Dosing Recommendation Based on the Effects of Different Meal Types on Pexidartinib Pharmacokinetics in Healthy Subjects: Implementation of Model-informed Drug Development Strategy.

Pexidartinib, an oral small molecule inhibitor of the colony-stimulating factor 1 receptor, is approved for treatment of adults with symptomatic tenosynovial giant cell tumor associated with severe morbidity or functional limitations and not amenable to improvement with surgery. The original dosing regimen is 400 mg of pexidartinib (2 × 200-mg capsules) twice daily, administered on an empty stomach at least 1 hour before or 2 hours after a meal or snack. Because pexidartinib is likely to be taken over an extended period of time, the ability to take pexidartinib with a meal would simplify timing of administration and potentially improve compliance.

Pharmacokinetics of the Multi-kinase Inhibitor Pexidartinib: Mass Balance and Dose Proportionality.

Pexidartinib is an oral small-molecule tyrosine kinase inhibitor that selectively targets colony-stimulating factor 1 receptor. Two phase 1 single-center trials were conducted in healthy subjects to determine the absorption, distribution, metabolism, and excretion of pexidartinib using radiolabeled drug and to assess the dose proportionality of pexidartinib following single oral doses. In the mass balance study, eight male subjects received a single oral dose of [ C]-pexidartinib 400 mg with radioactivity assessed in plasma, urine, and feces samples taken at various timepoints postdose.

Evaluation of Absorption and Metabolism-Based DDI Potential of Pexidartinib in Healthy Subjects.

Background And Objective: Pexidartinib is a novel oral small-molecule inhibitor that selectively targets colony-stimulating factor 1 receptor, KIT proto-oncogene receptor tyrosine kinase, and FMS-like tyrosine kinase 3 harboring an internal tandem duplication mutation. It is approved in the United States for the treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and not amenable to improvement with surgery. Pexidartinib in vitro data indicate the potential for absorption- and metabolism-related drug-drug interactions (DDIs).

Effect of Mild and Moderate Hepatic Impairment (Defined by Child-Pugh Classification and National Cancer Institute Organ Dysfunction Working Group Criteria) on Pexidartinib Pharmacokinetics.

Pexidartinib is a novel oral small-molecule tyrosine kinase inhibitor targeting the colony-stimulating factor 1 receptor. Pexidartinib undergoes extensive hepatic metabolism via multiple cytochrome P450 and uridine 5'-diphospho-glucuronosyl transferase enzymes, with ZAAD-1006a as the only major metabolite in human plasma. As pexidartinib is extensively metabolized, hepatic impairment (HI) could lead to increased exposure to pexidartinib.

Apixaban Single-Dose Pharmacokinetics, Bioavailability, Renal Clearance, and Pharmacodynamics Following Intravenous and Oral Administration.

This randomized, double-blind, placebo-controlled, ascending single intravenous (IV) bolus-dose study evaluated safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of apixaban, a direct factor Xa (FXa) inhibitor approved for multiple indications. Eight healthy subjects were randomized 3:1 (apixaban:placebo) within each IV dose cohort (0.5, 1.

Model-based assessments of CYP3A-mediated drug-drug interaction risk of milademetan.

Milademetan is a small-molecule inhibitor of murine double minute 2 (MDM2) that is in clinical development for advanced solid tumors and hematological cancers, including liposarcoma and acute myeloid leukemia. Milademetan is a CYP3A and P-glycoprotein substrate and moderate CYP3A inhibitor. The current study aims to understand the drug-drug interaction (DDI) risk of milademetan as a CYP3A substrate during its early clinical development.

Exposure-Response Relationships in Patients With HER2-Positive Metastatic Breast Cancer and Other Solid Tumors Treated With Trastuzumab Deruxtecan.

Trastuzumab deruxtecan (T-DXd) is a HER2-targeting antibody-drug conjugate composed of a novel enzyme-cleavable linker and membrane-permeable topoisomerase I inhibitor payload. T-DXd has been approved for HER2-positive metastatic breast cancer and for HER2-positive metastatic gastric cancer. The approval in breast cancer was based on results from the DESTINY-Breast01 (U201; NCT03248492) and J101 (NCT02564900) trials.

Population Pharmacokinetics of Trastuzumab Deruxtecan in Patients With HER2-Positive Breast Cancer and Other Solid Tumors.

Trastuzumab deruxtecan (DS-8201) is a human epidermal growth factor receptor 2 (HER2)-targeting antibody-drug conjugate with a novel enzyme-cleavable linker, a topoisomerase I inhibitor payload, and a drug-to-antibody ratio of ≈ 8. We have characterized the population pharmacokinetics (PK) of trastuzumab deruxtecan and released drug (topoisomerase I inhibitor) in patients with HER2-positive breast cancer or other solid tumor malignancies. This analysis includes pooled data from five clinical studies with 639 patients.

Evaluation of the single-dose pharmacokinetics and pharmacodynamics of apixaban in healthy Japanese and Caucasian subjects.

Purpose: This double-blind, placebo-controlled, intra-subject, dose-escalation study assessed single-dose safety, pharmacokinetics, and pharmacodynamics of apixaban in healthy Japanese and Caucasian subjects.

Subjects And Methods: Sixteen healthy male Japanese and sixteen healthy male Caucasian subjects, matched for age, weight, and smoking status were randomized to receive four sequential single oral doses of either apixaban (2.5, 10, 25, and 50 mg) or matched placebo.

Population Pharmacokinetics of Apixaban in Subjects With Nonvalvular Atrial Fibrillation.

This analysis describes the population pharmacokinetics (PPK) of apixaban in nonvalvular atrial fibrillation (NVAF) subjects, and quantifies the impact of intrinsic and extrinsic factors on exposure. The PPK model was developed using data from phase I-III studies. Apixaban exposure was characterized by a two-compartment PPK model with first-order absorption and elimination.

First-in-human study to assess the safety, pharmacokinetics and pharmacodynamics of BMS-962212, a direct, reversible, small molecule factor XIa inhibitor in non-Japanese and Japanese healthy subjects.

Aims: The aims of the present study were to assess the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of BMS-962212, a first-in-class factor XIa inhibitor, in Japanese and non-Japanese healthy subjects.

Methods: This was a randomized, placebo-controlled, double-blind, sequential, ascending-dose study of 2-h (part A) and 5-day (part B) intravenous (IV) infusions of BMS-962212. Part A used four doses (1.

Effects of a Fixed-Dose Co-Formulation of Daclatasvir, Asunaprevir, and Beclabuvir on the Pharmacokinetics of a Cocktail of Cytochrome P450 and Drug Transporter Substrates in Healthy Subjects.

Background: A fixed-dose combination of daclatasvir (DCV; hepatitis C virus NS5A inhibitor), asunaprevir (ASV; non-structural protein 3 inhibitor), and beclabuvir (BCV; non-structural protein 5B inhibitor) is approved in Japan for hepatitis C virus genotype 1.

Objective: The objective of this study was to assess the combination's drug-drug interaction potential in vivo using a validated cocktail of eight cytochrome P450 (CYP) and transporter probes.

Methods: We conducted an open-label single-sequence study in healthy adults (n = 20) given single-dose caffeine (CYP1A2 substrate), metoprolol (CYP2D6), flurbiprofen (CYP2C9), montelukast (CYP2C8), omeprazole (CYP2C19), midazolam (CYP3A4), digoxin (P-glycoprotein), and pravastatin (organic anion-transporting polypeptide), alone or with steady-state twice-daily DCV/ASV/BCV 30/200/75 mg (with or without additional BCV 75 mg to adjust for higher exposure in hepatitis C virus infection).

Reversal of apixaban anticoagulation by four-factor prothrombin complex concentrates in healthy subjects: a randomized three-period crossover study.

Unlabelled: Essentials Prothrombin complex concentrates (PCCs) may reverse the effect of factor Xa (FXa) inhibitors. We conducted an open-label, randomized, placebo-controlled, three-period crossover study in 15 subjects. Both PCCs rapidly reversed apixaban-mediated decreases in mean endogenous thrombin potential.

Model-Based Evaluation of Exenatide Effects on the QT Interval in Healthy Subjects Following Continuous IV Infusion.

Investigation of the cardiovascular proarrhythmic potential of a new chemical entity is now an integral part of drug development. Studies suggest that meals and glycemic changes can influence QT intervals, and a semimechanistic model has been developed that incorporates the effects of changes in glucose concentrations on heart rate (HR) and QT intervals. This analysis aimed to adapt the glucose-HR-QT model to incorporate the effects of exenatide, a drug that reduces postprandial increases in glucose concentrations.

The effect of apixaban on the pharmacokinetics of digoxin and atenolol in healthy subjects.

Purpose: Apixaban is often coadministered with treatments for cardiovascular comorbidities, which may lead to unintended drug-drug interactions (DDIs). The effects of apixaban on pharmacokinetics (PK) of multidose Lanoxin (digoxin) and single-dose Tenormin (atenolol) and the effects of single-dose atenolol on apixaban PK in healthy subjects were investigated in two Phase 1 studies.

Patients And Methods: The digoxin DDI study was an open-label, multidose, two-treatment, single-sequence study in which subjects received digoxin 0.

UHPLC-MS/MS bioanalysis of urinary DHEA, cortisone and their hydroxylated metabolites as potential biomarkers for CYP3A-mediated drug-drug interactions.

Aim: A UHPLC-MS/MS assay was developed to quantify urinary dehydroepiandrosterone (DHEA), 7β-hydroxy-DHEA, cortisone and 6β-hydroxycortisone as potential biomarkers to predict CYP3A activity.

Results: A sensitive assay at LLOQ of 0.500 ng/ml with good accuracy and precision was developed for the four analytes in human urine.

Lack of a Pharmacokinetic Interaction Between Saxagliptin and Dapagliflozin in Healthy Subjects: A Randomized Crossover Study.

Purpose: This single-dose, open-label, randomized, 3-period, 3-treatment crossover drug-drug interaction study was conducted to evaluate differences in the pharmacokinetic properties of saxagliptin and dapagliflozin when coadministered.

Methods: Healthy subjects (N = 42) were randomized to receive saxagliptin 5 mg alone, dapagliflozin 10 mg alone, or saxagliptin 5 mg plus dapagliflozin 10 mg coadministered; there was a washout period of ≥6 days between treatments. Serial blood samples for determining saxagliptin, 5-hydroxy saxagliptin (5-OH saxagliptin; major active metabolite) and dapagliflozin plasma concentrations and pharmacokinetic parameters were collected before and up to 60 hours after the dose.

Bioequivalence and food effect of heat-stressed and non-heat-stressed dapagliflozin 2.5- and 10-mg tablets.

Physical storage of formulations may result in physical composition changes that affect pharmacokinetics. Dapagliflozin, an oral sodium-glucose cotransporter 2 inhibitor used for type 2 diabetes mellitus, stored under prolonged exposure to heat converts crystalline dapagliflozin to an amorphous form. Bioequivalence of the amorphous to crystalline form and food effects of each form in the 2.

Using Population Pharmacokinetic and Pharmacodynamic Analyses of Entecavir in Pediatric Subjects to Simplify Dosing Recommendations.

Background: Entecavir is an orally administered guanosine nucleoside analog with activity against hepatitis B virus (HBV) polymerase, which is approved for the treatment of chronic hepatitis B (CHB) infection in adults and children ≥2 years old (USA and EU).

Objective: To develop simplified entecavir dosing recommendations for young children infected with CHB.

Methods: Data from recent clinical trials were used to develop a population pharmacokinetic (PPK) model, which allowed us to estimate entecavir exposures in children and compare them to ranges known to be efficacious in adults.

Evaluation of Crushed Tablet for Oral Administration and the Effect of Food on Apixaban Pharmacokinetics in Healthy Adults.

Purpose: These studies evaluate the relative bioavailability of crushed apixaban tablets and the effect of food on apixaban pharmacokinetic properties.

Methods: An open-label, randomized, crossover study in 33 healthy adults compared the bioavailability of 2 × 5-mg apixaban tablets administered whole (reference), crushed and suspended in 30 mL of water, and crushed and mixed with 30 g of applesauce. A second open-label, randomized, crossover study in 22 healthy adults compared apixaban 1 × 5-mg tablet administered when fasted (reference) or immediately after consumption of a high-fat, high-calorie meal.

Pharmacokinetics and pharmacodynamics of dapagliflozin in children and adolescents with type 2 diabetes mellitus.

Aims: To evaluate the pharmacokinetic (PK)/pharmacodynamic (PD) and safety profile of dapagliflozin in paediatric patients aged 10-17 years with type 2 diabetes mellitus (T2DM).

Methods: Patients were randomized to a single oral dose of dapagliflozin 2.5, 5 or 10 mg.

Bioequivalence of saxagliptin/dapagliflozin fixed-dose combination tablets compared with coadministration of the individual tablets to healthy subjects.

Saxagliptin and dapagliflozin are individually indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. The bioequivalence of saxagliptin/dapagliflozin 2.5/5 mg and 5/10 mg fixed-dose combination (FDC) tablets compared with coadministration of the individual tablets and the food effect on both strengths of saxagliptin/dapagliflozin FDCs were evaluated in this open-label, randomized, single-dose crossover study.

Effect of Rifampin on the Pharmacokinetics of Apixaban, an Oral Direct Inhibitor of Factor Xa.

Objective: Apixaban is a substrate of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein. The effects of rifampin, a strong inducer of CYP3A4 and P-glycoprotein, on the pharmacokinetics of oral and intravenous apixaban were evaluated in an open-label, randomized, sequential crossover study.

Methods: Twenty healthy participants received single doses of apixaban 5 mg intravenously on day 1 and 10 mg orally on day 3, followed by rifampin 600 mg once daily on days 5-15.