Multiple Administration Study Research Articles

Pharmacokinetics of Single and Multiple Oral Administration of a Self-emulsifying Formulation of Highly Purified Eicosapentaenoic Acid Ethyl Ester (MND-2119) Compared With the Nonself-emulsifying Formulation in Healthy Male Subjects.

MND-2119 is a self-emulsifying formulation of highly purified eicosapentaenoic acid ethyl ester (EPA-E) designed to be administered once daily due to improved absorption compared with the nonself-emulsifying formulation. In these studies, MND-2119 was administered to healthy adult males in single or multiple doses. In the single administration study, MND-2119 (0.5-4g) was administered under fed and fasted conditions to evaluate MND-2119 pharmacokinetics and safety under these conditions. This study showed that Cmax and AUC0-72h of plasma EPA concentration after single administration were higher under fed conditions than under fasted conditions, for all doses. In the multiple administration study, subjects received either MND-2119 (0.5-4g) immediately after breakfast or EPA-E (0.9g) immediately after breakfast and dinner for 11days to compare pharmacokinetics and safety of MND-2119 to EPA-E. In this study, the rate of rise in Cmin of the plasma EPA concentration with MND-2119 decreased from days 6 to 8 after administration and was thought to have reached a steady state on day 11. The mean Css,max of MND-2119 administered as 1g once daily, and the mean Css,min and the mean AUCss,0-24h of MND-2119 administered as 2g once daily were higher than those of EPA-E administered as 0.9g twice daily. No safety-related issues occurred in either study. These results suggest that MND-2119 administered once daily may achieve equivalent or higher plasma EPA concentrations compared to the nonself-emulsifying formulation administered twice daily.

Extensive preclinical evaluation of an infliximab biosimilar candidate

Infliximab is therapeutic monoclonal antibody (mAb) against TNF-α employed in the treatment of immunoinflammatory diseases. The development of biosimilar mAbs is a global strategy to increase drug accessibility and reduce therapy-associated costs. Herein we compared key physicochemical characteristics and biological activities produced by infliximab and infliximab-Probiomed in order to identify functionally relevant differences between the mAbs. Binding of infliximab-Probiomed to TNF-α was specific and had kinetics comparable to that of the reference product. Both mAbs had highly similar neutralizing efficacy in HUVEC cell cultures stimulated with TNF-α. In vitro induction of CDC and ADCC were also similar between the evaluated products. In vivo comparability was assessed using a transgenic mouse model of arthritis that expresses human TNF-α in a 13-week multiple-administration study. Infliximab and infliximab-Probiomed showed comparable efficacy, safety, and pharmacokinetic profiles. Our results indicate that infliximab-Probiomed has highly similar activities to infliximab in preclinical models, warranting a clinical evaluation of its biosimilarity.

In vivo use of the CYP inhibitor 1-aminobenzotriazole to increase long-term exposure in mice.

1-Aminobenzotriazole (ABT) is a well-known in vivo nonspecific inhibitor of cytochrome P450 (CYP) enzymes. An effective dosing regimen of ABT for a multiple-administration study is needed to conduct pharmacological studies for proof-of-concept, although it has been established for single-administration study, to characterize the pharmacokinetics of drug candidates. This study demonstrated a suitable dosing vehicle of ABT for continuous administration and increased exposure to antipyrine, which is a nonspecific probe of CYP, using ABT for a long period in mice. The dosing vehicle of ABT was 0.5% (w/v) hydroxypropyl methylcellulose and 0.5% (v/v) Tween 80 in N,N-dimethylacetamide/20% hydroxypropyl-β-cyclodextrin aqueous solution (2:8, v/v) based on the duration of apparent solubility. After implantation of an ALZET osmotic pump with ABT, the plasma concentrations of ABT were maintained at more than 4.1μg/ml over 336h. Compared with the vehicle group, the CLtot of antipyrine with ABT decreased to approximately one-fourth, and the BA of antipyrine with ABT increased up to 3-fold. In addition, the enhancement of exposure of antipyrine by ABT was maintained over the 336h. The body weight, food consumption and hematological parameters of mice did not change with ABT administration for 16days. These findings demonstrated that pretreatment of ABT can increase long-term exposure using continuous administration with the ALZET osmotic pump in mice with no overt toxicity. It is concluded that the in vivo use of 1-aminobenzotriazole can be applied to pharmacological studies for proof-of-concept, thus contributing to the selection of drug candidates at an early drug discovery stage. Copyright © 2016 John Wiley & Sons, Ltd.

Antihyperglycemic Activity of Bacosine, a Triterpene fromBacopa monnieri, in Alloxan-Induced Diabetic Rats

This article describes the antihyperglycemic activity, in vivo antioxidant potential, effect on hemoglobin glycosylation, estimation of liver glycogen content, and in vitro peripheral glucose utilization of bacosine, a triterpene isolated from the ethyl acetate fraction (EAF) of the ethanolic extract of Bacopa monnieri. Bacosine produced a significant decrease in the blood glucose level when compared with the diabetic control rats both in the single administration as well as in the multiple administration study. It was observed that the compound reversed the weight loss of the diabetic rats, returning the values to near normal. Bacosine also prevented elevation of glycosylated hemoglobin in vitro with an IC₅₀ value of 7.44 µg/mL, comparable with the one for the reference drug α-tocopherol. Administration of bacosine and glibenclamide significantly decreased the levels of malondialdehyde (MDA), and increased the levels of reduced glutathione (GSH) and the activities of superoxide dismutase (SOD) and catalase (CAT) in the liver of diabetic rats. Bacosine increased glycogen content in the liver of diabetic rats and peripheral glucose utilization in the diaphragm of diabetic rats in vitro, which is comparable with the action of insulin. Thus, bacosine might have insulin-like activity and its antihyperglycemic effect might be due to an increase in peripheral glucose consumption as well as protection against oxidative damage in alloxanized diabetes.

Design of Nateglinide Controlled Release Tablet Containing Erosion Matrix Tablet and Multiple Administration Study in Normal Beagle Dogs

We designed a single unit type tablet formulation containing nateglinide to decrease both postprandial blood glucose level (PBG) and fasting blood glucose level (FBG) in normal beagle dogs. The tablet was a dry coated tablet comprising both a core tablet (an erosion matrix tablet: a controlled release portion(nateglinide: 90 mg)) and an outer shell (an immediate release portion (nateglinide: 60 mg)). The weight, the diameter and the hardness of the obtained tablet were 416.1 mg, 10 mmpsi, about 60 N, respectively. The dissolution study of the obtained tablet in pH 1.2 or 6.8 showed that the nateglinide in the immediate release portion dissolved in almost 30 min., and that 30 min after the dissolution test started, the nateglinide in the controlled release portion had dissolved slowly. An in vivo single oral administration study using normal beagle dogs showed the bioavailability value of the obtained nateglinide dry coated tablets against nateglinide immediate release tablets was 73.6%, although the value of nateglinide controlled release tablets containing enteric coated granules was 57.2-60.8%. An in vivo multiple oral administration study (b.i.d. (interval: 12 h), 8 d) using normal beagle dogs showed the reproducibility of nateglinide absorption. In addition, decreases in both PBG and FBG were observed. The ability to decrease the blood glucose level did not weaken during a multiple administration. On the basis of the above results, a controlled release formulation containing a short-acting type oral blood glucose regulator, not only nateglinide but meglitinides (repaglinide, mitiglinide, etc.) was suggested to enable control of both PBG and FBG for moderate and severe diabetes patients.

Novel oral insulin delivery systems based on complexation polymer hydrogels: Single and multiple administration studies in type 1 and 2 diabetic rats

Insulin-loaded polymer microparticles (ILP) composed of crosslinked poly(methacrylic acid) and poly(ethylene glycol) are multi-functional carriers showing high insulin incorporation efficiency, a rapid insulin release in the intestine based on their pH-dependent complexation properties, enzyme-inhibiting effects and mucoadhesive characteristics. Thus, they are potential carriers for insulin delivery via an oral route. Recent studies suggest that the polymer composition and particle size of ILP strongly influenced insulin bioavailability. Therefore, the present study aimed at finding an optimal formulation and designing carriers for oral insulin delivery using in vivo experiments. Various types of ILPs were prepared and administered orally to healthy and type 1 and 2 diabetic rats. The most promising formulation was subsequently used for in vivo multiple oral administration studies using diabetic rats. The microparticles of diameters of < 53 μm (SS-ILP) composed of a 1 : 1 molar ratio of methacrylic acid / ethylene glycol units showed the most pronounced hypoglycaemic effects following oral administration to healthy rats, achieving a 9.5% pharmacological availability compared to subcutaneous insulin injection. Their usefulness was also confirmed with both type 1 and 2 diabetic rat groups. In a multiple administration study, SS-ILP significantly suppressed the postprandial rise in blood glucose and showed continuous hypoglycaemic effects following 3 times/day oral administration to both diabetic rat groups in the presence of foods. These results indicate that the blood glucose levels of diabetic rats can be effectively controlled by oral SS-ILP administration, and thus SS-ILP would be a promising delivery carrier of insulin via the oral route.

Searching for new markers of endogenous steroid administration in athletes: “looking outside the metabolic box”

A simple means of detecting the abuse of steroids that also occur naturally is a problem facing doping control laboratories. Specific markers are required to allow the detection of the administration of these steroids. These markers are commonly measured using a set of data obtained from the screening of samples by gas chromatography–mass spectrometry (GC–MS). Doping control laboratories further need to confirm identified abuse using techniques such as gas chromatography–combustion–isotope ratio mass spectrometry (GC–C–IRMS). An interesting urinary species was found while following the pharmacokinetics and changes to the steroid profile from single and multiple oral doses of the International Olympic Committee/World Anti Doping Agency (IOC/WADA) prohibited substance, dehydroepiandrosterone (DHEA). The urine samples collected from the administration studies were subject to GC–MS and GC–C–IRMS steroid analysis following cleanup by solid phase extraction techniques. A useful urinary product of DHEA administration was detected in the urine samples from each of the administration studies and was identified by GC–MS experiments to be 3α,5-cyclo-5α-androstan-6β-ol-17-one (3α,5-cyclo). This compound occurs naturally but the concentrations of 3α,5-cyclo were elevated following both the single DHEA administration (up to 385 ng/mL) and multiple DHEA administrations (up to 1240 ng/mL), in relation to those observed prior to these administrations (70 and 80 ng/mL, respectively). A reference distribution of urine samples collected from elite athletes ( n=632) enabled the natural concentration range of 3α,5-cyclo to be established (0–280 ng/mL), with a mean concentration of 22 ng/mL. Based on this an upper 3α,5-cyclo concentration limit of 140 ng/mL is proposed as a GC–MS screening marker of DHEA abuse in athletes. GC–C–IRMS analysis revealed significant 13C depletion of 3α,5-cyclo following DHEA administration. In the single administration study, the δ 13C value of 3α,5-cyclo changed from −24.3‰ to a minimum value of −31.1‰ at 9 h post-administration, before returning to its original value after 48 h. The multiple administration study had a minimum δ 13C 3α,5-cyclo of −33.9‰ during the administration phase in contrast to the initial value of −24.2‰. Preliminary studies have shown 3α,5-cyclo to most likely be produced from DHEA sulfate found at high levels in urine. The complementary use of GC–MS and GC–C–IRMS to identify new markers of steroid abuse and the application of screening criteria incorporating such markers could also be adapted by doping control laboratories to detect metabolites of androstenedione, testosterone and dihydrotestosterone abuse.

In vivo effects of highly purified docosahexaenoic acid on rectal insulin absorption

The purpose of this study was to evaluate the effectiveness and the toxicity of polyunsaturated fatty acid, such as oleic acid, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), as a potential absorption enhancer for rectal delivery of insulin, using a water-in-oil-in-water (W/O/W) multiple emulsion. In a single administration study, rectal insulin absorption was enhanced markedly, and marked hypoglycemia was induced by the emulsion incorporating various fatty acids in an insulin dose-related fashion. The pharmacological availability of the emulsion incorporating 2% oleic acid, EPA and DHA was ≈7.7, 11.0 and 25.4%, respectively. The insulin absorption enhancement effect was not increased in proportion to the amount of DHA in the emulsion at >1%. In addition, by incorporating Pluronic F 127 (PF 127) into the emulsion, the mean T max value of the serum glucose–time curve could be extended to twice that of the emulsion without PF 127. In a multiple administration study, the mean AUC glucose values of the emulsion incorporating DHA showed almost the same value on the first and the tenth day. From the morphological appearance of the mucosal surface, the emulsion incorporating DHA induced no or little mucosal damage. Our findings demonstrated that DHA has a strong insulin permeability enhancement effect and little toxicity. Thus, DHA is an attractive candidate as an absorption enhancer for intestinal delivery of insulin.

Phase I Clinical Studies of S-1108: Safety and Pharmacokinetics in a Multiple-Administration Study with Special Emphasis on the Influence on Carnitine Body Stores

Phase I Clinical Studies of S-1108: Safety and Pharmacokinetics in a Multiple-Administration Study with Special Emphasis on the Influence on Carnitine Body Stores

新しい抗不整脈薬ｐｉｒｍｅｎｏｌの薬物動態および心室期外収縮抑制効果

The pharmacokinetics of pirmenol hydrochloride (pirmenol), a new antiarrhythmic agent, and its suppressive effects on ventricular premature contractions (VPC) were studied in 16 patients following single oral administration of 75mg, 100mg, and 150mg of the drug. In 8 of 16 patients, suppressive effects on VPC were also studied following multiple oral administration of pirmenol of 75mg b. i. d. or 100mg b. i. d. Blood samples were drawn before and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 and 48hr after single oral administration. In the multiple oral administration study, blood samples were collected before and 2hr after morning dose during the treatment period. Plasma and urine drug concentration were measured using high performance liquid chromatography (HPLC). Plasma protein binding of pirmenol was determined by an ultrafiltration method. A 48-hr continuous ECG and standard 12-lead ECGs were recorded to assess the effects of pirmenol on VPC and ECG parameters.The Cmax and AUC after single administration were 0.799μg/ml & 9.23μg·hr/ml in 75mg group (n=6), 0.784μg/ml & 11.23μg·hr/ml in 100mg group (n=6) and 1.156μg/ml & 15.70μg·hr/ml in 150mg group (n=4), respectively. The Cmax and AUC increased in a dose-dependent manner. The Tmax, t1/2 β, urinary excretion rate and protein binding rate were independent of the dosage. The Cmax and Cmin at the steady state during multiple administration were 1.149 & 0.235μg/ml in 75mg b. i. d. group (n=2) and 1.472 & 0.598μg/ml in 100mg b. i, d, group (n=6). Suppressive effects of pirmenol on VPC were observed in 5 out of 12 patients with more than 3, 000VPC/day in the single administration study and also in 3 out of 4 patients in the multiple administration study. The minimum effective plasma concentration of pirmenol was 0.361±0.133μg/ml. The PQ & QT interval and QTc were prolonged significantly after single and multiple administration. Serious adverse events were not observed in any patients during the study.We conclude that pirmenol is a useful antiarrhythmic agent for the treatment on VPC, and that 100mg b. i, d, is safe and suitable for chronic management of the patients with frequent VPC.

NEPHROTOXICITY OF CEFPIROME SULFATE IN RABBITS : Single and Multiple Intravenous Administration

Nephrotoxic potential of cefpirome sulfate (CPR) was examined by single and multiple intravenous administrations to Japanese white male rabbits. In single administration studies, no nephrotoxic symptoms were observed at the dose level of 320 mg/kg of CPR or less. At the dose level of 500 mg/kg or more, nephrotoxic findings were noted in both CPR and cefazolin sodium(CEZ) groups, such as proteinuria, glucosuria, increase in serum level of urea nitrogen, creatinine and uric acid, and necrosis and calcification in the proximal tubular epithelium of kidney. Renal phenolsulfonphthalein(PSP) excretion was suppressed at the dose level of 500 mg/kg of CPR or more, and 2000 mg/kg of CEZ. In 14 and 21 days repeated administration studies, no nephrotoxic symptoms were observed at the dose level of 100 mg/kg of CPR and CEZ or less. At the dose level of 200 mg/kg of CPR or more, urinary and serum biochemical findings mentioned above were observed, and histopathological changes in the kidney described above were added in 400 mg/kg group. The similar nephrotoxic symptoms including histopathological changes of the kidney were observed in the groups of 100 mg/kg of cefaloridine(CER) and 200 mg/kg of CEZ. In addition, renal PSP excretion was suppressed in the group of 200 mg/kg of CEZ. The results would suggest that CPR is less nephrotoxic than CER and that the nephrotoxic potential of CPR is comparable to CEZ because CPR caused more severe renal failures in single administration study and less severe renal failures in multiple administration study than CEZ.