Clinical Pharmacology in Drug Development

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...

Amenamevir (formerly ASP2151) induces cytochrome P450 (CYP)2B6 and CYP3A4 and inhibits CYP2C8.  We conducted 2 studies, 1 using montelukast as a probe to assess CYP2C8 and the other bupropion to assess CYP2B6.  The montelukast study examined the effect of amenamevir on the pharmacokinetics of montelukast in 24 healthy men: each subject received montelukast 10 mg alone, followed by montelukast 10 mg with amenamevir 400 mg, or vice versa after a washout period.  In the bupropion study, 24 subjects received a single dose of 150 mg bupropion on days 1, 15, 22, and 29, and repeated once-daily doses of 400 mg amenamevir on days 6-15...

GSK2330672 is an inhibitor of the ileal bile acid transporter, designed to have minimal systemic exposure, and is under development as a potential therapeutic for pruritus associated with primary biliary cholangitis and other cholestatic liver diseases. A phase 1, double-blind, placebo-controlled, 4-period crossover study was conducted to evaluate the safety, tolerability, and pharmacokinetic/pharmacodynamic characteristics of GSK2330672 in healthy Japanese participants. Sixteen healthy male participants received single oral doses of GSK2330672 (10-180 mg) or placebo in each period...

Tofacitinib is an oral Janus kinase (JAK) inhibitor. This study characterized the pharmacokinetics of tofacitinib in patients with psoriasis and evaluated the impact of patient factors on disposition. Pooled phase 2/3 data (2981 patients: 9735 concentrations, dose range: 2-15 mg twice daily) up to 56 weeks were used for modeling. A one-compartment model parameterized in terms of apparent oral clearance (CL/F), apparent volume of distribution, zero-order absorption (duration, D), with interindividual variability and inter-occasion variability terms, described tofacitinib pharmacokinetics...

The phase 1-2 study CO-338-010 (Study 10; NCT01482715) is evaluating single-agent rucaparib, a poly(ADP-ribose) polymerase inhibitor, administered orally to patients with an advanced solid tumor. In the dose escalation phase (Part 1), we characterized the single-dose and steady-state pharmacokinetic profiles of rucaparib administered once daily (QD; dose range, 40-500 mg; n = 16) or twice daily (BID; dose range, 240-840 mg; n = 30). Across all dosing schedules examined, the plasma exposure of rucaparib was approximately dose proportional; half-life was approximately 17 hours, and median time to maximum concentration (tmax ) ranged from 1...

In this randomized double-blind study, 4 groups of healthy subjects (50 per arm) participated to evaluate the effect of laquinimod, an oral treatment in development for multiple sclerosis and Huntington disease, on the QTc interval. Subjects received a dose of either 0.6 or 1.2 mg/day laquinimod for 14 days, placebo for 14 days, or 13 days of placebo followed by a dose of 400 mg moxifloxacin on day 14. Continuous 12-lead electrocardiograms were recorded on day -1 (baseline) and days 14 to 17,  and quadruplicate electrocardiograms were extracted at predefined time points...

Ertugliflozin, a sodium-glucose cotransporter 2 inhibitor for the treatment of adults with type 2 diabetes mellitus, is expected to be coadministered with sitagliptin, metformin, glimepiride, and/or simvastatin. Four separate open-label, randomized, single-dose, crossover studies were conducted in healthy adults to assess the potential pharmacokinetic interactions between ertugliflozin 15 mg and sitagliptin 100 mg (n = 12), metformin 1000 mg (n = 18), glimepiride 1 mg (n = 18), or simvastatin 40 mg (n = 18)...

We evaluated the effects of therapeutic and supratherapeutic doses of tramadol hydrochloride on the corrected QT (QTc) interval in healthy adults (aged 18-55 years) in a randomized, phase I, double-blind, placebo- and positive-controlled, multiple-dose, 4-way crossover study. Participants were randomized to receive 1 of 4 treatments (A-D), 1 each in 4 treatment periods (1-4), separated by a washout period (7-15 days). Treatment A comprised tramadol 400 mg (therapeutic dose) on days 1 through 3, tramadol 100 mg and moxifloxacin-matched placebo on day 4, and placebo on all 4 days...

Ceftobiprole is a broad-spectrum cephalosporin. The objective of this study was to test the hypothesis that the pharmacokinetics (PK) and exposure of ceftobiprole in Asian subjects are similar to those in non-Asian subjects. Three approaches were followed. The first compared the individual PK estimates between the 2 subgroups derived from a population PK model previously built. Next, it was determined whether "Asian subject" was a significant covariate. Finally, a pharmacodynamic analysis was performed by comparing measures of exposure and target attainment...

Single-and multiple-dose pharmacokinetics and safety were investigated in this phase 1 study of dichlorphenamide, a carbonic anhydrase inhibitor approved in the United States for treatment of primary periodic paralysis. Dichlorphenamide was administered to 6 cohorts (n = 6 each) of healthy adults. Cohorts A through E received single doses of 25-400 mg followed by 50-800 mg/day in divided doses for 10 total doses. Cohort F (safety analysis only) received up to 28 titrated doses from 100-800 mg/day. Plasma for pharmacokinetics sampling was obtained predose and up to 48 hours postdose...

Despite widespread availability of acetaminophen in Mexico, data on its pharmacokinetic properties in Mexican populations are limited. This single-center, single-blind, randomized, 2-period, 2-treatment, crossover, single-dose-per-period, 2-sequence study evaluated the bioequivalence of a test acetaminophen product available in Mexico compared with a reference 500-mg acetaminophen product in 28 healthy adults under fasting conditions. Blood samples were collected predose and at specified intervals across a 16-hour period following administration and were analyzed for acetaminophen using a validated reverse-phase high-performance liquid chromatography method...

Dalfampridine is a medication that is approved by the US Food and Drug Administration to improve walking impairments in patients with multiple sclerosis (MS). The branded dalfampridine is enormously expensive; hence, the availability of generic dalfampridine will provide better access to the medication, especially for uninsured patients with MS. Bioequivalence studies are demanded by the regulatory authorities to allow the marketing of new generics of dalfampridine. The aim of this study was to assess the bioavailability of the generic (test) and branded (reference) formulations of 10 mg dalfampridine of extended-release tablets after oral administration to healthy adults under fed conditions...

Pomalidomide is an immunomodulatory drug and the dosage of 4 mg per day taken orally on days 1-21 of repeated 28-day cycles has been approved in the European Union and United States to treat patients with relapsed/refractory multiple myeloma. Because pomalidomide is extensively metabolized prior to excretion, a total of 32 subjects (8 healthy subjects in group 1; 8 subjects with severe hepatic impairment in group 2; 8 subjects with moderate hepatic impairment in group 3; and 8 subjects with mild hepatic impairment in group 4) were enrolled in a multicenter, open-label, single-dose study to assess the impact of hepatic impairment on pomalidomide exposure...