Comparative Bioavailability Research Articles

Single-Dose Crossover Comparative Bioavailability Study of Two Different Posaconazole 100 mg Gastro-Resistant Tablets Under Fasted and Fed Conditions in Healthy Volunteers.

This study aimed to compare the bioavailability of two different gastro-resistant oral tablet formulations of posaconazole under fasted and fed conditions and to evaluate a potential food effect on the bioavailability of each formulation. Healthy volunteers randomly assigned to receive a test product (Posagil® 100 mg gastro-resistant tablet) or reference product (Noxafil® 100 mg gastro-resistant tablet) were included in this single-center, randomized, four-period (days 1, 15, 29 and 43), four-sequence crossover comparative bioavailability study. Data on posaconazole plasma concentrations and related pharmacokinetic profile (the maximum observed plasma concentration [Cmax] from time 0 to the time of last observed quantifiable plasma concentration [AUC0-T] and from time zero to infinity [AUC0-∞]) were recorded to evaluate efficacy of the test product in relation to the reference product under both fasted and fed conditions, based on bioequivalence (T-fasted vs. R-fasted and T-fed vs. R-fed) and food effect (T-fasted vs. T-fed and R-fasted vs. R-fed) assessments. Safety was evaluated through assessment of adverse events (AEs), standard laboratory evaluations, and vital signs. The bioequivalence criteria were met under fed conditions (T-fed vs. R-fed: geometric LSMean ratios of Cmax, AUC0-T, and AUC0-∞ of posaconazole were 97.41%, 97.45%, and 97.08%, respectively; all within the range of 80% to 125%) but not under fasted conditions. There was a food effect on the reference product (R-fed vs. R-fasted: geometric LSMean ratios of Cmax, AUC0-T, and AUC0-∞ of posaconazole were 145.32%, 138.84%, and 138.46%, respectively) but not on the test product. No safety concerns were identified. Our findings suggest that the pharmacokinetic profile of Posagil® is similar to the pharmacokinetic profile of Noxafil®. The generic Posagil® seems to have similarly high bioavailability under fed and fasted conditions, offering a higher posaconazole exposure than the original Noxafil® in the fasted state. Hence, Posagil® may be considered a value-added generic product that offers adequate posaconazole exposure under fasted state and fed state, regardless of the concomitant high-fat meal intake.

Bioequivalence/bioavailability study of a new formulation of imatinib mesylate 100 mg coated tablets versus Glivec® in Brazilian healthy male volunteers in fed state

Introduction: Imatinib mesylate is currently the first-line oral treatment for all stages of chronic myeloid leukemia (CML) and is also used in some cases of gastrointestinal stromal tumor (GIST) and acute lymphoblastic leukemia (ALL). Objective: Investigate the bioavailability of two products containing imatinib mesylate, 100 mg coated tablet, to determine if they are bioequivalent. Method:The study was conducted using an open-label, randomized, balanced design and the formulations were administered orally in a single dose to 48 healthy adult males, in fed state, followed by sequential blood withdraws for the next 72 hours. Forty-eight male healthy volunteers were selected to participate in the study. Test formulation from Eurofarma Laboratórios S.A. Brazil was compared to that from Novartis Biociências S.A. The comparative bioavailability of the formulations was assessed based on statistical comparisons of relevant pharmacokinetic parameters obtained from drug concentration data from collected blood samples measured using an analytical method based on high-performance liquid chromatography coupled to mass spectrometry. Results: The ratio of the geometric means between the test and the reference, with a 90% confidence interval, of pharmacokinetic parameters for Cmax was 102.26% (94.17-111.04%) and for AUC0-t was 101.24% (95.19-107.68%). Conclusion: Imatinib mesylate 100 mg (test product) from Eurofarma Laboratórios S.A. was considered bioequivalent to the reference Glivec® 100 mg manufactured by Novartis Biociências S.A, and the test product can be interchangeable with the reference, based on their pharmacokinetic performance.

Bioequivalence assessment of two formulations of empagliflozin in healthy adult subjects

Objective: The objective of the study was to evaluate the bioequivalence (BE) between Izaban® (test) and Jardiance® (reference) empagliflozin 25 mg, oral tablets, in healthy adult subjects. Materials and Methods: A randomized, open-label, two-sequence, and two-period crossover comparative oral bioavailability study was conducted on healthy adult subjects. It was tested BE in vivo using a comparative pharmacokinetic (PK) evaluation. Serial blood samples were collected up to 72 h following oral administration of the study drugs, plasma concentrations of empagliflozin were using liquid chromatography mass spectrometry (LC-MS-MS) method. Results: The test and reference drug products were considered bioequivalent when the geometric means of the test (T)/reference (R) ratios and 90% confidence intervals (CIs) fall within the range of 80.00–125.00%. For PK parameters, % T/R ratios and 90% CIs were Cmax: 105.11% (100.28–110.18%), area under curve (AUC0-t): 103.25% (99.62–107.00%), and AUC0-∞ 102.71% (99.26–106.28%). Conclusion: Our study demonstrated in vivo BE between the two empagliflozin formulations tested in healthy subjects under fasting conditions.

Comparison of Berberine Bioavailability between Oral and Rectal Administrations in Rats.

The oral bioavailability of berberine is quite low due to extensive first-pass metabolism. To increase the bioavailability of berberine (BBR), the efficacy of rectal administration that can avoid intestinal and hepatic first-pass metabolism partly was evaluated using BBR sulfate in rats. BBR sulfate was administered intravenously (1 mg/kg as BBR), orally (10 mg/kg as BBR) and rectally (1, 3, or 10 mg/kg as BBR) using Witepsol® H15 suppository base to evaluate bioavailability in rats. Concentrations of BBR in plasma were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). When BBR sulfate was administered orally, the average oral bioavailability was 0.26%. When BBR sulfate was administered rectally, the average bioavailabilities were 17.0% at 1 mg/kg, 24.3% at 3 mg/kg, and 12.3% at 10 mg/kg as BBR, respectively. Thus, rectal administration of BBR sulfate greatly increased the bioavailability of BBR as compared with oral administration, which would also increase the pharmacological activities of BBR in vivo.

Methylcobalamin injection 1500 mcg SC route versus IM route: A randomized parallel comparative bioavailability study

Corona Remedies developed B-29 AQ PFS (Methylcobalamin Injection 1500 mcg) SC route for better patient compliance and ease of administration. The study outcome will explain pharmacokinetic behaviour of Methylcobalamin SC injection and non-inferiority over IM injection. The study was conducted to compare bioavailability, safety and tolerability of two different Methylcobalamin Injection formulation 1500 mcg with SC versus IM route. This was randomized, two treatment, parallel, comparative bioavailability study conducted on 24 normal, healthy, adult, human subjects. The dosage of the investigational product (IP) was given either as a 1500 mcg SC injection into the abdominal muscle or as an intramuscular injection into the gluteal muscle (buttock region) following an overnight fast of at least 10 hours. To assess the plasma concentrations of methylcobalamin, a number of blood samples were collected both before and after the injection. Maximum plasma concentration (C), time to maximum plasma concentration (T) and the area under the concentration-time curve (AUC) were compared. Pharmacokinetic (PK) parameters were statistically analysed using Statistical Analysis Software (SAS) Version 9.4 or above. The mean T for methylcobalamin absorption from SC administration and IM injection was 1.38 hours and 1.49 hours, respectively. In terms of bioavailability, the SC injection is comparable to the IM injection (the ratio of population geometric means for the SC and IM routes is 103.62 for AUC). In this study, a higher C for the SC route than the IM route was found (57.01 versus 45.82). Based on log transformed primary PK parameters (C and AUC), the geometric least squares mean ratio was observed >80.00%. According to safety evaluations, both therapies were safe and well-tolerated.Methylcobalamin is a safe and well-tolerated alternative to the current one that is non-inferior to IM route and faster in absorption after SC route.

Green Synthesis and Bioactivity of Aliphatic N-Substituted Glycine Derivatives.

Standard amino acids have an asymmetric α-carbon atom to which -COOH, -NH2, -H, and -R groups are bonded. Among them, glycine is the simplest (R = -H) with no asymmetric carbon, and other natural amino acids are C-substituted of glycine. Here, we have designed and made a green synthesis of some new N-substituted glycine derivatives with R-(NH)CH2-COOH formula, where R is flexible and hydrophobic with different chain lengths and benches of the type propyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, tert-pentyl, hexyl, 2-aminoheptyl, and octyl. These glycine derivatives were characterized by recording their melting points and FT-IR, mass, 1H NMR, and 13C NMR spectra. DFT studies revealed that 2-aminoheptyl glycine had the highest electronegativity value and can thus act as a good bidentate ligand for the metal centers. ADME comparative results and bioavailability radars indicated that both octyl- and 2-aminoheptyl glycine had the most lipophilicity, making them good agents in cell passing. Furthermore, lipophilicity determination showed that octyl glycine was the best and propylgly was more soluble than others. Based on solubility, lipophilicity, and dipole moment values, propyl- and 2-aminoheptyl-glycine were considered for bio-macromolecular interaction studies. Thus, the interaction of these two agents with DNA and HSA was studied using absorption spectroscopy and circular dichroism techniques. Due to the presence of the R-amine group, they can interact with the DNA by H-binding and hydrophobicity, while electrostatic mode could not be ruled out. Meanwhile, molecular docking studies revealed that octyl- and 2-aminoheptyl glycine had the highest negative docking energy, which reflects their higher tendency to interact with DNA. The DNA binding affinity of two candidate AAs was determined by viscosity measurement and fluorescence emission recording, which confirms that groove binding occurs. Also, the toxicity of these synthesized amino acid derivates was tested against the human foreskin fibroblast (HFF) cell line. They showed IC50 values within the range of 127-344 μM after 48 h with the highest toxicity for 2-aminoheptyl glycine.

Relationship between Pharmacokinetic Profile and Clinical Efficacy Data of Three Different Forms of Locally Applied Flurbiprofen in the Mouth/Throat.

This study aimed to link pharmacokinetic (PK) data from different flurbiprofen preparations for the treatment of sore throat with published data to elucidate whether early efficacy is due to the local action of flurbiprofen or a systemic effect after absorption of the swallowed drug. Three comparative bioavailability studies conducted in healthy subjects provided data from flurbiprofen 8.75 mg formulations, including spray solution, spray gel, lozenges, and granules. A parallel interstudy comparison was made of PK parameters, including partial AUCs (pAUCs), using an ANOVA model with the calculation of 90% confidence intervals (CI) for the differences between least squares (LS) means for each of the test groups versus the respective reference groups. All three studies showed bioequivalence for the respective product comparisons. The interstudy comparison showed a slower rate of absorption for granules compared to spray solution (reference) based on Tmax, Cmax, and pAUCs for 1 h and 2 h. When AUC0.25h and AUC0.5h were considered, slower rates of absorption were also seen for lozenges and spray gel. The differences correlated with the reported time of onset of action, which is faster for the spray solution (20 min) compared to lozenges (26 min) and granules (30 min). These pAUCs provide useful data that allow for the discrimination between formulations. Moreover, the pAUC values represent <5% of the total AUC, suggesting that the early onset of pain relief is a response to immediate local absorption at the site of action rather than a systemic effect.

Content and Availability of Minerals in Plant-Based Burgers Compared with a Meat Burger.

Increasing numbers of individuals follow plant-based diets. This has sparked interest in the nutritional evaluation of the meat substitute sector. Nutritional understanding of these products is vital as plant-based eating becomes more common. For example, animal products are rich sources of iron and zinc, and plant-based foods could be inadequate in these minerals. The main aim was to analyse the mineral composition and absorption from a range of plant-based meat-free burgers and compare them to a typical beef burger. Total and bioaccessible mineral contents of plant-based burgers and a beef burger were determined using microwave digestion and in vitro simulated gastrointestinal digestion, respectively. Mineral bioavailability was analysed by in vitro simulated gastrointestinal digestion of foods, followed by exposure of Caco-2 cells to the sample digests and assessment of mineral uptake. Mineral quantification for all samples was achieved using inductively coupled ICP-optical emission spectrometry (ICP-OES). The content of minerals varied significantly amongst the burgers. Significantly greater quantities of Fe and Zn were found in the beef burger compared to most meat substitutes. Bioaccessible Fe was significantly higher in the beef compared to most of the plant-based meat alternatives; however, bioavailable Fe of most plant-based burgers was comparable to beef (p > 0.05). Similarly, bioaccessible Zn was significantly (p < 0.001) higher from the beef burger. Moreover, beef was superior regarding bioavailable Zn (p ≤ 0.05-0.0001), with only the mycoprotein burger displaying comparable Zn bioavailability (p > 0.05). Beef is an excellent source of bioaccessible Fe and Zn compared to most plant-based substitutes; however, these plant-based substitutes were superior sources of Ca, Cu, Mg and Mn. The quantity of bioaccessible and absorbable Fe varies dramatically among the meat alternatives. Plant-based burgers have the potential to provide adequate quantities of iron and zinc to those consuming such burgers as part of a varied diet. Thus, guiding consumer choices will depend on the variety of the vegetable constituents and their iron nutritional quality in different burgers.

The Comparative Bioavailability of Fluticasone and Azelastine Delivered as a Single Fixed Dose Combination (MP-AzeFlu) in Comparison to Two Different Formulations of Azelastine and Fluticasone Propionate Following Intranasal Administration in Healthy Chinese Volunteers.

Two studies (Study I and Study II) were conducted in healthy Chinese volunteers to confirm that there was no pharmacokinetic drug interaction between AZE and FLU in MP-AzeFlu. The secondary objective was to evaluate the pharmacokinetic parameters of MP-AzeFlu compared with the commercially available mono-components. Both studies were a randomized, open-label, three-period, six-sequence, single-dose cross-over trial (William's design) conducted at Beijing Hospital (Beijing, China) in September and October of 2019 in 30 healthy adult male and female volunteers. The natural log transformed parameters: AUC0-tlast, AUC0-∞ and Cmax were analyzed. The comparison of PK parameters between MP-AzeFlu and Aze (commercially available) showed that the LS mean ratios (90% CI) values for, AUC0-tlast, AUC 0-∞ and Cmax were 100.29% (94.31-106.66%), 100.76% (94.60-107.32%) and 93.14% (81.47-106.48%). The comparison of PK parameters between MP-AzeFlu and Flu (commercially available) for the bioavailability evaluation showed that the LS mean ratios (90% CI) values for, AUC0-tlast, AUC 0-∞ and Cmax were 83.48% (69.81-99.82%), 100.19% (87.34-114.94%) and 81.91% (68.50-97.95%). The study results confirm that neither the FLU or the AZE component in the combination product (MP-AzeFlu), nor the existing qualitative and quantitative differences in the formulation between the currently marketed AZE and FLU mono-product, display significant potential to impact the systemic exposure of AZE or FLU in Chinese subjects.

Experience with the prolonged release of iron in iron deficiency patients

Iron deficiency is one of the leading factors in the global burden of disease, affecting mainly children, premenopausal women and low- and middle-income people. With prolonged iron deficiency, iron deficiency anemia (IDA) develops, which, according to the World Health Organization (WHO), remains the most common type of anemia worldwide. The most common causes of IDA include gastrointestinal bleeding, menstrual blood loss and pregnancy in women. Currently, divalent iron preparations are considered the “gold standard” of IDA therapy. To date, there are preparations of divalent iron with delayed release. The advantage of this form is that such drugs are better tolerated, they have a lower incidence of side effects with comparable bioavailability and efficacy compared to conventional forms. Such drugs include Tardyferon®.In our study, it was noted that against the background of taking Tardyferon®, the level of ferritin by the end of the 1st month of therapy in patients with latent iron deficiency increased from 12.4 ± 0.93 to 27.8 ± 4.1 µg/L (p ≤ 0.05). In patients with IDA, it increased from 9.7 ± 1.3 to 25.4 = 5.1 µg/L. By the end of the 3rd month of treatment, the ferritin level in patients with latent iron deficiency was 200.1 ± 30.8 (p &lt; 0.05), and in patients with IDA – 246.7 µg/L (p &lt; 0.05). We noted a similar dynamic in the hemoglobin level: in patients with IDA, it increased from 97.4 ± 9.3 g/L to 125.8 ± 10.2 g/l (p &lt; 0.05), and in 21 (75%) of 28 patients it reached normal values (more than 120 g/L) by the end of the 1st months of therapy.By the 3rd month of therapy, all patients with IDA had already reached the target level, and the average hemoglobin value in the group was 142.1 ± 5.6 g/L (p = 0.05).Thus, in patients with IDA, against the background of therapy with Tardyferon®, hemogram indicators normalize, the concentration of hemoglobin and ferritin increases by the end of the 1st month of therapy.

New Entries into the Migraine Market: 2018-2021

Migraine is a chronic condition of recurring headaches, often severe and disabling, not in the least because of the associated gastrointestinal symptoms. The focus of its treatment is pharmacological, which we traditionally divide into abortive or acute and preventive or prophylactic. In the 4-year period, 2018-2021, the United States (US) Food and Drug Administration (FDA) approved twelve new entries into the migraine market, six for abortive treatment and six for preventive treatment, including one for both. Three of them are reformulations of already marketed medications, four are CGRP antibodies, three are small-molecule CGRP-receptor antagonists or gepants, and one is a serotonin-1F receptor agonist or ditan. In this paper, we review the twelve new migraine entries in light of the abortive and preventive migraine medications marketed prior to 2018. We present the efficacy of four of the new entries for migraine abortion – the FDA approved the remaining two based on comparable bioavailability – and of all six of the new entries for migraine prevention, focusing on 2-hour pain-free and 50%-responder rates, respectively. We conclude that preventively we have made progress if only because of the (much) better tolerability of the CGRP antibodies and gepants, in comparison to the traditional oral preventive migraine medications. In terms of efficacy, we probably have made progress as well although supported by only one randomized, double-blinded, head-to-head comparative trial. Abortively, the three new chemical entities in the classes of gepants and ditans lack vasoconstrictor activity and, hence, we can prescribe them where the ergots and triptans are contraindicated. This is a step ahead in safety while tolerability and efficacy seem similar to that of the triptans, the mainstay in abortive migraine treatment.

Interchangeability of generic drugs for subpopulations: Bioequivalence simulation from a nonparametric PK model of gabapentin generic drugs.

We aim to identify pathophysiological pharmacokinetic subpopulations for whom there is a difference in comparative bioavailability compared to a healthy population. We used simulated exposures from a nonparametric model of multiple generics and the originator gabapentin. Exposure was simulated for virtual populations with pharmacokinetic characteristics beyond those of healthy subjects with regard to rate of absorption, volume of distribution and reduced renal function. Virtual parallel design bioequivalence studies were performed using a random sample of 24 simulated subjects, with standard acceptance criteria. Results indicated increased pharmacokinetic variability for patient populations with a lower rate of absorption or a reduced renal function, but no change in the average comparable bioavailability ratio. This increased variability results in a reduced likelihood of demonstrating bioequivalence. Observations were similar for comparisons between all different formulations, as well as between subjects who received the identical formulation in a repeated fashion. No relevant effect was observed for simulations with increased volume of distribution. Our simulations indicate that the reduced likelihood of demonstrating bioequivalence for subjects with altered pharmacokinetics is not influenced by a formulation switch, nor does the average comparable bioavailability ratio change, therefore these results support generic interchangeability and current approval requirements for generics.

A Comparative Bioavailability of Sebetralstat Following Administration of Orally Disintegrating Tablets and Film-Coated Tablets in Healthy Volunteers

Sebetralstat is an investigational oral plasma kallikrein inhibitor for the on-demand treatment of HAE attacks. This trial compares PK characteristics, safety, and tolerability of sebetralstat administered as orally disintegrating tablets (ODT) and film coated tablets (FCT) in healthy volunteers. ODT may improve ease of treatment administration in pediatric and adult HAE populations.

Comparison of whole blood concentrations of oral human generic modified ciclosporin capsules with microemulsified ciclosporin capsules approved for canine atopic dermatitis following a single oral administration to healthy dogs.

There have been no comparative bioavailability studies between the microemulsified ciclosporin formulation, approved for the treatment of canine atopic dermatitis (cAD), and the generic modified formulation of ciclosporin for humans. To compare whole blood ciclosporin concentrations of oral generic modified ciclosporin (Treatment A; Teva Pharmaceuticals) and ciclosporin brand Atopica (Treatment B; Elanco Animal Health) in healthy dogs at 1 and 1.5h following a single oral administration. Whole blood concentrations were evaluated at 1 and 1.5h post-oral administration of treatments A and B in a randomised, blinded, cross-over study with an 8-day wash-out, after a single administration at 4.4-5.3mg/kg/day in eight healthy, male-castrated research beagle dogs. Ciclosporin blood concentrations were measured through the Auburn University Clinical Pharmacology Laboratory. Ciclosporin blood concentrations were below the detection limit before the start of treatment for both groups. Blood ciclosporin concentrations for Treatment A (median 1192 ng/ml) were significantly higher at 1 h post-oral administration than those for Treatment B (median 499 ng/ml; p=0.001). However, no significant differences (p=0.75) in ciclosporin values were observed at 1.5h post-administration between treatments A (median 945 ng/ml) and B (median 809 ng/ml). Generic modified ciclosporin achieved higher blood concentrations at 1h post-administration than Atopica after a single oral administration in healthy dogs; no difference was noted at 1.5h. Further clinical studies using generic modified ciclosporin in client-owned dogs affected with cAD are advocated to confirm its therapeutic efficacy.

Pharmacokinetics and Comparative Bioavailability of Test or Reference Capecitabine and Discrepant Pharmacokinetics Among Various Tumors in Chinese Solid Cancer Patients.

The main objective of this study was to compare the pharmacokinetic (PK) bioequivalence of two capecitabine tablets and explore the different PK profiles of various tumors in Chinese patients with cancer. All 76 patients with a confirmed cancer diagnosis were included in this study. A single dose of 2000mg of test or reference capecitabine (Xeloda, Hoffmann-La Roche) was orally administered postprandially. After 24hours of washout, the patients were administered the test or the reference capecitabine alternately. PK samples were taken at the time of predose up to 6hours postdose. Bioequivalence evaluation was performed using the geometric mean ratios of peak concentration in plasma (Cmax) , area under the concentration-time curve from time 0 to 6 h (AUC0-t) , and area under the concentration-time curve from time 0 to infinity (AUC0-∞ ) for capecitabine and 5-fluorouracil (5-FU). In this study, 90% confidence intervals of test/reference mean ratios of Cmax , AUC0-t , AUC0-∞ of capecitabine and 5-FU were in the range of 80%-125%. Both the test and reference capecitabine regimens were well tolerated in this study. Furthermore, we found that patients with esophageal-gastrointestinal cancers had higher exposure to capecitabine and a shorter time to Cmax (Tmax) than those with breast cancer. In conclusion, a single oral dose of 2000mg of test capecitabine tablets after postprandial administration was bioequivalent to the reference drug.

Comparative pharmacokinetics of florfenicol in heifers after intramuscular and subcutaneous administration.

Florfenicol was administered to five heifers intramuscularly at a dose rate of 20 mg/kg bwt and following wash-out period, subcutaneously at a dose rate of 40 mg/kg bwt. Blood plasma samples were collected from heifers before injection of florfenicol and up to 120 h after intramuscular (IM) injection and up to 264 h after subcutaneous (SC) injection. Florfenicol concentrations in plasma were measured by high-performance liquid chromatography with mass-spectrometric detection. Pharmacokinetics of florfenicol was estimated using non-compartment analysis. Mean maximum plasma concentration, area under the concentration-time curve and elimination half-life for florfenicol were 3.2μg/ml, 101.5μg × h/ml and 24.5h, respectively, after IM injection at 20 mg/kg bwt, and 2.7μg/ml, 194.5μg × h/ml and 103.8h, respectively, after SC injection at 40 mg/kg bwt. The obtained results indicated that both administration routes provided comparable bioavailability, whereas SC route was attributed with lower peak levels and markedly slower absorption of florfenicol from injection site. Both administration routes provided plasma florfenicol levels which are expected to be effective against prevalent infectious agents of cattle.

Pharmacokinetics of a Modified-Release Dexamphetamine Sulfate Formulation Following Single and Multiple Dosing in Healthy Adults: Comparative Bioavailability with Immediate-Release Dexamphetamine Sulfate, between Strengths, Assessment of Food and Meal Composition Effects.

A modified-release dexamphetamine sulfate formulation (DEX-MR) is under development for the treatment of attention-deficit/hyperactivity disorder. We investigated the bioequivalence of once-daily DEX-MR to twice-daily immediate-release dexamphetamine sulfate (DEX-IR) after single and multiple dosing and between strengths, and effects of food and meal types. Three randomized, open-label, crossover studies in healthy males were conducted. In the single-dose study, participants received DEX-MR 20 mg, DEX-MR 10 mg (20 mg dose), and twice-daily DEX-IR 10 mg under fasted conditions and after a high-fat, high-calorie breakfast. In the breakfast study, participants received DEX-MR 20 mg and twice-daily DEX-IR 10 mg after a normocaloric and a high-fat, high-calorie breakfast. In the multiple-dose study, participants received DEX-MR 20 mg and twice-daily DEX-IR 10 mg for seven days each. In the run-in period (five days), participants consumed a normocaloric breakfast; on profile days, participants consumed a normocaloric breakfast (day 6) or a high-fat, high-calorie breakfast (day 7). Once-daily DEX-MR at a dose of 20 mg was bioequivalent to twice-daily DEX-IR 10 mg after single dosing under fasted and fed conditions and after multiple dosing under fed conditions. DEX-MR 10 mg and DEX-MR 20 mg were bioequivalent when administered as a single 20 mg dose. Food slightly reduced the rate and extent of absorption of DEX-MR and delayed the time to peak plasma concentration (tmax) by approximately two hours compared to the fasted state. Bioavailability of DEX-MR was comparable under different meal conditions (normocaloric vs. high-fat, high-calorie breakfast) both after single and multiple dosing. Bioequivalence of once-daily DEX-MR and twice-daily DEX-IR was established. 1×2 DEX-MR 10 mg was bioequivalent to 1×1 DEX-MR 20 mg. DEX-MR should be administered with/after a meal to achieve the targeted pharmacokinetic profile (delayed tmax). Bioavailability of DEX-MR is not affected by meal composition (i.e., fat and caloric content).

Comparative Bioavailability and Benefits on Mental Functions of Novel Extended-Release Caffeine Capsules against Immediate-Release Caffeine Capsules: An Open-Label, Randomized, Cross-over, Single-Dose Two-Way Crossover Study

Present study aimed compared pharmacokinetic profile of sustained-release CaffXtend® capsules (SR-Caffeine) with immediate-release caffeine capsules (IR-Caffeine), and the effect of SR-caffeine on memory, motivation, concentration, and attention. This open-label, randomized, single-dose, two-treatment, two-sequence, two-period, two-way crossover oral bioavailability study block randomized (1:1) healthy subjects (N = 15) to receive SR-Caffeine (200 mg) and IR-Caffeine (200 mg). Blood samples were collected at 0.25, 0.50, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36 and 48 h in each period. Primary study outcome included comparing relative bioavailability of SR-Caffeine 200 mg and IR-Caffeine 200 mg under fasting conditions, and changes in caffeine research visual analogue scale (Caff-VAS) scores (‘relaxed’, ‘alert’, ‘jittery’, ‘tired’, ‘tense’, ‘headache’, ‘overall mood’ and ‘mentally fatigued’) were also evaluated. Fifteen subjects completed the study. Mean tmax was 4.08 ± 2.13h for SR-Caffeine compared to 0.83 ± 0.39h for IR-Caffeine, (p < 0.0001). Similarly, mean t½ was 7.07 ± 3.48h for SR-Caffeine compared to 5.78 ± 2.11h for IR-Caffeine (p = 0.04189). However, total exposure was similar for SR-Caffeine and IR-Caffeine (90% CI: 89.89–120.50% to 94.49–123.82% for geometric least square mean of ln-transformed AUC0-t and AUC0-∞). In the Caff-VAS evaluation, the SR-Caffeine group showed significantly better scores for ‘jitteriness’, ‘tiredness’, ‘alertness’ and ‘overall mood’ for 8–12 h than the IR-Caffeine group. No adverse events were reported. Results demonstrated sustained release of caffeine over 24 h from SR-Caffeine as compared to IR-Caffeine, which showed significant improvements in the scores for ‘relaxed’, ‘alertness’ and ‘overall mood’ and significantly lower scores for the parameters-‘jittery’ and ‘tired’ for extended period. Clinical trial registration: CTRI/2021/06/034185

Comparison of zinc bioavailability in zinc-glycine and zinc-methionine chelates for broilers fed with a corn-soybean meal diet.

The objective of this study was to compare the bioavailability of zinc (Zn) from zinc-glycine (Zn-Gly) and zinc-methionine (Zn-Met) as compared with zinc sulfate (ZnSO4) used as a standard in broilers. A total of 1,200 one-day-old male broilers (Cobb 500) were randomly allotted to one of 10 treatments with eight replicate cages of 15 birds each. The broilers were fed a corn-soybean meal basal diet (containing 26.46mg Zn/kg; control) or the basal diet added with 40, 80, and 120mg Zn/kg as Zn-Gly, Zn-Met, or ZnSO4 for 14days. The relative bioavailability value (RBV) was calculated based on multiple linear regression slope ratios of Zn concentrations in tibia and pancreas, pancreas metallothionein (MT) concentration, and pancreas MT mRNA abundance on added Zn intake. When comparing the control with all Zn-supplemented treatments, Zn addition did not significantly affect average feed intake and bodyweight gain during days 1-14 (p > 0.10). However, Zn concentrations in the tibia, pancreas, and liver and pancreas MT concentration and MT mRNA abundance increased in all Zn-supplemented treatments compared with the control (p < 0.05), and these indices increased linearly (p < 0.001) with increasing added Zn levels on days 7 and 14. The RBV of Zn as Zn-Met was similar to that as Zn-Gly or ZnSO4 (p > 0.40) on days 7 and 14, based on tibia and pancreas Zn. In contrast, on days 7 and 14, the RBVs of Zn were in the following order: Zn-Met > Zn-Gly > ZnSO4 (p < 0.05), based on pancreas MT concentration. The bioavailable Zn from Zn-Met was 1.20 or 1.25 times that from Zn-Gly on day 7 or 14, respectively, evaluated by pancreas MT content. The RBV of Zn as Zn-Met was similar to that as Zn-Gly or ZnSO4 on day 7, whereas it was higher than that as Zn-Gly or ZnSO4 on day 14, based on pancreas MT mRNA abundance. In conclusion, Zn-Met had higher bioavailable Zn than Zn-Gly for the starter broilers fed with the corn-soybean meal diet, using pancreas MT concentration as the response criterion.

RF23 | PSAT259 Comparable Bioavailability of a Novel Levothyroxine Solution when Administered with Coffee

Abstract Levothyroxine (LT4) is the treatment of choice for hypothyroidism and the second most prescribed medication in the United States. Despite its established efficacy and widespread availability, approximately 40% of patients treated with LT4 fail to achieve thyroid stimulating hormone (TSH) levels within the normal range. Current LT4 product guidelines recommend administration in the fasting state 30-60 minutes before breakfast to avoid a food interaction leading to reduced intestinal absorption of LT4. This recommendation may impact compliance, as over 50% of adult Americans drink coffee every day, 65% of which is consumed during breakfast.While the majority of patients receive LT4 tablets, there is evidence that liquid formulations that bypass the gastric dissolution phase may mitigate the interference with coffee. ThyquidityTM (levothyroxine sodium) oral solution has demonstrated bioequivalence to Synthroid® under fasting conditions and allows individualized dosing flexibility in a variety of clinical scenarios. A bioavailability study was conducted to assess the rate and extent of absorption of the oral LT4 solution (100 mcg /5 mL) administered with coffee compared to administration under fasting conditions in an open label, randomized, two-period, two-treatment, two-sequence, crossover, single dose bioavailability study in 40 healthy adults. A single 600 μg oral dose of LT4 solution (ThyquidityTM, 30 mL) was administered 5 minutes before drinking 8 ounces of American coffee (without milk or sweeteners) or under fasting conditions in each study period. Blood samples were collected for total (bound and free) T4 for 48 hours after drug administration. Treatment periods were separated by a 40-day wash-out period.The ratios of geometric LS means with corresponding 90% confidence intervals (CI) were calculated from the exponential of the difference between the LT4 solution administration 5 minutes prior to coffee and administration under fasting condition for AUC0-48 and Cmax. An absence of a food effect would be concluded if the baseline corrected 90% CIs of this ratio fell within 80.00% to 125.00% for Ln-transformed AUC0-48 and Cmax.Forty healthy adults participated in the trial. There were no serious adverse events (AE) or discontinuations due to AEs. The geometric LS mean ratio of AUC0-48 and Cmax for baseline-adjusted LT4 were 93.98% (90.06-98.07%) and 95.99% (92.64- 99.45%) respectively. The corresponding 90% CIs were included within the acceptance range for bioequivalence.This study demonstrated comparable bioavailability of a single oral 600 μg dose of Thyquidity oral solution administered, 5 minutes prior to coffee or under fasting conditions. These results are consistent with earlier evidence that liquid LT4 overcomes the interference from coffee seen with LT4 tablets and may offer additional flexibility for patients. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Sunday, June 12, 2022 1:06 p.m. - 1:11 p.m.