Improved pharmacokinetics of HIV-neutralizing VRC01-class antibodies achieved by reduction of net positive charge on variable domain
Young Do KwonAmarendra PeguEun Sung YangBaoshan ZhangMichael F. BenderMangaiarkarasi AsokanQingbo LiuKrisha McKeeBob C. LinTracy LiuMark K. LouderReda RawiMateo ReveizAndrew J. SchaubChen‐Hsiang ShenNicole A. Doria‐RosePaolo LussoJohn R. MascolaPeter D. Kwong
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The amino-acid composition of the immunoglobulin variable region has been observed to impact antibody pharmacokinetics (PK). Here, we sought to improve the PK of the broad HIV−1-neutralizing VRC01-class antibodies, VRC07-523LS and N6LS, by reducing the net positive charge in their variable domains. We used a structure-guided approach to generate a panel of antibody variants incorporating select Arg or Lys substituted to Asp, Gln, Glu, or Ser. The engineered variants exhibited reduced affinity to heparin, reduced polyreactivity, and improved PK in human FcRn-transgenic mice. One variant, VRC07-523LS.v34, with three charge substitutions, had an observed in vivo half-life and an estimated human half-life of 10.8 and 60 days, respectively (versus 5.4 and 38 days for VRC07-523LS) and retained functionality, neutralizing 92% of a 208-strain panel at a geometric mean IC80 <1 µg/mL. Another variant, N6LS.C49, with two charge substitutions, had an observed in vivo half-life and an estimated human half-life of 14.5 and 80 days (versus 9.0 and 44 days for N6LS) and neutralized ~80% of 208 strains at a geometric mean IC80 <1 µg/mL. Since Arg and Lys residues are prevalent in human antibodies, we propose substitution of select Arg or Lys with Asp, Gln, Glu, or Ser in the framework region as a general means to improve PK of therapeutic antibodies.Comparison of the pharmacokinetic parameters obtained for dideoxyinosine (ddI) in monkeys with those obtained for humans indicates that the monkey is an appropriate animal model for ddI pharmacokinetics in humans. Following intravenous administration of 20 mg of ddI per kg of body weight and measurement of ddI in plasma and urine by high-performance liquid chromatography, pharmacokinetic parameters were determined by noncompartmental analysis. Total systemic clearance was 0.74 liters/h/kg, volume of distribution was 0.92 liters/kg, and the elimination half-life of ddI was 1.22 h. The pharmacokinetics of ddI in five monkeys were determined following intravenous administration of 20 mg/kg and were found to be comparable to those obtained in patients with AIDS.
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Background/Aim. Methotrexate (MTX) plays a significant role in the treatment of various diseases, but the toxicity remains the main issue of its use, especially when administered in high doses. Considering altered pharmacokinetics of MTX as a factor strongly implicated in the large interpatient variability and unexpected toxicity in certain patients, the accurate description of MTX pharmacokinetic behaviour of both low and high doses is of the utmost importance. Therefore, the objective of this study was to determine the pharmacokinetics of MTX after intravenous (iv) administration in ascending doses of 5, 40, 80 and 160 mg/kg in rats and to select the appropriate mathematical model describing MTX pharmacokinetics. Methods. Plasma concentrations of MTX were measured using the liquid chromatography - mass spectrometry (LC/MS) method. Pharmacokinetic parameters were calculated by non-compartmental and two-compartmental integer-order analyses. Results. MTX showed linear pharmacokinetics following iv administration up to the dose of 80 mg/kg. The administration of a high dose of MTX (160 mg/kg) resulted in the similar pharmacokinetic behaviour as when applied in the twice lower dose (80 mg/kg), which can be explained by dose-dependent changes in the expression of solute carrier (SLC) and ATP binding cassette (ABC) transport proteins and intracellular metabolism. Furthermore, the classical two-compartment model could not explain the pharmacokinetics of MTX in a small percentage of experimental animals, which opens up new strategies for the use of fractional order pharmacokinetic models in MTX therapy optimisation. Conclusion. These results of pharmacokinetic analyses may be helpful in adjusting the dosage regimen of MTX, but the application of novel pharmacokinetic models, such as those based on fractional calculus, is still needed in the process of MTX therapy optimisation.
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Abstract The pharmacokinetic properties of vitacoxib have not been established completely; current dosage recommendations are based on clinical experiences. The primary objective of this study was to describe plasma concentrations and characterize the pharmacokinetics of vitacoxib formulation following oral administrations in horses. Also, the effect of the state of stomach contents on the absorption of vitacoxib was investigated in fed/fasted horses. Blood samples were collected prior to and at various times up to 72 hr post‐administration. Drug concentrations were measured using ultra high‐performance liquid chromatography–tandem mass spectrometry. Pharmacokinetic parameters were calculated using Non‐Compartmental Analysis Model 200 in WinNonlin™ software. No complications resulting from the vitacoxib administration were noted. All procedures were tolerated well by the horses throughout the study. C max was 17.5 ± 9.36 ng/ml (fasted) and 9.47 ± 3.53 ng/ml (fed) following oral administrations. AUC last was 173.7 ± 137.9 ng hr/ml (fasted) and 113.2 ± 70.8 ng h/ml (fed). No significant differences in pharmacokinetic parameters were noted and the results from the pharmacokinetic analysis were similar between the studies, regardless of precision of dosage and fasted and fed conditions. The study extends previous studies describing the pharmacokinetics of vitacoxib following p.o. administration to the horses. Further studies investigating the pharmacokinetics/pharmacodynamics of vitacoxib are necessary to establish adequate therapeutic protocols (optimal dosage and frequency of administration) in horses.
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Objective To study the pharmacokinetics and tissue distribution of Chuanhuning-emulsion( CHE) in rats. Methods The commercial ordinary Chuanhuning injection was used as the reference( CHR) to evaluate the pharmacokinetics and tissue distribution of CHE. After intravenous administration of CHE or CHR( 40 mg / kg) in rats,the concentration of dehydroandrographolide succinate( DAS,the active ingredients of CHE in vivo) was detected by LC-MS / MS. Pharmacokinetic analysis was performed using WinNolin 6. 2. Tissue distribution and targeting were evaluated through tissue concentrations. Results First,a suitable detection method was set up to study the pharmacokinetics of DAS. Second,there was no significant difference between CHR and CHE in the pharmacokinetic parameters. However,the concentrations of DAS in lungs of CHE group were higher than those in CHR group even at 2 h after iv administration of CHE or CHR. Conclusion CHE has a similar pharmacokinetic profile as CHR in rats. Furthermore,the cumulation of DAS in lungs is increased,which illustrates that CHE could enhance DAS targeted in lungs.
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The pharmacokinetics of 131I-labelled HAb18 McAb against primary hepatocellular carcinoma (PHC) and its F(ab^2) and Fab fragments following i.v. administration in BALB/c mice was investigated. Dynamic observations showed that the pharmacokinetics of 131I-labelled HAb18 was significantly different from that of the fragments. (1) The pharmacokinetics of HAb 18 conformed to a onecompart-mental open pharmacokinetic model. The clearance rate was relevant to injection doses, and the higher doses produced lower clearance values. (2) The pharmacokinetics of the F(ab^)_(2) was similar to that of the Fab and fitted to a two-compartmental pharmacokinetic model. The clearance process of the fragments was significantly fast than intact HAb18 McAb.
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