included patients from Japan and group 2 included patients from Hong Kong and Taiwan.

An Exposure-Response Modeling Approach to Examine the Relationship Between Potency of CYP3A Inducer and Plasma 4β-Hydroxycholesterol in Healthy Subjects.

The objectives of this analysis were to establish the exposure-response relationship between plasma rifampicin and 4β-hydroxycholesterol (4βHC) concentration and to estimate the effect of weak, moderate, and potent CYP3A induction. Plasma rifampicin and 4βHC concentration-time data from a drug-drug interaction study with rifampicin 600 mg were used for model development. An indirect response model with an effect compartment described the relationship between rifampicin and 4βHC concentrations.

Pharmacokinetic drug-drug interaction assessment between LCZ696, an angiotensin receptor neprilysin inhibitor, and hydrochlorothiazide, amlodipine, or carvedilol.

LCZ696 is a first-in-class angiotensin receptor neprilysin inhibitor in development for treatments of hypertension and heart failure indications. In 3 separate studies, pharmacokinetic drug-drug interactions (DDIs) potential was assessed when LCZ696 was coadministered with hydrochlorothiazide (HCTZ), amlodipine, or carvedilol. The studies used a open-label, single-sequence, 3-period, crossover design in healthy subjects.

Development and clinical validation of an LC-MS/MS method for the quantification of pazopanib in DBS.

Background: Pazopanib is approved for the treatment of renal cell carcinoma and soft tissue sarcoma. Analyses show increased benefit in patients with plasma trough concentrations ≥20.5 μg/ml compared with patients with lower concentrations.

Exact and asymptotic inference in clinical trials with small event rates under inverse sampling.

In this paper, we discuss statistical inference for a 2 × 2 table under inverse sampling, where the total number of cases is fixed by design. We demonstrate that the exact unconditional distributions of some relevant statistics differ from the distributions under conventional sampling, where the sample size is fixed by design. This permits us to define a simple unconditional alternative to Fisher's exact test.

The emerging role of positron emission tomography in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide. HCC a heterogeneous disease occurring on the background of cirrhosis. The presence of cirrhosis limits the sensitivity of conventional imaging modalities in differentiating HCC from surrounding cirrhotic parenchyma.

Challenges and considerations for development of therapeutic proteins in pediatric patients.

Target specificity and generally good tolerability of therapeutic proteins (TPs) present desirable treatment opportunities for pediatric patients. However, little is known on the ontogeny of processes related to the pharmacokinetics (PK) and disposition of TPs. The science, regulatory requirements and strategy of developing TPs for children are evolving.

Clinical pharmacology of deferasirox.

Iron accumulation is a consequence of regular red cell transfusions, and can occur as a result of ineffective erythropoiesis secondary to increased intestinal iron absorption, in patients with various anemias. Without appropriate treatment, iron overload can lead to increased morbidity and mortality. Deferasirox is an oral iron chelator effective for reduction of body iron in iron-overloaded patients with transfusion-dependent anemias and non-transfusion-dependent thalassemia, with a well-established safety profile.

Population pharmacokinetics and pharmacodynamics of BYL719, a phosphoinositide 3-kinase antagonist, in adult patients with advanced solid malignancies.

Aims: The aim was to characterize the population pharmacokinetics of BYL719 in cancer patients and assess the time course of tumour response in relation to drug exposure and dosing schedule.

Methods: Plasma samples and longitudinal tumour size measurements were collected from 60 patients with advanced solid malignancies who received oral BYL719 once daily (30-450 mg) or twice daily at 120 mg or 200 mg. Non-linear mixed effect modelling was employed to develop the population pharmacokinetic and pharmacodynamic model.

Pharmacokinetics, metabolism, and excretion of [14C]axitinib, a vascular endothelial growth factor receptor tyrosine kinase inhibitor, in humans.

The disposition of a single oral dose of 5 mg (100 μCi) of [(14)C]axitinib was investigated in fasted healthy human subjects (N = 8). Axitinib was rapidly absorbed, with a median plasma Tmax of 2.2 hours and a geometric mean Cmax and half-life of 29.

Relationship between everolimus exposure and safety and efficacy: meta-analysis of clinical trials in oncology.

Background: In patients with solid tumours, daily everolimus dosing demonstrated dose proportionality and linear pharmacokinetics. A meta-analysis was conducted to characterise the relationship between everolimus Cmin and efficacy and safety and the effect of CYP3A4 and P-glycoprotein (PgP) substrate/inhibitor/inducer coadministration on everolimus trough concentration (Cmin).

Methods: Individual patient data from five phase 2/3 studies, in which steady state, predose pharmacokinetic samples were taken from patients with solid tumours administered everolimus 10mg/day, were pooled.

Correlation between nasal membrane permeability and nasal absorption rate.

The objective of this study was to investigate the relationship between in vitro permeability (Papp) values obtained from isolated nasal tissues and the absorption rates (ka) of the same compounds following nasal administration in animals and humans. The Papp of a set of 11 drug compounds was measured using animal nasal explants and plasma time-concentration profiles for each of the same compounds following intravenous (IV) and intranasal (IN) administration were experimentally determined or obtained from literature reports. The plasma clearance was estimated from the IV plasma time-concentration profiles, and ka was determined from the IN plasma time-concentration profiles using a deconvolution approach.