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•Fixed-dose combination (FDC) was bioequivalent to individual components (ICs) in Western and Korean adults.•Pharmacokinetic parameters of FDC and IC were generally similar.•No clinically relevant pharmacokinetic differences in Western vs Korean participants.•FDC and ICs were well tolerated, with no serious adverse events. We evaluated the pharmacokinetics, safety, and tolerability of a fixed-dose combination (FDC) of dapagliflozin/sitagliptin versus individual component (IC) tablets in healthy Western and Korean participants. The combination of these antihyperglycemic drugs provides efficient glucose control, and the use of FDC has generally been shown to improve medication adherence in individuals with type 2 diabetes mellitus (T2DM). Two randomized, open-label, two-period, two-treatment, single-dose, single-center, crossover bioequivalence studies conducted on healthy fasted German participants (aged 18–55 years; Western study) and South Korean participants (aged 19–55 years; Korean study) were included. In both studies, pharmacokinetic parameters (maximum [peak] plasma concentration [Cmax], area under the plasma concentration–time curve from zero to the last quantifiable concentration [AUClast], and area under the plasma concentration–time curve from zero to infinity [AUCinf]) were used to assess the bioequivalence of 10 mg dapagliflozin/100 mg sitagliptin FDC (Treatment A) with their ICs (Treatment B) under fasted conditions. Safety and tolerability were assessed throughout the study. Forty-six healthy participants (male, 60.9%; mean age, 39.5 years; mean body mass index [BMI], 23.9 kg/m2) were randomized in the Western study, and 51 healthy participants (male, 100.0%; mean age, 24.6 years; mean BMI, 23.9 kg/m2) were randomized in the Korean study. In both studies, the participants were randomized 1:1 into treatment sequence AB and treatment sequence BA. Dapagliflozin/sitagliptin FDC was bioequivalent to IC tablets in both Western and Korean studies, as the 90% confidence interval of the FDC to IC ratios of the geometric least-squares means of the pharmacokinetic parameters for both dapagliflozin and sitagliptin was within the 0.8000–1.2500 bioequivalence criterion limit. The observed differences in pharmacokinetic parameters, such as Cmax, AUClast, and AUCinf, between the Western and Korean studies were not clinically meaningful. Dapagliflozin/sitagliptin FDC and their ICs were well tolerated, with no serious adverse events reported in any of the study populations. The 10 mg dapagliflozin/100 mg sitagliptin FDC and IC formulations were bioequivalent in fasted healthy Western and Korean participants, with no new safety concerns identified, thus offering a useful alternative for patients currently receiving individual medications as part of their treatment regimen. Western study (clinicaltrials.gov: NCT05266404) and Korean study (clinicaltrials.gov: NCT05453786).

Patients with type 2 diabetes mellitus require strict blood glucose control, and combination therapy with a thiazolidinedione and dipeptidyl peptidase-4 inhibitors, such as lobeglitazone and sitagliptin, is one of the recommended treatments. The objective of this study was to investigate a possible pharmacokinetic interaction between lobeglitazone and sitagliptin after multiple oral administrations in healthy Korean men. Two randomized, open-label, multiple-dose, 2-way crossover studies were conducted simultaneously in healthy men. In study 1, men were randomly assigned to 1 of 2 sequences, and 1 of the following treatments was administered in each period: 1 tablet of lobeglitazone sulfate (0.5 mg) once daily for 5 days and or 1 tablet each of lobeglitazone sulfate (0.5 mg) and sitagliptin (100 mg) once daily for 5 days. In study 2, men were also randomly assigned to 1 of 2 sequences and the treatments were as follows: 1 tablet of sitagliptin (100 mg) once daily for 5 days or 1 tablet each of sitagliptin (100 mg) and lobeglitazone sulfate (0.5 mg) once daily for 5 days. Serial blood samples were collected up to 48 h after dosing on the fifth day. Plasma drug concentrations were measured by LC-MS/MS. Pharmacokinetic parameters, including Cmax,ss and AUC0–τ , were determined by noncompartmental analysis. The geometric least-square mean (GLSM) ratios and associated 90% CIs of log-transformed Cmax,ss and AUC0–τ for separate or coadministration were calculated to evaluate pharmacokinetic interactions. Nineteen men from study 1 and 17 from study 2 completed the pharmacokinetic sampling and were included in the analyses. The GLSM ratios of Cmax,ss and AUC0–τ were 0.9494 (95% CI, 0.8798–1.0243) and 1.0106 (95% CI, 0.9119–1.1198) for lobeglitazone (from study 1) and 1.1694 (95% CI, 1.0740–1.2732) and 1.0037 (95% CI, 0.9715–1.0369) for sitagliptin (from study 2), respectively. Except for the slight 17% increase in the sitagliptin Cmax,ss value, the pharmacokinetic parameters of lobeglitazone and sitagliptin met the pharmacokinetic equivalent criteria when administered separately or in combination. The increase in Cmax of sitagliptin when coadministered with lobeglitazone would not be clinically significant in practice. ClinicalTrials.gov Identifier: NCT02824874 and NCT02827890. •Sitagliptin Cmax,ss increased after multiple administrations with lobeglitazone.•Not a clinically significant increase in sitagliptin Cmax,ss.•Lobeglitazone and sitagliptin may be used in combination without dose adjustment.

Serum fibroblast growth factor 23 (FGF23) is a novel phosphaturic factor and important for the regulation of inorganic phosphate (Pi) homeostasis. In this study, we examined an acute effect of oral Pi loading on serum FGF23 levels to clarify the role in rapid adjustment of serum Pi level. We performed a randomized, double-blind, crossover study in eight healthy male volunteers. The subjects were alternately served one of three test meals containing different Pi amounts (400mg (P400), 800mg (P800), and 1200mg (P1200)) as lunch at noon. The postprandial changes in serum levels of Pi, Ca, 1,25-dihydroxyvitamin D, intact-parathyroid hormone (iPTH), intact-FGF23 (iFGF23), and urinary excretion of Pi and Ca until 8h after Pi loading were estimated. Serum Pi levels and urinary Pi excretion significantly increased within 1h after P400 and P800 intake. Serum iPTH levels at 1–2 and 4–6h after P1200 intake was significantly higher than those of P400 intake. Serum iFGF23 levels slightly decreased up to 8h after P400 intake and up to 6h after P800 intake, but not changed in P1200 intake. Significant increase of iFGF23 was observed at 8h after P1200 intake compared with both P400 and P800 intake. Additionally, negative association was detected between iFGF23 and serum Pi, whereas positive association was observed between iPTH and serum Pi during the short period. We conclude that oral Pi loading cannot rapidly increase serum FGF23 level. FGF23 may be not associated with rapid adaptation of Pi homeostasis.

Casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) nanocomplexes incorporated into sugar-free chewing gum have been shown to remineralize enamel subsurface lesions in situ. The aim of this study was to compare the ability of CPP-ACP, with that of other forms of calcium, to be retained in supragingival plaque and remineralize enamel subsurface lesions in situ when delivered in a mouthrinse or sugar-free gum in randomized, double-blind trials. In the mouthrinse study, only the CPP-ACP-containing mouthrinse significantly increased plaque calcium and inorganic phosphate levels, and the CPP were immunolocalized to the surfaces of bacterial cells as well as the intercellular matrix. In the chewing gum studies, the gum containing the CPP-ACP, although not containing the most calcium per piece of gum, produced the highest level of enamel remineralization independent of gum-chewing frequency and duration. The CPP could be detected in plaque extracts 3 hrs after subjects chewed the CPP-ACP-containing gum. The results showed that CPP-ACP were superior to other forms of calcium in remineralizing enamel subsurface lesions.

Objective To evaluate the single‐dose pharmacokinetics (PK), pharmacodynamics (PD), and safety of sitagliptin in pediatric patients with type 2 diabetes mellitus (T2DM). Study Design This was a randomized, placebo‐controlled, double‐blind evaluation of sitagliptin in 35 patients 10 to 17 years old with T2DM at 7 clinical research sites. The safety, tolerability, PK, and PD (dipeptidyl peptidase‐4 [DPP‐4] inhibition and aspects of glucose metabolism) of single doses of 50, 100, and 200 mg were assessed. Appropriate transformations on the PK parameters were used and back‐transformed summary statistics are reported. Results Adverse experiences were reported by eight study participants; all were of mild intensity except one (intravenous site pain of moderate intensity). PK characteristics in the young patients were comparable to reference adult data, with geometric mean ratios (youths/adults) for AUC0−∞, Cmax, and C24hr of 0.82, 1.04, and 0.74, respectively. Single doses of 50, 100, and 200 mg sitagliptin inhibited 67.2%, 73.8%, and 81.2% of plasma DPP‐4 activity over 24 hours, respectively. Least squares (LS) mean glucose concentrations 2 hours after an oral glucose tolerance test or a meal tolerance test decreased in study participants treated with sitagliptin, compared to placebo, while active LS mean glucagon‐like peptide 1 concentrations increased significantly at all sitagliptin doses in both tests. Conclusions Single doses of sitagliptin as high as 200 mg were generally well tolerated in 10‐ to 17‐year‐old male and female study participants with T2DM, and a daily sitagliptin dose of 100 mg is appropriate for evaluation in Phase III safety and efficacy studies in pediatric patients with T2DM. (ClinicalTrials.gov: NCT00730275).

Amifampridine (3,4-diaminopyridine) has been approved in the European Union for the treatment of Lambert-Eaton myasthenic syndrome. Amifampridine has a narrow therapeutic index, and supratherapeutic exposure has been associated with dose-dependent adverse events, including an increased risk for seizure. This study assessed the effect of food on the relative bioavailability of amifampridine in healthy subjects and informed on conditions that can alter exposure. This randomized, open-labeled, 2-treatment, 2-period crossover study enrolled 47 healthy male and female subjects. Subjects were randomly assigned to receive 2 single oral doses of amifampridine phosphate salt (20 mg base equivalents per dose) under fed or fasted conditions separated by a washout period. Blood and urine samples for pharmacokinetic analyses were taken before and after dosing. Plasma concentrations of amifampridine and an inactive 3-N-acetyl metabolite were determined. The relative bioavailability values of amifampridine and metabolite were assessed based on the plasma PK parameters AUC0–∞, AUC0–t, and Cmax in the fed and fasted states using noncompartmental pharmacokinetic analysis. Parent drug and metabolite excretion were calculated from urinary concentrations. A food effect on bioavailability would be established if the 90% CI of the ratio of population geometric mean value of AUC0–∞, AUC0–t, or Cmax between fed and fasted administration was not within the bioequivalence range of 80% to 125%. Tolerability was assessed based on adverse-event reporting, clinical laboratory assessments, physical examination including vital sign measurements, 12-lead ECG, and concurrent medication use. Food slowed and somewhat decreased the absorption of amifampridine. There was a decrease in exposure (Cmax, 44%; AUC, 20%) after oral administration of amifampridine phosphate salt in the presence of food, and mean Tmax was 2-fold longer in the fed state. The extent of exposure and plasma elimination half-life of the major metabolite was greater than those of amifampridine in the fed and fasted conditions. Mean AUCs in the fed and fasted states were slightly greater in women than men, with no difference in mean Cmax. Orally administered amifampridine was renally eliminated (>93%) as the parent compound and metabolite within 24 hours. Single oral doses of 20 mg of amifampridine phosphate salt were considered well tolerated in both the fed and fasted conditions. High intersubject variability (%CVs, >30%) in amifampridine pharmacokinetic parameter values was observed. At the intended dose under fasting conditions, amifampridine exposure may be increased. European Union Drug Regulating Authorities Clinical Trials identifier: 2011-000596-13.

Hypophosphataemia is frequently encountered in dairy cows during early lactation. Although supplementation of P is generally recommended, controversy exists over the suitability of oral P supplementation in animals with decreased or absent rumen motility. Since the effects of transruminal P absorption and the reticular groove reflex on the absorption kinetics of P are not well understood, it is unclear in how far treatment efficacy of oral P supplementation is affected by decreased rumen motility. Phosphate absorption was studied in six phosphate-depleted dairy cows fitted with rumen cannulas and treated with test solutions containing either NaH2PO4 or CaHPO4 with acetaminophen. Each animal was treated orally, intraruminally and intra-abomasally in randomised order. Absorption kinetics of P were studied and compared with the absorption kinetics of acetaminophen, a marker substance only absorbed from the small intestine. Intra-abomasal treatment with NaH2PO4 resulted in the most rapid and highest peaks in plasma inorganic P (Pi) concentration. Oral and intraruminal administration of NaH2PO4 resulted in similar increases in plasma Pi concentration from 4 to 7 h in both groups. Treatment with NaH2PO4 caused more pronounced peaks in plasma Pi concentration compared with CaHPO4. Neither transruminal P absorption nor the reticular groove reflex affected P absorption kinetics as determined by comparing plasma concentration–time curves of P and acetaminophen after administration of 1 m-phosphate salt solutions. It is concluded that oral treatment with NaH2PO4 but not CaHPO4 is effective in supplementing P in hypophosphataemic cows with adequate rumen motility. Decreased rumen motility is likely to hamper the efficacy of oral phosphate treatment.

Inorganic phosphate (Pi) plays a critical function in many tissues of the body: for example, as part of the hydroxyapatite in the skeleton and as a substrate for ATP synthesis. Pi is the main source of dietary phosphorus. Reduced bioavailability of Pi or excessive losses in the urine causes rickets and osteomalacia. While critical for health in normal amounts, dietary phosphorus is plentiful in the Western diet and is often added to foods as a preservative. This abundance of phosphorus may reduce longevity due to metabolic changes and tissue calcifications. In this review, we examine how dietary phosphorus is absorbed in the gut, current knowledge about Pi sensing, and endocrine regulation of Pi levels. Moreover, we also examine the roles of Pi in different tissues, the consequences of low and high dietary phosphorus in these tissues, and the implications for healthy aging.

Additive manufacturing enables the fabrication of scaffolds with defined architecture. Versatile printing technologies such as extrusion-based 3D plotting allow in addition the incorporation of biological components increasing the capability to restore functional tissues. We have recently described the fabrication of calcium phosphate cement (CPC) scaffolds by 3D plotting of an oil-based CPC paste under mild conditions. In the present study, we have developed a strategy for growth factor loading based on multichannel plotting: a biphasic scaffold design was realised combining CPC with VEGF-laden, highly concentrated hydrogel strands. As hydrogel component, alginate and an alginate–gellan gum blend were evaluated; the blend exhibited a more favourable VEGF release profile and was chosen for biphasic scaffold fabrication. After plotting, two-step post-processing was performed for both, hydrogel crosslinking and CPC setting, which was shown to be compatible with both materials. Finally, a scaffold was designed and fabricated which can be applied for testing in a rat critical size femur defect. Optimization of CPC plotting enabled the fabrication of highly resolved structures with strand diameters of only 200  µ m. Micro-computed tomography revealed a precise strand arrangement and an interconnected pore space within the biphasic scaffold even in swollen state of the hydrogel strands.

Background: Perfluorinated carboxylic acids (PFCAs) are ubiquitous in human sera worldwide. Biotransformation of the polyfluoroalkyi phosphate esters (PAPs) is a possible source of PFCA exposure, because PAPs are used in food-contact paper packaging and have been observed in human sera. Objectives: We determined pharmacokinetic parameters for the PAP monoesters (monoPAPs) and PAP diesters (diPAPs), as well as biotransformation yields to the PFCAs, using a rat model. Methods: The animals were dosed intravenously or by oral gavage with a mixture of 4:2, 6:2, 8:2, and 10:2 monoPAP or diPAP chain lengths. Concentrations of the PAPs and PFCAs, as well as metabolic intermediates and phase II metabolites, were monitored over time in blood, urine, and feces. Results: The diPAPs were bioavailable, with bioavailability decreasing as the chain length increased from 4 to 10 perfluorinated carbons. The monoPAPs were not absorbed from the gut; however, we found evidence to suggest phosphate-ester cleavage within the gut contents. We observed biotransformation to the PFCAs for both monoPAP and diPAP congeners. Conclusions: Using experimentally derived biotransformation yields, perfluorooctanoic acid (PFOA) sera concentrations were predicted from the biotransformation of 8:2 diPAP at concentrations observed in human serum. Because of the long human serum half-life of PFOA, biotransformation of diPAP even with low-level exposure could over time result in significant exposure to PFOA. Although humans are exposed directly to PFCAs in food and dust, the pharmacokinetic parameters determined here suggest that PAP exposure should be considered a significant indirect source of human PFCA contamination.