Clinical Pharmacology in Drug Development

The rate and extent of absorption of drugs belonging to Biopharmaceutics Classification System class II are rate-limited by dissolution and highly dependent on the performance of the formulated product. The purpose of the present study was to investigate the potential impact of a surfactant and the particle size of the active substance on the in vitro drug dissolution profiles and in vivo pharmacokinetics of the poorly soluble drug posaconazole. A comparative physicochemical evaluation was conducted, and 3 formulations of posaconazole oral suspension were tested in various dissolution media compared with the reference product...

This was a first-time-in-human randomized, double-blind, single-center, placebo-controlled dose-escalation study to determine the safety, tolerability, and pharmacokinetic (PK) profiles of GSK3342830 after single and repeat intravenous doses in healthy adult subjects (NCT0271424). Sixty-two subjects were enrolled: 48 subjects in part 1 (single dose) and 14 subjects in part 2 (multiple doses). Following single intravenous infusions, total systemic exposure of GSK3342830 was dose proportional over the 250- to 6000-mg dose range evaluated, whereas peak exposure was approximately dose proportional over the dose range...

Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) is an oral once-daily single-tablet regimen for the treatment of human immunodeficiency virus-1 infection. Different administration modalities for the D/C/F/TAF fixed-dose combination tablet were explored in this phase 1 randomized, open-label, 3-period, 3-treatment crossover study enrolling 30 healthy adults. The primary objective was to assess the relative bioavailability of each component after a single dose of D/C/F/TAF (800/150/200/10 mg) administered as a split or crushed tablet (tests) versus swallowed whole (reference)...

There is an urgent need to identify safe and effective combination treatments for multidrug-resistant (MDR) Mycobacterium tuberculosis infection (TB). Bedaquiline, a new diarylquinoline, is approved for the treatment of MDR pulmonary TB in combination with other drugs, which could include rifabutin, which is also used to treat drug-resistant TB. Both rifabutin and bedaquiline are metabolized via cytochrome P450 3A4, and rifabutin is an inducer of this enzyme. Bedaquiline is metabolized into its primary N-monodesmethyl metabolite, M2, and further desmethylated into an N-didesmethyl metabolite, M3...

Model-informed precision dosing (MIPD) is biosimulation in healthcare to predict the drug dose for a given patient based on their individual characteristics that is most likely to improve efficacy and/or lower toxicity compared with traditional dosing. Despite widespread use of biosimulation in drug development, MIPD has not been adopted beyond academic-hospital centers. A reason for this is that MIPD requires more supporting evidence in the language that everyday doctors understand-evidence-based medicine...

Saxagliptin is an orally administered, highly potent, and selective dipeptidyl peptidase-4 inhibitor for the management of type 2 diabetes mellitus. This study was conducted to determine the effect of magnesium and aluminum hydroxides plus simethicone, famotidine, and omeprazole on the pharmacokinetics of saxagliptin and its active metabolite, 5-hydroxy saxagliptin. This was an open-label, randomized, 5-treatment, 5-period, 3-way crossover study in 15 healthy subjects. Mean Cmax of saxagliptin was 26% lower, but AUC was almost unchanged when saxagliptin was coadministered with Maalox Max...

The chymase inhibitor fulacimstat is developed as a first-in-class treatment option for the inhibition of adverse cardiac remodeling in patients with left ventricular dysfunction (LVD) after acute myocardial infarction (MI). The aim of the study was to examine the safety and tolerability of fulacimstat in patients with LVD after remote MI. A multicenter, multinational randomized, placebo-controlled study was performed in clinically stable patients (40-79 years of age, left ventricular ejection fraction ≤ 45% because of MI in medical history) who were on stable evidence-based standard-of-care therapies for LVD post-MI including an angiotensin converting enzyme inhibitor or angiotensin receptor blocker at doses of at least half the recommended target dose...

The pharmacokinetics (PK) and safety of single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) after single and repeat dosing in healthy Chinese adults were assessed. In this open-label study (NCT02837380), subjects received once-daily FF/UMEC/VI 100/62.5/25 μg on day 1 and repeat doses on days 2-7. PK parameters (days 1 and 7) included maximum observed concentration (Cmax ) and area under the plasma concentration-time curve (AUC) from time zero (predose) to last time of quantifiable concentration (AUC0-t )...

Ertugliflozin, an inhibitor of sodium-glucose cotransporter 2, is approved in the United States and European Union for the treatment of type 2 diabetes in adults, both as monotherapy and as part of fixed-dose combination (FDC) therapies with either sitagliptin or immediate-release metformin. The effect of a standard, high-fat breakfast on the pharmacokinetics of the highest strengths of ertugliflozin monotherapy (15 mg), ertugliflozin/sitagliptin FDC (15-/100-mg), and ertugliflozin/metformin FDC (7.5-/1000-mg) tablets was evaluated...

Nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) signaling is central to the regulation of several physiological processes, including blood flow and inflammation. Deficient NO signaling is implicated in multiple diseases. sGC stimulators are small molecules that enhance sGC activity, particularly in combination with NO. In a randomized, placebo-controlled phase 1 study, the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple ascending doses of the sGC stimulator praliciguat were assessed in 44 healthy adults...

Amenamevir is an inhibitor of the helicase-primase enzyme complex developed for the treatment of varicella zoster virus. This mass balance study investigated the absorption, metabolism, and excretion of a single dose (200 mg) of 14 C-labeled amenamevir in healthy male volunteers. Blood, urine, and feces samples were collected for up to 8 days after the dose. Safety and tolerability were assessed through voluntary reporting of adverse events, physical examination, and clinical laboratory testing. Amenamevir was rapidly absorbed, with a median time to peak drug concentration of 1...

The effect of food on the bioavailability of the components of the once-daily, single-tablet human immunodeficiency virus (HIV) type 1 regimen containing darunavir (DRV 800 mg), cobicistat (COBI 150 mg), emtricitabine (FTC 200 mg), and tenofovir alafenamide (TAF 10 mg) (D/C/F/TAF) (NCT02475135) and the bioequivalence of D/C/F/TAF versus combined intake of the separate agents (NCT02578550) were evaluated. These were 2 phase 1, open-label, randomized, 2-period crossover studies (7-day washout between treatments) in HIV-negative healthy volunteers...

This study aimed to compare the pharmacokinetic profile of combined CKD-395 0.5/1000 mg treatment with that of the coadministration of lobeglitazone sulfate 0.5 mg and metformin hydrochloride (HCl) extended-release (XR) 1000 mg and assess the effect of food on the pharmacokinetics of CKD-395 0.5/1000 mg. Two clinical trials were conducted as part of an open-label, single-dose, randomized, 2-period, 2-sequence crossover study. In study 1, a total of 26 subjects received either CKD-395 0.5/1000 mg as a test drug or coadministration of lobeglitazone sulfate 0...

Sarpogrelate is widely used to treat peripheral vascular disorders. However, it has been demonstrated to have a poor pharmacokinetic (PK) profile and marked within-subject variability. Here, the bioequivalence of 2 formulations of sarpogrelate (100-mg tablets) was assessed by using the reference-scaled average bioequivalence (RSABE) method, and the PK parameters were quantified in healthy Chinese subjects under fasting (n = 38) and fed (n = 35) conditions. In this open and randomized 4-way replicate study, a single dose of sarpogrelate was administered followed by a 3-day washout period...

A fixed-dose combination of tenofovir alafenamide (TAF) and emtricitabine (FTC) is available in 2 tablet strengths in Japan (FTC/TAF 200/10 mg and FTC/TAF 200/25 mg). These are used once daily in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 infection. The primary objective of this study was to investigate if there is any clinically relevant pharmacokinetic difference for TAF, tenofovir (TFV), and FTC between Japanese and non-Japanese with historical data...

Tylerdipine hydrochloride is a novel L-type and T-type dual calcium channel antagonist that has the potential effects of expanding blood vessels and lowering blood pressure. It is expected to reduce the side effect of ankle edema observed with other drugs in the same class. A randomized, open-label, crossover phase 1 study was performed to evaluate the effect of food on the bioavailability of tylerdipine. Fourteen healthy male volunteers were enrolled. The administration of tylerdipine after a high-fat meal increased the bioavailability of tylerdipine...

The aim of the study was to assess the safety, tolerability, and pharmacokinetics of single and repeat doses of nemiralisib administered via a dry powder inhaler to healthy Japanese subjects. This was a single-center, double-blind, randomized, placebo-controlled, parallel, single- and repeat-ascending-dose study. Thirty-six healthy Japanese male subjects were randomized to receive either 1 dose strength of nemiralisib or placebo. The study consisted of a screening period, a single-dose session (session 1), a repeat-dose session (session 2), a 10-day washout period between the sessions, and then a follow-up visit 10 ± 1 days after the last dose of session 2...

In this open-label study (NCT02142920), we investigated the distribution, pharmacokinetics, and metabolism of the pan-class-I isoform phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor gedatolisib (PF-05212384), following a single intravenous administration in healthy male subjects. A single, 89-mg, intravenous dose of gedatolisib was associated with a favorable safety profile in the 6 healthy subjects evaluated. Peak plasma concentrations for unchanged gedatolisib and total radioactivity were observed at the end of the 30-minute infusion...

This 2-part study evaluated the QT/QTc prolongation potential and safety and pharmacokinetics of the antiemetic rolapitant, a neurokinin-1 receptor antagonist. Part 1 was a randomized, placebo-controlled single-dose-escalation study assessing the safety of a single high dose of rolapitant. Part 2 was a randomized, placebo- and positive-controlled, double-blind parallel-group study including 4 treatment arms: rolapitant at the highest safe dose established in part 1, placebo, moxifloxacin 400 mg (positive control), and rolapitant at the presumed therapeutic dose (180 mg)...

CSL112 (Apolipoprotein A-I [human]) is an intravenous preparation of apolipoprotein A-I (apoA-I), formulated with phosphatidylcholine (PC) and stabilized with sucrose, in development to prevent early recurrent cardiovascular events following acute myocardial infarction (AMI). This phase 1 study was designed to determine if moderate renal impairment (RI) influenced the pharmacokinetics (PK) and safety of CSL112. Thirty-two subjects, 16 with moderate RI (estimated glomerular filtration rate [eGFR] ≥ 30 and < 60 mL/min/1...