Probabilistic risk assessment of residential exposure to electric arc furnace steel slag using Bayesian model of relative bioavailability and PBPK modeling of manganese.

Electric arc furnace (EAF) slag is a coproduct of steel production used primarily for construction purposes. Some applications of EAF slag result in residential exposures by incidental ingestion and inhalation of airborne dust. To evaluate potential health risks, an EAF slag characterization program was conducted to measure concentrations of metals and leaching potential (including oral bioaccessibility) in 38 EAF slag samples. Arsenic, hexavalent chromium, iron, vanadium, and manganese (Mn) were identified as constituents of interest (COIs). Using a probabilistic risk assessment (PRA) approach, estimated distributions of dose for COIs were assessed, and increased cancer risks and noncancer hazard quotients (HQs) at the 50th and 95th percentiles were calculated. For the residents near slag-covered roads, cancer risk and noncancer HQs were <1E - 6 and 1, respectively. For residential driveway or landscape exposure, at the 95th percentile, cancer risks were 1E - 6 and 7E - 07 based on oral exposure to arsenic and hexavalent chromium, respectively. HQs ranged from 0.07 to 2 with the upper bound due to ingestion of Mn among children. To expand the analysis, a previously published physiologically based pharmacokinetic (PBPK) model was used to estimate Mn levels in the globus pallidus for both exposure scenarios and further evaluate the potential for Mn neurotoxicity. The PBPK model estimated slightly increased Mn in the globus pallidus at the 95th percentile of exposure, but concentrations did not exceed no-observed-adverse-effect levels for neurological effects. Overall, the assessment found that the application of EAF slag in residential areas is unlikely to pose a health hazard or increased cancer risk.

Pharmacokinetic of two oral doses of a 1:20 THC:CBD cannabis herbal extract in cats.

Objective: To determine the pharmacokinetics (PK) of two oral doses of a Cannabis herbal extract (CHE) containing 1:20 THC:CBD in 12 healthy Domestic Shorthair cats. Methods: Single-dose PK were assessed after oral administration of CHE at low or high dose (2 mg CBD + 0.1 mg THC, or 5 mg CBD + 0.25 mg THC per kg bw, respectively; n = 6 per group) in fasting cats. Blood samples were drawn up to 48 h following CHE administration. Plasma samples were analyzed for CBD, THC, and metabolites 6-OH-CBD, 7-OH-CBD, 11-OH-THC, and THC-COOH using a previously validated LC-MS/MS method. Results: CBD and THC were quickly absorbed (mean Tmax of 2.4-2.9 h). Maximum plasma concentrations (Cmax) ranged from 36-511 ng/mL and 6.8-61 ng/mL for CBD and THC, respectively. Elimination was initially rapid for both CBD and THC, though a prolonged elimination phase was noted for CBD in some cats (T1/2 λ up to 26 h). Dose-adjusted Cmax and AUC0-last values were not statistically significantly different (p > 0.05) between dose groups indicating CBD and THC concentrations increased in a manner proportional (linear) to the dose. Dose-adjusted THC Cmax and AUC0-last were significantly higher than the corresponding dose-adjusted CBD parameters (p < 0.01). Low concentrations of the metabolite 6-OH-CBD were quantified but metabolites 7-OH-CBD, 11-OH-THC, and THC-COOH were not detected in any plasma samples. Inter-individual variance was notable. Salivation shortly after dosing was observed in two cats in the high dose group; these animals had substantially lower cannabinoid concentrations than other cats in this group. No adverse clinical signs (including vomiting, change in mentation or other neurological signs) were noted. Clinical significance: Although cats did not display adverse effects after administration of a single oral dose of 1:20 THC:CBD CHE formulation at 2 or 5 mg CBD/kg bw, observed plasma concentrations were highly variable but generally lower than in dogs receiving the same dose and formulation. Administration of CHE in the fasting state may not optimize CBD absorption, and oral dosing may be challenging when administering an oil-based CHE in some cats.

Pharmacokinetics and relative bioavailability study of two cefquinome sulfate intramammary infusions in cow milk.

In this study, two intramammary infusions of cefquinome sulfate were investigated for pharmacokinetics and bioavailability. Twelve lactating cows for each group were administered an effective dose of 75 mg/gland for cefquinome, with milk samples collected at various time intervals. The concentrations of cefquinome in milk at different times were determined by the UPLC-MS/MS method. Analyses of noncompartmental pharmacokinetics were conducted on the concentration of cefquinome in milk. Mean pharmacokinetic parameters of group A and group B following intramammary administration were as follows: AUClast 300558.57 ± 25052.78 ng/mL and 266551.3 ± 50654.85 ng/mL, Cmax 51786.35 ± 11948.4 ng/mL and 59763.7 ± 8403.2 ng/mL, T1/2 5.69 ± 0.62 h and 5.25 ± 1.62 h, MRT 7.43 ± 0.79 h and 4.8 ± 0.78 h, respectively. Pharmacokinetic experiments showed that the relative bioavailability of group B was 88.69% that of group A. From our findings, group B (3 g: 75 mg) shows a quicker drug elimination process than group A (8 g: 75 mg), which suggests that the withdrawal period for the new formulation may be shorter.

Arsenic, cadmium, lead, antimony bioaccessibility and relative bioavailability in legacy gold mining waste.

Bioaccessibility and relative bioavailability of As, Cd, Pb and Sb was investigated in 30 legacy gold mining wastes (calcine sands, grey battery sands, tailings) from Victorian goldfields (Australia). Pseudo-total As concentration in 29 samples was 1.45-148-fold higher than the residential soil guidance value (100 mg/kg) while Cd and Pb concentrations in calcine sands were up to 2.4-fold and 30.1-fold higher than the corresponding guidance value (Cd: 20 mg/kg and Pb: 300 mg/kg). Five calcine sands exhibited elevated Sb (31.9-5983 mg/kg), although an Australian soil guidance value is currently unavailable. Arsenic bioaccessibility (n = 30) and relative bioavailability (RBA; n = 8) ranged from 6.10-77.6% and 10.3-52.9% respectively. Samples containing > 50% arsenopyrite/scorodite showed low As bioaccessibility (<20.0%) and RBA (<15.0%). Co-contaminant RBA was assessed in 4 calcine sands; Pb RBA ranged from 73.7-119% with high Pb RBA associated with organic and mineral sorbed Pb and, lower Pb RBA observed in samples containing plumbojarosite. In contrast, Cd RBA ranged from 55.0-67.0%, while Sb RBA was < 5%. This study highlights the importance of using multiple lines of evidence during exposure assessment and provides valuable baseline data for co-contaminants associated with legacy gold mining activities.

Can arsenic bioavailability be predicted in soils using in vitro gastro-intestinal simulation?

Many gastrointestinal simulation methods have been used to predict bioavailability, but the suitability of different methods for the same metal(loid)s varies widely, which inevitably affects the accuracy of human health risk assessment. Arsenic is a common and important contaminant in many contaminated land situations. It can be readily absorbed and has teratogenic and mutagenic toxicity. Therefore, in this study, four the most commonly used in vitro simulation methods (the Physiologically Based Extraction Test (PBET), In Vitro Gastrointestinal Method (IVG), Soluble Bioavailability Research Consortium (SBRC), the Unified BARGE Method (UBM)) were tested against an in vivo animal live model, to evaluate their effectiveness for the prediction of soil As bioavailability in 10 industrially contaminated soils. The soil As relative bioavailability (RBA) varied between 15% and 68% in the different soils. As bioaccessibility differed between the 4 gastro-intestinal simulation methods. Gastric phase of UBM (UBMG) predicted As relative bioavailability the best of the 4 assays (R2 = 0.81). This study provides theoretical and technical support to refine human health risk assessment of As in soils from urban industrial legacy contaminated sites.

Two-Part Phase 1 Study to Evaluate the Taste Profile of Novel Belumosudil Oral Suspensions and Assess the Relative Bioavailability and Food Effect of the Selected Belumosudil Oral Suspension Compared With Oral Tablet Reference in Healthy Male Participants.

Belumosudil is a selective rho-associated coiled-coil-containing protein kinase 2 inhibitor in clinical use for the treatment of chronic graft-versus-host disease. The current tablet formulation may be inappropriate for children or adults with dysphagia and/or upper gastrointestinal manifestations of chronic graft-versus-host disease. This study (NCT04735822) assessed the taste and palatability of oral suspensions of belumosudil, evaluated the relative bioavailability of an oral suspension versus the tablet formulation, and characterized the effect of food on the pharmacokinetics of an oral suspension. Addition of sweetener and/or flavor vehicle improved the taste. Relative bioavailability of 200-mg doses of the oral suspension and tablet in the fed state was similar for belumosudil and its metabolites (KD025m1 and KD025m2), but absorption was faster with the oral suspension (median time to maximum concentration: 2 vs 3 hours). Administration of the oral suspension with food increased exposure compared with fasted administration, with maximum observed concentration being increased by 16% and area under the concentration-time curve from time 0 to the last measurable concentration (AUC0-last) by 19%. Safety and tolerability were consistent with the known safety profile of belumosudil. These results may support administration of a 200-mg belumosudil oral suspension with or without food.

A Relative Bioavailability, Bioequivalence, and Food Effect Study of Niraparib Tablets in Patients with Advanced Solid Tumors.

PURPOSE: The poly (ADP-ribose) polymerase inhibitor niraparib is indicated as maintenance treatment in patients with certain subtypes of advanced ovarian cancer, and is being investigated in patients with other solid tumors. Niraparib is available in 100-mg capsules with a starting dosage of 200 or 300 mg/d. This study assessed the relative bioavailability (BA) and bioequivalence (BE) between a 1 × 300-mg tablet relative to 3 × 100-mg niraparib capsules. In addition, the food effect (FE) of a high-fat meal on the pharmacokinetic (PK) properties of tablet-formulated niraparib was investigated. METHODS: This was a US-based, 3-stage, open-label, multicenter, single-crossover, randomized-sequence study. Enrolled patients were 18 years and older, with histologically or cytologically confirmed advanced solid tumors (metastatic or local) and disease progression despite standard therapy. Patients were randomly assigned 1:1 to receive niraparib 1 × 300-mg tablet or 3 × 100-mg capsules in the BA and BE stages or 1 × 300-mg tablet in a fasted or fed (high-fat meal) state in the FE stage. Across all study stages, PK parameters were assessed for 7 days after each dose (tablet or capsule) or prandial state (fasted or fed). In the BA stage, patients crossed over to the other treatment after a 7-day washout period, which was extended to 14 days in the BE and FE stages. Tolerability was assessed for patients who received any amount of niraparib. FINDINGS: The BA-, BE-, and FE-evaluable populations comprised 23, 108, and 19 patients, respectively, who completed both treatment periods in each study stage, had sufficient concentration data to accurately estimate PK parameters without niraparib carryover, and did not experience disqualifying events. PK parameters were similar after dosing with tablet or capsule formulations; the 90% CIs of the geometric least square means for Cmax, AUC0-t, and AUC0-∞ were within the 0.80 to 1.25 BE limits. In the FE stage, Cmax, AUC0-t, and AUC0-∞ were 11%, 32%, and 28% higher, respectively, in the fed versus fasted state. The safety population included 29, 168, and 28 patients in the BA, BE, and FE stages, respectively, who received niraparib. No new safety signals were identified. IMPLICATIONS: Niraparib tablets were found to be bioequivalent to capsules. A modest (≤32%) FE was observed with a high-fat meal, but was not considered to be clinically meaningful, given niraparib's PK variability. CLINICALTRIALS: gov identifier: NCT03329001. (Clin Ther. 2024;46:XXX-XXX) © 2024 Elsevier HS Journals, Inc.

Innovative accumulative risk assessment of co-exposure to Cd, As, and Pb in contaminated rice based on their in vivo bioavailability and in vitro bioaccessibility.

The consumption of cadmium (Cd), arsenic (As), and lead (Pb) co-contaminated rice exposes humans to multiple heavy metals simultaneously, with relative bioavailability (RBA) and bioaccessibility (BAc) being important determinants of potential health risks. This study evaluated the relationship between in vivo RBA and in vitro BAc of Cd, As, and Pb in rice and their cumulative risk to humans. A total of 110 rice samples were collected in Zhejiang Province, China, and 10 subsamples with varying concentration gradients were randomly selected to measure RBA using a mouse model (liver, kidney, femur, blood, and urine as endpoints) and BAc using four in vitro assays (PBET, UBM, SBRC, and IVG). Our results indicated that Cd-RBA varied from 21.2 % to 67.5 %, As-RBA varied from 23.2 % to 69.3 %, and Pb-RBA varied from 22.2 % to 68.9 % based on mouse liver plus kidneys. The BAc values for Cd, As, and Pb in rice varied according to the assay. Compared to Cd and As, Pb exhibited a lower BAc in the gastric (GP) and intestinal (IP) phases. According to the relationship between the BAc and RBA values, IVG-GP (R2 = 0.92), SBRC-IP (R2 = 0.73), and UBM-GP (R2 = 0.80) could be used as predictors of Cd-, As-, and Pb-RBA in rice, respectively. The health risks associated with co-exposure to Cd, As, and Pb in contaminated rice for both adults and children exceeded the acceptable threshold, with Cd and As being the primary risk factors. The noncarcinogenic and carcinogenic risks were markedly reduced when the RBA and BAc values were incorporated into the risk assessment. Due to the risk overestimation inherent in estimating the risk level based on total metal concentration, our study provides a realistic assessment of the cumulative health risks associated with co-exposure to Cd, As, and Pb in contaminated rice using in vivo RBA and in vitro BAc bioassays.

Remediation options to reduce bioaccessible and bioavailable lead and arsenic at a smelter impacted site - consideration of treatment efficacy.

In this study, smelter contaminated soil was treated with various soil amendments (ferric sulfate [Fe2(SO4)3], triple superphosphate [TSP] and biochar) to determine their efficacy in immobilizing soil lead (Pb) and arsenic (As). In soils incubated with ferric sulfate (0.6M), gastric phase Pb bioaccessibility was reduced from 1939 ± 17 mg kg-1 to 245 ± 4.7 mg kg-1, while intestinal phase bioaccessibility was reduced from 194 ± 25 mg kg-1 to 11.9 ± 3.5 mg kg-1, driven by the formation of plumbojarosite. In TSP treated soils, there were minor reductions in gastric phase Pb bioaccessibility (to 1631 ± 14 mg kg-1) at the highest TSP concentration (6000 mg kg-1) although greater reductions were observed in the intestinal phase, with bioaccessibility reduced to 9.3 ± 2.2 mg kg-1. Speciation analysis showed that this was primarily driven by the formation of chloropyromorphite in the intestinal phase following Pb and phosphate solubilization in the low pH gastric fluid. At the highest concentration (10% w/w), biochar treated soils showed negligible decreases in Pb bioaccessibility in both gastric and intestinal phases. Validation of bioaccessibility outcomes using an in vivo mouse assay led to similar results, with treatment effect ratios (TER) of 0.20 ± 0.01, 0.76 ± 0.11 and 1.03 ± 0.10 for ferric sulfate (0.6M), TSP (6000 mg kg-1) and biochar (10% w/w) treatments. Results of in vitro and in vivo assays showed that only ferric sulfate treatments were able to significantly reduce As bioaccessibility and bioavailability with TER at the highest application of 0.06 ± 0.00 and 0.14 ± 0.04 respectively. This study highlights the potential application of ferric sulfate treatment for the immobilization of Pb and As in co-contaminated soils.

Relative Oral Bioavailability and Food Effects of Two Sepiapterin Formulations in Healthy Participants.

Sepiapterin is an orally administered drug in development for the treatment of phenylketonuria, an inborn error of metabolism characterized by the deficiency of the phenylalanine-metabolizing enzyme phenylalanine hydroxylase. This study characterized the pharmacokinetics, safety, and tolerability of 2 clinical sepiapterin formulations (Phase 1/2, Phase 3) and the effects of food on the pharmacokinetics of the Phase 3 formulation in healthy participants. In Part A, 18 participants were randomized to one of 2 treatment sequences, each with 4 dosing periods comprising a single dose (20 or 60 mg/kg) of the Phase 1/2 or the Phase 3 formulation with a low-fat diet. In Part B, 14 participants were randomized to one of 2 sequences, each comprising 4 dosing periods of a single dose (20 or 60 mg/kg) of the Phase 3 formulation under fed (high-fat) or fasted conditions. Following oral administration, sepiapterin was quickly absorbed and rapidly and extensively converted to tetrahydrobiopterin (BH4). BH4 was the major circulating active moiety. Under low-fat conditions, the Phase 3 formulation was bioequivalent to the Phase 1/2 formulation at 20 mg/kg, while slightly lower BH4 exposure (approximately 0.81×) for the Phase 3 formulation was observed at 60 mg/kg. BH4 exposure increased to approximately 1.7× under the low-fat condition and approximately 2.8× under the high-fat condition at a dose of either 20 or 60 mg/kg for the Phase 3 formulation, compared with the fasted condition. Both sepiapterin formulations were well tolerated, with no serious or severe adverse events reported. All treatment-emergent adverse events were mild or moderate in severity.

Comparison of a novel tablet formulation of tacrolimus and conventional capsule formulation in de novo kidney transplant recipients: a systematic review and meta-analysis.

Background: The work aimed to compare the pharmacokinetic (PK) profiles and other outcomes reported in observational studies in de novo kidney transplant recipients (KTRs) receiving novel once-daily extended-release tablet tacrolimus (LCPT; LCP-tacrolimus; Envarsus XR) or receiving standard-of-care capsule tacrolimus (PR-Tac; prolonged-release tacrolimus; Advagraf/IR-Tac; immediate-release tacrolimus; Prograf). Methods: A systematic review was conducted for all randomized controlled trials (RCTs) and cohort studies investigating the outcomes in KTRs receiving LCPT or PR-Tac/IR-Tac. We systematically searched PubMed, Web of Science, and EMBASE, with no language restriction. The registered trials and references listed in relevant studies were also searched. Data were extracted for the PK profile, tacrolimus trough level (TTL), and changes in the estimated glomerular filtration rate (eGFR) and serum creatinine (Scr), biopsy-proven acute rejection (BPAR) rate, delayed graft function (DGF) rate, post-transplant diabetes mellitus (PTDM) rate, tremor rate (TR), death rate (DR), and rate of infection by cytomegalovirus (CMV). This study was registered with PROSPERO (registration number: CRD42023403787). Results: A total of seven eligible articles including 1,428 patients with 712 in the LCPT group versus 716 in the PR-Tac/IR-Tac group were included in this study for evidence synthesis. The baseline characteristics of the LCPT, PR-Tac, and IR-Tac groups were similar. The pooled analysis showed a higher PK profile in the LCPT group, and this result was consistent with those of all the included studies. In addition, no significant difference was observed for other outcomes. Conclusion: Considering heterogeneity between studies and potential bias, care providers should select agents based on patient-specific factors and their clinical experience for the immunosuppressive treatment of de novo KTRs.

Comprehensive clinical pharmacology characterization of AZD4635 in healthy participants to support dosing considerations.

AIMS: Two phase 1 studies characterized the oral bioavailability of AZD4635 (potential anticancer therapy) and factors that may influence its pharmacokinetics (PKs; food, smoking, proton-pump inhibitors [PPIs] and CYP1A2 inhibitors) to support continued clinical development of AZD4635. METHODS: Study 1 (comparative PK study; nonsmokers) consists of Part A and Part B. Participants (fasted) in Part A were administered 50 mg of AZD4635 either as nanosuspension or capsule. In Part B, these participants were administered a 50-mg capsule either following a high-fat meal or with a PPI in the fasted state. In Study 2 (CYP1A2 mediated drug-drug interaction study), a 25-mg AZD4635 capsule was administered to smokers and nonsmokers (fasted) with or without 100 mg of fluvoxamine. RESULTS: In Study 1 (N = 21), AZD4635 exposure was comparable between the capsule and nanosuspension. The high-fat meal produced a 12% decrease in AUCinf , a ≥50% reduction in Cmax and delayed absorption (Tmax : 4.0 h vs 1.5 h) for the capsule. The PPI did not affect the oral bioavailability of the AZD4635 capsule. In Study 2 (N = 28), AZD4635 + fluvoxamine (compared with AZD4635 alone) produced ~5-fold increases in AUCinf , 2-fold increases in Cmax and prolonged AZD4635 elimination half-life in smokers (22.7 vs 9.0 h) and nonsmokers (22.4 vs 9.2 h). All treatment regimens were well tolerated. The most common adverse events included dizziness, nausea and headache. CONCLUSIONS: The high-fat meal reduced the rate but not the extent of AZD4635 absorption. The effect of gastric pH on AZD4635 was minimal. Smoking had no effect on the exposure (Cmax and AUCinf ) of AZD4635, while fluvoxamine increased AZD4635 Cmax and total exposure. No new safety concerns were identified.

Innovative accumulative risk assessment strategy of co-exposure of As and Pb in medical earthworms based on in vivo-in vitro correlation.

Recent studies on risks assessment of heavy metal(loid) are usually based on their total concentrations. Nevertheless, such an analysis does not assess their real amounts absorbed by human body. To scientifically assess the health risks, in this study medical earthworms were analyzed for relative bioavailability (RBA) of arsenic (As) and lead (Pb) using a multiple gavage mouse model with liver, kidneys, brain, and leg bones as biomarkers for the first time. Metal(loid) bioaccessibility was determined using in vitro physiologically based extraction (PBET) assay. We are the first to develop a novel accumulative health risk assessment strategy by combinational analyzing bioavailability of heavy metal(loid) levels to calculate target organ toxicity dose (TTD) modification of the HI and total cancer risk (TCR), which has capacity to evaluate the health risks of co-exposure of Pb and As in medical earthworms. As a result, As-RBA ranged from 7.2% to 45.1%, and Pb-RBA ranged from 16.1% to 49.8%. Additionally, As and Pb bioaccessibility varied from 6.7% to 48.3% and 7.8% to 52.5%, respectively. Moreover, strong in vivo-in vitro correlations (IVIVCs) were observed between metal-RBA and bioaccessibility, indicating the robustness of the in vitro PBET assay to predict metal-RBA in medical earthworms. The refined accumulative assessment strategy revealed that when adjusted by heavy metal(loid) bioavailability, the TTD modification of HI method typically exhibited an acceptable health risk caused by the co-exposure of Pb and As for cardiovascular, hematological, neurological, and renal system. The TCR levels associated with exposure to Pb and As due to the ingestion of medical earthworms were also acceptable after adjustment by bioavailability. Collectively, our innovation on accumulative risk assessment based on in vivo-in vitro correlation provides a novel approach engaging in assessing the risks due to co-exposure of As and Pb in medical earthworms.

Manganese relative oral bioavailability in electric arc furnace steel slag is influenced by high iron content and low bioaccessibility.

Electric arc furnace (EAF) slag is a rock-like aggregate produced with carbon steel and used for construction, including residential ground cover. It is enriched with manganese (Mn) and other metals, including iron (Fe), but because metals are bound in mineral matrices, in vitro bioaccessibility (BA) is limited. We conducted a relative bioavailability (RBA) study using F344 rats to assess Mn RBA from EAF slag ingestion, compared with Mn in diet. Mn and Fe were measured in liver, and Mn in lung and striatum, the target tissue of the brain. Mn levels in each tissue were fit by dose-to-tissue concentration (D-TC) curves. The D-TC relationship was the most highly significant for the linear model using liver Mn, and the RBA was 48%. The D-TC relationship in lung showed a positive slope for chow, but that for EAF slag was slightly negative, and the RBA was 14%. In comparison, the striatum D-TC remained relatively constant, supporting that homeostasis was maintained. Increased Fe was observed in the liver of EAF slag-dosed groups, suggesting that Mn absorption was inhibited by the high Fe content of slag. Lung and striatum D-TC curves demonstrated that systemic delivery of Mn from EAF slag ingestion is limited and support an RBA of 14% for risk assessment. Although Mn levels in slag are elevated compared with health-based screening guidelines, this study supports that incidental ingestion of Mn in EAF slag is unlikely to pose a neurotoxicity hazard due to homeostatic controls, low BA, and high Fe content.

Physiologically based biopharmaceutics modeling of regional and colon absorption in humans.

Colon absorption is a key determinant for successful development of extended release and colon targeted drug products. This is the first systematic evaluation of the ability to predict in vivo regional differences in absorption and the extent of colon absorption in humans using mechanistic physiologically based biopharmaceutics modeling (PBBM). A new dataset, consisting of 19 drugs with a wide range of biopharmaceutics properties and extent of colon absorption in humans, was established. Mechanistic predictions of the extent of absorption and plasma exposure after oral, or jejunal and direct colon administration were performed in GastroPlus and GI-Sim using an a priori approach. Two new colon models developed in GI-Sim, were also evaluated to assess if the prediction performance could be improved. Both GastroPlus and GI-Sim met the pre-defined criteria for accurate predictions of regional and colon absorption for high permeability drugs irrespective of formulation type, while the prediction performance was poor for low permeability drugs. For solutions, the two new GI-Sim colon models improved the colon absorption prediction performance for the low permeability drugs while maintaining the accurate prediction performance for the high permeability drugs. In contrast, the prediction performance decreased for non-solutions using the two new colon models. In conclusion, PBBM can be used with sufficient accuracy to predict regional and colon absorption in humans for high permeability drugs in candidate selection as well as early design and development of extended release or colon targeted drug products. The prediction performance of the current models needs to be improved to allow high accuracy predictions for commercial drug product applications including highly accurate predictions of the entire plasma concentration-time profiles as well as for low permeability drugs.

Relative Bioavailability of Cadmium in Rice: Assessment, Modeling, and Application for Risk Assessment.

Rice consumption is the primary route of cadmium (Cd) exposure to the populations with rice as the staple food. To accurately assess the potential health risks of Cd exposure via rice consumption, determination of Cd relative bioavailability (RBA) in rice is necessary. However, large variations exist in Cd-RBA, hindering the application of source-specific Cd-RBA values to different rice samples. In this study, we collected 14 rice samples from Cd contaminated areas and determined both rice compositions and Cd-RBA using in vivo mouse bioassay. Total Cd concentration varied from 0.19 to 2.54 mg/kg in the 14 rice samples, while Cd-RBA in rice ranged from 42.10% to 76.29%. Cadmium-RBA in rice correlated positively with calcium (Ca) (R = 0.76) and amylose content (R = 0.75) but negatively with the concentrations of sulfur (R = -0.85), phosphorus (R = -0.73), phytic acid (R = -0.68), and crude protein (R = -0.53). Cd-RBA in rice can be predicted by Ca and phytic acid concentrations in a regression model (R2 = 0.80). Based on the total and bioavailable Cd concentrations in rice, weekly dietary Cd intake for adults was estimated to be 4.84-64.88 and 2.04-42.29 µg/kg bw/week, respectively. This work demonstrates the possibility of Cd-RBA prediction based on rice compositions and provides valuable suggestions for health risk assessment with consideration of Cd-RBA.

Relative bioavailability of delamanid 50 mg tablets dispersed in water in healthy adult volunteers.

AIM: Delamanid is a novel drug for the treatment of drug-resistant tuberculosis, manufactured as 50-mg solid and 25-mg dispersible tablets. We evaluated the effects of dispersing the 50-mg tablet, focusing on the relative bioavailability. METHODS: Delamanid, 50-mg tablets administered dispersed vs swallowed whole, was investigated in a phase I, four-period, crossover study. Two of three dose strengths of delamanid (25, 50 or 100 mg) were given to healthy adult participants, in both whole and dispersed forms, with a 7-day washout period. Blood samples were collected over 168 h after each dose. Delamanid and its metabolite DM-6705 were analysed with a validated liquid chromatography tandem mass spectrometry assay. The pharmacokinetics of both analytes were analysed using nonlinear mixed-effect modelling. Palatability and acceptability were determined using a standardized questionnaire. RESULTS: Twenty-four participants completed the study. The bioavailability of dispersed tablets was estimated to be 107% of whole tablets, with a 90% confidence interval of 99.7-114%, fulfilling bioequivalence criteria. The two formulations were not significantly different regarding either bioavailability or its variability. Bioavailability increased at lower doses, by 34% (26-42%) at 50 mg and by 74% (64-86%) at 25 mg, relative to 100 mg. The majority of participants (93%) found the dispersed formulation acceptable in palatability across all delamanid doses. CONCLUSIONS: Dispersed 50-mg delamanid tablets have similar bioavailability to tablets swallowed whole in adult volunteers. This can be an option for children and other patients who cannot swallow whole tablets, improving access to treatment.

Contribution and Effects of PM2.5-Bound Lead to the Cardiovascular Risk of Workers in a Non-Ferrous Metal Smelting Area Considering Chemical Speciation and Bioavailability.

Lead is known to have toxic effects on the cardiovascular system. Owing to its high concentration, transmission range, and absorption efficiency in organisms, inhalation of fine particulate matter (PM2.5)-bound lead (PM2.5-Pb) may cause significant cardiovascular damage. However, the contribution and adverse effects of PM2.5-Pb on workers and residents in non-ferrous metal smelting areas are not fully understood. In this work, the concentration and chemical speciation of PM2.5-Pb were analyzed to determine its pollution characteristics at a typical non-ferrous metal smelting site. A panel study conducted among factory workers revealed that PM2.5-Pb exposure makes an important contribution to the human absorption of Pb. Although the chemical speciation of PM2.5-Pb suggested poor water solubility, a high bioavailability was observed in mice (tissue average value: 50.1%, range: 31.1-71.1%) subjected to inhalation exposure for 8 weeks. Based on the bioavailability data, the relationship between PM2.5-Pb exposure and cardiovascular damage was evaluated in animal simulation experiments. Finally, a damage threshold and cardiovascular-specific risk assessment model were established for the non-ferrous metal smelting area. Our project not only accurately estimates the risk of PM2.5-bound heavy metals on the cardiovascular system but also offers a scientific basis for future prevention and therapy of PM2.5-Pb-related diseases.

Characterization and bioavailability of a novel coenzyme Q10 nanoemulsion used as an infant formula supplement.

Supplementation with Coenzyme Q10 (CoQ10), in patients with its deficiency, has greater odds of success if the treatment is carried out early with an appropriate formulation. For neonatal CoQ10 deficiency, infant formula supplementation could be an attractive option. However, solid CoQ10 cannot be solubilized or dispersed in milk matrix leading to an inefficient CoQ10 dosage and poor intestinal absorption. We developed and characterized a high-dose CoQ10 oil-in-water (O/W) nanoemulsion suitable to supplement infant formula without modifying its organoleptic characteristics. CoQ10 powder and soy lecithin were solubilized in an oil phase consisted of Labrasol® and LabrafacTM. The aqueous phase was Tween 80, TPGS, methylparaben and propylparaben. O/W nanoemulsion was prepared by adding dropwise the oil phase to the aqueous phase under stirring to a final concentration of CoQ10 9.5 % w/w followed by ultrasonic homogenization. Pharmacotechnical parameters were determined. This formulation resulted to be easily to be dispersed in milk matrix, stable for at least 90 days, with no cytotoxicity in in vitro assays, and higher bioavailability than CoQ10 powder. CoQ10 nanoemulsion supplementation in the infant formula facilitates the individualized administration for the child with accurate dosage, overcome swallowing difficulties and in turn could increase the treatment adherence and efficacy.

Pharmacokinetic, Safety, and Tolerability Evaluations of Gepotidacin (GSK2140944) in Healthy Japanese Participants.

Gepotidacin is a novel, bactericidal, first-in-class triazaacenaphthylene antibiotic in late-phase development for uncomplicated urinary tract infection and uncomplicated urogenital gonorrhea. Two clinical studies were conducted to assess the pharmacokinetics (PK) and interethnic comparisons of oral gepotidacin (free-base and to-be-marketed mesylate formulations) administered as single doses ranging from 1500 to 3000 mg in fed and fasted states, and as 2 × 3000-mg doses given 12 hours apart under fed conditions in healthy participants of Japanese ancestry. Dose proportionality was observed in plasma exposures, and comparable area under the concentration-time curve (AUC) and maximum concentration were observed in fed and fasted states. Interethnic comparisons for Japanese versus non-Japanese participant data showed slightly higher plasma maximum concentration (7%-30%) yet similar plasma AUCs; slightly lower urine AUCs (11%-18%) were observed. The slightly higher plasma exposures in healthy Japanese versus White participants in the same study were attributed to lower mean body weights (64 kg versus ≈80 kg). Adverse events were primarily gastrointestinal, and when administered with food, gastrointestinal tolerability was improved. Overall, the gepotidacin PK and safety-risk profiles in healthy Japanese support potential evaluation of the global clinical doses in future studies.