ABSTRACT
Hong-Hua-Xiao-Yao tablet (HHXYT) is attracting attention increasingly because of its use in treatment of mammary gland hyperplasia (MGH) and menopausal syndrome. However, its pharmacokinetics remains unclear. This study developed a sensitive and rapid method for simultaneous determination of 10 compounds of HHXYT in rat plasma by liquid chromatography-tandem mass spectrometry and to compare the pharmacokinetics of these compounds in MGH rats and sham operated rats. The linearity, accuracy, precision, stability and matrix effect were within acceptable ranges. This established method was successfully applied to a pharmacokinetics study of 10 compounds in sham operated and MGH rats. According to the results, the bioavailability of glycyrrhetinic acid was highest in MGH rats and sham operated rats. The mean residence times of glycyrrhetinic acid and glycyrrhetinic acid 3-O-glucuronide were higher than those of the other compounds while the mean residence time and half-life of liquiritin, isoliquiritin and paeoniflorin were lower. Some pharmacokinetic parameters of ormononetin, liquiritigenin, isoliquiritigenin, liquiritin, isoliquiritin, paeoniflorin, protocatechuic acid and senkyunolide I were significantly different between MGH rats and sham operated rats. This study elucidated the dynamic changes of multiple components in rats after oral administration of HHXYT systematically and comprehensively, which provided guidance for clinical application.
Subject(s)
Drugs, Chinese Herbal , Rats, Sprague-Dawley , Tandem Mass Spectrometry , Animals , Rats , Drugs, Chinese Herbal/pharmacokinetics , Drugs, Chinese Herbal/administration & dosage , Drugs, Chinese Herbal/chemistry , Tandem Mass Spectrometry/methods , Reproducibility of Results , Female , Linear Models , Chromatography, Liquid/methods , Tablets/pharmacokinetics , Chalcones/pharmacokinetics , Chalcones/chemistry , Chalcones/blood , Biological Availability , Limit of Detection , Glycyrrhetinic Acid/pharmacokinetics , Glycyrrhetinic Acid/blood , Glycyrrhetinic Acid/chemistryABSTRACT
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.
Subject(s)
Antineoplastic Agents , Indazoles , Neoplasms , Piperidines , Humans , Antineoplastic Agents/pharmacology , Area Under Curve , Biological Availability , Cross-Over Studies , Fasting , Neoplasms/drug therapy , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , Tablets/pharmacokinetics , Therapeutic EquivalencyABSTRACT
PURPOSE: Methicillin-resistant Staphylococcus aureus infections are increasing in prevalence in patients with cystic fibrosis (CF) and are associated with worsening lung function and increased mortality. Lefamulin is a pleuromutilin antimicrobial approved to treat community-acquired bacterial pneumonia based on potent in vitro activity and clinical efficacy. This Phase I, open-label, randomized crossover study assessed the safety and pharmacokinetic profile of oral and intravenous (IV) lefamulin in adults with CF. METHODS: The study comprised 2 dosing periods in which adults with CF (N = 13) received a single dose of lefamulin via a 150-mg IV infusion or 600-mg immediate-release orally administered tablet, separated by a 4- to 7-day washout period. Pharmacokinetic and safety parameters were assessed after lefamulin treatment. FINDINGS: Single doses of lefamulin administered via oral tablet or IV infusion resulted in comparable drug exposure, and sputum analysis suggested rapid penetration of lefamulin into the lung. Comparison of the present results with those obtained from prior single-dose studies of healthy volunteers indicate no meaningful difference in the pharmacokinetic properties of lefamulin in patients with CF. Treatment-emergent adverse events were consistent with previous reports, and the majority were mild in severity. IMPLICATIONS: These results show similar lefamulin pharmacokinetic and safety profiles between patients with CF and healthy volunteers receiving the same oral and IV doses, suggesting no need for lefamulin dose adjustment in patients with CF and indicating the potential of lefamulin as therapy for lung infections in patients with CF. CLINICALTRIALS: gov identifier: NCT05225805.
Subject(s)
Cystic Fibrosis , Diterpenes , Methicillin-Resistant Staphylococcus aureus , Pneumonia , Polycyclic Compounds , Thioglycolates , Adult , Humans , Anti-Bacterial Agents , Cystic Fibrosis/drug therapy , Cystic Fibrosis/chemically induced , Cross-Over Studies , Pneumonia/drug therapy , Tablets/pharmacokineticsABSTRACT
The prediction of intestinal absorption of various drugs based on computer simulations has been a reality. However, in vivo pharmacokinetic simulations and virtual bioequivalence evaluation based on GastroPlus™ have not been found. This study aimed to simulate plasma concentrations with different dissolution profiles and run population simulations to evaluate the bioequivalence of test and reference products of atorvastation using GastroPlus software. The dissolution profiles of the reference and test products of atorvastatin (20 mg tablets), and clinical plasma concentration-time data of the reference product were used for the simulations. The results showed that the simulated models were successfully established for atorvastatin tablets. Population simulation results indicated that the test formulation was bioequivalent to the reference formulation. The findings suggest that modelling is an essential tool to demonstrating the possibility of pharmacokinetic and bioequivalence for atorvastatin. It will contribute to understanding the potential risks during the development of generic products.
Subject(s)
Models, Biological , Software , Therapeutic Equivalency , Atorvastatin , Computer Simulation , Tablets/pharmacokinetics , SolubilityABSTRACT
This study aimed to develop extended-release tablets containing 25 mg IMM-H014, an original drug formulated by a direct powder pressing method based on pharmaceutical-grade hydrophilic matrix polymers such as hydroxypropyl methylcellulose, to establish an in vitro-in vivo correlation (IVIVC) to predict bioavailability. The tablets' mechanical properties and in vitro and in vivo performance were studied. The formulation was optimized using a single-factor experiment and the reproducibility was confirmed. The in vitro dissolution profiles of the tablet were determined in five dissolution media, in which the drug released from the hydrophilic tablets followed the Ritger-Peppas model kinetics in 0.01 N HCl medium for the first 2 h, and in phosphate-buffered saline medium (pH 7.5) for a further 24 h. Accelerated stability studies (40 °C, 75% relative humidity) proved that the optimal formulation was stable for 6 months. The in vivo pharmacokinetics study in beagle dogs showed that compared to the IMM-H014 immediate release preparation, the maximum plasma concentration of the extended-release (ER) preparation was significantly decreased, while the maximum time to peak and mean residence time were significantly prolonged. The relative bioavailability was 97.9% based on the area under curve, indicating that the optimal formulation has an obvious ER profile, and a good IVIVC was established, which could be used to predict in vivo pharmacokinetics based on the formulation composition.
Subject(s)
Liver Diseases , Animals , Dogs , Reproducibility of Results , Tablets/pharmacokinetics , Delayed-Action Preparations/chemistry , Biological Availability , SolubilityABSTRACT
The study reported here aimed to develop and optimize the S-SNEDDS tablet of bosentan (BOS) and to investigate its pharmacokinetic and biodistribution properties. The BOS-loaded SNEDDS have been developed and characterized in a previous study. The BOS-loaded SNEDDS formulation was converted to S-SNEDDS using Neusilin® US2. The S-SNEDDS tablets were obtained using the direct compression technique, and in vitro dissolution, in vitro lipolysis, and ex-vivo permeability studies of the tablets were performed. The S-SNEDDS tablet and reference tablet (Tracleer®) were administered to male Wistar rats at 50 mg/kg dose by oral gavage in fasted and fed state conditions. The biodistribution of the S-SNEDDS tablet was investigated in Balb/c mice using fluorescent dye. The tablets were dispersed in distilled water before administration to animals. The relationship between in vitro dissolution data and in vivo plasma concentration was examined. The S-SNEDDS tablets showed 2.47, 7.49, 3.70, and 4.39 increases in the percentages of cumulative dissolution in FaSSIF, FeSSIF, FaSSIF-V2, and FeSSIF-V2, respectively, when compared to the reference, and increased the Cmax and AUC 2.65 and 1.28-fold and 4.73 and 2.37-fold in fasted and fed states, respectively, when compared to the reference. S-SNEDDS tablets also significantly reduced interindividual variability in both fasted and fed states (p < 0.05). The XenoLight™ DiR and VivoTag® 680XL labeled S-SNEDDS tablet formulation increased the real-time biodistribution in the body by factors of 2.4 and 3.4 and organ uptake and total emission increased by factors of 2.8 and 3.1, respectively. The IVIVR has been successfully established for S-SNEDDS tablets (R2 > 0.9). The present study confirms the potential of the S-SNEDDS tablet to enhance the in vitro and in vivo performance of BOS.
Subject(s)
Drug Delivery Systems , Nanoparticles , Rats , Animals , Mice , Male , Drug Delivery Systems/methods , Bosentan , Tissue Distribution , Rats, Wistar , Biological Availability , Emulsions , Tablets/pharmacokinetics , Solubility , Administration, Oral , Particle SizeABSTRACT
This single-center, randomized, open-label, single-dose, 2-group, 2-stage crossover trial evaluated the bioequivalence of 15 mg of mirogabalin as orally disintegrating tablets (ODTs) with conventional mirogabalin tablets in healthy Japanese men. The trial involved two studies: in Study 1, the ODT formulation was taken without water, and in Study 2, the ODT formulation was taken with water. The conventional tablet was taken with water in both studies. We investigated the pharmacokinetic parameters and bioequivalence of the 2 formulations, including the maximum plasma concentration and the area under the plasma concentration-time curve up to the last quantifiable time. The plasma concentrations of mirogabalin were determined by a validated liquid chromatography with tandem mass spectrometry method. A total of 72 participants were enrolled and completed the trial. The geometric least-squares mean ratios of maximum plasma concentration of the ODT formulation to the conventional formulation were within the prespecified bioequivalence range of 0.80-1.25 (Study 1, 0.995; Study 2, 1.009), as was the area under the plasma concentration-time curve up to the last quantifiable time (Study 1, 1.023; Study 2, 1.035). No serious adverse events were observed. In conclusion, mirogabalin 15-mg ODTs, either with or without water, were bioequivalent to conventional 15-mg tablets.
Subject(s)
Bridged Bicyclo Compounds , East Asian People , Humans , Male , Bridged Bicyclo Compounds/administration & dosage , Bridged Bicyclo Compounds/blood , Bridged Bicyclo Compounds/pharmacokinetics , Tablets/administration & dosage , Tablets/pharmacokinetics , Therapeutic Equivalency , Administration, Oral , Drug Liberation , Healthy VolunteersABSTRACT
Posaconazole is a globally approved broad-spectrum triazole antifungal compound. In Japanese patients, posaconazole has identical dosing regimens as those approved globally for both tablet and intravenous formulations. This article aims to describe a model-informed approach for dose justification of posaconazole in the Japanese population as either high-risk patients with fungal infections (prophylaxis patients) or patients with fungal infections (treatment patients). A simultaneous population pharmacokinetic (PK) model for tablet and intravenous formulation was developed on the basis of a data set including Japanese data from healthy participants and treatment patients. The PK profiles and exposure distributions in Japanese patients were predicted and compared against foreign patients, that is, patients outside of Japan. Relationships between the post hoc posaconazole exposures and frequently observed clinical adverse events were evaluated. Although clinical trials for Japanese prophylaxis patients were not conducted, PK profiles in Japanese prophylaxis patients were predicted using the population PK model and demographic covariate information obtained from the published literature. Based upon the globally approved dosing regimen, posaconazole exposure distribution was predicted to be the highest in Japanese treatment patients, and generally similar between Japanese and foreign prophylaxis patients. Exposures in Japanese patients exceeded the efficacy target level (500 ng/mL). Safety profiles in Japanese treatment patients with the highest exposures were clinically acceptable without specific concerns to Japanese patients and appeared to have no relationship with posaconazole exposures. From PK, safety, and efficacy perspectives, the use of the same dosing regimen as in foreign patients was justified in Japanese prophylaxis and treatment patients.
Subject(s)
East Asian People , Mycoses , Humans , Administration, Oral , Mycoses/drug therapy , Triazoles , Antifungal Agents , Tablets/pharmacokineticsABSTRACT
A modified in vitro-in vivo correlation (IVIVC) of the oral solid dosage forms has been proposed as a linear correlation between in vitro and in vivo dissolution. Nevertheless, the analysis of in vivo dissolution is limited by the lack of available methods. In this proof-of-concept study, a novel pharmacokinetic (PK) model containing the in vivo dissolution process and its quantification was presented to directly estimate the in vivo dissolution rate constant (kd). The new model was validated with a hypothetical oral solution (kd â +∞). The accuracy of the new method was clarified by comparing with the relatively true value of kd from the literature. Isosorbide mononitrate (ISMN) was used as a model drug to explore the practicability of the novel method. The dissolution capacities of ISMN reference and test tablets were discriminated by an improved in vitro dissolution method. Following the human PK studies, the kd values and corresponding in vivo dissolution profiles of two formulations were obtained using the novel method. Finally, a modified level A IVIVC between in vitro and in vivo dissolution of ISMN tablets was established, which is expected to guide the optimization of the tablet formulation containing ISMN.
Subject(s)
Isosorbide Dinitrate , Humans , Solubility , Biological Availability , Tablets/pharmacokineticsABSTRACT
Gastroretentive drug delivery systems (GRDDS) are modified-release dosage forms designed to prolong their residence time in the upper gastrointestinal tract, where some drugs are preferentially absorbed, and increase the drug bioavailability. This work aimed the development of a novel GRDDS containing 60 mg of sildenafil citrate, and the evaluation of the feasibility of the proposed formulation for use in the treatment of pulmonary arterial hypertension (PAH), for once a day administration, by using in silico pharmacokinetic (PK) modeling and simulations using GastroPlusTM. The Model-Informed Drug Development (MIDD) approach was used in formulation design and pharmacokinetic exposure prospecting. A 22 factorial design with a central point was used for optimization of the formulation, which was produced by direct compression and characterized by some tests, including buoyancy test, assay, impurities, and in vitro dissolution. A compartmental PK model was built using the GatroPlusTM software for virtual bioequivalence of the proposed formulations in comparison with the defined target release profile provided by an immediate release (IR) tablet formulation containing 20 mg of sildenafil administered three times a day (TID). The results of the factorial design showed a direct correlation between the dissolution rate and the amount of hydroxypropyl methyl cellulose (HPMC) in the formulations. By comparing the PK parameters predicted by the virtual bioequivalence, the formulations F1, F2, F3 and F5 failed on bioequivalence. The F4 showed bioequivalence to the reference and was considered the viable formulation to substitute the IR. Thus, GRDDS could be a promising alternative for controlling the release of drugs with a pH-dependent solubility and narrow absorption window, specifically in the gastric environment, and an interesting way to reduce dose frequency and increase the drug bioavailability. The MIDD approach increases the level of information about the pharmaceutical product and guide the drug development for more assertive ways.
Subject(s)
Drug Delivery Systems , Drug Development , Sildenafil Citrate , Delayed-Action Preparations/pharmacokinetics , Biological Availability , Solubility , Tablets/pharmacokineticsABSTRACT
The in-vitro cytotoxicity, in-vitro permeability and in-vivo pharmacokinetics of a BCS Class-II drug - rufinamide - in a 3DP tablet formulation were evaluated. The cytotoxicity of the 3DP tablet formulation was evaluated with an MTT test; in-vitro permeability was evaluated with a Caco-2 cell culture study; and in-vivo pharmacokinetics were evaluated in Wistar albino male rats. The pharmacokinetic studies were performed following a two-sequence and single-period design approach. The highest Caco-2 permeability was obtained with the 3DP tablet formulation; and the highest cell viability was achieved with the 3DP tablet in both the Hep G2 and Caco-2 cell lines. In the in-vivo pharmacokinetic study, AUC and Cmax values were higher in the 3DP tablet formulation than in the Inovelon® film tablet at a 40 mg/kg dose. Thanks to the increased solubility of the active substance, higher in-vitro permeability and in-vivo absorption were achieved with the 3DP tablet formulation, and with lower cytotoxicity. Based on these promising findings, the 3DP tablet formulation can be considered an effective lower-dose treatment than commercial preparations.
Subject(s)
Orphan Drug Production , Water , Humans , Rats , Animals , Biological Availability , Caco-2 Cells , Rats, Wistar , Tablets/pharmacokinetics , Solubility , Cell Culture Techniques , TechnologyABSTRACT
This study aimed to develop a novel in silico modeling and simulation that considers the disintegration rate in the stomach to predict the in vivo performance of oral solid dosage forms with slow disintegration rates containing poorly soluble weak base drugs. Oxatomide and manidipine hydrochloride were used as model drugs. First, the in vitro disintegration rate and dissolution rate were determined in biorelevant media that simulate the gastrointestinal fluids in fasted humans using a USP apparatus II paddle dissolution tester. Next, the oral absorption of the dosage forms was predicted using the novel simulation model coupled with not only the dissolution rate but also the estimated disintegration rate. As the in vitro disintegration time was 45 min or longer for both drugs in Fasted State Simulated Gastric Fluid, the disintegration rate of these dosage forms was considered slow as immediate release (IR) tablets. While the predicted and observed pharmacokinetic profiles of both drugs were comparable using the new model, the conventional model, which did not consider the disintegration step, underestimated the oral absorption of both drugs. Thus, our novel simulation model coupled with the disintegration rate estimated from in vitro tests is promising for predicting the in vivo performance of oral solid dosage forms with slow disintegration rates containing poorly soluble weak base drugs.
Subject(s)
Models, Biological , Stomach , Humans , Solubility , Administration, Oral , Tablets/pharmacokinetics , Computer SimulationABSTRACT
OBJECTIVES: This study aimed to describe the absolute oral bioavailability of the solid oral formulation of posaconazole and the impact of severe intestinal mucositis in haematology patients. This study also aimed to describe posaconazole protein binding in haematology patients. METHODS: A pharmacokinetic study was performed of patients receiving induction chemotherapy or a haematopoietic cell transplantation who were randomized to receive 7 days of intravenous posaconazole therapy followed by 9 days of oral therapy, or vice versa. Patients received a posaconazole licensed dose until day 12, after which a reduced once-daily dose of 200 mg was given. At days 7, 12, and 16, blood samples were obtained for pharmacokinetic curves, and trough samples were collected on all other days. Total and unbound posaconazole pharmacokinetics were analyzed by population pharmacokinetic modelling. The presence of severe intestinal mucositis was assessed by plasma citrulline levels and analyzed as a binary covariate using 10 µmol/L as the cut-off. Monte Carlo simulations were performed to simulate posaconazole exposure at a steady state. RESULTS: Twenty-three patients were included for analysis, with 581 total posaconazole concentrations and 91 paired unbound concentrations. Absolute bioavailability in the final model was estimated at 51.4% (percentage relative standard error (%RSE): 56.5) and 67.6% (%RSE: 75.0) in patients with and without severe intestinal mucositis, respectively. Posaconazole unbound fraction was estimated at 2.7% (%RSE: 3.9). DISCUSSION: Posaconazole bioavailability is reduced in haematological patients with severe intestinal mucositis, requiring an increase in oral posaconazole dose to 400 mg twice daily on day 1, followed by 400 mg once daily or a switch to intravenous therapy.
Subject(s)
Mucositis , Administration, Oral , Antifungal Agents , Biological Availability , Humans , Mucositis/chemically induced , Tablets/adverse effects , Tablets/pharmacokinetics , TriazolesABSTRACT
We propose a Bayesian population modeling and virtual bioequivalence assessment approach to establishing dissolution specifications for oral dosage forms. A generalizable semi-physiologically based pharmacokinetic absorption model with six gut segments and liver, connected to a two-compartment model of systemic disposition for bupropion hydrochloride oral dosage forms was developed. Prior information on model parameters for gut physiology, bupropion physicochemical properties, and drug product properties were obtained from the literature. The release of bupropion hydrochloride from immediate-, sustained- and extended-release oral dosage forms was described by a Weibull function. In vitro dissolution data were used to assign priors to the in vivo release properties of the three bupropion formulations. We applied global sensitivity analysis to identify the influential parameters for plasma bupropion concentrations and calibrated them. To quantify inter- and intra-individual variability, plasma concentration profiles in healthy volunteers that received the three dosage forms, each at two doses, were used. The calibrated model was in good agreement with both in vitro dissolution and in vivo exposure data. Markov Chain Monte Carlo samples from the joint posterior parameter distribution were used to simulate virtual crossover clinical trials for each formulation with distinct drug dissolution profiles. For each trial, an allowable range of dissolution parameters ("safe space") in which bioequivalence can be anticipated was established. These findings can be used to assure consistent product performance throughout the drug product life-cycle and to support manufacturing changes. Our framework provides a comprehensive approach to support decision-making in drug product development.
Subject(s)
Bupropion , Drugs, Generic , Administration, Oral , Bayes Theorem , Biological Availability , Humans , Models, Biological , Tablets/pharmacokinetics , Therapeutic EquivalencyABSTRACT
BACKGROUND AND OBJECTIVES: Omecamtiv mecarbil (OM) is a cardiac myosin activator under development for the treatment of heart failure. The pharmacokinetics of single and multiple doses of OM were investigated in healthy Japanese subjects in two clinical studies. METHODS: Study 1 (n = 36) evaluated the bioavailability and pharmacokinetics after intravenous infusion (15 mg/h for 4 h) and an oral modified release (MR) tablet in healthy Japanese and Caucasian subjects using 25 mg single and multiple doses and 50 mg single dose. Study 2 (n = 50) evaluated the pharmacokinetics of OM with multiple oral doses of 25 mg MR tablets twice a day (BID) followed by up-titration to either 37.5 mg or 50 mg BID in healthy Japanese subjects. RESULTS: In Study 1, the maximum observed plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) from time 0 to infinity (AUCinf) in Japanese subjects after a single oral dose of 50 mg were twice that at the 25 mg dose, consistent with that observed in Caucasian subjects. Following single oral doses of 25 mg and 50 mg, absolute bioavailability was 56.5% and 59.2% for Japanese subjects and 63.1 and 83.6% for Caucasian subjects, respectively. No ethnic differences were observed in the pharmacokinetics of OM and its metabolites following single and multiple doses of 25 mg and 50 mg. In Study 2, the mean accumulation ratios based on AUC from 0 to 12 h (AUC12) were approximately four-fold from day 1 to day 8 and from day 20 to day 27 across ethnic groups. The mean ratios of Cmax to predose concentrations (Cpredose) ranged from 1.25 to 1.38 across subgroups. CONCLUSIONS: OM showed consistent and predictable pharmacokinetics after multiple dosing in Japanese subjects.
Subject(s)
Urea/analogs & derivatives , Administration, Oral , Adult , Area Under Curve , Asian People , Biological Availability , Female , Half-Life , Healthy Volunteers , Humans , Japan , Male , Tablets/adverse effects , Tablets/pharmacokinetics , Urea/adverse effects , Urea/pharmacokineticsABSTRACT
PURPOSE: A new sustained-release (SR) pregabalin formulation (YHD1119) designed for once-daily dosing has recently been developed to improve patient adherence. This study aimed to compare the pharmacokinetics of pregabalin SR and immediate-release (IR) formulations after multiple oral doses and to assess the effect of food on the pharmacokinetic profile of the pregabalin SR formulation after a single dose in healthy individuals. METHODS: Two clinical trials were conducted: a randomized, open-label, multiple-dose, 2-treatment, 2-period crossover study to evaluate the steady-state pharmacokinetic properties of SR treatment (pregabalin SR 300 mg once daily for 3 days) and IR treatment (pregabalin IR 150 mg twice daily for 3 days) under fed conditions and a randomized, open-label, single-dose, 2-treatment, 2-period, crossover study to evaluate the effect of food intake on the pharmacokinetic properties of the pregabalin SR formulation. Plasma concentrations of pregabalin were measured using LC-MS/MS. The AUC and Cmax for pregabalin were calculated using noncompartmental method and compared between treatments in each study. FINDINGS: Thirty-one individuals in the bioequivalence study and 23 in the food effect study completed the pharmacokinetic sampling. The geometric mean ratios of Cmax,ss and AUC0-τ between the SR and IR formulations were 1.1642 (90% CI, 1.1043-1.2272) and 0.9704 (90% CI, 0.9372-1.0047), respectively. The geometric mean ratios of Cmax and AUC0-last between the SR formulation in the fed state and in the fasted state were 1.6514 (90% CI, 1.3820-1.9732) and 1.7899 (90%CI, 1.4499-2.2097), respectively. IMPLICATIONS: The bioavailability of the pregabalin SR 300 mg formulation is increased if taken with a high-fat meal. Once-daily pregabalin SR 300 mg is bioequivalent to twice-daily pregabalin IR 150 mg under fed conditions at steady state. The pregabalin SR formulation is expected to improve patient adherence. ClinicalTrials.gov identifiers: NCT02783183 (bioequivalence study) and NCT03191136 (food effect study).
Subject(s)
Pregabalin/pharmacokinetics , Area Under Curve , Biological Availability , Chromatography, Liquid , Cross-Over Studies , Delayed-Action Preparations/pharmacokinetics , Healthy Volunteers , Humans , Male , Tablets/pharmacokinetics , Tandem Mass Spectrometry , Therapeutic EquivalencyABSTRACT
Levodopa (L-Dopa) is the "gold-standard" medication for symptomatic therapy of Parkinson disease (PD). However, L-Dopa long-term use is associated with the development of motor and non-motor complications, primarily due to its fluctuating plasma levels in combination with the disease progression. Herein, we present the first example of individualized therapeutic drug monitoring for subjects upon intake of standard L-Dopa oral pill, centered on dynamic tracking of the drug concentration in naturally secreted fingertip sweat. The touch-based non-invasive detection method relies on instantaneous collection of fingertip sweat on a highly permeable hydrogel that transports the sweat to a biocatalytic tyrosinase-modified electrode, where sweat L-Dopa is measured by reduction of the dopaquinone enzymatic product. Personalized dose-response relationship is demonstrated within a group of human subjects, along with close pharmacokinetic correlation between the finger touch-based fingertip sweat and capillary blood samples.
Subject(s)
Biosensing Techniques/methods , Drug Monitoring/methods , Electrochemical Techniques/methods , Levodopa/pharmacokinetics , Sweat/chemistry , Administration, Oral , Enzymes, Immobilized/chemistry , Humans , Hydrogels/chemistry , Levodopa/administration & dosage , Levodopa/chemistry , Monophenol Monooxygenase/chemistry , Oxidation-Reduction , Tablets/administration & dosage , Tablets/chemistry , Tablets/pharmacokineticsABSTRACT
Formulation development of amorphous solid dispersions (ASD) still is challenging although several poorly water-soluble drugs have been marketed using this technique. During development of novel drugs, the selection of the preparation technique and polymer matrix is commonly performed for the certain drug via screening tools. However, if general trends regarding material properties are to be investigated, this approach is not beneficial, although often utilized in literature. The main component of the ASD usually is the polymer and thus it predominantly determines the material properties of the system. Therefore, to study the impact of different drugs and their drug loads on mechanical properties and wettability, three poorly soluble model drugs with drug loads ranging from 10% to 40% were incorporated into copovidone via hot-melt extrusion. The obtained extrudates were subsequently characterized regarding mechanical properties by applying diametral compression test and nanoindentation and the results were compared to the performance during tablet compression. Incorporation of all tested drugs resulted in a similar increase in brittleness of the ASDs, whereas the Young's modulus and hardness changed differently in dependence of the incorporated drug. These observations correlated well with the performance during tablet compression and it was concluded, that the brittleness seemed to be the predominant factor influencing the compression behavior of copovidone-based ASDs. Furthermore, the degree of water absorption and wettability was assessed by applying dynamic vapor sorption experiments and contact angle measurements. Here, the incorporated drugs impacted the contact angle to different degrees and a strong correlation between the contact angle and disintegration time was observable. These results highlight the importance of thorough characterization of the ASDs as it helps to predict their performance during tablet compression and thus facilitates the optimal selection of excipients.
Subject(s)
Drug Compounding/methods , Drug Development/methods , Excipients/chemistry , Tablets/chemistry , Absorption, Physicochemical , Drug Liberation , Hot Melt Extrusion Technology , Polymers/chemistry , Solubility , Solvents/chemistry , Tablets/pharmacokinetics , Water/chemistry , WettabilityABSTRACT
Different dosage regimens of hydroxychloroquine (HCQ) have been used to manage COVID-19 (coronavirus disease 2019) patients, with no information on lung exposure in this population. The aim of our study was to evaluate HCQ concentrations in the lung epithelial lining fluid (ELF) in patients infected with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), the virus that causes COVID-19. This was a retrospective, observational, multicentre, pharmacokinetic study of HCQ in critically ill COVID-19 patients. No additional interventions or additional samples compared with standard care of these patients were conducted in our teaching hospital. We included all intubated COVID-19 patients treated with crushed HCQ tablets, regardless of the dosage administered by nasogastric tube. Blood and bronchoalveolar lavage samples (n = 28) were collected from 22 COVID-19 patients and total HCQ concentrations in ELF were estimated. Median (interquartile range) HCQ plasma concentrations were 0.09 (0.06-0.14) mg/L and 0.07 (0.05-0.08) mg/L for 400 mg × 1/day and 200 mg × 3/day, respectively. Median HCQ ELF concentrations were 3.74 (1.10-7.26) mg/L and 1.81 (1.20-7.25) for 400 mg × 1/day and 200 mg × 3/day, respectively. The median ratio of ELF/plasma concentrations was 40.0 (7.3-162.7) and 21.2 (18.4-109.5) for 400 mg × 1/day and 200 mg × 3/day, respectively. ELF exposure is likely to be underestimated from HCQ concentrations in plasma. In clinical practice, low plasma concentrations should not induce an increase in drug dosage because lung exposure may already be high.
Subject(s)
Antiviral Agents/pharmacokinetics , COVID-19 Drug Treatment , Hydroxychloroquine/pharmacokinetics , Adult , Aged , Aged, 80 and over , Antiviral Agents/administration & dosage , Antiviral Agents/blood , Bronchoalveolar Lavage Fluid/chemistry , Critical Illness , Female , Humans , Hydroxychloroquine/administration & dosage , Hydroxychloroquine/blood , Intubation, Gastrointestinal , Lung/drug effects , Lung/virology , Male , Middle Aged , Retrospective Studies , Tablets/administration & dosage , Tablets/pharmacokineticsABSTRACT
The aim of the study was to determine the various pharmacokinetic parameters of the newly developed cost-effective aceclofenac 100 mg tablet formulation (F-15) and to establish the bioequivalence against the marketed brand (ACEMED). Both products (test and reference) were given to 12 healthy non-smokers male subjects with overnight fasting of >10hr. The study was a randomized, single-dose, open-label, two sequence, and two treatment crossover design, with a washout period of 2 weeks. Blood samples (5 mL) from the human subjects were collected before (0 hr) and after drug administration at 13different time points (0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12 and 18 hrs). The drug plasma concentration was analyzed by a validated RP-HPLC method using a solvent system containing acetonitrile and deionized water (60:40% v/v). Linearity was found to be 0.999 over the drug concentration range of 50µg/mL to 0.05µg/mL with LLOQ and LOD of 0.05µg/mL and 0.025µg/mL respectively. Non-compartmental pharmacokinetic analysis was performed using Kinetica® (ver. 5.1) software. Using the log-transformed data Cmax, AUC0-t, AUC0-∞, AUMCtot, and MRT were calculated. The Cmax of the test and brand was found to be 8.629±1.251µg/mL and 8.478±0.913µg/mL. The AUC0-t and AUC0-∞ of the test and the reference were computed to be 20.890 ±2.2021µg/mL.h, 23.272 ±1.914 µg/mL.h and 19.850 ±2.911 µg/mL.h, 22.890 ± 2.110 µg/mL.h correspondingly. Two-way analysis of variance (ANOVA) test and two one-sided t-test (p>0.05; non-significant) were applied to assess the variation in the period, sequence, subjects, and treatment. Geometric mean ratios for above mentioned pharmacokinetic parameters of reference/test were found within the acceptable FDA limits of 80-125% using 90% CI. There was no inter and intrasubject variation (p> 0.05) that was observed. Therefore, the directly compressible aceclofenac (100 mg) test formulation and the commercial reference tablets were declared to be biosimilar.