Multiple-dose Oral Administration Research Articles

Safety, pharmacokinetics, and food-effect of pivmecillinam after single- and multiple-dose in healthy Chinese subjects: a phase I study.

Urinary tract infection (UTI) is one of the most prevalent bacterial infectious diseases worldwide. However, the resistance of urinary pathogens to other UTI antibiotics such as trimethoprim and trimethoprim/sulphamethoxazole increased. Pivmecillinam is a prodrug of mecillinam, which is effective for the treatment of urinary tract infections. The purpose of this study was to assess the safety, and pharmacokinetics of pivmecillinam and mecillinam after single- and multiple-dose oral administration of pivmecillinam tablets in healthy Chinese subjects. The study also investigated the profile of urinary excretion of mecillinam, as well as the effect of food and gender on the pharmacokinetics of pivmecillinam and mecillinam. This study was a single-center, open-label phase I study carried out in three groups. In total, 34 subjects were included in the study: group 1-food effect study with pivmecillinam 200mg (n = 12); group 2-single- and multiple-dose study with pivmecillinam 400mg (n = 12); group 3-single dose study with pivmecillinam 600mg (n = 10). The plasma and urine concentrations of pivmecillinam and mecillinam were measured, and their pharmacokinetics were calculated. Treatment-emergent adverse events were evaluated and recorded in safety assessments for three groups. No severe adverse events were found in this study. After a single dose of pivmecillinam was taken orally, the maximum plasma concentration (Cmax) and the area under the concentration-time curve (AUC) of pivmecillinam increased in a dose-proportional manner, nor did mecillinam. Food had significant effects on Cmax and AUC0-t of pivmecillinam and Cmax of mecillinam. The mean cumulative percentage of urine excretion of mecillinam at 0 to 24h ranged from 35.5 to 44.0%. Urinary cumulative excretion is relative to the drug dose, but the diet and multiple-dose administration did not affect the urinary cumulative excretion rate. The safety and pharmacokinetics of pivmecillinam and mecillinam after single- (200/400/600mg) or multiple-dose (400mg) administration were demonstrated in healthy Chinese subjects. Food affected the pharmacokinetics of pivmecillinam and mecillinam.

Novel protocol for multiple-dose oral administration of the L-type Ca2+ channel blocker isradipine in mice: A dose-finding pharmacokinetic study

ABSTRACT Studies in genetically modified animals and human genetics have recently provided new insight into the role of voltage-gated L-type Ca2+ channels in human disease. Therefore, the inhibition of L-type Ca2+ channels in vivo in wildtype and mutant mice by potent dihydropyridine (DHP) Ca2+ channel blockers serves as an important pharmacological tool. These drugs have a short plasma half-life in humans and especially in rodents and show high first-pass metabolism upon oral application. In the vast majority of in vivo studies, they have therefore been delivered through parenteral routes, mostly subcutaneously or intraperitoneally. High peak plasma concentrations of DHPs cause side effects, evident as DHP-induced aversive behaviors confounding the interpretation of behavioral readouts. Nevertheless, pharmacokinetic data measuring the exposure achieved with these applications are sparse. Moreover, parenteral injections require animal handling and can be associated with pain, discomfort and stress which could influence a variety of physiological processes, behavioral and other functional readouts. Here, we describe a noninvasive oral application of the DHP isradipine by training mice to quickly consume small volumes of flavored yogurt that can serve as drug vehicle. This procedure does not require animal handling, allows repeated drug application over several days and reproducibly achieves peak plasma concentrations over a wide range previously shown to be well-tolerated in humans. This protocol should facilitate ongoing nonclinical studies in mice exploring new indications for DHP Ca2+ channel blockers.

Urinary excretion profile of higenamine in females after oral administration of supplements – Doping scenario

In 2017, higenamine was added to the World Antidoping Agency’s (WADA) Prohibited list under group S3: beta-2 agonists and it is banned for athletes both in – and out of competition. Aim of this study was to characterize the urinary excretion profile of higenamine and its metabolite coclaurine after oral administration of multiple doses of higenamine capsules. For this purpose, an administration study including female basketball players was performed.For the detection of higenamine and cocalurine in the collected urine samples, a new, fast, and highly sensitive quantitative on-line SPE LC HRMS method was developed and validated. The method was applied for the quantification of higenamine and cocalurine in urine and their excretion pattern was defined. Results obtained show substantial inter-individual differences in the excretion profile of higenamine and coclaurine. For higenamine, half-lives were estimated to be between 4 and 27 h, and for coclaurine between 5 and 25 h. Furthermore, the data indicate that the elimination of coclaurine is rate-limited by its formation. Higenamine could be detected at a urine concentration above 10 ng/mL for at least 20 h after the last application for all study participants.

Detection of FG-4592 and metabolites in equine plasma, urine and hair following oral administration.

FG-4592 is a hypoxia-inducible factor inhibitor that has been approved for therapeutic use in some countries. This class of compounds can increase the oxygen carrying capacity of the blood and thus have the potential to be used as performance enhancing agents in sports. The purpose of this study was to investigate the detection of FG-4592 and metabolites in equine plasma and mane hair following a multiple dose oral administration to two Thoroughbred racehorses, to identify the best analytical targets for doping control laboratories. Urine samples were also analysed, and the results compared to previously published urine data. Liquid chromatography-high resolution mass spectrometry was used for metabolite identification in urine and plasma. Liquid chromatography-tandem mass spectrometry was used for full sample analysis of urine, plasma and hair samples and generation of urine and plasma profiles. FG-4592 and a mono-hydroxylated metabolite were detected in plasma. FG-4592 was detected with the greatest abundance and gave the longest duration of detection, up to 312 h post-administration, and would be the recommended target in routine doping samples. FG-4592 was detected in all mane hair samples collected post-administration, up to 166 days following the final dose, showing extended detection can be achieved with this matrix. To the best of the authors' knowledge, this is the first report of FG-4592 and metabolites in equine plasma and hair samples. Urine results were consistent with the previously published data, with FG-4592 offering the best target for detection and longest detection periods.

Increased Antithrombotic Properties of Unfractionated Heparin in Rats Following Oral Administration of Multiple Doses and Its Correlation with Endothelial Heparin Concentration

In a rat model of venous thrombosis, a single oral dose of 7.5mg kg-1 of Unfractionated Heparin (UFH) lowers thrombosis by 50%. Since clinical long-term use is necessary, our goals were to investigate the antithrombotic effects of repeated oral UFH administration. Rats were given three doses of 7.5mg kg-1 every 12, 24, 48, and 72 hours apart—as well as three or fifteen doses of 1 mg kg—1 every 48 hours—by oral gavage of cow lung UFH. The final dosage was injecting 10% formalin in methanol into the jugular vein right after thrombus start. Four hours later, the vessel was checked for thrombosis. Heparin levels in endothelium and tissue as well as plasma anticoagulant activity were assessed. As 3×7.5 When heparin (mg kg-1) was administered, the incidence of thrombosis was notably lower during 48-hour dosing intervals than with a single dose. Endothelial heparin concentration and thrombotic incidence were negatively correlated, while anticoagulant activity was not. Treatment with three doses of 1mg kg-1 every 48 hours resulted in a thrombotic incidence comparable to that of a single dosage. The total thrombotic incidence after 15 doses was comparable to that following s.c. treatment and was lower than that of 3 doses. Oral UFH delivery resulted in increased antithrombotic activity and antithrombotic effects that were comparable to those of s.c. administration. Heparin’s antithrombotic effect on endothelium was linked to it.

Pharmacokinetics, Tissue Residues, and Withdrawal Times of Oxytetracycline in Rainbow Trout (Oncorhynchus mykiss) after Single- and Multiple-Dose Oral Administration.

The aim of this study was to compare the pharmacokinetics of oxytetracycline (OTC) following single- (60 mg/kg) and multiple-dose oral administrations (60 mg/kg, every 24 h for 7 days) in rainbow trout. It also aimed to determine bioavailability after a single dose and tissue residues and withdrawal times after multiple doses. This study was carried out on 420 rainbow trout at 9 ± 0.8 °C. This study was carried out in two stages: single-dose (intravascular and oral) and multiple-dose treatment. The OTC concentrations in plasma and tissues were measured by high-performance liquid chromatography and analyzed by a non-compartmental method. The withdrawal time (WT) was estimated using the WT 1.4 software. OTC exhibited a long terminal elimination half-life (t1/2ʎz) after IV and oral administration. The oral bioavailability of OTC was very low (2.80%). In multiple-dose treatment, t1/2ʎz, the area under the plasma concentration-time curve and peak plasma concentration increased significantly after the last day compared to the first day. OTC showed strong accumulation after multiple doses with a value of 5.33. OTC concentrations were obtained in the order liver > kidney > muscle+skin > plasma. At 9 ± 0.8 °C, the WT calculated for muscle+skin was 56 days for Europe and 50 days for China, respectively. The t1/2ʎz (68.94 h) and time (68 h) above the 1 µg/mL MIC following a single OTC dose may support the extension of the 24 h dosing interval following multiple dosing. However, further studies are required to determine the optimal dosage regimen in multiple-dose OTC treatment in the treatment of infections caused by susceptible pathogens.

Novel aspects of taxifolin pharmacokinetics: Dose proportionality, cumulative effect, metabolism, microemulsion dosage forms

Taxifolin (TFL) is a small drug molecule with a broad therapeutic potential limited by its poor aqueous solubility and excessive metabolism. Despite comprehensive research, some aspects of the TFL pharmacokinetics, e.g., dose proportionality and possible cumulative effect, remain unexplored. In the current study, we have tried to fill this gap. Our results revealed that the TFL pharmacokinetics in rats had nonlinear character in the dose range of 10–50 mg/kg after its single oral administration (AUC). For Cmax, the data are ambiguous: linearity was confirmed via the equivalence criterion and was disproved using the power model approach. Also, the cumulative drug effect was observed on the 4th day after its multiple-dose oral administration (25 mg/kg; compared to the 1st day). Interestingly, biologically active TFL metabolites such as aromadendrin and luteolin were putatively found in plasma samples, although they were previously detected only in feces. In addition, oil-in-water and water-in-oil microemulsions were fabricated to design novel drug delivery systems. These carrier dosage forms did not improve the TFL bioavailability but significantly affected its metabolism. To support pharmacokinetic studies, the bioanalytical liquid chromatography–tandem mass spectrometry method was developed and validated in the concentration range of 1–1000 ng/mL using candesartan as an internal standard. Liquid-liquid extraction with methyl tert-butyl ether was used to isolate the analytes from plasma followed by evaporation and reconstitution of the residues in acetonitrile. Thus, the present findings broaden our understanding of the TFL behavior in vivo and provide novel ideas and reference directions for its continued use in medical practice.

A Comparative Pharmacokinetic Study of Fexuprazan 10 mg: Demonstrating Bioequivalence with the Reference Formulation and Evaluating Steady State.

Fexuprazan is a potassium-competitive acid blocker approved for treating gastric-acid-related diseases. Although the effectiveness of the recent formulation fexuprazan 10 mg has been demonstrated in Phase 3 clinical trials, data on the pharmacokinetics (PKs) of administering fexuprazan 10 mg twice daily at a 12 h interval are lacking. Moreover, it is imperative to ensure the bioequivalence of the new formulation with the previously approved 40 mg formulation. This study evaluated the pharmacokinetics (PKs) of the single- and multiple-dose oral administration of fexuprazan 10 mg tablets in healthy participants (Part 1) and investigated their bioequivalence with 40 mg tablets (Part 2). Part 1 comprised a single- and multiple-dose, one-sequence, two-period design and eight participants, while Part 2 comprised a single-dose, 2 × 2 crossover design and 24 participants. In Part 1, in Periods 1 and 2, participants received single and multiple doses (twice daily) of fexuprazan 10 mg, respectively. The maximum plasma concentration (Cmax) area under the concentration-time curve from 0 to 12 h (AUC0-12h) of the multiple-dose participants was approximately double that of the single-dose participants. In Part 2, the geometric mean ratios (90% confidence intervals) for Cmax and AUC from zero to the time of the last quantifiable concentration (AUClast) of the use of four fexuprazan 10 mg tablets to those of one fexuprazan 40 mg tablet were 1.0290 (0.9352-1.1321) and 1.0290 (0.9476-1.1174), respectively, meeting the bioequivalence criteria. Favorable PKs were observed after single and multiple administrations of one fexuprazan 10 mg tablet, and four fexuprazan 10 mg tablets were pharmacokinetically equivalent to one fexuprazan 40 mg tablet.

Analysis of Complex Absorption After Multiple Dosing: Application to the Interaction Between the P-glycoprotein Substrate Talinolol and Rifampicin

PurposeIn order to clarify the effect of rifampicin on the bioavailability of the P-glycoprotein substrate talinolol, its absorption kinetics was modeled after multiple-dose oral administration of talinolol in healthy subjects.MethodsA sum of two inverse Gaussian functions was used to calculate the time course of the input rate into the systemic circulation.ResultsThe estimated rate of drug entry into the systemic circulation revealed two distinct peaks at 1 and 3.5 h after administration. Rifampicin did not affect bioavailability of talinolol, but did shift the second peak of the input function by 1.3 h to later times. Elimination clearance and one of the intercompartmental distribution clearances increased significantly under rifampicin treatment.ConclusionsRifampicin changes the time course of absorption rate but not the fraction absorbed of talinolol. The model suggests the existence of two intestinal absorption windows for talinolol.

†Pharmacokinetics, Pharmacodynamics, and Safety of Bempedoic Acid in a Phase 1 Clinical Trial in Healthy Japanese, Chinese, and White subjects

Lead Author's Financial Disclosures Benny M. Amore is a current employee of Esperion Therapeutics, Inc., and may own Esperion stock and/or stock options. Study Funding Esperion Therapeutics, Inc. Background/Synopsis Bempedoic acid (BA) is an inhibitor of ATP-citrate lyase that significantly lowers LDL-C levels, after single and multiple oral dose administration. Objective/Purpose To investigate the pharmacokinetics (PK), pharmacodynamics (PD), and safety of BA, in White and first-, second-, or third-generation Japanese and Chinese subjects living in the US. Methods This double-blind, placebo-controlled study was conducted at a single US site in a total of 40 healthy subjects randomized (3:1) to receive BA or placebo. The PK, PD, and safety of BA were assessed in Japanese subjects after a single dose of BA 60, 120, or 180mg; and in Japanese, Chinese, and White subjects (baseline LDL-C 70−190 mg/dL; not receiving a statin) after daily BA 180mg dosing for 14 days. Results Enrolled subjects (28% female) ranged 23 - 59 years of age. In Japanese subjects, single dose maximum BA plasma concentrations increased proportionally, and AUC increased slightly greater than proportional to dose. After 14 days of BA 180mg, mean estimates of BA elimination half-life were 25.2, 20.0 and 23.9 hours in Japanese, Chinese, and White subjects, respectively. Active metabolite ESP15228 AUC exposures were approximately 20% of BA across subjects. Mean oral clearance (CL/F) in Japanese (0.494 L/h) and Chinese (0.592 L/h) subjects was 29% and 15% less and volume of distribution (Vz/F) in Japanese (18.0 L) and Chinese (19.2 L) subjects was 32% and 27% less than in White subjects, respectively. Differences in CL/F and Vz/F were decreased after body weight (BW) normalization, with higher mean BW for White subjects (80.6 kg) observed relative to Japanese (67.4 kg) and Chinese (74.1 kg) subjects. A reduction in fasting LDL-C, non-HDL-C, and hsCRP was observed with BA. The mean (SD) percent change from baseline in LDL-C among subjects (n=6 each) receiving BA 180 mg was −29% (14) for Japanese subjects, −39% (8) for Chinese subjects, and −17% (28) for White subjects compared with +17% (21) for subjects receiving placebo. Conclusions Results from this study suggest that administration of BA 180mg once daily over 14 days markedly reduced LDL-C and was well tolerated in all subjects. PK differences, largely explained after normalizing CL/F and Vz/F by subject BW, are not expected to result in clinically meaningful differences in the efficacy or safety profiles of BA. Benny M. Amore is a current employee of Esperion Therapeutics, Inc., and may own Esperion stock and/or stock options.

Controlling drug release by introducing lipase inhibitor within a lipid formulation

Drug overdose connected to marketed pharmaceutical products, particularly opioids, occurs at an alarming rate. Novel strategies through innovative formulation approaches that reduce the likelihood of overdose while allowing safe therapeutic outcomes are urgently required. The current study provides a proof-of-concept for a new formulation approach by co-formulating drug with a lipase inhibitor within a solid lipid formulation in order to prevent or reduce the harmful effects of taking multiple doses of an oral solid dose form. Lipase inhibitor controlled-release (LICR) formulations were created using a simple hot melt method to co-formulate the inhibitor (orlistat) and ibuprofen, as the model drug, within the lipid matrix. The digestion and drug release kinetics were determined using an in vitro lipolysis model. Above a threshold level of orlistat there was decreased digestibility of multiple doses of the LICR formulations, leading to reduced drug release. Upon administration of the formulations in capsules to rats, the LICR formulation displayed the lowest exposure of ibuprofen during the pharmacokinetic studies. This novel formulation approach shows promise in preventing accidental drug overdose after oral administration of multiple doses of formulation.

Pharmacokinetics, Safety, and Synovial Fluid Concentrations of Single- and Multiple-Dose Oral Administration of 1 and 3 mg/kg Cannabidiol in Horses

Cannabidiol (CBD) products are widely marketed to horse owners, trainers, and veterinarians and are readily available to the consumer despite minimal pharmacokinetic or safety data being available. The objectives of this study were to determine the plasma pharmacokinetics, short-term safety, and synovial fluid levels of CBD following oral administration in horses. A prospective, randomized, controlled study design was used. Twelve horses were administered sunflower lecithin oil-based CBD at either 1 mg/kg (Group 1) or 3 mg/kg (Group 2) for a 24-hour pharmacokinetic study. Horses then received 0.5 mg/kg (Group 1) or 1.5 mg/kg (Group 2) CBD q12 PO for 6 weeks, with steady state and elimination sampling performed up to 96 hours post-final dose. Synovial fluid CBD concentrations were evaluated at 12 and 24 hours, and 5 weeks. Horses were monitored daily and clinicopathologic parameters were evaluated. Mean ± SD Cmax and tmax were 4.3 ± 2.1 ng/ml and 4.1 ± 4.1 hours, and 19.9 ± 15.6 ng/ml and 5.0 ± 3.7 hours for Groups 1 and 2, respectively. CBD was detectable in synovial fluid in 8/12 horses during steady state. Mild hypocalcemia was seen in all horses and elevated liver enzymes were observed in 8/12 horses, but these changes improved or normalized within 10 days after the final CBD dose. CBD had dose-dependent, but variable, oral bioavailability at 1 mg/kg and 3 mg/kg daily dosing and was consistently detectable at steady state in synovial fluid at the higher dose. Further investigation is needed to establish clinically effective doses.

Abstract 9741: Pharmacokinetics, Pharmacodynamics and Safety of Bempedoic Acid in a Phase 1 Clinical Trial in Healthy Japanese, Chinese and White Subjects

This study investigated the pharmacokinetics (PK), pharmacodynamics (PD), and safety of bempedoic acid (BA), an inhibitor of ATP-citrate lyase that significantly lowers LDL-C levels, after single and multiple oral dose administration in White and first-, second-, or third-generation Japanese and Chinese subjects living in the US. This double-blind, placebo-controlled study was conducted at a single US site in a total of 40 healthy subjects randomized (3:1) to receive BA or placebo. The PK, PD, and safety of BA were assessed in Japanese subjects after a single dose of BA 60, 120, or 180 mg; and in Japanese, Chinese, and White subjects (baseline LDL-C 70–190 mg/dL; not receiving a statin) after daily BA 180-mg dosing for 14 days. Enrolled subjects (28% female) ranged 23-59 years of age. In Japanese subjects, single dose maximum BA plasma concentrations increased proportionally, and AUC increased slightly greater than proportional to dose. After 14 days of BA 180 mg, mean estimates of BA elimination half-life were 25.2, 20.0 and 23.9 hours in Japanese, Chinese, and White subjects, respectively. Active metabolite ESP15228 AUC exposures were approximately 20% of BA across subjects. Mean oral clearance (CL/F) in Japanese (0.494 L/h) and Chinese (0.592 L/h) subjects was 29% and 15% less and volume of distribution (V z /F) in Japanese (18.0 L) and Chinese (19.2 L) subjects was 32% and 27% less than in White subjects, respectively. Differences in CL/F and V z /F were decreased after body weight (BW) normalization, with higher mean BW for White subjects (80.6 kg) observed relative to Japanese (67.4 kg) and Chinese (74.1 kg) subjects. A reduction in fasting LDL-C, non-HDL-C, and hsCRP was observed with BA. The mean (SD) percent change from baseline in LDL-C among subjects (n=6 each) receiving BA 180 mg was –29% (14) for Japanese subjects, –39% (8) for Chinese subjects, and –17% (28) for White subjects compared with +17% (21) for subjects receiving placebo. Results from this study suggest that administration of BA 180 mg once daily over 14 days markedly reduced LDL-C and was well tolerated in all subjects. PK differences, largely explained after normalizing CL/F and V z /F by subject BW, are not expected to result in clinically meaningful differences in the efficacy or safety profiles of BA.

Pharmacokinetics of sarafloxacin hydrochloride in the pacific white shrimp, Litopenaeus vannamei, following multiple-dose oral administration

The present study was designed to explore the pharmacokinetics and tissue distribution levels of sarafloxacin hydrochloride in the pacific white shrimp, Litopenaeus vannamei, after oral administration of multiple doses (30 mg/kg, twice a day for 5 days). Eighteen shrimps per sampling point were examined during and after treatment. Sarafloxacin hydrochloride concentrations in the hemolymph, hepatopancreas, and muscle of the pacific white shrimp were determined using HPLC. Pharmacokinetic parameters were analyzed based on the statistical moment theory. The results showed rapid absorption of sarafloxacin hydrochloride in hepatopancreas, hemolymph, and muscles (Tmax = 2 h) after oral administration. Sarafloxacin hydrochloride peak concentration in the hemolymph, hepatopancreas, and muscle were 12.236 mg/L, 376.939 mg/kg, and 6.17 mg/kg, respectively. Tissue distribution (AUC)0-∞ followed the order hepatopancreas > hemolymph > muscle, indicating the hepatopancreas was the main organ involved in sarafloxacin hydrochloride metabolism in the pacific white shrimp. After multiple-dose oral administration, some accumulation occurred in the hepatopancreas, while in the hemolymph and muscle, sarafloxacin hydrochloride reached a steady state following multiple-dose administration. The t1/2z values of sarafloxacin hydrochloride in hemolymph, hepatopancreas, and muscle were 27.403 h, 20.456 h, and16.852 h, respectively. The values of AUCss, Ctrough, and Cav were graded as hepatopancreas > hemolymph > muscle, showing hepatopancreas played an important role in drug metabolism and elimination in shrimp. In addition, the withdrawal period of 4 days after the last oral medication was recommended based on the calculated value of WT1.4 software and the actual detected value of sarafloxacin hydrochloride in the muscle of the pacific white shrimp. When Vibrio parahaemolyticus was used as an indicator, the ratio of AUC0-t/MIC90 and Cmax/MIC90 were 101.15 and 12.24, respectively.

A Method to Custom-build Equations of Drug Concentration as a Function of Real Time in the One-Compartment Open Model and Their Application in Multiple Intravenous Bolus and Multiple Oral Doses

A method to custom-build expressions of drug concentration as a function of total time in a one-compartment pharmacokinetic model for multiple-dose schedules is developed and successfully applied in four dosing schedules that combined administration of multiple IV bolus and oral maintenance and loading doses. The method consists of writing the terms of the mathematical sequence from the analytical solutions to drug concentration using total time, instead of time within dosing interval, extracting the pattern of the respective sequences, and finally, determining the partial sums of the series that relate to drug concentration to dose number and real-time, for each particular administration route and dosing schedule. Multiple subroutines written in Fortran language demonstrated the potential of these equations to investigate the effect of dose size on peak plasma drug concentration and peak time after multiple oral administrations and for calculating and refining experimentally determined time-dependent pharmacokinetic parameters such as non steady-state average concentration values and Area Under the Curve (AUC). It is shown that the only truly independent of dose size peak time is that of the first oral dose (). A mathematical expression was derived that relates the time to reach non steady-state peak times after multiple oral doses to the absorption and elimination rate constants for the first time. For repetitive oral dose administration, the will always be the longest peak time, while the shortest time to reach maximum plasma drug concentration will be at steady-state conditions.

Case Reports: Safety, Tolerability, and Efficacy of 5-Aminolevulinic Acid Phosphate, an Inducer of Heme Oxygenase 1, in Combination with Sodium Ferrous Citrate for the Treatment of COVID-19 Patients

Background: The COVID-19 pandemic is the greatest life-threatening disaster currently facing the worldwide population. COVID-19 patients with concomitant diseases such as chronic obstructive pulmonary disease and cardiovascular problems quickly develop severe pneumonia with low arterial oxygen saturation and multiorgan failure, resulting in sudden death. These symptoms are caused by deadly inflammation that occurs in various organs. Objective: Various types of inflammation caused by RNA virus infection have been known to be manageable by the induction of heme oxygenase-1 (HO-1) in local tissues. HO-1 is also known to be a key enzyme for the suppression of RNA viral replication. Therefore, in addition to standard medical care for pneumonic viral infection, we have attempted to treat COVID-19 patients with a highly effective HO-1 inducer, 5-aminolevulinic acid phosphate, in combination with ferrous sodium citrate (5-ALA with SFC). Methods: 5-ALA with SFC is a supplement formulation registered in Japan as food with functional claims. Six patients with typical symptoms of COVID-19 and some suspected COPD associated with heavy smoking were given oral administration of multiple doses of 5-ALA with SFC at the Maximum Tolerated Dose (MTD) for 3 to 7 days, followed by treatment with a lower amount of 5-ALA with SFC for 2 to 3 weeks. Results and Conclusion: Each patient's recovery time was considerably shorter than reported for patients who received only standard care for SARS-CoV-2 infection. The results confirm the safety, tolerability, and efficacy of 5-ALA with SFC as a therapeutic supplement for patients with acute-phase COVID-19.

MM-013 Phase 2, Multicenter Study of Pomalidomide (POM) Plus Low-Dose Dexamethasone (LoDEX) in Patients (pts) with Relapsed/Refractory Multiple Myeloma (RRMM) and Renal Impairment (RI): Pharmacokinetics (PK) Analysis

MM-013 Phase 2, Multicenter Study of Pomalidomide (POM) Plus Low-Dose Dexamethasone (LoDEX) in Patients (pts) with Relapsed/Refractory Multiple Myeloma (RRMM) and Renal Impairment (RI): Pharmacokinetics (PK) Analysis

Pharmacokinetics of mycophenolate mofetil following single-dose intravenous and single- and multiple-dose oral administration and clinicopathologic effects of mycophenolate mofetil following long-term oral administration in healthy horses.

To characterize the pharmacokinetics of mycophenolate mofetil (MMF) following single-dose IV or PO administration, characterize the pharmacokinetics of MMF following long-term PO administration, and describe the clinicopathologic effects of long-term MMF administration in horses. 12 healthy adult horses. In phase 1, 6 horses received a single IV (2.5 mg/kg) or PO (5 mg/kg) dose of MMF in a randomized balanced crossover assessment (≥ 2-week interval between administrations). In phase 2, 6 other horses received MMF for 60 days (5 mg/kg, PO, q 24 h for 30 days and then 5 mg/kg, PO, q 48 h for an additional 30 days). Following IV (single-dose) or PO (single- or multiple-dose) administration, MMF was rapidly converted to mycophenolic acid. For single-dose PO administration, mean ± SD maximum plasma mycophenolic acid concentration was 1,778.3 ± 441.5 ng/mL at 0.71 ± 0.29 hours. For single-dose IV administration, mean systemic clearance and volume of distribution at steady state were 0.689 ± 0.194 L/h/kg and 1.57 ± 0.626 L/kg, respectively. Following single doses, mean terminal half-life was 3.99 ± 0.865 hours for IV administration and 4.02 ± 1.01 hours for PO administration. The accumulation index following long-term PO administration was 1.0 ± 0.002, and the terminal half-life was 4.59 ± 1.25 hours following the final dose on day 60. None of the horses developed abnormal clinical signs or had any consistently abnormal clinicopathologic findings. Further investigation of the clinical efficacy of long-term MMF treatment of horses with autoimmune diseases is warranted.

Tolerability, Pharmacokinetic, and Pharmacodynamic Profiles of Henagliflozin, a Novel Selective Inhibitor of Sodium-Glucose Cotransporter 2, in Healthy Subjects Following Single- and Multiple-dose Administration

BackgroundHenagliflozin, a novel selective inhibitor of sodium–glucose cotransporter 2, is under development as a treatment for type 2 diabetes mellitus. PurposeTo evaluate the tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of henagliflozin in healthy Chinese volunteers. MethodsTwo clinical studies were conducted. One was a single ascending dose (SAD) study (2.5–200 mg) involving 80 healthy subjects, and the other was a multiple ascending dose (MAD) study (1.25–100 mg for 10 days) involving 48 healthy subjects. The tolerability, PK profiles of henagliflozin and its main metabolites, and the urinary glucose excretion over 24 h were characterized in these 2 studies. FindingsNo serious adverse events were observed in the healthy subjects after single- and multiple-dose oral administration of henagliflozin, suggesting that this drug was well tolerated. Henagliflozin was rapidly absorbed, with a Tmax of 1.5–3 h, and then eliminated from plasma with a half-life of 11–15 h. It was not accumulated following once-daily oral administration. Plasma exposure of henagliflozin exhibited dose-proportional PK properties over the dose ranges of 2.5–200 mg (SAD) and 1.25–100 mg (MAD). The excretion of henagliflozin in urine was found to be very low, with 3.00%–5.13% of the dose. The glucuronide metabolites M5-1, M5-2 and M5-3 were the main metabolites detected in plasma samples, which accounted for up to 54.3%, 19.8%, and 27.5%, respectively, of the parent drug at steady state. Both the SAD and MAD studies demonstrated that the urinary glucose excretion over 24 h was dose-dependently increased and displayed saturation kinetics at >25 mg. No significant changes in the levels of serum glucose and urine electrolytes were found following a single or multiple doses of henagliflozin administration. ImplicationsHenagliflozin was well tolerated and showed predictable PK/PD profiles in these healthy subjects. Henagliflozin did not affect blood glucose level or urinary electrolyte excretion. It is best characterized for once-daily administration with a maximum dose of 25 mg. ChinaDrugTrials.org.cn identifiers: CTR20131986 and CTR20140132.

Pharmacokinetics of doxycycline after oral administration of multiple doses in dogs.

The aim of this study was to determine the pharmacokinetic parameters of doxycycline in dogs and assess the efficacy of an oral drug dosage regimen of 10mg/kg daily for 28days through Pharmacokinetic/Pharmacodynamic (PK/PD) target analysis based on Monte Carlo simulation, using previously published data for the zoonotic pathogen Staphylococcus pseudintermedius. After a multiple-dosage regimen, the accumulation index was 1.88±0.82. The Cmaxss and Cminss values were 5.18±1.81µg/ml and 1.91±1.35µg/ml, respectively. There were statistically significant differences for Cmax, Cmin at 24hr, MRTt, AUCt and AUC∞ between days 1 and 28. The Cminss value was over the MIC of the principal pathogens, and Cmaxss was higher than the resistance values (>2μg/ml). For AUC/MIC indices of 12, 25 and 40, the cumulative fraction responses (CFR) were 94.01%, 69.55% and 60.86%, respectively; for an MIC value of 2µg/ml, the corresponding probability of target attainment (PTA) was 99.94%, 84.78% and 45.16%, respectively. Doxycycline was used against numerous localized infections in different organs and tissues. For the strains with MIC<1μg/mL, PTA was close to 100%, even for the most demanding ones, specifically 94.98% for an index of 40% and 99.9% for an index of 25.