Supplementary Material from An Anti-EGFR IgA That Displays Improved Pharmacokinetics and Myeloid Effector Cell Engagement <i>In Vivo</i>
Stefan LohseSaskia MeyerLaura A.P.M. MeulenbroekJ.H. Marco JansenMaaike NederendAnna KretschmerKatja KlauszUwe MögingerStefanie DererThies RösnerChristian KellnerDenis M. SchewePeter SondermannSanjay TiwariDaniel KolarichMatthias PeippJeanette H.W. LeusenThomas Valerius
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<p>Material and Methods Glycoprofiling</p>Ex vivo
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To study the pharmacokinetics of rhGH decorated by polyethylene glycol (PEG-rhGH) after sc administration in rat, serum PEG-rhGH concentrations were measured by 125I labeled method after sc in rat, the pharmacokinetic model and parameters were fitted and calculated by the 3P97 program. After sc injection at doses of 150, 300, and 600 microg x kg(-1) in rat, the serum PEG-rhGH concentration-time curves were fitted to a one-compartment model. The rhGH decorated by polyethylene glycol could prolong the action duration of rhGH in vivo, and reach the goal of long-action.
Compartment (ship)
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Acyclovir(ACV) sustained release tablets(SRT) were prepared. The releasing characteristics in vitro and the pharmacokinetics in vivo were studied primitively. UV method was established for assaying release of SRT in vitro . The HPLC fluorescence method was established to monitor plasma level in vivo . Four healthy volunteers were chosen to perform in vivo study, each two with single dose of ACV SRT and commercial tablets. Pharmacokinetics of the SRT was characterized preliminarily. It was concluded from the study of four healthy volunteers that T max and AUC increased, C max decreased, and the curve of plasma concentration versus time became more flat and extended longer compared with reference tablets.
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This is a comparative pharmacokinetics study of linezolid (Lzd), and two novel oxazolidinone antibacterial agents-PH027 and PH051-in rabbits to determine if the discrepancy between the in vitro and in vivo activities of the novel compounds is due to pharmacokinetic factors. The pharmacokinetics after IV and oral administration, plasma protein binding and tissue distribution for the three compounds were compared. The elimination half-lives were 52.4 ± 6.3, 68.7 ± 12.1 and 175 ± 46.1 min for Lzd, PH027 and PH051, respectively. The oral bioavailability for Lzd, PH027 and PH051 administered as suspension were 38.7%, 22.1% and 4.73%, which increased significantly when administered as microemulsion to 51.7%, 72.9% and 13.9%. The plasma protein binding were 32-34%, 37-38% and 90-91% for Lzd, PH027 and PH051. The tissue distribution for PH027 and PH051 in all investigated tissues were higher than that for Lzd. It can be concluded that the lower bioavailability of PH027 and PH051 compared to Lzd when administered as suspension is the main cause of their lower in vivo activity, despite their comparable in vitro activity. Differences in the other pharmacokinetic characteristics cannot explain the lower in vivo activity. The in vivo activity of the novel compounds should be re-evaluated using formulations with good oral bioavailability.
Linezolid
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1. AMG 232 is a novel inhibitor of the p53–MDM2 protein–protein interaction currently in Phase I clinical trials for multiple tumor indications. The objectives of the investigations reported in this article were to characterize the pharmacokinetic and drug metabolism properties of AMG 232 in pre-clinical species in vivo and in vitro, and in humans in vitro, and to predict its pharmacokinetics in humans through integrating PKDM data.2. AMG 232 exhibited low clearance (<0.25 × Qh) and moderate to high oral bioavailability in mice, rats and monkeys (>42%), but high clearance (0.74 × Qh) and low oral exposure in dogs (18%).3. Biotransformation was the major route of elimination of AMG 232 in rats, with only 7% of intravenously administered 14C-labeled AMG 232 recovered as parent molecule in bile. The major metabolite was an acyl glucuronide as measured by in vivo rat studies and in vitro hepatocyte incubations in multiple species.4. The in vitro–in vivo correlation of AMG 232 clearance was within 2-fold in pre-clinical species using hepatocytes. AMG 232 was predicted to exhibit low clearance, high volume distribution and long half-life in humans. The predictions are consistent with the preliminary human pharmacokinetic parameters of AMG 232 in clinical trials.
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It is important to be able to simulate and predict formulation effects on the pharmacokinetics of a drug in order to optimize effectivity in clinical practice and drug development. Two formulations containing doxorubicin are used in the treatment of hepatocellular carcinoma (HCC): a Lipiodol-based emulsion (LIPDOX) and a loadable microbead system (DEBDOX). Although equally effective, the formulations are vastly different, and little is known about the parameters affecting doxorubicin release in vivo. However, mathematical modeling can be used to predict doxorubicin release properties from these formulations and its in vivo pharmacokinetic (PK) profiles. A porcine semi-physiologically based pharmacokinetic (PBPK) model was scaled to a human physiologically based biopharmaceutical (PBBP) model that was altered to include HCC. DOX in vitro and in vivo release data from LIPDOX or DEBDOX were collected from the literature and combined with these in silico models. The simulated pharmacokinetic profiles were then compared with observed porcine and human HCC patient data. DOX pharmacokinetic profiles of LIPDOX-treated HCC patients were best predicted from release data sets acquired by in vitro methods that did not use a diffusion barrier. For the DEBDOX group, the best predictions were from the in vitro release method with a low ion concentration and a reduced loading dose. The in silico modeling combined with historical release data was effective in predicting in vivo plasma exposure. This can give useful insights into the release method properties necessary for correct in vivo predictions of pharmacokinetic profiles of HCC patients dosed with LIPDOX or DEBDOX.
Biopharmaceutical
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Objective The single-dose and multi-dose pharmacokinetics of two sustained-release tablet formulations of metformin hydrochloride in fed, 40 healthy volunteers were compared, and their in vitro-in vivo correlations were evaluated. Methods Self-made and imported (Glucophage XP) sustained-release tablets of metformin hydrochloride were administered orally in a single-dose, 1000 mg/d for two times with a 6-day interval, or the multi-dose regimen of 1000 mg/d for two blocks of five-consecutive days with a 14-day interval. The plasma concentrations and pharmacokinetics of metformin hydrochloride were analyzed after administration. The in vivo drug release rate was compared with in vivo Absorption percentage calculated from Wagner-Nelson method for getting the in vitro-in vivo correlation. Result and Conclusion The two formulations have similar phamarcokinetics and bioequivalent, and their in vitro-in vivo correlations are good.
Bioequivalence
Metformin Hydrochloride
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The taccalonolides are microtubule stabilizers that covalently bind tubulin and circumvent clinically relevant forms of resistance to other drugs of this class. Efforts are under way to identify a taccalonolide with optimal properties for clinical development. The structurally similar taccalonolides AF and AJ have comparable microtubule-stabilizing activities in vitro, but taccalonolide AF has excellent in vivo antitumor efficacy when administered systemically, while taccalonolide AJ does not elicit this activity even at maximum tolerated dose. The hypothesis that pharmacokinetic differences underlie the differential efficacies of taccalonolides AF and AJ was tested. The effects of serum on their in vivo potency, metabolism by human liver microsomes and in vivo pharmacokinetic properties were evaluated. Taccalonolides AF and AJ were found to have elimination half-lives of 44 and 8.1 min, respectively. Furthermore, taccalonolide AJ was found to have excellent and highly persistent antitumor efficacy when administered directly to the tumor, suggesting that the lack of antitumor efficacy seen with systemic administration of AJ is likely due to its short half-life in vivo. These results help define why some, but not all, taccalonolides inhibit the growth of tumors at systemically tolerable doses and prompt studies to further improve their pharmacokinetic profile and antitumor efficacy.
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Objective:To investigate in vivo pharmacokinetics and tissue distribution of silybin gelatin microspheres in rats.Method: With silybin injection as reference,pharmacokinetic model and parameters were calculated by 3P97.In vivo tissue distribution and targeting of silybin gelatin microspheres in rats were evaluated by targeting efficiency.Result: Pharmacokinetic data fitted a two-compartment model,main pharmacokinetic parameters of silybin gelatin microspheres were as follows: t1/2α=(0.572 8±0.108 6) h,t1/2β=(20.686 6±1.058 8) h,CL=(0.003 8±0.001 4) mL·h·kg-1,AUC0→∞=(211.095 0±10.272 8) mg·h·L-1.Targeting efficiency of it in liver,spleen,heart and kidney were 2.093,1.986,0.634,0.259.Conclusion: Compared to silybin injection,silybin gelatin microspheres could improve tendency for liver and spleen,and help improving its therapeutic effect.
Gelatin
Tissue distribution
Liver tissue
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AIM:To estabalish the methodology of microdialysis technique in pharmacokinetic(PK) reseach of anticancer drugs in vivo. METHODS:Gemcitabine(GEM) was injected into mice's tail vein.The microdialysate samples from blood were collected after dosing in gemcitabine-treated mices.The concentration of GEM was detected real-time continuously and pharmacokinetic parameters were evaluated.RESULTS:The recovery rate of GEM in vivo was(11.9±2.0)%.It showed that the pharmacokinetics of gemcitabine was two-compartment model in vivo and the elimination and distribution of GEM meets the first kinetics.There were no serious side effects in model mice.CONCLUSION:Microdialysis can be successfully employed in living body to detect the concentration of GEM continuously,which prompts it is possible to study the PK of anticancer drugs in malignant tissues in vivo.
Microdialysis
Pharmacodynamics
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