ABSTRACT
Emicizumab (ACE910) is a bispecific antibody that is a novel, subcutaneously injectable treatment for patients with hemophilia A. This study assessed the relative bioavailability of emicizumab between old and new drug products (DPs) and among 3 commonly used subcutaneous injection sites (abdomen, upper arm, and thigh), together with its absolute bioavailability in healthy volunteers. Forty-eight healthy volunteers were randomized into 4 groups to receive a single subcutaneous injection of 1 mg/kg with the old or new DP, and another 12 volunteers each received a single, 90-minute, intravenous infusion of 0.25 mg/kg with the new DP. Similar pharmacokinetic profiles were observed between the DPs, with geometric mean ratios of 1.199 (90% confidence interval [CI] 1.060-1.355) for the maximum plasma concentration and 1.083 (90% CI 0.920-1.275) for area under the plasma concentration-time curve extrapolated to infinity. The geometric mean ratios of maximum plasma concentration and area under the plasma concentration-time curve extrapolated to infinity for upper arm versus abdomen were 0.823 (90% CI 0.718-0.943) and 0.926 (90% CI 0.814-1.053), respectively, and those for thigh versus abdomen were 1.168 (90% CI 1.030-1.324) and 1.073 (90% CI 0.969-1.189), respectively. Absolute bioavailability ranged from 80.4% to 93.1%. These results suggested that no emicizumab dose adjustment would be needed when switching the DPs or injecting to different sites interchangeably and that emicizumab injected subcutaneously is highly bioavailable.
Subject(s)
Antibodies, Bispecific/administration & dosage , Antibodies, Bispecific/pharmacokinetics , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/pharmacokinetics , Adult , Biological Availability , Drug Compounding , Healthy Volunteers , Humans , Injection Site Reaction , Injections, Subcutaneous , Japan , Male , Young AdultABSTRACT
AIMS: Codrituzumab (GC33) is a recombinant, humanized mAb that binds to glypican-3 (GPC3), an oncofetal protein highly expressed in hepatocellular carcinoma (HCC). This investigation aimed to identify clinically relevant factors that may affect the overall survival (OS) in HCC patients treated with codrituzumab and to quantitatively annotate their effects. METHODS: Codrituzumab exposure was estimated by a population pharmacokinetics model with a nonlinear elimination pathway. Analysis of OS was performed using a time-to-event model in 181 patients with advanced HCC. The model was tested with the addition of various covariates, including levels of immune biomarkers, such as CD16 (measured in terms of molecules of equivalent soluble fluorophore; CD16MESF ) and CD4, codrituzumab exposure and potential prognostic biomarkers of HCC such as baseline tumour size and soluble GPC3. RESULTS: The time-to-event model estimated a prolonged OS (>3 months) in patients with codrituzumab exposure of ≥230 µg ml-1 and high CD16MESF level (>5.26 × 105 MESF at least). The Weibull model was selected as the base hazard model. The baseline tumour size was included in the hazard model as a parameter independent of the drug effect. A logistic model was applied to explain the effects of drug exposure and CD16MESF level. CONCLUSIONS: The final model indicates that adequate drug exposure plus a favourable immune environment are associated with prolonged OS. This quantitative model should be further validated with emerging data so as to guide study design in future clinical trials.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , CD4 Antigens/blood , Carcinoma, Hepatocellular/drug therapy , Glypicans/blood , Liver Neoplasms/drug therapy , Receptors, IgG/blood , Antibodies, Monoclonal, Humanized/blood , Antibodies, Monoclonal, Humanized/pharmacokinetics , Biomarkers, Tumor/blood , Carcinoma, Hepatocellular/blood , Carcinoma, Hepatocellular/mortality , Double-Blind Method , Humans , Proportional Hazards Models , Survival AnalysisABSTRACT
BACKGROUND: Emicizumab (ACE910) is a bispecific antibody mimicking the cofactor function of activated coagulation factor VIII. In phase I-I/II studies, emicizumab reduced the bleeding frequency in patients with severe hemophilia A, regardless of the presence of factor VIII inhibitors, at once-weekly subcutaneous doses of 0.3, 1, and 3 mg/kg. METHODS: Using the phase I-I/II study data, population pharmacokinetic and repeated time-to-event (RTTE) modeling were performed to quantitatively characterize the relationship between the pharmacokinetics of emicizumab and reduction in bleeding frequency. Simulations were then performed to identify the minimal exposure expected to achieve zero bleeding events for 1 year in at least 50% of patients and to select the dosing regimens to be tested in phase III studies. RESULTS: The RTTE model adequately predicted the bleeding onset over time as a function of plasma emicizumab concentration. Simulations suggested that plasma emicizumab concentrations of ≥ 45 µg/mL should result in zero bleeding events for 1 year in at least 50% of patients. This efficacious exposure provided the basis for selecting previously untested dosing regimens of 1.5 mg/kg once weekly, 3 mg/kg every 2 weeks, and 6 mg/kg every 4 weeks for phase III studies. CONCLUSIONS: A pharmacometric approach guided the phase III dose selection of emicizumab in hemophilia A, without conducting a conventional dose-finding study. Phase III studies with the selected dosing regimens are currently ongoing. This case study indicates that a pharmacometric approach can substitute for a conventional dose-finding study in rare diseases and will streamline the drug development process.
Subject(s)
Antibodies, Bispecific , Antibodies, Monoclonal, Humanized , Factor VIII , Hemophilia A/drug therapy , Hemorrhage/prevention & control , Models, Biological , Rare Diseases/drug therapy , Adolescent , Adult , Antibodies, Bispecific/administration & dosage , Antibodies, Bispecific/pharmacokinetics , Antibodies, Bispecific/therapeutic use , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/pharmacokinetics , Antibodies, Monoclonal, Humanized/therapeutic use , Dose-Response Relationship, Drug , Factor VIII/antagonists & inhibitors , Factor VIII/immunology , Humans , Male , Young AdultABSTRACT
Combination therapy of erlotinib plus bevacizumab improves progression-free survival of patients with epidermal growth factor receptor-mutated (EGFR-mutated) advanced non-small-cell lung cancer (NSCLC) compared with erlotinib alone. Although improved delivery and distribution of erlotinib to tumours as a result of the normalization of microvessels by bevacizumab is thought to be one of the underlying mechanisms, there is insufficient supporting evidence. B901L cells derived from EGFR-mutated NSCLC were subcutaneously implanted into mice, and mice were treated with bevacizumab or human IgG followed by treatment with erlotinib. The distribution of erlotinib in their tumours at different times after erlotinib administration was analysed by matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI). We also analysed the distribution of erlotinib metabolites and the distribution of erlotinib in tumours refractory to erlotinib, which were established by long-term treatment with erlotinib. We found that erlotinib was broadly diffused in the tumours from B901L-implanted xenograft mice, independently of bevacizumab treatment. We also found that erlotinib metabolites were co-localized with erlotinib and that erlotinib in erlotinib-refractory tumours was broadly distributed throughout the tumour tissue. Multivariate imaging approaches using MALDI MSI as applied in this study are of great value for pharmacokinetic studies in drug development.
Subject(s)
Bevacizumab/pharmacokinetics , Carcinoma, Non-Small-Cell Lung/genetics , ErbB Receptors/genetics , Erlotinib Hydrochloride/pharmacokinetics , Lung Neoplasms/genetics , Mutation , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization , Animals , Bevacizumab/administration & dosage , Biomarkers , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line, Tumor , Disease Models, Animal , Drug Therapy, Combination , Erlotinib Hydrochloride/administration & dosage , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Male , Mice , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/genetics , Tumor Burden , Xenograft Model Antitumor AssaysABSTRACT
Ibandronate is a drug widely used outside Japan for the treatment of osteoporosis. It is available in formulations for intermittent intravenous (i.v.) administration and for intermittent (once monthly) oral administration. Ibandronate was recently approved in Japan as an i.v. injection with a dosing regimen of 1.0 mg once a month. To establish the optimal dose for oral administration of ibandronate in Japanese osteoporotic patients, we investigated the pharmacokinetics of and pharmacodynamic response to ibandronate following oral and intravenous administrations to Japanese subjects. Ibandronate (20, 50, 100, or 150 mg) was given orally to healthy postmenopausal Japanese women and to Japanese patients with primary osteoporosis. Serial measurements were obtained for the concentrations of serum ibandronate and urinary cross-linked C-telopeptide of Type I collagen (uCTX). Pharmacokinetic parameters and the time profiles of creatinine-corrected uCTX were compared with those obtained from postmenopausal Japanese women with osteopenia after administration of 1.0 mg i.v. ibandronate. Following oral administration of ibandronate, the area under the serum ibandronate concentration-time curve (AUCinf) increased dose-proportionally for doses up to 100 mg; at 150 mg, AUCinf increased beyond the dose-proportionality seen with doses up to 100 mg. The AUCinf within the linear range following administration of 100 mg oral ibandronate was similar to that following 1.0 mg i.v. ibandronate. Additionally, corrected uCTX decreased after administration of 100 mg oral ibandronate and remained decreased for 1 month; the magnitude of the decrease was similar to or greater than that obtained after 1.0 mg i.v. ibandronate. From a clinical pharmacological perspective, administration of 100 mg/month oral ibandronate was equivalent to that of 1.0 mg/month i.v. ibandronate.
Subject(s)
Diphosphonates/administration & dosage , Diphosphonates/pharmacokinetics , Osteoporosis/drug therapy , Administration, Oral , Area Under Curve , Asian People , Collagen Type I/metabolism , Double-Blind Method , Drug Administration Schedule , Female , Humans , Ibandronic Acid , Injections, Intravenous/methods , Middle Aged , Osteoporosis/metabolism , Peptides/metabolismABSTRACT
ACE910 is a recombinant humanized bispecific antibody that binds to activated factor IX and factor X and mimics the cofactor function of factor VIII (FVIII). This first-in-human study examined the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of ACE910 in healthy male adults. A total of 40 Japanese and 24 white subjects were randomized to receive a single subcutaneous injection of ACE910 (Japanese: 0.001, 0.01, 0.1, 0.3, or 1 mg/kg; white: 0.1, 0.3, or 1 mg/kg; n = 6 per dose group) or placebo (n = 2 per dose group). ACE910 exhibited a linear PK profile and had a half-life of â¼4 to 5 weeks. In FVIII-neutralized plasma, ACE910 shortened activated partial thromboplastin time and increased peak height of thrombin generation in a dose-dependent manner. All adverse events were nonserious and did not lead to any subject's withdrawal. Neither clinical findings nor laboratory abnormalities indicating hypercoagulability were observed. Two of 48 subjects receiving ACE910 (1 Japanese and 1 white) were positive for anti-ACE910 antibodies (anti-drug antibodies [ADAs]). One subject tested positive for ADAs both before and after ACE910 administration, whereas the other became ADA positive after receiving ACE910. The PK and PD profiles of ACE910 were similar in healthy Japanese and white subjects and suggest that ACE910 will be an effective and convenient prophylactic treatment of hemophilia A. This trial was registered at www.clinicaltrials.jp as #JapicCTI-121934.
Subject(s)
Antibodies, Bispecific/administration & dosage , Antibodies, Monoclonal, Humanized/administration & dosage , Adult , Antibodies, Bispecific/adverse effects , Antibodies, Bispecific/pharmacokinetics , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/pharmacokinetics , Biomimetic Materials/administration & dosage , Biomimetic Materials/adverse effects , Biomimetic Materials/pharmacokinetics , Dose-Response Relationship, Drug , Factor VIII/therapeutic use , Healthy Volunteers , Humans , Injections, Subcutaneous , Male , Maximum Tolerated Dose , Young AdultABSTRACT
OBJECTIVE: Bioequivalence and comparability studies are necessary for changing formulations of large-molecule drugs, such as antibody drugs and protein products, and in the development of their biosimilars. This study is the first application of modeling and simulation (M&S) in the design of bioequivalence and comparability studies of erythropoietin as an example of a large-molecule drug. METHODS: A novel population pharmacokinetic and pharmacodynamic (PPK/PD) model was developed for erythropoietin. Based on this PPK/PD model, the probabilities of success of bioequivalence and comparability studies were simulated with various numbers of subjects and samples. RESULTS: The simulation indicated that the minimum numbers of subjects and samples required to satisfy the criteria for bioequivalence and comparability studies were as follows: fewest for the area under the serum concentration-time curve, more for the area under the efficacy-time curve, and most for the maximum serum concentration of erythropoietin. CONCLUSION: These results suggested that M&S could be successfully applied in the design of bioequivalence and comparability studies of large-molecule drugs.
Subject(s)
Computer Simulation , Erythropoietin/pharmacokinetics , Hematinics/pharmacokinetics , Models, Biological , Research Design , Area Under Curve , Cross-Over Studies , Drug Monitoring , Erythropoietin/blood , Erythropoietin/chemistry , Healthy Volunteers , Hematinics/blood , Hematinics/chemistry , Humans , Japan , Male , Metabolic Clearance Rate , Molecular Weight , Reticulocyte Count , Software , Therapeutic EquivalencyABSTRACT
Ibandronate, a nitrogen-containing bisphosphonate, is a bone resorption inhibitor widely used to prevent and treat osteoporosis. To optimize the design for a long-term clinical study of ibandronate, modeling and simulation (M&S) was performed based on the result of population pharmacodynamic analysis using the data of a short-term clinical study. A population pharmacodynamic model was constructed by the urinary C-terminal telopeptide of type I collagen (uCTx) and the lumbar spine bone mineral density (BMD) data obtained in clinical studies, including a phase II study of Japanese osteoporosis patients treated with ibandronate for 6 months. Changes in BMD over a period of 3 years were simulated from the population pharmacodynamic parameters of the patients in this phase II study. The relationship between uCTx and BMD was well described by this modeling. The functions of disease progression and supplemental treatment were incorporated into the model to simulate a long-term clinical study with high accuracy. A long-term clinical study with a 3-year treatment was conducted after this M&S. The percentage change from baseline in observed BMD values were found to be similar to the prospectively simulated values. This study showed that M&S could be a useful and powerful tool for designing and conducting long-term clinical studies when carried out in the following sequence: (1) conduct a short-term clinical study; (2) perform M&S; and (3) conduct the long-term clinical study. Application of this procedure to various other treatment agents will establish the usefulness of M&S for long-term clinical studies and bring further efficiencies to drug development.
Subject(s)
Diphosphonates/administration & dosage , Osteoporosis, Postmenopausal/drug therapy , Biomarkers, Pharmacological/urine , Bone Density/drug effects , Bone Density Conservation Agents/administration & dosage , Clinical Trials as Topic/methods , Collagen Type I/metabolism , Computer Simulation , Drug Administration Schedule , Female , Humans , Ibandronic Acid , Models, Biological , Osteoporosis, Postmenopausal/metabolism , Osteoporosis, Postmenopausal/urine , Peptides/metabolismABSTRACT
Orlistat is used clinically worldwide as anti-obesity drug. It is a chemically synthesized hydrogenated derivative of lipstatin and is an inhibitor of gastric and pancreatic lipases. It has been found to reduce the absorption of dietary fat in the gastrointestinal tract. Modeling and simulation based on pharmacokinetic/pharmacodynamic analysis is becoming increasingly used in the design of clinical trials to assure that the trials are of high quality and are conducted efficiently. We developed a clinical trial simulation model for orlistat based on Phase III clinical study data. This innovative weight loss model includes the relationships between orlistat dose, changes in fecal fat excretion, and weight loss, and also incorporates a dropout function. The model guided the dose-finding strategy and allowed simulation of long-term clinical outcomes of orlistat.
Subject(s)
Body Weight/drug effects , Lactones/pharmacology , Obesity/drug therapy , Weight Loss/drug effects , Anti-Obesity Agents/pharmacology , Clinical Trials, Phase III as Topic , Humans , Models, Theoretical , OrlistatABSTRACT
OBJECTIVES: TP300 is a novel topoisomerase I inhibitor with neutropenia as a significant toxicity. We developed and evaluated a pharmacokinetic-pharmacodynamic (PK-PD) model, using data from Phase I and II trials to predict neutrophil decrease in patients treated with TP300. METHODS: Plasma drug concentrations of TP300, its active form TP3076 and active metabolite TP3011 and absolute neutrophil counts (ANCs) from a Phase I trial were analysed as a training dataset. A two-plus-two-compartment model was applied to the pharmacokinetics of TP3076 and TP3011. A semi-mechanistic model was used to describe the PK-PD relationship between the plasma concentration of TP3076 and TP3011, and changes in ANC. KEY FINDINGS: The model fitted well to plasma concentrations of TP3076 and TP3011. Model appropriateness was confirmed in a Phase II trial validation dataset. Body weight and liver biochemistry values were identified as covariates. A semi-mechanistic PK-PD model was applied and the longitudinal decrease in ANC was simulated. Neutrophil counts reached their nadir approximately 2 weeks after administration of TP300, and the proportion of subjects affected increased with dose. CONCLUSIONS: This PK-PD model to predict neutropenia following treatment with TP300 fitted well the decrease in ANC with total concentration of TP3076 and TP3011.
Subject(s)
Dipeptides , Heterocyclic Compounds, 4 or More Rings , Models, Biological , Neutropenia/chemically induced , Topoisomerase I Inhibitors , Biotransformation , Clinical Trials, Phase I as Topic , Clinical Trials, Phase II as Topic , Computer Simulation , Dipeptides/adverse effects , Dipeptides/pharmacokinetics , Dipeptides/pharmacology , Heterocyclic Compounds, 4 or More Rings/adverse effects , Heterocyclic Compounds, 4 or More Rings/pharmacokinetics , Heterocyclic Compounds, 4 or More Rings/pharmacology , Humans , Molecular Structure , Monte Carlo Method , Predictive Value of Tests , Research Design , Topoisomerase I Inhibitors/adverse effects , Topoisomerase I Inhibitors/pharmacokinetics , Topoisomerase I Inhibitors/pharmacologyABSTRACT
Peg-interferon-alpha-2a (PEG-IFN) has been used all over the world including Japan as the standard of care for chronic hepatitis C (CHC). PEG-IFN causes platelet count decrease, while CHC patients with compensated liver cirrhosis have a low baseline of platelets. To use PEG-IFN more safely in these patients, we analyzed the effect of PEG-IFN on the longitudinal platelet profile with a pharmacokinetic-pharmacodynamic model. Platelet count and serum PEG-IFN concentration obtained from a Japanese clinical study on 40 patients were analyzed. The serum PEG-IFN concentration profile was fitted with an open 1-compartment model and the platelet profile was fitted with a turnover model. After the final model was fixed, the platelet profiles were simulated with various platelet baselines. The simulation revealed that according to PEG-IFN administration platelets decreased gradually and reached steady state within 12 weeks, and almost subjects would not have a lower platelet count than the criteria for discontinuation of the treatment. Once administration was discontinued, platelets recovered up to the baseline within several weeks. In conclusion, platelet count was predicted to be about a 30% (5th-95th percentiles in 1,000 simulation: 11-66%) decrease and to return to the baseline value in 4 to 8 weeks after the last administration of PEG-IFN.
Subject(s)
Blood Platelets/drug effects , Interferon-alpha/pharmacology , Interferon-alpha/pharmacokinetics , Polyethylene Glycols/pharmacology , Polyethylene Glycols/pharmacokinetics , Adult , Aged , Blood Platelets/cytology , Female , Hepatitis C, Chronic/blood , Hepatitis C, Chronic/drug therapy , Humans , Interferon-alpha/blood , Liver Cirrhosis/blood , Liver Cirrhosis/drug therapy , Longitudinal Studies , Male , Middle Aged , Models, Biological , Platelet Count , Recombinant Proteins/blood , Recombinant Proteins/pharmacokinetics , Recombinant Proteins/pharmacologyABSTRACT
A robust and sensitive method using liquid chromatography-tandem mass spectrometry was developed and validated for the simultaneous determination of a novel topoisomerase 1 inhibitor CH0793076 (3076), the prodrug CH4556300 (TP300), and the active metabolite CH0793011 (3011) in human plasma. All plasma analyzed with this method was acidified with 1M HCl and 46% citric acid solution in a ratio of 100:10:1 (v:v:v) to avoid the pH-based degradation of TP300 and to shift the equilibria of 3076 and 3011 between the lactone and carboxylate forms towards the lactone forms. After the plasma proteins were precipitated with methanol:acetonitrile:HCl 1M (50:50:1, v:v:v) containing stable isotopic internal standards, the analytes were trapped on an Xterra MS C18 column (10×2.1 mm i.d., 5 µm) and separated on a Gemini C18 column (50×2.0 mm i.d., 5 µm) using column-switching liquid chromatography. Electrospray ionization in the positive-ion mode and multiple reaction monitoring were used to quantify the analytes with transitions m/z 587.2>441.2 for TP300, 459.1>415.2 for 3076, and 475.1>361.1 for 3011. The inter- and intra-day precisions were below 12%, and the accuracy was between -16% and 16% at the lower limit of quantitation (LLOQ) and between -11% and 14% at the other quality controls. The LLOQs of TP300, 3076, and 3011 were 0.8, 0.04, and 0.04 ng/mL, respectively. The validated method was successfully applied to clinical sample analysis and incurred sample reanalysis was also conducted.
Subject(s)
Camptothecin/analogs & derivatives , Chromatography, Liquid/methods , Dipeptides/blood , Heterocyclic Compounds, 4 or More Rings/blood , Tandem Mass Spectrometry/methods , Topoisomerase I Inhibitors/blood , Camptothecin/blood , Drug Stability , Humans , Reproducibility of Results , Sensitivity and SpecificityABSTRACT
OBJECTIVES: The objective of this study was to build a ceftriaxone population pharmacokinetic model for Japanese paediatric patients and to examine the dosing regimen of ceftriaxone based on pharmacokinetic/pharmacodynamic (PK/PD) analysis. METHODS: The population pharmacokinetic analysis using NONMEM was based on published serum concentrations of ceftriaxone. A Monte Carlo simulation was examined to evaluate the time above the minimum inhibitory concentration (TAM) in 20 and 60 mg/kg body weight dose regimen using the population pharmacokinetic parameters. KEY FINDINGS: The time course of the serum concentration of ceftriaxone in paediatric patients was fitted to a two-compartment model and body weight was incorporated to pharmacokinetic parameters as the covariate. Based on the percent TAM estimated from the final population pharmacokinetic model and the minimum inhibitory concentration (MIC) of ceftriaxone in 2004, we have predicted that the once daily administration of 20 mg/kg ceftriaxone would be effective on various infecting organisms. CONCLUSIONS: A population pharmacokinetic model of ceftriaxone was built for Japanese paediatric patients based on the available data. The estimated PK/PD result confirmed the appropriateness of once daily dose of 20 mg/kg. In some patients for whom no efficacy was observed at 20 mg/kg, an increase to 60 mg/kg may be required.
Subject(s)
Anti-Bacterial Agents/pharmacokinetics , Ceftriaxone/pharmacokinetics , Computer Simulation , Models, Biological , Adolescent , Anti-Bacterial Agents/administration & dosage , Bacteria/drug effects , Bacterial Infections/drug therapy , Bacterial Infections/microbiology , Body Weight , Ceftriaxone/administration & dosage , Child , Child, Preschool , Dose-Response Relationship, Drug , Drug Administration Schedule , Humans , Infant , Infant, Newborn , Japan , Microbial Sensitivity Tests , Nonlinear Dynamics , Time FactorsABSTRACT
OBJECTIVE: By using a population pharmacokinetic analysis method, we predicted the efficacy of Ceftriaxone (CTRX) based on the pharmacokinetics of CTRX in Japanese adults and the sensitivity of infective organisms to CTRX in 2004. In addition, we clarified the difference in efficacy between once-a-day administration and twice-a-day administration. METHODS: The population pharmacokinetic analysis was based on the serum concentrations of CTRX already published by NONMEM. The possible effect of body weight and age on the pharmacokinetics of CTRX was examined using a model which incorporated the change of a specific protein-binding ratio of CTRX. A Monte Carlo simulation was conducted based on the population pharmacokinetic parameters obtained by this analysis, and thereby the time above MIC (TAM) was determined from the MIC values of CTRX administered once at 0.5, 1, and 2 g and twice at 1 g. The efficacy ratio was predicted from the TAM thus obtained. RESULTS: Because the time course of serum concentration of CTRX in adult subjects was fitted to a 2-compartment model and both body weight and age were not incorporated as the covariate, the dosing method by which a fixed amount of CTRX is administered to patients has been thought to be adequate. Based on the efficacy ratio estimated from the MIC of CTRX, we have predicted that the once-a-day administration of CTRX even at 0.5g is effective on various infecting organisms.
Subject(s)
Anti-Bacterial Agents/pharmacokinetics , Bacteria/drug effects , Ceftriaxone/pharmacokinetics , Adolescent , Adult , Age Factors , Aged , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/therapeutic use , Asian People , Body Weight , Ceftriaxone/administration & dosage , Ceftriaxone/therapeutic use , Clinical Trials as Topic , Dose-Response Relationship, Drug , Drug Administration Schedule , Humans , Japan , Microbial Sensitivity Tests , Middle Aged , Models, Biological , Monte Carlo Method , Nonlinear Dynamics , Protein Binding , Young AdultABSTRACT
The objective was to investigate the mechanism of nonlinear pharmacokinetics of mitemcinal, the first acid-resistant non-peptide motilin agonist, in rats. Super-proportional increases of the cumulative rates of radioactivity excreted into bile and urine following oral administration of [3H]-mitemcinal suggested nonlinear absorption of mitemcinal in rats. To evaluate the fraction dose absorbed (Fa) and intestinal availability (Fg), [3H]-mitemcinal was orally administrated to rats, and tritium radioactivity and unchanged mitemcinal concentration were determined in the portal blood. Fa values for 0.2 mg/kg1, 0.5 mg/kg, and 5.0 mg/kg dose groups were 0.314, 0.353, and 0.569, respectively. Corresponding Fg values were 0.243, 0.296, and 0.513, respectively. In Caco-2 experiments, the permeation of [3H]-mitemcinal in the secretory direction was larger than in the absorptive direction and was inhibited by P-glycoprotein (P-gp) substrate digoxin. The results indicate that the saturation of P-gp-mediated membrane permeation and intestinal metabolism causes the nonlinear pharmacokinetics of mitemcinal in rats.
Subject(s)
Erythromycin/analogs & derivatives , Intestinal Mucosa/metabolism , Receptors, Gastrointestinal Hormone/antagonists & inhibitors , Receptors, Neuropeptide/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , Administration, Oral , Animals , Bile/metabolism , Caco-2 Cells , Cell Membrane Permeability/drug effects , Digoxin/pharmacology , Dose-Response Relationship, Drug , Erythromycin/pharmacokinetics , Humans , Intestinal Absorption/drug effects , Male , Rats , Rats, Sprague-DawleyABSTRACT
A liquid chromatography-electrospray ionization tandem mass spectrometric (LC/ESI-MS/MS) method for the determination of 2beta-(3-hydroxypropoxy)-1alpha,25-dihydroxy vitamin D3 (ED-71) in human serum has been developed. ED-71 in human serum was extracted using two solid-phase extraction steps on Bond Elut C18 and NH2 cartridge. The separation of ED-71 and preED-71 isomer was attained by LC using 2 mmol/L ammonium acetate-methanol (15:85, v/v) as a mobile phase on a Symmetry C18 column (5 microm, 150 mm x 2.1mm i.d.). ESI-MS/MS analysis was operated using selected reaction monitoring (SRM) in positive ion mode. The method achieved a lower limit of quantitation of 25 pg/mL. The calibration curve (25-3200 pg/mL) gave acceptable linearity (r>0.9964). Intra-assay precision ranged from 2.3 to 9.7%. Inter-assay precision ranged from 1.0 to 3.4%. The accuracy was within 90.8-107.0%. This highly sensitive and reproducible method is able to determine only biologically active ED-71 by separating it from preED-71, which is considered to be applicable for the determination of serum samples from pharmacokinetic studies in human.