Patient-centric microsampling for abrocitinib pharmacokinetics: multiple-analytes assay bridging using Tasso device.

The feasibility of using Tasso devices (Tasso-SST and Tasso) collecting capillary blood samples for measuring abrocitinib and its metabolites were evaluated, and assay concordance established between capillary and venous blood samplings. Capillary serum and venous plasma concentrations were measured using their respective qualified and validated assays. Concentration and exposure comparisons were conducted for abrocitinib and its metabolites (M1, M2 and M4) to establish assay concordance.

Meta-Analysis of Noncompartmental Pharmacokinetic Parameters to Evaluate the Impact of CYP2C19 and CYP2C9 Genetic Polymorphisms on Abrocitinib Exposure.

Abrocitinib is a selective Janus kinase 1 inhibitor approved for the treatment of atopic dermatitis. It is metabolized primarily by cytochrome P450 (CYP) 2C19 (approximately 53%) and CYP2C9 (approximately 30%), which form 2 active metabolites. The pharmacologic activity of abrocitinib is attributable to the unbound exposures of abrocitinib and those metabolites with active moiety area under the plasma concentration-time curve (AUC) considered the best measure of the total pharmacological effect.

Assessment of the Effects of Abrocitinib on the Pharmacokinetics of Probe Substrates of Cytochrome P450 1A2, 2B6 and 2C19 Enzymes and Hormonal Oral Contraceptives in Healthy Individuals.

Background And Objective: Abrocitinib is an oral small-molecule Janus kinase (JAK)-1 inhibitor approved for the treatment of moderate-to-severe atopic dermatitis. In vitro studies indicated that abrocitinib is a weak time-dependent inhibitor of cytochrome P450 (CYP) 2C19/3A and a weak inducer of CYP1A2/2B6/2C19/3A. To assess the potential effect of abrocitinib on concomitant medications, drug-drug interaction (DDI) studies were conducted for abrocitinib with sensitive probe substrates of these CYP enzymes.

Population Pharmacokinetic and Pharmacodynamic Modeling of Fesoterodine in Pediatric Patients with Neurogenic Detrusor Overactivity.

Background And Objective: Fesoterodine is a muscarinic receptor antagonist approved for the treatment of overactive bladder (OAB) in adults and neurogenic detrusor overactivity (NDO) in pediatric patients. This work aimed to characterize the population pharmacokinetics of 5-hydroxymethyl tolterodine (5-HMT, the active metabolite of fesoterodine) and its pharmacokinetic/pharmacodynamic relationship in pediatric patients with OAB or NDO following administration of fesoterodine.

Methods: 5-HMT plasma concentrations from 142 participants of age ≥ 6 years were analyzed, and a nonlinear mixed-effects model was developed.

Fesoterodine treatment of pediatric patients with neurogenic detrusor overactivity: A 24-week, randomized, open-label, phase 3 study.

Background: Neurogenic detrusor overactivity (NDO) can damage the upper urinary tract leading to chronic renal impairment. Antimuscarinic therapy is used to improve urinary incontinence and protect the upper urinary tract in patients with NDO.

Objective: This study investigated safety and efficacy of fesoterodine, a muscarinic receptor antagonist, in 6‒<18-year-old patients with NDO (NCT01557244).

The Pharmacokinetics, Metabolism, and Clearance Mechanisms of Abrocitinib, a Selective Janus Kinase Inhibitor, in Humans.

Abrocitinib is an oral once-daily Janus kinase 1 selective inhibitor being developed for the treatment of moderate-to-severe atopic dermatitis. This study examined the disposition of abrocitinib in male participants following oral and intravenous administration using accelerator mass spectroscopy methodology to estimate pharmacokinetic parameters and characterize metabolite (M) profiles. The results indicated abrocitinib had a systemic clearance of 64.

Population Pharmacokinetic/Pharmacodynamic Modeling of the Effect of Abrocitinib on QT Intervals in Healthy Volunteers.

Abrocitinib is a selective Janus kinase 1 inhibitor for the treatment of moderate to severe atopic dermatitis (AD). To assess the relationship between abrocitinib plasma concentrations and heart rate (HR)-corrected QT (QTc) and HR and calculate the effect of abrocitinib on these parameters at supratherapeutic concentrations, 36 healthy volunteers received single doses of abrocitinib 600 mg, placebo, and moxifloxacin 400 mg in a 3-period crossover study. The relationship between change from baseline in Fridericia-corrected QTc (∆QTcF) values and abrocitinib plasma concentrations was modeled using a prespecified linear mixed-effects model.

Evaluation of the Effect of Abrocitinib on Drug Transporters by Integrated Use of Probe Drugs and Endogenous Biomarkers.

Abrocitinib is an oral Janus kinase 1 (JAK1) inhibitor currently approved in the United Kingdom for the treatment of moderate-to-severe atopic dermatitis (AD). As patients with AD may use medications to manage comorbidities, abrocitinib could be used concomitantly with hepatic and/or renal transporter substrates. Therefore, we assessed the potential effect of abrocitinib on probe drugs and endogenous biomarker substrates for the drug transporters of interest.

Population pharmacokinetic-pharmacodynamic modelling of platelet time-courses following administration of abrocitinib.

Aims: Abrocitinib is a selective Janus kinase 1 inhibitor for the treatment of moderate-to-severe atopic dermatitis. Herein we describe the time-course of drug-induced platelet reduction following abrocitinib administration, identify covariates affecting platelet counts, and determine the probability of patients experiencing thrombocytopaenia while receiving abrocitinib.

Methods: This analysis included data from two Phase 2 and three Phase 3 studies in psoriasis and atopic dermatitis patient populations administered abrocitinib 10-400 mg QD orally for up to 12 weeks, with platelet counts determined up to week 16.

Assessment of the Effects of Inhibition or Induction of CYP2C19 and CYP2C9 Enzymes, or Inhibition of OAT3, on the Pharmacokinetics of Abrocitinib and Its Metabolites in Healthy Individuals.

Background And Objective: Abrocitinib is a Janus kinase 1-selective inhibitor for the treatment of moderate-to-severe atopic dermatitis. Abrocitinib is eliminated primarily by metabolism involving cytochrome P450 (CYP) enzymes. Abrocitinib pharmacologic activity is attributable to the unbound concentrations of the parent molecule and 2 active metabolites, which are substrates of organic anion transporter 3 (OAT3).

Population Pharmacokinetics of Abrocitinib in Healthy Individuals and Patients with Psoriasis or Atopic Dermatitis.

Background And Objective: Abrocitinib is a Janus kinase 1 inhibitor in development for the treatment of atopic dermatitis (AD). This work characterized orally administered abrocitinib population pharmacokinetics in healthy individuals, patients with psoriasis, and patients with AD and the effects of covariates on abrocitinib exposure.

Methods: Abrocitinib concentration measurements (n = 6206) from 995 individuals from 11 clinical trials (seven phase I, two phase II, and two phase III) were analyzed, and a non-linear mixed-effects model was developed.

Comparing abrocitinib and dupilumab in the treatment of atopic dermatitis: a plain language summary.

Atopic dermatitis (AD, also called atopic eczema) is a long-term skin disease that causes intensely itchy, red skin. Healthcare providers can prescribe medicated creams and ointments to reduce the signs and symptoms of AD. However, these treatments are not always enough to provide relief.

Effects of Renal Impairment on the Pharmacokinetics of Abrocitinib and Its Metabolites.

Abrocitinib, an oral once-daily Janus kinase 1 selective inhibitor, is under development for the treatment of atopic dermatitis. This phase 1, nonrandomized, open-label, single-dose study (NCT03660241) investigated the effect of renal impairment on the pharmacokinetics, safety, and tolerability of abrocitinib and its metabolites following a 200-mg oral dose. Twenty-three subjects with varying degrees of renal function (normal, moderate, and severe impairment) were enrolled.

Abrocitinib versus Placebo or Dupilumab for Atopic Dermatitis.

Background: The oral Janus kinase 1 (JAK1) inhibitor abrocitinib, which reduces interleukin-4 and interleukin-13 signaling, is being investigated for the treatment of atopic dermatitis. Data from trials comparing JAK1 inhibitors with monoclonal antibodies, such as dupilumab, that block interleukin-4 receptors are limited.

Methods: In a phase 3, double-blind trial, we randomly assigned patients with atopic dermatitis that was unresponsive to topical agents or that warranted systemic therapy (in a 2:2:2:1 ratio) to receive 200 mg or 100 mg of abrocitinib orally once daily, 300 mg of dupilumab subcutaneously every other week (after a loading dose of 600 mg), or placebo; all the patients received topical therapy.

Effects of naltrexone exposure observed in two phase three studies with ALO-02, an extended-release oxycodone surrounding sequestered naltrexone.

Objective: To evaluate the clinical effects of naltrexone following ALO-02 administration.

Design: Two phase three studies: an open-label, single-arm safety study, and a double-blind, placebo-controlled, randomized withdrawal, efficacy study (ClinicalTrials.gov identifiers: NCT01428583, NCT01571362).

Physiologically Based Pharmacokinetic Modeling Suggests Limited Drug-Drug Interaction for Fesoterodine When Coadministered With Mirabegron.

5-Hydroxymethyl tolterodine (5-HMT; the active fesoterodine metabolite) is metabolized via the cytochrome P450 (CYP) 2D6 and CYP3A pathways. Mirabegron is a moderate CYP2D6 inhibitor and weak CYP3A inhibitor. Potential drug-drug interactions (DDIs) following coadministration of these 2 overactive bladder treatments were estimated using physiologically based pharmacokinetic models, developed and verified by comparing predicted and observed pharmacokinetic profiles from clinical studies.

Effects of intravenous oxycodone alone or in combination with naltrexone on measures of respiratory depression: a randomized placebo-controlled study.

Background: Abuse of prescription opioids, particularly by intravenous (IV) administration, can cause respiratory depression and death. ALO-02, an abuse-deterrent opioid formulation, is designed to release sequestered naltrexone upon manipulation by crushing, thereby antagonizing the pharmacologic effects of oxycodone. This exploratory analysis examined the effects of IV administration of simulated crushed ALO-02 on end-tidal carbon dioxide (EtCO), a surrogate marker of respiratory depression.

Physiological based pharmacokinetic modeling to estimate in vivo Ki of ketoconazole on renal P-gp using human drug-drug interaction study result of fesoterodine and ketoconazole.

This study was conducted to estimate in vivo inhibition constant (Ki) of ketoconazole on renal P-glycoprotein (P-gp) using human drug-drug interaction (DDI) study result of fesoterodine and ketoconazole. Fesoterodine is a prodrug which is extensively hydrolyzed by non-specific esterases to the active metabolite 5-hydroxymethyl tolterodine (5-HMT). 5-HMT is then further metabolized via Cytochrome P450 (CYP) 2D6 and CYP3A4.

Abuse Potential Study of ALO-02 (Extended-Release Oxycodone Surrounding Sequestered Naltrexone) Compared with Immediate-Release Oxycodone Administered Orally to Nondependent Recreational Opioid Users.

Objective: To evaluate the abuse potential of ALO-02, an abuse-deterrent formulation comprising pellets of extended-release oxycodone hydrochloride surrounding sequestered naltrexone hydrochloride.

Design: Randomized, double-blind, placebo-/active-controlled, 6-way crossover study, with naloxone challenge, drug discrimination, and treatment phases.

Subjects: Nondependent, recreational opioid users.

Intravenous abuse potential study of oxycodone alone or in combination with naltrexone in nondependent recreational opioid users.

Background: ALO-02, comprising pellets of extended-release oxycodone surrounding sequestered naltrexone, is intended to deter abuse.

Objective: Determine the abuse potential of intravenous oxycodone combined with naltrexone, which represents simulated crushed ALO-02 in solution, compared with intravenous oxycodone in nondependent, recreational opioid users.

Methods: A randomized, double-blind, placebo-controlled, three-way crossover study with naloxone challenge, drug discrimination, and treatment phases.

Effect of food on the pharmacokinetics of oxycodone and naltrexone from ALO-02, an extended release formulation of oxycodone with sequestered naltrexone.

What Is Known And Objective: ALO-02 is being developed as an abuse-deterrent formulation of extended-release oxycodone hydrochloride with naltrexone hydrochloride sequestered in the core of pellets contained in capsules. The primary objective of this study was to assess the effects of administration of ALO-02 capsule whole under fed conditions or sprinkling the pellets from ALO-02 capsule on applesauce under fasting conditions on the pharmacokinetics (PK) of oxycodone, naltrexone and 6-ß-naltrexol compared with ALO-02 capsule administered whole under fasting conditions. The plasma naltrexone and 6-ß-naltrexol concentrations were used to assess the sequestration of naltrexone in the ALO-02 formulation.

Pharmacoscintigraphy studies to assess the feasibility of a controlled release formulation of ziprasidone.

Ziprasidone, like many BCS Class II drugs with low intrinsic solubility and a strong tendency to crystallize from supersaturated solutions, presents significant technical challenges when developing an oral controlled release dosage form. In order to achieve acceptable bioavailability and prolonged exposures for once-daily dosing, good colonic absorption and a reliable controlled release (CR) technology are necessary. To this end, a novel solubilized drug form--coated crystals made by spray drying (CCSD), was formulated and progressed into human clinical studies.

Intranasal administration of crushed ALO-02 (extended-release oxycodone with sequestered naltrexone): A randomized, controlled abuse-potential study in nondependent recreational opioid users.

ALO-02 is an abuse-deterrent formulation consisting of capsules filled with pellets of extended-release oxycodone surrounding sequestered naltrexone. This randomized, double-blind, placebo-/active-controlled, 4-way crossover study examined the abuse potential of crushed ALO-02 administered intranasally to healthy, nondependent, recreational opioid users. Following drug discrimination and naloxone challenge, eligible participants (n = 32) entered a 4-way crossover treatment phase: crushed single dose of 1 of 2 placebos, ALO-02 30 mg/3.