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Canagliflozin is a sodium-glucose cotransporter 2 inhibitor approved for the treatment of type 2 diabetes mellitus (T2DM). Because T2DM is often associated with renal or hepatic impairment, understanding the effects of these comorbid conditions on the pharmacokinetics of canagliflozin, and further assessing its safety, in these special populations is essential. Two open-label studies evaluated the pharmacokinetics, pharmacodynamics (renal study only), and safety of canagliflozin in participants with hepatic or renal impairment. Participants in the hepatic study (8 in each group) were categorized based on their Child-Pugh score (normal hepatic function, mild impairment [Child-Pugh score of 5 or 6], and moderate impairment [Child-Pugh score of 7–9]) and received a single oral dose of canagliflozin 300 mg. Participants in the renal study (8 in each group) were categorized based on their creatinine clearance (CLCR) (normal renal function [CLCR ≥80 mL/min]; mild [CLCR 50 to <80 mL/min], moderate [CLCR 30 to <50 mL/min], or severe [CLCR <30 mL/min] renal impairment; and end-stage renal disease [ESRD]) and received a single oral dose of canagliflozin 200 mg; the exception was those with ESRD, who received 1 dose postdialysis and 1 dose predialysis (10 days later). Canagliflozin’s pharmacokinetics and pharmacodynamics (urinary glucose excretion [UGE] and renal threshold for glucose excretion [RTG]) were assessed at predetermined time points. Mean maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time zero to infinite (AUC)0–∞ values differed by <11% between the group with normal hepatic function and those with mild and moderate hepatic impairment. In the renal study, the mean Cmax values were 13%, 29%, and 29% higher and the mean AUC0–∞ values were 17%, 63%, and 50% higher in participants with mild, moderate, and severe renal impairment, respectively; values were similar in the ESRD group relative to the group with normal function, however. The amount of UGE declined as renal function decreased, whereas RTG was not suppressed to the same extent in the moderate to severe renal impairment groups (mean RTG, 93–97 mg/dL) compared with the mild impairment and normal function groups (mean RTG, 68–77 mg/dL). Canagliflozin’s pharmacokinetics were not affected by mild or moderate hepatic impairment. Systemic exposure to canagliflozin increased in the renal impairment groups relative to participants with normal renal function. Pharmacodynamic response to canagliflozin, measured by using UGE and RTG, declined with increasing severity of renal impairment. A single oral dose of canagliflozin was well tolerated by participants in both studies. ClinicalTrials.gov identifiers: NCT01186588 and NCT01759576.

The primary aim was to demonstrate bioequivalence between the 10/20 mg fixed‐dose combination (FDC) of macitentan/tadalafil in a single tablet and the free combination of both drugs, and to evaluate the food effect on the 10/20 mg FDC in healthy participants. In this single‐center, randomized, open‐label, 3‐way crossover, single‐dose Phase 1 study in healthy adult participants, macitentan/tadalafil was administered as a 10/20 mg FDC formulation and compared with the free combination of macitentan and tadalafil. The food effect on the FDC was also evaluated. Pharmacokinetic sampling (216 h) was conducted. The 90% confidence intervals (CIs) for the geometric mean ratios of maximum observed plasma analyte concentration (Cmax) and area under the plasma analyte concentration–time curves (AUCs) for Treatment A (FDC, fasted) versus C (free combination, fasted) were within bioequivalence limits demonstrating that the FDC formulation can be considered bioequivalent to the free combination. The 90% CIs for the geometric mean ratios of Cmax and AUC for Treatment B (FDC, fed) versus A (FDC, fasted) were contained within bioequivalence limits demonstrating that there was no food effect. The administration of the 10/20 mg FDC was generally safe and well tolerated in healthy participants. This study demonstrated bioequivalence between the FDC of macitentan/tadalafil (10/20 mg) in a single tablet and the free combination of both drugs in healthy participants, and that the FDC can be taken without regard to food, similarly to the individual components. The FDC was generally safe and well tolerated. Arithmetic mean plasma concentration versus time profiles for macitentan, aprocitentan and tadalafil during the first 24 hours and 216 hours after administration of Treatment A (FDC, fasted), Treatment B (FDC, fed), and Treatment C (free combination, fasted).

Canagliflozin, an orally active sodium–glucose cotransporter 2 inhibitor, is approved in many countries as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. The recommended dose of canagliflozin is 100 or 300 mg once daily. This Phase I study was conducted to evaluate the pharmacokinetics, pharmacodynamics, and safety profile of canagliflozin in healthy Chinese subjects. In this double-blind, single-dose, 3-way crossover study, 15 healthy subjects were randomized (1:1:1) to receive single oral doses of canagliflozin 100 mg, canagliflozin 300 mg, or placebo. Pharmacokinetic, pharmacodynamic, and safety assessments were made at prespecified time points. All participants are healthy Chinese adults. Mean AUC and Cmax of canagliflozin increased in a dose-dependent manner after single-dose administration (AUC0–∞, 10,521 ng · h/mL for 100 mg, 33,583 ng · h/mL for 300 mg; Cmax, 1178 ng/mL for 100 mg, 4113 ng/mL for 300 mg). The mean apparent t½ and the median Tmax of canagliflozin were independent of dose (t½, 16.0 hours for 100 mg, 16.2 hours for 300 mg; Tmax, ~1 hour). Mean CL/F and renal clearance of canagliflozin were comparable between the 2 doses. Mean plasma metabolite to parent molar ratios for Cmax and AUC0–∞ were similar with both doses. Canagliflozin decreased the 24-hour mean renal threshold for glucose, calculated by using measured creatinine clearance to estimate the glomerular filtration rate (67.9 and 60.7 mg/dL for canagliflozin 100 and 300 mg, respectively) and 24-hour increased urinary glucose excretion (33.8 and 42.9 g for canagliflozin 100 and 300 mg, respectively) in a dose-dependent manner; the 24-hour plasma glucose profile remained largely unchanged. No deaths, hypoglycemic events, or discontinuations due to adverse events were observed. Pharmacokinetics (AUC and Cmax) of canagliflozin increased in a dose-dependent manner after single oral doses of canagliflozin (100 and 300 mg) in these healthy Chinese subjects. Tmax and t½ of canagliflozin were independent of the dose. Canagliflozin decreased the 24-hour mean renal threshold for glucose and increased urinary glucose excretion in a dose-dependent manner; these results are consistent with those observed in other patient populations. Canagliflozin was generally safe and well tolerated in these healthy Chinese subjects. ClinicalTrials.gov identifier: NCT01707316.

Canagliflozin, an orally active selective inhibitor of sodium glucose cotransporter 2, has been approved in several countries for the treatment of type 2 diabetes mellitus. This study assessed the pharmacokinetic (PK) and pharmacodynamic (PD) properties and tolerability of single-dose canagliflozin 200 or 300 mg in healthy Indian participants. In this Phase 1, single-center, open-label, 2-period crossover study, healthy adult participants were randomly assigned to receive a single dose of canagliflozin 200 mg in period 1, followed by canagliflozin 300 mg in period 2, or vice versa. The 2 periods were separated by a washout interval of 14 days. The PK and PD properties and tolerability of canagliflozin were assessed at prespecified time points. Of 15 randomized participants, 14 completed the study. After the administration of single doses of 200 and 300 mg, the mean (SD) Cmax values were 1792 (430) ng/mL and 2789 (941) ng/mL, respectively; AUC0–∞, values were 18,706 (3818) ng·h/mL and 28,207 (5901) ng·h/mL, respectively. The Tmax and t½ of canagliflozin were independent of dose (Tmax, 1.5 hours at both doses; t½, 13.0 and 12.6 hours with 200 and 300 mg). Over the first 4 hours, mean (SD) renal threshold for glucose (RTG) values were 60.8 (8.90) and 61.2 (7.04) mg/dL with the 200- and 300-mg doses, respectively. No effect on plasma glucose concentrations over 0 to 4 hours relative to baseline was observed with either dose. The only treatment-emergent adverse event (TEAE) reported in >1 participant was dizziness (2 participants with the 200-mg dose). None of the participants in the 300-mg group reported any TEAEs. No deaths, discontinuations due to TEAEs, or hypoglycemic episodes were reported. The mean plasma exposure (Cmax and AUC) to canagliflozin increased in a dose-dependent manner after the administration of single-dose oral canagliflozin 200 and 300 mg in these healthy Indian participants. The Tmax and t½ of canagliflozin appeared to be independent of dose. Overall, PK characteristics were consistent with previous findings in other ethnic populations. The reductions in RTG with canagliflozin were similar to those reported in Western participants, whereas the amount of urinary glucose excretion was somewhat less than those previously observed in studies in Western participants. Canagliflozin was generally well tolerated in these healthy Indian participants. ClinicalTrials.gov identifier: NCT01748526.

The COVID‐19 pandemic has forced clinical studies to accommodate imposed limitations. In this study, the bioequivalence part could not be conducted as planned. Thus, the aim was to demonstrate bioequivalence, using an adaptive study design, of tadalafil in fixed‐dose combination (FDC) tablets of macitentan/tadalafil with single macitentan and tadalafil (Canadian‐sourced) tablets and assess the effect of food on FDC tablets in healthy subjects. This Phase 1, single‐center, open‐label, single‐dose, two‐part, two‐period, randomized, crossover study enrolled 62 subjects. Tadalafil bioequivalence as part of FDC of macitentan/tadalafil (10/40 mg) with single‐component tablets of macitentan (10 mg) and tadalafil (40 mg) was determined by pharmacokinetic (PK) assessment under fasted conditions. The effect of food on FDC was evaluated under fed and fasted conditions. Fasted 90% confidence intervals (CIs) for geometric mean ratios (GMRs) were within bioequivalence limits for tadalafil and macitentan. Fed and fasted 90% CIs for area under the curve (AUC) GMR were within bioequivalence limits. However, 90% CIs for maximum plasma concentration (Cmax) GMR for macitentan and tadalafil were outside bioequivalence limits. One FDC‐treated subject experienced a serious adverse event of transient ischemic attack (bioequivalence part). To address pandemic‐imposed limitations, an adaptive study design was implemented to demonstrate that the FDC tablet was bioequivalent to the free combination of macitentan and tadalafil (Canadian‐sourced). No clinically significant differences in PK were determined between fed and fasted conditions; the FDC formulation could be taken irrespective of meals. The FDC formulation under fasted and fed conditions was well tolerated with no clinically relevant differences in safety profiles between the treatment groups. NCT Number: NCT04235270. The macitentan 10 mg/tadalafil 40 mg Fixed Dose Combination is bioequivalent to the free combination. No clinically significant differences in PK were determined between fed and fasted conditions of the FDC formulation.

Capillary microsampling of 15 μl whole blood from fingersticks or heelsticks was used to collect pharmacokinetic (PK) samples from pediatric subjects in two projects. In a mebendazole multisite study in Ethiopia and Rwanda in subjects between 1 and 16 years old, complete PK profiles (7 timepoints) could be obtained, although some of the fingerstick samples were contaminated by the dosing formulation. In a multisite study with a respiratory syncytial virus drug in children between 1 and 24 months old, sparse PK sampling was done (2 samples). All samples were successfully analyzed even though some capillaries were not properly filled. CMS shows potential for PK sampling in pediatrics but may need further optimization.

Following the request of a regulatory authority, a rat study was conducted to compare pharmacokinetic parameters from traditional large volume sampling and capillary microsampling. Rats were dosed with a proprietary compound in three dose groups and blood samples were collected via capillary microsampling (32 μl), immediately followed by traditional large volume sampling (300 μl) up to 24 h postdose. Resulting plasma samples were analyzed for parent drug and two metabolites. AUCs were compared between sampling techniques. There was no statistical difference between AUCs from traditional and microsampling across different doses and analytes.   Toxicokinetic parameters generated from plasma collected as a capillary microsample or traditional large volume sample are highly comparable.

Purpose Abiraterone acetate (AA) was recently approved for castration-resistant prostate cancer in Japan. Two phase 1 studies were conducted to assess the pharmacokinetics of abiraterone after single-dose administration in Japanese healthy men and to evaluate the effects of food timing on abiraterone pharmacokinetics after single-dose administration of AA in Japanese and Caucasian healthy men. Methods In the dose-proportionality study, subjects ( n  = 30 Japanese) were randomly assigned to receive single doses of 250, 500, and 1,000 mg AA, and in the food-timing study, subjects ( n  = 22 Japanese and n  = 23 Caucasian) randomly received single doses of 1,000 mg AA under fasted (overnight) and three different modified fasting conditions. Results Mean C max and AUC ∞ for abiraterone increased dose-dependently in Japanese healthy men; however, 90 % confidential interval (CI) was outside the predefined dose-proportionality criteria. Based on geometric mean ratios and 90 % CIs (versus overnight fasting condition), abiraterone exposure (AUC) increased significantly with dosing 1 h premeal, 2 h postmeal, or in between two meals 4 h apart by 57 %, 595 %, and 649 %, respectively. Conclusion No clinically meaningful difference was observed in the pharmacokinetics of abiraterone between Caucasian and Japanese subjects.

Abstract Objectives Safety, tolerability, pharmacokinetics, and pharmacodynamics of a novel β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor, JNJ-54861911, were assessed after single and multiple dosing in healthy participants. Methods Two randomized, placebo-controlled, double-blind studies were performed using single and multiple ascending JNJ-54861911 doses (up to 14 days) in young and elderly healthy participants. Regular blood samples and frequent CSF samples, up to 36 hours after last dose, were collected to assess the pharmacokinetic and pharmacodynamic (Aβ, sAPPα,β,total levels) profiles of JNJ-54861911. Results JNJ-54861911 was well-tolerated, adverse events were uncommon and unrelated to JNJ-54861911. JNJ-54861911 showed dose-proportional CSF and plasma pharmacokinetic profiles. Plasma- and CSF-Aβ and CSF-sAPPβ were reduced in a dose-dependent manner. Aβ reductions (up to 95%) outlasted exposure to JNJ-54861911. APOE ε4 carrier status and baseline Aβ levels did not influence Aβ/sAPPβ reductions. Conclusion JNJ-54861911, a potent brain-penetrant BACE1 inhibitor, achieved high and stable Aβ reductions after single and multiple dosing in healthy participants.

The quantification of fiber integrity is central to the clinical application of diffusion imaging. Compared to diffusion tensor imaging (DTI), Q-ball imaging (QBI) allows for the depiction of multiple fiber directions within a voxel. However, this advantage has not yet been shown to translate directly to superior quantification of fiber integrity. Furthermore, recent developments in QBI reconstruction with solid angle consideration have led to sharper and intrinsically normalized orientation distribution functions. The implications of this technique on quantification are also unknown. To investigate this, the generalized fractional anisotropy (GFA) from the original and the more recent QBI reconstruction scheme and the DTI derived fractional anisotropy (FA) were evaluated comparatively using Monte Carlo simulations and real MRI measurements of crossing fiber phantoms. Contrast-to-noise ratio, accuracy, independence of the acquisition setup and the relation of single fiber anisotropies to measured anisotropy in crossings were assessed. In homogeneous single-fiber regions at b-values around 1000 s/mm2, the FA performed best. While the original QBI reconstruction does not show a clear advantage even at higher b-values and in crossing regions, the new reconstruction scheme yields superior properties and is recommended for quantification at higher b-values and especially in regions of heterogeneous fiber configuration.