Maximum Serum Concentration Research Articles

Effects of quercetin on pharmacokinetics of cefprozil in Chinese-Han male volunteers

1. The primary objective of this study was to evaluate the effects of quercetin on the pharmacokinetics of cefprozil. The secondary objective was to evaluate the safety of the combined use of cefprozil and quercetin.2. An open-label, two-period, crossover phase I trial among 24 Han Chinese male subjects was conducted. Participants were given 500 mg of quercetin orally once daily for 15 d followed by single dose of cefprozil (500 mg) on day 15. Serum concentrations of cefprozil were then measured in all participants on day 15. A 15-d washout period was then assigned after which a 500 mg dose of cefprozil was administered and measured in the serum on day 36.3. All subjects completed the trial, and no serious adverse events were reported. We measured mean serum concentrations of cefprozil in the presence and absence of quercetin in all participants. The maximum serum concentration of cefprozil in the presence of quercetin was 8.18 ug/ml (95% CI: 7.55–8.81) versus a maximum cefprozil concentration of 8.35 ug/ml (95% CI: 7.51–9.19) in the absence of quercetin. We conclude that the concurrent use of quercetin has no substantial effect on serum concentrations of orally administered cefprozil.4. Co-administration of quercetin showed no statistically significant effects on the pharmacokinetics of cefprozil in healthy Chinese subjects.

One Against All: A Broadly Influenza Neutralizing Man-made Monoclonal Antibody Passes Phase I

One Against All: A Broadly Influenza Neutralizing Man-made Monoclonal Antibody Passes Phase I

Comparable long-term efficacy, as assessed by patient-reported outcomes, safety and pharmacokinetics, of CT-P13 and reference infliximab in patients with ankylosing spondylitis: 54-week results from the randomized, parallel-group PLANETAS study.

BackgroundCT-P13 (Remsima®, Inflectra®) is a biosimilar of the infliximab reference product (RP; Remicade®) and is approved in Europe and elsewhere, mostly for the same indications as RP. The aim of this study was to compare the 54-week efficacy, immunogenicity, pharmacokinetics (PK) and safety of CT-P13 with RP in patients with ankylosing spondylitis (AS), with a focus on patient-reported outcomes (PROs).MethodsThis was a multinational, double-blind, parallel-group study in patients with active AS. Participants were randomized (1:1) to receive CT-P13 (5 mg/kg) or RP (5 mg/kg) at weeks 0, 2, 6 and then every 8 weeks up to week 54. To assess responses, standardized assessment tools were used with an intention-to-treat analysis of observed data. Anti-drug antibodies (ADAs), PK parameters, and safety outcomes were also assessed.ResultsOf 250 randomized patients (n = 125 per group), 210 (84.0 %) completed 54 weeks of treatment, with similar completion rates between groups. At week 54, Assessment of Spondylo Arthritis international Society (ASAS)20 response, ASAS40 response and ASAS partial remission were comparable between treatment groups. Changes from baseline in PROs such as mean Bath Ankylosing Spondylitis Disease Activity Index (BASDAI; CT-P13 −3.1 versus RP −2.8), Bath Ankylosing Spondylitis Functional Index (BASFI; −2.9 versus –2.7), and Short Form Health Survey (SF-36) scores (9.26 versus 10.13 for physical component summary; 7.30 versus 6.54 for mental component summary) were similar between treatment groups. At 54 weeks, 19.5 % and 23.0 % of patients receiving CT-P13 and RP, respectively, had ADAs. All observed PK parameters of CT-P13 and RP, including maximum and minimum serum concentrations, were similar through 54 weeks. The influence of ADAs on PK was similar in the two treatment groups. Most adverse events were mild or moderate in severity. There was no notable difference between treatment groups in the incidence of adverse events, serious adverse events, infections and infusion-related reactions.ConclusionsCT-P13 and RP have highly comparable efficacy (including PROs) and PK up to week 54. Over a 1-year period, CT-P13 was well tolerated and displayed a safety profile comparable to RP; no differences in immunogenicity were observed.Trial registrationClinicalTrials.gov identifier: NCT01220518. Registered 4 October 2010.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-0930-4) contains supplementary material, which is available to authorized users.

Serum and milk concentrations of enrofloxacin in cows intramammarily treated with a new enrofloxacin-polymorph

The success rate in treatment against Staphylococcus aureus mastitis with antibacterial drugs is marginal. Low antibacterial drug concentrations in the mammary tissue is part of the reason for this failure. Enrofloxacin has only been administered on few occasions through the intramammary route i.e., combined with gentamicin in an undisclosed vehicle or dose. A new solvate form of enrofloxacin (enrofloxacin hydrochloride-dihydrate [enro-C]) prepared as 1.5% suspension pH 5.5 was tested in a field mastitis outbreak due to coagulase-negative S. aureus (CNS) in F1 (Holstein/Zebu) cows aged 5-8 years destined to be culled. Enro-C was administered intramammarily daily (300 mg/infected quarter) for 8 days both to healthy and mastitic cows; milk and serum enro-C concentrations were determined on days 1 and 8. Maximum serum concentration (CMAX) values were similar in both groups (9.4 to 10.7 µg/mL). The area under the moment curve (AUMC) for enrofloxacin increased only by 11% in healthy cows and by 10% in infected cows from day 1 to day 8, a fact that suggests little accumulation with this dose regime. Peak concentrations in milk ranged from 18.5 to 19.8 µg/mL on day 1 and from 20.2 to 22 µg/mL on day 8. Cure rates on day 21 after treatment were 75% (12 out of 16 cows) or 69.4% (26 out of 36 glands). Somatic cell counts and California mastitis test showed a positive trend in cured animals. Uniquely high milk enrofloxacin and ciprofloxacin concentrations were obtained after intramammary administration of enro-C. These concentrations seem effective for treating CNS mastitis. The feasibility of incorporating this experimental pharmaceutical preparation of enrofloxacin is discussed.

Cure of tuberculosis despite serum concentrations of antituberculosis drugs below published reference ranges.

Therapeutic target serum concentrations of first-line antituberculosis drugs have not been well defined in clinical studies in tuberculosis (TB) patients. We retrospectively investigated the estimated maximum serum concentrations (eC max) of antituberculosis drugs and clinical outcome of TB patients with therapeutic drug monitoring performed between 2010-2012 at our institution, and follow-up until March 2014. The eC max was defined as the highest serum concentration during a sampling period (2, 4 and 6 hours after drug ingestion). We compared the results with published eC max values, and categorised them as either "within reference range", "low eC max", or "very low eC max".Low/very low eC max-levels were defined as follows: isoniazid 2-3/<2 mg/l, rifampicin 4-8/<4 mg/l, rifabutin 0.2-0.3/<0.2 mg/l, ethambutol 1-2/<0.1 mg/l and pyrazinamide <20 mg/l. Concentrations of antituberculosis drugs in 175 serum samples of 17 patients with TB were analysed. In 12 (71%) patients, multiple therapeutic drug monitoring samples were collected over time, in 5 (29%) patients only one sample was available for therapeutic drug monitoring. Overall, 94% of all patients had at least one low antituberculosis drug concentration. Overall, 64% of all eC max levels were classified as "low" or "very low". The eC max was below the relevant reference range in 80% of isoniazid, 95% of rifampicin, 30% of pyrazinamide, and 30% of ethambutol measurements. All but one patient were cured of tuberculosis. Although many antituberculosis drug serum concentrations were below the widely used reference ranges, 16 of 17 patients were cured of tuberculosis. These results challenge the use of the published reference ranges for therapeutic drug monitoring.

An exploratory analysis of the ability of a cefepime trough concentration greater than 22 mg/L to predict neurotoxicity.

Cefepime trough concentrations >22 mg/L (T(>22)) have been associated with neurotoxicity in a single study. Neurotoxicity outcomes for 28 cefepime-treated adult patients with febrile neutropenia were abstracted from the literature. The precision of T(>22) to predict neurotoxicity was quantified using 95% confidence intervals. Thirty-two cefepime-treated patients contributed serum concentrations for a pharmacokinetic model, fit using the Nonparametric Adaptive Grid algorithm within the Pmetrics package for R. Concentration-time curves were simulated for common dosing schemes and 3 renal dispositions. Probabilities of neurotoxicity and numbers needed to harm were calculated from simulations according to the proposed pharmacokinetic/toxicodynamic threshold of T(>22). Bayesian modeling was utilized to explore other pharmacokinetic parameters relationships with neurotoxicity. The mean probability of neurotoxicity at T(>22) was 51.4% (95% CI: 16.4-85.0%). Among the schemes and renal dispositions simulated, the combination of cefepime 2 g every 8 h and a creatinine clearance of 60 mL/min produced the greatest probability of neurotoxicity (48.3%). Estimated numbers needed to harm according to T(>22) ranged from 2.1 to 18.5 persons. Explorations of maximal serum concentration and area under the curve demonstrated high levels of collinearity, making it impossible to identify trough concentrations as the driver of neurotoxicity. T(>22) had low precision as a predictive neurotoxic threshold. When a neurotoxic threshold of T(>22) was assumed, projected neurotoxicity rates and numbers needed to harm greatly exceeded observed neurotoxicity rates in the general population and in high risk subpopulations. Other drug exposure metrics should be explored.

Pharmacokinetics and lung and muscle concentrations of tulathromycin following subcutaneous administration in white-tailed deer (Odocoileus virginianus).

Respiratory tract infections are common in farmed North American white-tailed deer (Odocoileus virginianus). Tulathromycin is approved for use in cattle but not deer but is often employed to treat deer. The pharmacokinetic properties and lung and muscle concentrations of tulathromycin in white-tailed deer were investigated. Tulathromycin was administered to 10 deer, and then, serum, lung, and muscle tulathromycin concentrations were measured using liquid chromatography-mass spectrometry (LC-MS). The mean maximal serum tulathromycin concentration in deer was 359 ng/mL at 1.3 h postinjection. The mean area under the serum concentration-time curve, apparent volume of distribution, apparent clearance, and half-life was 4883 ng·h/mL, 208 L/kg, 0.5 L/h/kg, and 281 h (11.7 days), respectively. The maximal tulathromycin concentration in lung and muscle homogenate from a single animal was 4657 ng/g (14 days) and 2264 ng/g (7 days), respectively. The minimum concentrations in lung and muscle were 39.4 ng/g (56 days) and 9.1 ng/g (56 days), respectively. Based on similarity in maximal serum concentrations between deer and cattle and high lung concentrations in deer, we suggest the recommended cattle dosage is effective in deer. Tissue concentrations persisted for 56 days, suggesting a need for longer withdrawal times in deer than cattle. Further tissue distribution and depletion studies are necessary to understand tulathromycin persistence in deer tissue; clinical efficacy studies are needed to confirm the appropriate dosage regimen in deer.

Comparative pharmacokinetics of cefoperazone following intravenous and intramuscular administration in goats

The pharmacokinetic profile of cefoperazone was studied in goats following intravenous and intramuscular administration of 20mg/kg body weight. Cefoperazone concentrations in serum were determined by microbiological assay technique using Escherichia coli (ATCC 10536) as test organism. Following i.v. administration, the cefoperazone serum concentration–time curve was best fitted in a two compartment open model. Cefoperazone has moderate distribution in the body of goats with Vdss of 0.44±0.03L/kg. The elimination half-life (T0.5(β)), area under curve (AUC) and total body clearance (Cltot) were 1.97±0.14h, 149.63±8.61μgml−1h−1, and 2.17ml/min/kg, respectively. Following i.m. administration, the drug was very rapidly absorbed, with an absorption half-life (T0.5(ab)) of 0.12±0.01h. The maximum serum concentration (Cmax) of 30.42±3.53μgml−1 was attained at (Tmax) 0.58±0.02h, with an elimination half-life (T0.5(el)) of 2.53±0.11h. The systemic bioavailability of cefoperazone in the goats after i.m. administration was 83.62% and in vitro protein binding was 20.34%. The serum concentrations of cefoperazone along 12h post i.m. injection in this study were exceeding the MIC of different susceptible micro-organisms responsible for serious disease problems. Consequently, a suitable intramuscular dosage regimen for cefoperazone was 20mg/kg repeated at 12h intervals in goats. The drug was detected in urine up to 12 and 18h following i.v. and i.m. administration, respectively.

Bactericidal effects of various concentrations of enrofloxacin, florfenicol, tilmicosin phosphate, and tulathromycin on clinical isolates of Mannheimia haemolytica.

To determine bactericidal effects of enrofloxacin, florfenicol, tilmicosin, and tulathromycin on clinical isolates of Mannheimia haemolytica at various bacterial densities and drug concentrations. 4 unique isolates of M haemolytica recovered from clinically infected cattle. Minimum inhibitory concentration (MIC) and mutant prevention concentration (MPC) were determined for each drug and isolate. Mannheimia haemolytica suspensions (10(6) to 10(9) CFUs/mL) were exposed to the determined MIC and MPC and preestablished maximum serum and tissue concentrations of each drug. Log10 reduction in viable cells (percentage of cells killed) was measured at various points. Bacterial killing at the MIC was slow and incomplete. After 2 hours of isolate exposure to the MPC and maximum serum and tissue concentrations of the tested drugs, 91% to almost 100% cell killing was achieved with enrofloxacin, compared with 8% growth to 93% cell killing with florfenicol, 199% growth to 63% cell killing with tilmicosin, and 128% growth to 43% cell killing with tulathromycin over the range of inoculum tested. For all drugs, killing of viable organisms was evident at all bacterial densities tested; however, killing was more substantial at the MPC and maximum serum and tissue drug concentrations than at the MIC and increased with duration of drug exposure. Rank order of drugs by killing potency was enrofloxacin, florfenicol, tilmicosin, and tulathromycin. Findings suggested that antimicrobial doses that equaled or exceeded the MPC provided rapid killing of M haemolytica by the tested drugs, decreasing opportunities for antimicrobial-resistant subpopulations of bacteria to develop during drug exposure.

Pharmacokinetics of hydrocodone and tramadol administered for control of postoperative pain in dogs following tibial plateau leveling osteotomy

To evaluate the pharmacokinetics of hydrocodone (delivered in combination with acetaminophen) and tramadol in dogs undergoing tibial plateau leveling osteotomy (TPLO). 50 client-owned dogs. Dogs were randomly assigned to receive tramadol hydrochloride (5 to 7 mg/kg, PO, q 8 h; tramadol group) or hydrocodone bitartrate-acetaminophen (0.5 to 0.6 mg of hydrocodone/kg, PO, q 8 h; hydrocodone group) following TPLO with standard anesthetic and surgical protocols. Blood samples were collected for pharmacokinetic analysis of study drugs and their metabolites over an 8-hour period beginning after the second dose of the study medication. The terminal half-life, maximum serum concentration, and time to maximum serum concentration for tramadol following naïve pooled modeling were 1.56 hours, 155.6 ng/mL, and 3.90 hours, respectively. Serum concentrations of the tramadol metabolite O-desmethyltramadol (M1) were low. For hydrocodone, maximum serum concentration determined by naïve pooled modeling was 7.90 ng/mL, and time to maximum serum concentration was 3.47 hours. The terminal half-life for hydrocodone was 15.85 hours, but was likely influenced by delayed drug absorption in some dogs and may not have been a robust estimate. Serum concentrations of hydromorphone were low. The pharmacokinetics of tramadol and metabolites were similar to those in previous studies. Serum tramadol concentrations varied widely, and concentrations of the active M1 metabolite were low. Metabolism of hydrocodone to hydromorphone in dogs was poor. Further study is warranted to assess variables that affect metabolism and efficacy of these drugs in dogs.

In vivo pharmacological evaluation of a lactose-conjugated luteinizing hormone releasing hormone analogue

In the current study, the efficacy and pharmacokinetic profile of lactose-conjugated luteinizing hormone releasing hormone (LHRH) was examined following oral administration in male rats. A rapid and sensitive liquid chromatography/mass spectrometry technique was developed and applied for measuring the concentration of lactose[Q1][w6]LHRH (compound 1) in rat plasma in order to allow measurement of pharmacokinetic parameters. LH release was evaluated using a sandwich ELISA. Maximum serum concentration (Cmax=0.11μg/ml) was reached at 2h (Tmax) following oral administration of the compound at 10mg/kg. The half-life was determined to be 2.6h. The absolute bioavailability of the orally administered compound was found to be 14%, which was a remarkable improvement compared to zero-to-low oral bioavailability of the native peptide. Compound 1 was effective in stimulating LH release at 20mg/kg after oral administration. The method was validated at a linear range of 0.01–20.0μg/ml and a correlation coefficient of r2≥0.999. The accuracy and precision values showed the reliability and reproducibility of the method for evaluation of the pharmacokinetic parameters. These findings showed that the lactose derivative of LHRH has a therapeutic potential to be further developed as an orally active therapeutics for the treatment of hormone-dependent diseases.

COMPARATIVE STUDY OF PHARMACOKINETICS OF OFLOXACIN IN A FREE AND NIOSOMAL FORMS IN EXPERIMENTS ON WHITE MICE WHEN ADMINISTERED Per Os

Aim: to study features of pharmacokinetics of ofloxacin as a part of anion PEGylated niosomes on a basis of sorbitan monostearate (Span 60) to experimental white mice per os. Materials and methods: ofloxacin was entrapped in niosomes consisting of Span 60, cholesterol, PEG 4000 and dicetylphosphate. Sizes of niosomes estimated by means of probe microscopy. Efficiency of inclusion of an antibiotic in niosomes defined after removal of free drug by a centrifugation. The analysis of the quantitative contents of ofloxacin in samples carried out a method of a high performance liquid chromatography. Results: we studied the main pharmacokinetic parameters of ofloxacin when used free and niosomal forms of antibiotic to experimental white mice per os. It is shown that use of oral niosomal forms leads to decrease of maximal concentration in serum and increase of ofloxacin half-life by 7,4 times in average compared to the free form. It is determined that bioavailability of ofloxacin in the niosomal form is 154% relative to the free form of the antibiotic. Conclusions: niosomal microcontainers are perspective technology of encapsulation and the directed transport of antibacterial preparations through biological barriers. Using of niosomal formulation of ofloxacin is able to afford to increase considerably efficiency of treatment in comparison with a free form and significantly decrease negative effects of antibiotic therapy.

Amino Acid Mixture Enriched With Arginine, Alanine, and Phenylalanine Stimulates Fat Metabolism During Exercise.

Although there have been many investigations of the beneficial effects of both exercise and amino acids (AAs), little is known about their combined effects on the single-dose ingestion of AAs for lipid metabolism during exercise. We hypothesize that taking a specific combination of AAs implicated in glucagon secretion during exercise may increase fat metabolism. We recently developed a new mixture, d-AA mixture (D-mix), that contains arginine, alanine, and phenylalanine to investigate fat oxidation. In a double-blind, placebo-controlled crossover study, 10 healthy male volunteers were randomized to ingest either D-mix (3 g/dose) or placebo. Subjects in each condition subsequently performed a physical task that included workload trials on a cycle ergometer at 50% of maximal oxygen consumption for 1 hr. After oral intake of D-mix, maximum serum concentrations of glycerol (9.32 ± 6.29 mg/L and 5.22 ± 2.22 mg/L, respectively; p = .028), free fatty acid level (0.77 ± 0.26 mEq/L and 0.63 ± 0.28 mEq/L, respectively; p = .022), and acetoacetic acid levels (37.9 ± 17.7 μmol/L and 30.3 ± 13.9 μmol/L, respectively; p = .040) were significantly higher than in the placebo groups. The area under the curve for glucagon during recovery was numerically higher than placebo (6.61 ± 1.33 μg/L · min and 6.06 ± 1.23 μg/L · min, respectively; p = .099). These results suggest that preexercise ingestion of D-mix may stimulate fat metabolism. Combined with exercise, the administration of AA mixtures could prove to be a useful nutritional strategy to maximize fat metabolism.

Abstract 2536: Assessing combinations of FDA approved chemotherapy in malignant peripheral nerve sheath tumor (MPNST) cell lines

Abstract Background: Malignant Peripheral Neural Sheath Tumors (MPNST) are a type of sarcoma that arise spontaneously from a peripheral nerve or plexiform neurofibroma. Approximately 1 in 10 people with a constitutional mutation in the NF1 gene, a negative regulator of RAS function, develop MPNST with a peak incidence in the adolescent and young adult years. Available chemotherapy treatment for MPNST has low response rates, and the prognosis for unresectable or metastatic tumors is poor. A clinically relevant system to rapidly evaluate the efficacy of many agents and combinations of agents on MPNSTs which can be translated into clinical trials is needed. Methods: Here, we seek to identify promising single drug and combination therapies using FDA approved and other agents of interest via high-throughput screening platforms, based on established MPNST cell line models (SNF02.2, SNF10.1, SNF94.3, and SNF96.2). Taking into consideration past lessons learned from in vitro experiments, we designed stringent screening conditions that assess the candidate compounds and combinations at clinically-relevant concentrations and exposure times that mimic the in vivo pharmacokinetics in an effort to maximize the translational potential of these results. Fifty-four agents with roughly ¼ inhibitors of the RAS downstream pathways, another ¼ kinase inhibitors, and the remainder a representation of many classes of agents with diverse mechanisms of action were screened across 4 cell lines with biological replicates. The majority of the agents are FDA approved. Others are in active clinical trials, demonstrate a promising mechanism of action, or have published preclinical data in MPNST models. CellTiter Glo assays were used to assess cell viability at the maximal achievable serum concentration from phase I studies and at two lower concentrations. Promising agents were then studied in two-drug combinations to evaluate for synergy in addition to efficacy of the combination. The combinations were selected with careful attention to known drug-drug interactions, metabolism, schedule and non-overlapping toxicities. Results: Our screening results indicate that a number of FDA approved chemotherapy agents, evaluated at clinically relevant concentrations and exposure times, significantly reduced cell viability across all cell lines tested. These findings suggest promising opportunities for developing combination clinical trials. Citation Format: Elliott Kahen, Diana Yu, Christopher Cubitt, Dan Sullivan, Damon R. Reed. Assessing combinations of FDA approved chemotherapy in malignant peripheral nerve sheath tumor (MPNST) cell lines. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2536. doi:10.1158/1538-7445.AM2015-2536

Linezolid extracorporeal removal during haemodialysis with high cut-off membrane in critically ill patients

Continuous venovenous haemodialysis with high cut-off membrane (HCO-CVVHD) is often used in critically ill septic patients with acute kidney injury (AKI) to sustain renal function and to remove circulating inflammatory mediators. The aim of this study was to analyse the extracorporeal removal of linezolid and related alterations in pharmacokinetic/pharmacodynamic (PK/PD) parameters during HCO-CVVHD. Three critically ill septic patients with AKI, treated with linezolid and HCO-CVVHD, were prospectively observed. To calculate the extracorporeal clearance of linezolid and the PK parameters, effluent, pre-filter and post-filter samples were contemporaneously collected before linezolid infusion, just after 1-h infusion (maximum serum concentration; Cmax), at 3h and 6h after dosing, and before the next dose (trough serum concentration; Cmin). Linezolid Cmax and Cmin (pre-filter) ranged from 10.4–23.5mg/L and from 2.9–10.3mg/L. The dialysate saturation coefficient was 0.66–0.85 and the extracorporeal clearance with a diffusive dose of 35mL/kg/h ranged from 2.1–2.5L/h. Total linezolid clearance was between 1.7L/h and 6.3L/h. The total area under the plasma concentration–time curve (AUC0–∞) ranged from 95.1mgh/L to 352.9mgh/L, in accordance with the different clinical conditions. AUCfree/MIC ratios were always <85 for an MIC of 4.0mg/L, and two of three patients did not reach the optimal PK/PD target of ≥85 even when using an MIC of 2.0mg/L. Although extracorporeal clearance may affect linezolid total clearance, the clinical features of critically ill septic patients appear to be mainly responsible for the high variability of linezolid serum concentrations.

Pharmacokinetics of Ferrous Sulphate (Tardyferon®) after Single Oral Dose Administration in Women with Iron Deficiency Anaemia.

Iron-containing preparations available on the market vary in dosage, salt, and chemical state of iron contained in the preparation, as well as in the iron delivery process (immediate or prolonged-release). The present study aimed at characterizing the serum pharmacokinetics of iron in non pregnant women with iron deficiency anaemia (IDA) following a single oral administration of a prolonged-release ferrous sulphate tablet. This multicenter, single dose, open-label study was conducted in 30 women aged between 18 and 45 years with IDA. A single 160 mg oral dose of ferrous sulphate was given as 2 tablets of 80 mg of Tardyferon(®) under fasting conditions. Blood samples were collected before dosing and until 24 h post-dosing. Serum iron concentrations were determined using a routine colorimetric analytical method. Pharmacokinetic parameters were determined from the serum concentration profiles using a non compartmental approach. Serum profiles showed elevated levels of iron up to 12 h after drug intake. The median time to maximum serum concentrations (Tmax) occurred 4 h post-dosing. Between 2 and 8 h post-dosing, mean serum iron concentrations fluctuated by only 20%. Additionally, C8h and C12h represented on average 78.6% and 47.5% of the Cmax, respectively. This study demonstrates that a single oral dose of 160 mg Tardyferon(®) administered under fasting condition to 30 women with IDA leads to an optimal long-lasting release of iron in the gastrointestinal tract in the targeted population. This allows the attainment and maintenance of elevated serum iron levels for up to 12 h after administration.

Pharmacokinetics, Safety and Tolerability of Melissa officinalis Extract which Contained Rosmarinic Acid in Healthy Individuals: A Randomized Controlled Trial

The aim of this study was to evaluate the safety, tolerability and pharmacokinetics of single dose of Melissa officinalis extract which contained rosmarinic acid, including food-effects in healthy individuals. A total of eleven healthy individuals were randomly assigned to treatment arms in the two studies [Study 1 (fasted state) and Study 2 (fed state)]. Rosmarinic acid in serum was measured by a coulometric detection method using High-Performance Liquid Chromatography electrochemical detector. The serum concentration of total rosmarinic acid peaked at 1 hour after administration of Melissa officinalis extract containing 500mg rosmarinic acid in fasted state, with a maximum serum concentration 162.20 nmol/ L. The area under the curve for intact rosmarinic acid was calculated from the serum concentration-time profile to be 832.13 nmol • hour/ L. Food intake increases area under the curve and delayed time at which the maximum serum concentration. Rosmarinic acid supplementation did not affect liver, kidney, or blood cell function parameters. No adverse event was reported by any of the participants due to the study treatment. Single dose of Melissa officinalis extract containing 500 mg rosmarinic acid appears to be safe and tolerable in healthy individuals. Food intake increased the exposure of rosmarinic acid and delayed absorption of rosmarinic acid in healthy individuals.Trial RegistrationTrial Registration: UMIN-CTR UMIN000004997

Relative Bioavailability of Orally Administered Fosphenytoin Sodium Injection Compared with Phenytoin Sodium Injection in Healthy Volunteers

To describe the pharmacokinetics of fosphenytoin (FPHT) sodium injection when administered orally, and to determine the relative oral bioavailability (FREL ) of FPHT sodium injection compared with PHT sodium injection based on pharmacokinetic modeling in healthy volunteers. Open-label, randomized, single-dose, two-period, two-sequence crossover study. University-affiliated clinical research center funded by the National Center of Research Resources. Ten healthy adult volunteers. Subjects were randomized to receive a single oral dose of either PHT sodium injection or FPHT sodium injection at a dose equivalent to 400mg PHT acid. Blood samples were collected at baseline (just prior to administration) and at 0.5, 1, 2, 4, 6, 12, 24, 48, and 72hours after dose administration. After a 7-14-day washout period, the subjects underwent the same study procedures for administration of the other agent (PHT or FPHT). The mean age and weight of the 10 subjects were 37years and 72.5kg, respectively, and the mean dose was 5.6mg/kg based on PHT acid equivalence. The mean FREL of FPHT was 1.21 (95% confidence interval [CI] 1.07-1.35). Serum PHT concentrations were determined by fluorescence polarization immunoassay. The median (range) maximum serum concentration (Cmax ) values were significantly higher after FPHT administration compared with PHT: 10.7 (9.0-19.4) mg/L versus 5.0 (3.2-8.9) mg/L (p=0.002). The PHT concentration after oral administration of FPHT displayed faster absorption compared with PHT, with a median (range) time to reach Cmax of 1.0 (0.5-2.0) hours versus 6.0 (2.0-24.0) hours (p=0.008). All subjects completed the study without any serious adverse events reported. FPHT sodium injection given orally was absorbed more rapidly and to a significantly greater extent than PHT sodium injection given orally to healthy volunteers. Further evaluation of oral FPHT as an alternative in patients requiring enteral feedings is warranted.

Pharmacokinetics and bioavailability of a therapeutic enzyme (idursulfase) in cynomolgus monkeys after intrathecal and intravenous administration.

Intravenous enzyme replacement therapy with iduronate-2-sulfatase is an approved treatment for Hunter syndrome, however, conventional intravenous delivery cannot treat the neurologic manifestations of the disease due to its limited central nervous system penetration. Intrathecal administration of iduronate-2-sulfatase for delivery to the central nervous system is currently under investigation. The objective of this study was to evaluate the pharmacokinetics of idursulfase in the central nervous system of cynomolgus monkeys (Macaca fasicularis) after intravenous and intrathecal administration. Twenty-seven monkeys, treatment-naïve to enzyme replacement therapy, were placed into 4 groups according to body weight: Group 1 was administered 0.5 mg/kg idursulfase intravenously, Groups 2–4 were administered an intrathecal formulation (1-, 10-, and 30-mg doses). Blood samples and cerebrospinal fluid (sampled at the cisterna magna or lumbar level) were collected at the same time points for 72 hours post dosing. Following intravenous administration, a high maximum serum concentration and rapid distribution of iduronate-2-sulfatase out of the central compartment were observed (elimination half-life: 4.3 hours). Iduronate-2-sulfatase exposure in the cerebrospinal fluid was limited, suggesting intravenous administration provided minimal penetration of the blood–brain barrier. Following intrathecal administration, a high maximum observed concentration was immediately noted and elimination half-life ranged between 7.8–10 hours and 5.9–6.7 hours (cisterna magna and lumbar sampling, respectively). Cerebrospinal fluid pharmacokinetic profiles at different doses of iduronate-2-sulfatase were similar and the dose/exposure relationship was proportional. After intrathecal administration, movement of iduronate-2-sulfatase from cerebrospinal fluid to serum was observed (systemic bioavailability was 40–83%). The clear penetration of iduronate-2-sulfatase into the cerebrospinal fluid and the dose response suggest that intrathecal delivery of iduronate-2-sulfatase may be suitable for treating the central nervous system manifestations associated with Hunter syndrome.

Improved Oral Pharmacokinetics of Diclofenac Sodium from SNEDDS in Human Volunteers

The pharmacokinetics of diclofenac sodium in SNEDDS formulation and tablet were compared in healthy human volunteers. In this, randomized study with a cross over design, diclofenac sodium was administered as a single dose to subjects before food. Blood samples were obtained before dosing as a control and at 0.5, 1, 1.5, 2, 4, 8, 12 and 24 hours after dosing. The serum concentrations were determined by high performance liquid chromatography. Possible adverse events were monitored during the entire study. After log-transformation of the comparable variables, statistically significant differences were found between the two formulations with respect to the time between dosing and the appearance of the drug in serum, time to reach maximum concentration, elimination half-life, absorption rate constant and mean residence time. The extent of absorption was assessed by estimating the area under the serum concentration-time curve (AUC). AUC0-8hr and AUMC0-24hr was statistically significantly higher for diclofenac sodium (DFS) self nanoemulsifying drug delivery systems (SNEDDS) (6.428mcg.hr/ml, 218.83mcg.hr/ml) than for voveran tablet (5.869mcg.hr/ml, 52.19mcg.hr/ml). No significant differences were found in AUC0-24hr. SNEDDS of diclofenac sodium showed a statistically significant higher maximum serum concentration than voveran tablet (2.289mcg/ml and 1.375mcg/ml for SNEDDS and tablet, respectively). The results of the present study suggest that SNEDDS of diclofenac sodium could be a clinically useful rapid release formulation for immediate relief without causing gastric ulcers.