Kinetic analysis of sequential metabolism of triazolam and its extrapolation to humans using an entero-hepatic two-organ microphysiological system

Lab on a Chip ◽  
2020 ◽  
Vol 20 (3) ◽  
pp. 537-547
Author(s):  
Hiroshi Arakawa ◽  
Shinji Sugiura ◽  
Takumi Kawanishi ◽  
Kazumi Shin ◽  
Hiroko Toyoda ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Kinetic Analysis ◽  
Pharmacokinetic Model ◽  
Concentration Profiles ◽  
Kinetic Information ◽  
System P ◽  
Sequential Metabolism

We have constructed a mechanism-based pharmacokinetic model for triazolam and its metabolites in the entero-hepatic two-organ MPS, and extrapolated the kinetic information obtained with the MPS to the plasma concentration profiles in humans.

CC-486 (Oral Azacitidine) Following Allogeneic Hematopoietic Stem Cell Transplantation (AlloHSCT) in Patients with Myelodysplastic Syndromes (MDS) or Acute Myeloid Leukemia (AML)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 990-990 ◽  
Author(s):  
Basem M. William ◽  
Marcos de Lima ◽  
Betul Oran ◽  
Richard Champlin ◽  
Esperanza B Papadopoulos ◽  
...  
Keyword(s):  
Stem Cell ◽  
Plasma Concentration ◽  
Febrile Neutropenia ◽  
Research Funding ◽  
Concentration Profiles ◽  
Employment Equity ◽  
Hematopoietic Stem ◽  
Post Transplant ◽  
Equity Ownership ◽  
Concomitant Medications

Abstract Background: Disease relapse and graft vs host disease (GvHD) following alloHSCT are major causes of treatment (Tx) failure in patients (pts) with MDS and AML (Paietta, 2012). Studies of parenteral azacitidine, an epigenetic modifier, have shown efficacy in preventing post-transplant relapse in MDS and AML pts, and possibly reducing GvHD severity (Platzbecker, 2012; de Lima, 2010). Azacitidine maintenance after alloHSCT may enhance graft vs leukemia (GvL) effects and reduce GvHD by expansion of regulatory T cells (Goodyear, 2010, 2012). CC-486 is a novel oral formulation of azacitidine which, as well as potentially allowing easier administration over extended schedules, could increase the duration of drug exposure to residual malignant cells. We now report preliminary results from a prospective phase I/II dose-finding study of CC-486 as maintenance Tx after alloHSCT in pts with MDS or AML. Objective: To evaluate the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics (PK), and safety outcomes of CC-486 following alloHSCT in pts with MDS or AML. Methods: Pts with WHO-defined MDS or AML who have undergone alloHSCT with myeloablative (MAC) or reduced-intensity conditioning (RIC) regimens and who had sibling or unrelated donors with ≤1 antigen mismatch at the HLA-A, -B, -C, -DRB1 or -DQB1 locus, are enrolled. CC-486 Tx is initiated between days (d) 42 and 84 after alloHSCT. Pts receive prophylactic Tx for GvHD and infections per institutional standard. A standard 3x3 MTD design is being used to evaluate 4 dosing schedules: CC-486 200 mg or 300 mg QD, administered for 7 d (Cohorts 1 and 2) or 14 d (Cohorts 3 and 4) of repeated 28d Tx cycles. MTD determination is based on DLT that occur during the first 2 Tx cycles (pts are not evaluable if unable to complete 2 Tx cycles for reasons other than a DLT). Adverse events (AEs) are graded using NCI-CTCAE v4.0. Pts are followed for safety, incidence of acute and chronic GvHD, and relapse. PK of azacitidine after CC-486 administration, alone or with standard concomitant medications, are evaluated on d 1 of CC-486 Tx cycles 1 and 2. Results: At data cut-off (7/17/2014), outcome data were available for 7 pts enrolled in the first 2 cohorts (Table): 1 pt had IPSS Int-2 MDS and 6 had AML with high-risk features. Stem cell source was from bone marrow (n=2) or peripheral blood (n=5) from unrelated (n=5) or sibling (n=2) donors. Two pts had 1 antigen mismatch and 5 had a full match.Conditioning included MAC (n=3) and RIC (n=4) regimens. One pt in Cohort 2 was not evaluable for DLT or PK assessments due to early discontinuation (AML relapse) during the first CC-486 Tx cycle. Of the 6 evaluable pts, 4 completed ≥6 CC-486 Tx cycles and 2 ongoing pts had not reached 6 cycles on-study at data cut-off (Table). One pt who had GvHD before CC-486 Tx subsequently withdrew from the study after developing febrile neutropenia and diarrhea related to GvHD of the bowel; 1 pt withdrew for personal reasons; and 1 pt discontinued after 6 Tx cycles due to relapse. At data cut-off, 3 pts remained on-study, all with continued CR (Table). No pt in Cohort 2 developed GvHD. For all pts, most AEs were grade 1-2. Grade 3-4 AEs were reported for 2 pts: both had nausea and vomiting, which were controlled with antiemetic agents upon onset; 1 also had device-related infection and dyspnea, and 1 also had febrile neutropenia and rash. No DLT emerged with these CC-486 regimens and no pt experienced secondary graft failure. Overall azacitidine plasma concentration profiles (Figure) and PK parameters were similar following CC-486 given alone or with concomitant medications, and were within range of values observed following similar CC-486 doses in pts with MDS, CMML, and AML (Garcia-Manero, 2011). The AUC range for oral CC-486 is ~10% of that seen with subcutaneous azacitidine administered at 75 mg/m2 (Garcia-Manero, 2011). Conclusion: Preliminary data from this analysis suggest that CC-486 administered at doses of 200 or 300 mg QD for 7 days every 4 weeks is safe and well tolerated in the post-transplant setting. Overall, azacitidine plasma concentration profiles and PK parameters were not affected by use of concomitant medications. No DLT and a low rate of GvHD support the ongoing evaluation of 14d extended CC-486 dosing regimens in this ongoing study, as a preliminary to a prospective, randomized trial of this new agent post-transplant. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures de Lima: Celgene: Consultancy. Champlin:Celgene: Consultancy. Giralt:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Scott:Celgene: Consultancy, Honoraria, Research Funding. Hetzer:Celgene: Employment, Equity Ownership. Wang:Celgene: Employment, Equity Ownership. Laille:Celgene: Employment, Equity Ownership. Skikne:Celgene: Employment, Equity Ownership. Craddock:Celgene: Honoraria, Research Funding.

Plasma concentration profiles of ketamine and norketamine after administration of various ketamine preparations to healthy Japanese volunteers

2002 ◽  
Vol 24 (1) ◽  
pp. 37-43 ◽  
Author(s):  
Yoshitsugu Yanagihara ◽  
Michiteru Ohtani ◽  
Satoru Kariya ◽  
Katsuyoshi Uchino ◽  
Teiko Hiraishi ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Concentration Profiles

scholarly journals The ‘anomalous’ absorption of labelled and unlabelled vitamin C in man

2005 ◽  
Vol 93 (5) ◽  
pp. 627-632 ◽  
Author(s):  
Leslie J. C. Bluck ◽  
Kerry S. Jones ◽  
W. Andy Coward ◽  
Christopher J. Bates
Keyword(s):  
Plasma Concentration ◽  
Stable Isotope ◽  
Vitamin C ◽  
Experimental Results ◽  
Concentration Profiles ◽  
Model Structure ◽  
Limited Information ◽  
Anomalous Absorption ◽  
Plasma Model ◽  
Isotope Measurement

Previous studies of vitamin C absorption in man using stable isotope probes have given results which cannot easily be reconciled with those obtained using non-isotope measurement. In order to investigate some of the apparent paradoxes we have conducted a study using two consecutive doses of vitamin C, one labelled and one unlabelled, given 90 min apart. Compatibility of the experimental results with two feasible models was investigated. In Model 1, ingested vitamin C enters a pre-existing pool before absorption, which occurs only when a threshold is exceeded; in Model 2, ingested vitamin C is exchanged with a pre-existing flux before absorption. The key difference between these two models lies in the predicted profile of labelled material in plasma. Model 1 predicts that the second unlabelled dose will produce a secondary release of labelled vitamin C which will not be observed on the basis of Model 2. In all subjects Model 1 failed to predict the observed plasma concentration profiles for labelled and unlabelled vitamin C, but Model 2 fitted the experimental observations. We speculate on possible physiological explanations for this behaviour, but from the limited information available cannot unequivocally confirm the model structure by identifying the source of the supposed flux.

scholarly journals A Three-Compartment Pharmacokinetic Model to Predict the Interstitial Concentration of Talaporfin Sodium in the Myocardium for Photodynamic Therapy: A Method Combining Measured Fluorescence and Analysis of the Compartmental Origin of the Fluorescence

2018 ◽  
Vol 6 (1) ◽  
pp. 1
Author(s):  
Yuko Uno ◽  
Emiyu Ogawa ◽  
Eitaro Aiyoshi ◽  
Tsunenori Arai
Keyword(s):  
Photodynamic Therapy ◽  
Plasma Concentration ◽  
Rate Constants ◽  
Pharmacokinetic Model ◽  
Interstitial Space ◽  
Differential Rate ◽  
Talaporfin Sodium ◽  
Interstitial Concentration ◽  
Sodium Plasma ◽  
Canine Myocardium

To evaluate the effectiveness of photodynamic therapy occurring in the interstitial space of the myocardium, we estimated the interstitial concentration of talaporfin sodium in the canine myocardium by constructing a three-compartment pharmacokinetic model based on measured changes in talaporfin sodium plasma concentration and myocardial fluorescence. Differential rate equations of talaporfin sodium concentration in the plasma, interstitial space, and cell compartment were developed with individual compartment volume, concentration, and rate constants. Using measured volume ratios based on histological examinations, we defined that the myocardial fluorescence consisted of the linear addition of fluorescence generated from these three compartments. The rate constants were obtained by fitting to minimize the sum of the squared errors between the measured talaporfin sodium concentrations and the calculated concentrations divided by the number of data points using the conjugate gradient method in MATLAB. We confirmed that this fitting operation may be appropriate, because a coefficient of determination between the measured talaporfin sodium changes and the calculated concentrations using our equations was 0.99. Consequently, to estimate the interstitial concentration in the canine myocardium, we propose a three-compartment pharmacokinetic model construction methodology using measured changes in talaporfin sodium plasma concentration and changes in myocardial fluorescence.

Bifidobacterium breve MCC1274 with glycosidic activity enhances in vivo isoflavone bioavailability

2019 ◽  
Vol 10 (5) ◽  
pp. 521-531 ◽  
Author(s):  
R. Yao ◽  
C.B. Wong ◽  
K. Nakamura ◽  
E. Mitsuyama ◽  
A. Tanaka ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Gut Microbiota ◽  
Oral Administration ◽  
Kinetic Analysis ◽  
Intestinal Absorption ◽  
Relative Abundance ◽  
Intestinal Metabolism ◽  
Control Groups ◽  
Bifidobacterium Breve

Polyphenols are plant derived compounds that exert many beneficial health effects to the human host. However, associated health benefits of dietary polyphenol are highly dependent on their intestinal metabolism, bioavailability, and absorption. Bifidobacteria, which represent the key members of gut microbiota, have been suggested to promote gut microbial homeostasis and may be involved in the metabolism of polyphenols. In this study, the capabilities of thirteen Bifidobacterium strains in hydrolysing polyphenol glycosides were evaluated. Among the tested strains, Bifidobacterium breve MCC1274 was found to possess the highest β-glucosidase activity and strong capability to convert daidzin and trans-polydatin to their aglycones; while kinetic analysis revealed that B. breve MCC1274 hydrolysed more than 50% of daidzin and trans-polydatin at less than 3 h of incubation. Further investigation using rats with an antibiotics-disturbed microbiome revealed that following the ingestion of daidzin glycoside, oral administration of B. breve MCC1274 significantly enhanced the plasma concentration of daidzein in rats pre-treated with antibiotics as compared to antibiotics-pre-treated control and non-treated control groups. The relative abundance of Actinobacteria and the total numbers of B. breve were also significantly higher in antibiotics-pre-treated rats administered with B. breve MCC1274 than that of the control groups. These findings suggest that B. breve MCC1274 is effective in enhancing the bioavailability of daidzein in the gut under dysbiosis conditions and may potentially improve intestinal absorption of isoflavones and promote human health.

scholarly journals Pharmacokinetics of Epinastine and a Possible Mechanism for Double Peaks in Oral Plasma Concentration Profiles.

2001 ◽  
Vol 24 (7) ◽  
pp. 790-794 ◽  
Author(s):  
Taro OGISO ◽  
Masafusa KASUTANI ◽  
Hiroaki TANAKA ◽  
Masahiro IWAKI ◽  
Tadatoshi TANINO
Keyword(s):  
Plasma Concentration ◽  
Concentration Profiles ◽  
Double Peaks

scholarly journals The Administration of Flumethasone, by Three Different Routes, its Measurement in the Plasma and Some Effects on Wool Growth in Merino Wethers

1978 ◽  
Vol 31 (6) ◽  
pp. 601 ◽  
Author(s):  
BA Panaretto ◽  
ALC Wallace
Keyword(s):  
Plasma Concentration ◽  
Equilibrium Concentration ◽  
Metabolic Clearance ◽  
Concentration Profiles ◽  
Clearance Rates ◽  
Wool Growth ◽  
Concentration Patterns

Flumethasone was given to Merino wethers weighing 30-50 kg at rates of 0�62-1� 35 mg/kgO'7 5 by intravenous (experiments 1 and 2), intraruminal (experiment 4) and subcutaneous (experiment 5) routes over 8 days. In experiment 3, 1� 2 mgflumethasone/kg'"?" was given intravenously over 4, 5 or 6 days. The plasma concentration profiles showed concentrations in the order: intravenous > subcutaneous > intraruminal. Plasma concentration patterns usually were highest during the first 48 h of infusion followed by relatively stable values. This last feature was not evident in experiments when the rate of hormone infusion was increased. Estimates of the metabolic clearance rates for flumethasone in experiments 1, 2 and 5 were 200-700 ml/min during the' equilibrium concentration periods.

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