Clinical Pharmacology in Drug Development

Mirogabalin is a novel, preferentially selective α2 δ-1 ligand under investigation to treat neuropathic pain. The purpose of this study was to evaluate the safety, tolerability, and pharmacokinetics of various doses of mirogabalin in healthy subjects of different ethnicities. This randomized, placebo-controlled, double-blind, sequential, ascending-dose study evaluated single (10-40 mg) and repeated (10, 15 mg twice a day) doses of mirogabalin in Japanese subjects, and a single dose of mirogabalin in Korean, Chinese, and white subjects...

This study evaluated the effects of eluxadoline, a mixed μ-opioid receptor (OR) and κ-OR agonist and δ-OR antagonist, on cardiac repolarization. This evaluator-blinded, placebo- and positive-controlled, 4-period crossover study randomized healthy men and women to single oral doses of eluxadoline (therapeutic dose 100 mg or supratherapeutic dose 1000 mg), moxifloxacin 400 mg, or placebo. QT data were corrected using individual custom correction (QTcI). The primary endpoint was the change from baseline in QTcI intervals (ΔQTcI) between eluxadoline and placebo (ΔΔQTcI)...

We sought to establish the bioequivalence of 2 weight-loss aids: orlistat 27-mg chewable tablet and orlistat 60-mg capsule, measured pharmacodynamically as percentage fecal fat excretion. Two open-label, single-center, randomized, 3-period, 3-treatment crossover studies were conducted in adults with body mass index 25-33 kg/m2 . For each 9-day treatment period, subjects received orlistat 27-mg chewable tablet, 60-mg capsule, or 120-mg capsules (2 60-mg capsules) 3 times daily; a 2-day washout separated treatments...

Anastrozole is currently used as first-line treatment in locally advanced or metastatic breast cancer. A generic anastrozole tablet was developed to offer an alternative to the marketed tablet formulation. The aim of the current study was to evaluate the bioequivalence between the test and reference formulations of anastrozole in a single-dose, 2-period, 2-sequence crossover study with a 14-day washout interval. A total of 20 healthy male Chinese volunteers were enrolled and completed the study, after oral administration of a single dose of 1...

Ropivacaine continuous wound infusions (CWIs) are extensively used as a component of multimodal analgesia. The rational application of CWI of ropivacaine requires a thorough understanding of its pharmacokinetics to investigate the risk of potential systemic toxicity. A population pharmacokinetic (popPK) study was undertaken to describe the pharmacokinetics of ropivacaine CWI during 75 hours. Women undergoing a unilateral mastectomy were scheduled to receive CWI for 40 hours for postoperative analgesia. A 10-mL ropivacaine 0...

Coffee is a primary dietary source of the chlorogenic acids (CGAs) of phenolic compounds. Coffee contains caffeine and other phytonutrients, including CGAs. Caffeine on its own has been well characterized and descried pharmacokinetically in the literature, less so for CGAs. The purpose of this double-blind crossover study was to determine the comparative pharmacokinetics of CGAs with caffeine (natural extract) with synthetic caffeine (US Pharmacopeia [USP] standard). Sixteen healthy male subjects were randomly assigned to take 1 dose of product 1, 60 mg of botanically sourced caffeine from 480 mg of green coffee bean extract, or product 2, 60 mg of synthetic USP caffeine, with 5 days between...

This study aimed to investigate the bioequivalence of 2 formulations of gliclazide modified-release tablets 60 mg in 48 healthy Caucasian volunteers under fasting conditions. A test product, Gliclazide MR (Ranbaxy Laboratories Limited, now Sun Pharmaceutical Industries, India), was compared with a reference product, Diamicron MR (Servier, France). The study was performed under a single-dose, 2-treatment, 2-period, 2-sequence crossover design in a fasted condition with a washout period of 21 days. Blood samples were collected for 96 hours after drug administration...

In this open-label, single-center study, the pharmacokinetics, safety, and tolerability of lamotrigine chewable/dispersible tablets were assessed in healthy Chinese volunteers. Each volunteer (N = 16) received repeat doses of oral lamotrigine titrated from 25 mg to 50 mg to 100 mg over 42 days and was followed up for 10-17 days. Safety and tolerability were assessed throughout the study. Lamotrigine pharmacokinetic parameters were estimated using noncompartmental analysis. Overall, 15 (94%) volunteers completed the study...

Ceftolozane/tazobactam is an antibacterial approved at 1.5 g (1g/0.5 g) every 8 hours (q8h); higher doses may provide additional benefits in difficult-to-treat infections. We conducted a phase I trial in healthy adults evaluating safety, tolerability, and pharmacokinetics of 3 g (2 g/1 g) ceftolozane/tazobactam administered q8h for 10 days. Sixteen participants were randomized (2:1:1) to 3 g ceftolozane/tazobactam, 1.5 g ceftolozane/tazobactam, or placebo. Participants underwent regular safety and plasma drug level assessments, with a follow-up safety visit 7 days after completion...

OBE022, a new orally active prostaglandin F2α  receptor antagonist (OBE022) with myometrial selectivity is being developed to reduce uterine contractions during preterm labor. This first-in-human study evaluated the effect of OBE022 following multiple doses on the QT interval in 23 healthy postmenopausal women, using the effect of a meal on QTc to demonstrate assay sensitivity. We report the cardiac safety outcome performed during the multiple ascending part of this trial. OBE022 was administered after a standardized breakfast on day 1 and in the fasted state from day 3 to day 9 wth a standardized lunch 4 hours after administration...

To investigate whether 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor (statin) use is associated with an increased risk of diabetes mellitus and hyperglycemia, we performed a nested case-control study using a postmarketing surveillance database in Japan. The database cohort included 26,849 cases of statin use and 5308 cases of other lipid-lowering drug use in patients with hyperlipidemia. Participants received at least 1 type of statin, had a clear medication history of statin use, and had no complications of diabetes mellitus...

Odanacatib (ODN), an oral selective inhibitor of cathepsin K, was an investigational agent previously in development for the treatment of osteoporosis. In this phase 1 open-label study, 12 healthy Chinese postmenopausal women received single-dose ODN 50 mg on day 1 and multiple-dose ODN 50 mg once weekly on days 15, 22, 29, and 36 under fasted conditions. Pharmacokinetic (PK) parameters were evaluated on days 1 and 36. Multiple-dose area under the concentration-time profile (AUC0-168h) and maximum plasma concentration (Cmax) were compared with historical data from 9 non-Chinese postmenopausal women who also received ODN 50 mg once weekly for 4 weeks...

Continuous glucose monitoring (CGM) systems allow patients with diabetes mellitus to closely track glucose concentrations over several days, identify trends in glucose levels, and avoid glucose excursions. This technology has not only advanced diabetes mellitus management but has increased patient safety through greater glycemic awareness. Due to these attributes, CGM is now being applied in therapeutic research as a pharmacodynamic tool to support early clinical drug development programs. However, to date only a handful of studies have utilized CGM in type 2 diabetes mellitus (T2DM) drug development...

Bazedoxifene, a selective estrogen receptor modulator with proestrogenic effects on bone and lipid metabolism and antiestrogenic effects on the breast and endometrium, is a treatment option for osteoporosis in postmenopausal women. It is extensively metabolized by the liver; therefore, a decrease in liver function was expected to decrease bazedoxifene clearance. This single-dose, open-label, inpatient/outpatient, nonrandomized study assessed the pharmacokinetics of bazedoxifene 20 mg in 18 postmenopausal women with hepatic impairment and 18 matched healthy postmenopausal women...

A subcutaneous risperidone implant (RI) formulation was developed to improve medication adherence in schizophrenia. Two phase 1 studies were conducted to evaluate the pharmacokinetics of RI in adult patients with schizophrenia. In study 1, all subjects were stable on 4 mg oral risperidone; subsequently, the first subject received 375 mg RI for 1 month, and the remaining subjects received 375 mg RI for 3 months. In study 2, all subjects were stable on oral risperidone 4 mg, 6 mg, or 8 mg and subsequently received RI 480 mg, 720 mg, or 960 mg, respectively, for 6 months...

Smoking continues to be a major preventable cause of early mortality worldwide, and nicotine replacement therapy has been demonstrated to increase rates of abstinence among smokers attempting to quit. Nicotine transdermal systems (also known as nicotine patches) attach to the skin via an adhesive layer composed of a mixture of different-molecular-weight polyisobutylenes (PIBs) in a specific ratio. This randomized, single-dose, 2-treatment, crossover pharmacokinetic (PK) trial assessed the bioequivalence of nicotine patches including a replacement PIB adhesive (test) compared with the PIB adhesive historically used on marketed patches (reference)...

Tapinarof cream is a novel topical nonsteroidal agent that represents a unique class of anti-inflammatory molecules targeting the aryl hydrocarbon receptor. Study 201851 was an open-label, 2-cohort sequential study that assessed the systemic pharmacokinetics, safety, and efficacy of tapinarof in adults with moderate to severe atopic dermatitis. A total of 11 participants were enrolled: 5 received 2% cream, and 6 received 1% cream. Tapinarof was systemically absorbed, and measurable amounts were detected in both cohorts...

The purpose of this article was to evaluate the potential for a pharmacokinetic interaction between bazedoxifene and ibuprofen. In a randomized crossover study, 12 healthy postmenopausal women (aged 45-65 years) received either a single oral dose of ibuprofen (600-mg tablet), bazedoxifene (20-mg capsule), or both ibuprofen and bazedoxifene during the 3 treatment periods. Serial blood samples were collected for pharmacokinetic analyses. There was no relationship between the UGT1A1 genotype and bazedoxifene clearance...

Two phase 1 studies (TGAA and TGAB) evaluated the safety, pharmacokinetics, pharmacodynamics, and efficacy of LY3016859 (LY), a monoclonal antibody that binds epiregulin and transforming growth factor α (TGF-α), administered intravenously or subcutaneously. In TGAA, 56 healthy subjects received a single dose of LY (0.1-750 mg intravenously, 50 mg subcutaneously) or placebo. In TGAB part A, 15 patients with diabetic nephropathy (DN) received 2 doses of LY (10-750 mg intravenously) or placebo, and in TGAB part B, 45 patients with DN received 5 doses of LY (50-750 mg intravenously) or placebo...

Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (EVG/COBI/FTC/TAF) is specified in its package insert to be taken with food to obtain sufficient exposure of EVG. It has been reported that a nutritional protein-rich drink shows comparable pharmacokinetics (PK) of EVG to those with a standard breakfast. In this study, the PK profiles of EVG and COBI were evaluated by administration of a single dose of EVG/COBI/FTC/TAF, after ingestion of either a nutritional protein-rich drink, milk, or apple juice...