Clinical Pharmacology in Drug Development

Pyruvate kinase deficiency is a chronic hemolytic anemia caused by mutations in PK-R, a key glycolytic enzyme in erythrocytes. These 2 phase 1 randomized, placebo-controlled, double-blind healthy-volunteer studies assessed the safety, tolerability, and pharmacokinetics/pharmacodynamics of AG-348, a first-in-class allosteric PK-R activator. Twelve sequential cohorts were randomized 2:6 to receive oral placebo or AG-348, respectively, as a single dose (30-2500 mg) in the single-ascending-dose (SAD) study (ClinicalTrials...

The study aim was to investigate the pharmacokinetics of single high doses and repeated therapeutic doses of fluticasone furoate (FF) and batefenterol (BAT; a bifunctional muscarinic antagonist and β2 -agonist) administered in combination (BAT/FF) or as monotherapy. In this open-label, 6-period, crossover study of 48 subjects, the treatment sequences were (1) single high-dose BAT/FF 900/300 μg followed by repeated therapeutic doses of BAT/FF 300/100 μg (once daily for 7 days); (2) single high-dose BAT 900 μg administered concurrently with FF 300 μg; (3) single high-dose BAT 900 μg followed by repeated therapeutic-dose BAT 300 μg; (4) single high-dose FF 300 μg followed by repeated therapeutic-dose FF 100 μg; (5) single high-dose FF 300 μg (magnesium stearate); and (6) single high-dose FF/vilanterol 300/75 μg...

Albiglutide, developed for treatment of type 2 diabetes mellitus, is provided in a dual-chamber cartridge (DCC) single-dose pen-injector containing lyophilized drug that must be reconstituted with diluent prior to use. A liquid formulation of albiglutide has been developed that does not require mixing. In this 2-period, randomized, crossover, double-blind, phase I study (NCT02660736) in 59 healthy volunteers, pharmacokinetic parameters were determined and the bioequivalence of the 2 formulations was assessed...

The objective of this study was to evaluate the relative bioavailability of olanzapine in 3 olanzapine-containing tablet formulations. ALKS 3831 is a fixed-dose combination of olanzapine (OLZ, an atypical antipsychotic) and samidorphan (SAM, a μ-opioid receptor antagonist with low intrinsic activity at δ- and κ-opioid receptors), intended to provide the efficacy of OLZ while mitigating its known weight and metabolic effects. Relative bioavailability of OLZ in ALKS 3831, a bilayer tablet containing OLZ and SAM, a matching bilayer tablet containing OLZ only (OLZ), and Zyprexa (brand olanzapine [B-OLZ]) was assessed in an open-label study...

Asciminib (ABL001) is an orally administered allosteric inhibitor of the BCR-ABL tyrosine kinase. The current study evaluated the relative bioavailability of its 2 tablet variants, AAA and NXA, compared with the capsule CSF and assessed the impact of food in healthy participants in a 2-arm, randomized, open-label, 4-way crossover design. The primary pharmacokinetic parameters analyzed were area under the plasma concentration-time curve (AUC) from time 0 to the time of last measurable concentration (AUClast ), AUC from time 0 to infinity (AUCinf ), and peak concentration (Cmax )...

Alicapistat is an orally active selective inhibitor of calpain 1 and 2 whose overactivation has been linked to Alzheimer disease (AD). Three studies were conducted in healthy subjects (18-55 years), 1 in healthy elderly subjects (≥65 years), and 1 in patients with mild to moderate AD. Four studies assessed pharmacokinetics, 1 study in healthy subjects assessed pharmacodynamics (sleep parameters, particularly rapid eye movement [REM], as a measure of central nervous system [CNS] penetration and activity), and all studies assessed safety...

Most new chemical entities with systemic availability are required to be tested in a study specifically designed to exclude drug-induced corrected QT interval (QTc) effects, the so-called thorough QT/QTc study. Mirtazapine (Remeron™) is an antidepressant indicated for the treatment of episodes of major depression, which was originally approved in 1994 without a thorough QT study. To evaluate the proarrhythmic potential of mirtazapine, we performed a QT/QTc study with a novel design including implementation of an analysis of the relationship between drug concentration and the QTc interval as the primary assessment of proarrhythmic potential of mirtazapine...

Amenamevir (formerly ASP2151) is a helicase-primase inhibitor being developed for the treatment of herpesvirus infection. Amenamevir is both a substrate and inducer of cytochrome P450 (CYP) 3A4. Three studies were done in healthy volunteers to investigate potential CYP3A pharmacokinetic interactions with the following drugs: (1) Midazolam (probe substrate for CYP3A): After 10 days' pretreatment with amenamevir 400 mg daily, geometric mean maximum concentration of drug in blood plasma (Cmax ) and area under the plasma drug concentration-time curve from time zero to infinity (AUC0-∞ ) of midazolam 7...

The pharmacokinetic profile of a new 800-mg tablet of nonanimal chondroitin sulfate (CS) (Mythocondro®, 800-mg tablets, Gnosis S.p.A., Italy) was investigated vs an animal CS in healthy volunteers for a total period of 48 hours. After a single 2400-mg dose of the test and the reference formulation, total CS, the compositional disaccharides (ΔDi6S, ΔDi4S and ΔDi0S), and the overall charge density were quantified in plasma. The safety and tolerability profile after a single dose of this new nonanimal CS tablets was excellent...

Roxadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor in late-stage clinical development for the treatment of anemia in chronic kidney disease. Spherical carbon adsorbent (SCA) is used in patients with chronic kidney disease and has been shown to impact absorption of certain concomitant drugs. Two phase 1, open-label, randomized, crossover studies were conducted in healthy adult Japanese males to investigate the effect of food and SCA on the pharmacokinetics of a single oral dose of roxadustat...

SCY-078 is an orally bioavailable triterpenoid glucan synthase inhibitor in clinical development as an intravenous and oral treatment of fungal infections caused by Candida and Aspergillus species. This was a sequential, single-center, open-label phase 1 study to assess the drug-drug interaction potential between SCY-078 and tacrolimus during concomitant administration in healthy subjects. In cohort 1, period 1, subjects received a single oral dose of tacrolimus 2 mg in the fasted state. In period 2 after a ≥15 day washout, subjects received a single loading dose of SCY-078 1250 mg on day 1 followed by maintenance doses of SCY-780 750 mg on days 2 through 8...

An orally disintegrating film formulation of sildenafil 50 mg (CL Pharm Co, Ltd) was used in this study and compared to the market-available product film coated tablets (Viagra® , Pfizer, Mexico). The objective was to compare the pharmacokinetic properties of these products after a single-dose administration to 47 healthy male volunteers (aged 19-48 years) in a randomized, open-label, 2-way crossover study. Each subject received a single oral dose of 50 mg of sildenafil test or reference product administered under fasting conditions at each of the 2 study periods according to a crossover design...

This study was designed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending subcutaneous doses of bapineuzumab in patients with mild to moderate Alzheimer disease. Forty patients were randomized across 5 cohorts (5 mg, 10 mg, 20 mg, 40 mg, 80 mg; 8 patients each [bapineuzumab 6; placebo 2]). The incidence of treatment-emergent adverse events (TEAEs) was higher in pooled bapineuzumab cohorts (83%) than in the pooled placebo group (27.7%). Most common TEAEs in the bapineuzumab group were gastrointestinal disorders and musculoskeletal and connective tissue disorders (bapineuzumab 17% each; placebo 0%)...

Vortioxetine is an antidepressant agent with multimodal activity that is approved for the treatment of major depressive disorder at doses of 5 to 20 mg once daily. Vortioxetine is a medium-clearance drug that undergoes extensive metabolism via several cytochrome P450 isozymes. A series of single- and multiple-dose pharmacokinetic studies were performed to evaluate the impact of intrinsic (ie, subject-related) factors, such as age, sex, race, and renal and hepatic function, on the pharmacokinetics of vortioxetine...

Rolapitant is a selective and long-acting neurokinin-1 receptor antagonist approved in an oral formulation in combination with dexamethasone and a 5-hydroxytryptamine type 3 receptor antagonist for the prevention of delayed chemotherapy-induced nausea and vomiting in adults. The pharmacokinetic and safety profiles of intravenous (IV) rolapitant were evaluated in two open-label, phase 1 trials in healthy subjects. Single ascending dose (SAD) and multiple ascending dose studies were conducted in one trial (PR-11-5012-C), and a supratherapeutic SAD study was conducted in a separate trial (PR-11-5022-C)...

This randomized, phase 1, single-dose, crossover study (NCT02189304) compared the 12-hour pharmacokinetic (PK) and safety profiles of budesonide/glycopyrronium/formoterol fumarate dihydrate metered dose inhaler (BGF MDI) 320/14.4/10 μg and budesonide/formoterol fumarate dihydrate (BFF) MDI 320/10 μg (both formulated using innovative co-suspension delivery technology) to an active comparator (budesonide/formoterol fumarate dihydrate dry powder inhaler [BUD/FORM DPI] 320/9-μg delivered dose) in healthy adults...

The orally available chymase inhibitor BAY 1142524 is currently being developed as a first-in-class treatment for left-ventricular dysfunction after myocardial infarction. Results from 3 randomized, single-center, phase 1 studies in healthy male volunteers examining the safety, tolerability, and pharmacokinetics of BAY 1142524 are summarized. In this first-in-human study, single oral doses of 1-200 mg were administered in fasted state as liquid service formulation or immediate release (IR) tablets. The relative bioavailability and the effect of a high-fat/high-calorie meal were investigated at the 5-mg dose...

BTI320 is a proprietary fractionated mannan polysaccharide being studied for attenuation of postprandial glucose excursion. The apparent blood glucose-lowering effect of this compound is effective in lowering postprandial hyperinsulinemia, participating in the metabolic regulation of other lipid molecules; the consequence of this activity is yet to be validated with BTI320 with respect to the risk of cardiovascular disease. The primary objective of the study was to determine the postprandial glucose and insulin responses to 3 test meals containing rice alone or consumed with BTI320 (study A) or 3 test meals (SpriteTM ) alone or consumed with BTI320 (study B)...

Four randomized, double-blind, placebo-controlled, 4-period drug-drug interaction studies were conducted in healthy subjects to evaluate the pharmacokinetic and pharmacodynamic (PD) interactions between mirogabalin and commonly used central nervous system depressants. Mirogabalin or placebo was administered alone or with single-dose lorazepam, zolpidem, tramadol, ethanol, or interacting drug placebo. Safety was assessed and serial samples for pharmacokinetic parameters were collected for up to 48 hours postdose...

Perampanel is a highly selective, orally active, noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist that has been approved in many countries as a treatment for partial-onset seizures and primary generalized tonic-clonic seizures. The pharmacokinetics (PK) of perampanel following multiple doses in healthy Korean, white, and Japanese male subjects were assessed in 3 studies. Noncompartmental PK parameters were derived from plasma concentration-time data. At steady state of perampanel 2-, 4-, and 6-mg oral multiple administration, perampanel was rapidly absorbed, as plasma perampanel concentration reached maximum concentration after 0...