scholarly journals Improvement of Certolizumab Fab′ properties by PASylation technology

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Somayeh Mazaheri ◽  
Yeganeh Talebkhan ◽  
Fereidoun Mahboudi ◽  
Leila Nematollahi ◽  
Reza Ahangari Cohan ◽  
...  
Keyword(s):  
Half Life ◽  
Certolizumab Pegol ◽  
Antibody Fragment ◽  
Random Coil ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Studies ◽  
Pharmaceutical Proteins ◽  
Coil Structure ◽  
Pharmacokinetic Properties ◽  
Potential Alternative

Abstract Certolizumab pegol is a Fab′ antibody fragment for treatment of rheumatoid arthritis and Crohn’s disease which is conjugated to a 40 kDa PEG molecule in order to increase the protein half-life. PEGylation may have disadvantages including immunogenicity, hypersensitivity, vacuolation, decreased binding affinity and biological activity of the protein. To overcome these problems, PASylation has been developed as a new approach. The nucleotide sequence encoding 400 amino acid PAS residues was genetically fused to the corresponding nucleotide sequences of both chains of certolizumab. Then, the bioactivity as well as physicochemical and pharmacokinetic properties of the recombinant PASylated expressed protein was assayed. Circular dichroism spectroscopy demonstrated that the random coil structure of PAS sequences did not change the secondary structure of the PASylated Fab′ molecule. It was observed that PASylation influenced the properties of the Fab′ molecule by which the hydrodynamic radius and neutralization activity were increased. Also, the antigen binding and binding kinetic parameters improved in comparison to the PEGylated Fab′ antibody. Pharmacokinetic studies also showed prolonged terminal half-life and improved pharmacokinetic parameters in PASylated recombinant protein in comparison to the PEGylated and Fab′ control molecules. The results reconfirmed the efficiency of PASylation approach as a potential alternative method in increasing the half-life of pharmaceutical proteins.

scholarly journals Characterization and pharmacokinetic parameters of recombinant soluble interleukin-4 receptor

Blood ◽  
1991 ◽  
Vol 77 (11) ◽  
pp. 2396-2403 ◽  
Author(s):  
CA Jacobs ◽  
DH Lynch ◽  
ER Roux ◽  
R Miller ◽  
B Davis ◽  
...  
Keyword(s):  
Half Life ◽  
Integral Membrane Protein ◽  
Interleukin 4 ◽  
Soluble Form ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Studies ◽  
Cdna Clones ◽  
Elimination Half ◽  
Interleukin 4 Receptor

Abstract The interleukin-4 receptor (IL-4R) is expressed as a 140-Kd membrane glycoprotein that binds IL-4 with high affinity. Recently, cDNA clones for the murine IL-4R have been isolated. One clone encodes an integral membrane protein, while another encodes a protein in which translation is terminated before the transmembrane region, thus producing a soluble form of the IL-4R (sIL-4R). HeLa cell clones overexpressing sIL-4R were isolated using a novel filter-overlay and 125I-IL-4 ligand binding technique. Quantitative analysis demonstrated that the kinetics and affinity of IL-4 binding to the recombinant sIL-4R were similar to the native membrane-bound IL-4R. As low doses of sIL-4R specifically inhibited IL-4-induced proliferative responses in vitro, sIL-4R biodistribution and elimination parameters were evaluated to assess the pharmacokinetic potential of sIL-4R as a therapeutic agent. Pharmacokinetic studies demonstrated that radiolabeled sIL-4R had a distribution half-life of 9 minutes and an elimination half-life of 2.3 hours following intravenous (IV) administration. When administered by intraperitoneal or subcutaneous (SC) injection, the elimination half- lives were prolonged to 4.2 hours and 6.2 hours, respectively. Although the initial blood level of sIL-4R was reduced if administered by SC injection, the bioavailability was comparable with IV administration. The main sites of sIL-4R elimination were the liver and kidney.

Pharmacokinetics and investigation of optimal dose ertapenem in intermittent hemodialysis patients

2018 ◽  
Vol 34 (10) ◽  
pp. 1766-1772 ◽  
Author(s):  
Lama M Hsaiky ◽  
Francine D Salinitri ◽  
Judy Wong ◽  
Sin-Ling T Jennings ◽  
Neha H Desai ◽  
...  
Keyword(s):  
Half Life ◽  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Optimal Dose ◽  
Hemodialysis Patients ◽  
Pharmacokinetic Parameters ◽  
Intermittent Hemodialysis ◽  
Pharmacokinetic Studies ◽  
Open Label ◽  
Serious Adverse Events

Abstract Background Previous pharmacokinetic studies demonstrated an increase in serum ertapenem concentrations with decreasing kidney function, including patients receiving renal replacement therapy. This study evaluated the pharmacokinetic parameters of ertapenem in patients receiving hemodialysis. Methods This prospective, single-center, open-label study examined the pharmacokinetics of a single intravenous (IV) dose of ertapenem 1 g in seven hospitalized noninfected patients undergoing hemodialysis. Blood samples were collected prior to ertapenem administration and at 0.5, 1, 2, 6, 12 and 48 hours (h) after administration. Ertapenem concentrations were determined by validated liquid chromatography mass spectrometry assay. Results Following an IV bolus of 1 g ertapenem, plasma concentrations declined relatively slowly with a mean ±standard deviation (SD) elimination half-life of 19.3 ±6.6 h. Plasma concentrations were similar in all subjects, with maximum mean plasma concentration observed of 343±48 µg/mL postdose. The mean ±SD values for systemic plasma clearance (CL) and volume of distribution at steady state (Vss) were 2±0.5 mL/min and 3295±1187 mL, respectively. The area under the curve for 0 h–∞ (AUCinf) was 7494 ±1424 h•µg/mL. No gender effect was observed and no serious adverse events were reported. Conclusions Ertapenem half-life was prolonged in hemodialysis patients. Considering the nonrenal clearance and the expected 70% removal with high-efficacy hemodialysis, the dose of 1 g ertapenem, three times weekly, after hemodialysis may produce pharmacodynamically sufficient exposure for potential antimicrobial efficacy. Further studies are warranted to assess the clinical efficacy and safety of this dose with prolonged duration of therapy.

scholarly journals In vitro and in vivo pharmacokinetic characterization of LMT-28 as a novel small molecular interleukin-6 inhibitor

2020 ◽  
Vol 33 (4) ◽  
pp. 670-677
Author(s):  
Sung-Hoon Ahn ◽  
Tae-Hwe Heo ◽  
Hyun-Sik Jun ◽  
Yongseok Choi
Keyword(s):  
Mdck Cell ◽  
Interleukin 6 ◽  
Cell Permeability ◽  
Oral Drug ◽  
Drug Candidate ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Studies ◽  
Pharmacokinetic Properties

Objective: Interleukin-6 (IL-6) is a T cell-derived B cell stimulating factor which plays an important role in inflammatory diseases. In this study, the pharmacokinetic properties of LMT-28 including physicochemical property, <i>in vitro</i> liver microsomal stability and an <i>in vivo</i> pharmacokinetic study using BALB/c mice were characterized.Methods: LMT-28 has been synthesized and is being developed as a novel therapeutic IL-6 inhibitor. The physicochemical properties and <i>in vitro</i> pharmacokinetic profiles such as liver microsomal stability and Madin-Darby canine kidney (MDCK) cell permeability assay were examined. For <i>in vivo</i> pharmacokinetic studies, pharmacokinetic parameters using BALB/c mice were calculated.Results: The logarithm of the partition coefficient value (LogP; 3.65) and the apparent permeability coefficient values (P<sub>app</sub>; 9.7×10<sup>–6</sup> cm/s) showed that LMT-28 possesses a moderate-high cell permeability property across MDCK cell monolayers. The plasma protein binding rate of LMT-28 was 92.4% and mostly bound to serum albumin. The metabolic half-life (t<sub>1/2</sub>) values of LMT-28 were 15.3 min for rat and 21.9 min for human at the concentration 1 μM. The area under the plasma drug concentration-time curve and C<sub>max</sub> after oral administration (5 mg/kg) of LMT-28 were 302±209 h∙ng/mL and 137±100 ng/mL, respectively.Conclusion: These data suggest that LMT-28 may have good physicochemical and pharmacokinetic properties and may be a novel oral drug candidate as the first synthetic IL-6 inhibitor to ameliorate mammalian inflammation.

scholarly journals Pharmacokinetics of saquinavir, zidovudine, and zalcitabine in combination therapy.

1997 ◽  
Vol 41 (11) ◽  
pp. 2428-2432 ◽  
Author(s):  
G F Vanhove ◽  
H Kastrissios ◽  
J M Gries ◽  
D Verotta ◽  
K Park ◽  
...  
Keyword(s):  
Half Life ◽  
Area Under The Curve ◽  
Chronic Administration ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Parameter Estimates ◽  
Pharmacokinetic Studies ◽  
Mean Values ◽  
Aids Clinical Trial Group ◽  
The Mean

We investigated the pharmacokinetics of zidovudine, zalcitabine, and saquinavir in AIDS Clinical Trial Group protocol 229. Patients received either saquinavir, zalcitabine, or a combination of both, together with zidovudine three times a day. Approximately 100 patients were enrolled in each treatment arm, and intensive pharmacokinetic studies were performed on about 25 patients per arm at weeks 1 and 12. We estimated the pharmacokinetic parameters of all three drugs by using parametric and nonparametric methods. The mean values of the pharmacokinetic parameters of zidovudine (clearance [CL]/bioavailability [F], 168 liters/h; volume of distribution [V]/F, 185 liters; half-life, 0.76 h) and zalcitabine (CL/F, 25 liters/h; V/F, 92.2 liters; half-life, 2.7 h) were similar to those reported previously. For saquinavir, the mean pharmacokinetic parameter estimates using parametric methods were as follows: maximum concentration of drug in serum [Cmax], 70.8 ng/ml; time to Cmax, 3.11 h; area under the curve, 809 ng x h/ml; CL/F, 989 liters/h; V/F, 1,503 liters; half-life, 1.38 h. For all three drugs, clearance decreased with age. Weight did not influence the clearance of zidovudine, but the clearance of zalcitabine and saquinavir increased with weight. There were no differences in pharmacokinetic parameters between study weeks and arms, suggesting that there is no change in kinetics with chronic administration and that there are no significant pharmacokinetic interactions among these three drugs.

Clinical Pharmacokinetics of Chlorpheniramine

1984 ◽  
Vol 18 (9) ◽  
pp. 701-707 ◽  
Author(s):  
Martha M. Rumore
Keyword(s):  
Half Life ◽  
The Body ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Studies ◽  
Elimination Kinetics ◽  
Clinical Pharmacokinetics ◽  
Interindividual Variations ◽  
First Pass ◽  
Dose Levels ◽  
Kinetics Of

The clinical pharmacokinetics of chlorpheniramine are reviewed. Recent studies have established that the half-life of chlorpheniramine is longer than previously reported. Chlorpheniramine has a serum half-life of ∼20 hours in adults, and elimination from the body is primarily by metabolism to monodesmethyl and didesmethyl compounds. The half-life is increased in the presence of renal dysfunction and decreased in children. The exact mechanism of the presystemic first-pass elimination and the effects of dose levels on the process presently are unclear. Biopharmaceutical and pharmacokinetic studies after single or multiple doses in humans reveal wide interindividual variations in pharmacokinetics. Age, dialysis, urinary pH and flow influence the elimination kinetics of chlorpheniramine. Attention is brought to major issues that need further clarification to optimize drug therapy with this antihistamine. The use of pharmacokinetic parameters of chlorpheniramine for clinical application is discussed.

scholarly journals PHARMACOKINETIC PROPERTIES OF A NEW KAPPA-OPIOID ANALGESIC RU-1205 COMPOUND AT A SINGLE PERORAL ADMINISTRATION

2021 ◽  
Vol 9 (2) ◽  
pp. 149-160
Author(s):  
A. A. Spasov ◽  
L. A. Smirnova ◽  
O. Yu. Grechko ◽  
N. V. Eliseeva ◽  
Yu. V. Lifanova ◽  
...  
Keyword(s):  
Oral Administration ◽  
Analgesic Activity ◽  
Half Life ◽  
The Body ◽  
Absolute Bioavailability ◽  
Peroral Administration ◽  
Pharmacokinetic Parameters ◽  
Tail Flick ◽  
Test Substance ◽  
Pharmacokinetic Properties

The aim of the study is the investigation of the pharmacokinetic properties of the RU-1205 compound, with previously identified kappa-agonistic and analgesic effects, at a single oral administration, as well as comparison of the relationship between its pharmacokinetic and analgesic properties.Materials and methods. Pharmacokinetic parameters of RU-1205 after the oral administration at the dose of 50 mg / kg were investigated using the method of High Performance Liquid Chromatography  with determination of the concentration of the compound according to the previously constructed calibration schedule. The indices of the area under the pharmacokinetic curve, clearance, half-life, residence time of the drug molecule in the body, a total (apparent) volume of distribution, as well as the indicator of absolute bioavailability, were calculated. The tissue distribution and excretion of RU-1205 were studied.Potential metabolites of RU-1205 were predicted using the PALLAS 3.00 program. The study of the analgesic activity was carried out on a model of central somatogenic pain with electricalstimulation, with the dynamics assessment of the voltage amplitude of the corresponding reaction of the "tail-flick" reflex.Results. The compound under study is rapidly adsorbed from the gastrointestinal tract, reaching a maximum concentration by the end of the first hour of the study, and is determined in plasma within 12 hours. Its half-life is 17.7 hours. The absolute oral bioavailability is 37.3%. It was found out that the compound is withdrawn within 3-4 days. The main route of excretion is extrarenal. Biotransformation of a substance probably proceeds mainly with the formation of oxidized forms of the initial molecule by reactions of the first phase of metabolic transformation. The analgesic effect is long-lasting: it starts after 15 minutes and lasts for 12 hours with flattening of the curve by the 8th hour.Conclusion. When administered orally, the test substance undergoes a long process of elimination, has the greatest tropism for the elimination organs and undergoes active biotransformation processes in the body of animals. As a result of it, active metabolic products with an analgesic activity are, possibly, formed.

scholarly journals Piperaquine pharmacokinetics during intermittent preventive treatment for malaria in pregnancy

2020 ◽  
Author(s):  
Palang Chotsiri ◽  
Julie Gutman ◽  
Rukhsana Ahmed ◽  
Jeanne Rini Poespoprodjo ◽  
Din Syafruddin ◽  
...  
Keyword(s):  
Pregnant Women ◽  
Intermittent Preventive Treatment ◽  
Preventive Treatment ◽  
Preventive Therapy ◽  
Malaria In Pregnancy ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Studies ◽  
Pharmacokinetic Properties ◽  
In Pregnancy

Background: Dihydroartemisinin-piperaquine (DP) is a long-acting artemisinin combination treatment that provides effective chemoprevention and has been proposed as an alternative antimalarial drug for intermittent-preventive therapy in pregnancy (IPTp). Several pharmacokinetic studies have shown that dose adjustment may not be needed for the treatment of malaria in pregnancy with DP. However, there are limited data on the optimal dosing for IPTp. Objective: This study aimed to evaluate the population pharmacokinetics of piperaquine given as IPTp in pregnant women. Methods: Pregnant women were enrolled in clinical trials conducted in Kenya and Indonesia and treated with standard 3-day courses of DP, administered in 4-8 weeks intervals from the second trimester until delivery. Pharmacokinetic blood samples were collected for piperaquine drug measurements before each treatment round, time of breakthrough symptomatic malaria, and at delivery. Piperaquine population pharmacokinetic properties were investigated using nonlinear mixed-effects modelling with a prior approach. Results: In total data from 366 Kenyan and 101 Indonesian women were analysed. The pharmacokinetic properties of piperaquine were adequately described using a flexible transit absorption (n=5) followed by a three-compartment disposition model. Gestational age did not affect the pharmacokinetic parameters of piperaquine. After three rounds of monthly IPTp, 9.45% (95% CI: 1.8-26.5) of pregnant women had trough piperaquine concentrations below the suggested target concentration (10.3 ng/mL). Translational simulations suggest that providing the full treatment dose of DP at monthly intervals provides sufficient protection to prevent malaria infection. Conclusions: Monthly administration of a DP has the potential to offer optimal prevention of malaria during pregnancy.

1424The diagnosis of non-adherence in hypertension using a urine biochemical screen is unaffected by drug pharmacokinetics

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
D Lane ◽  
R Alghamdi ◽  
M Muscat ◽  
M S Kaur ◽  
T Davis ◽  
...  
Keyword(s):  
Urinary Excretion ◽  
European Society ◽  
Half Life ◽  
Diagnostic Tools ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Studies ◽  
Antihypertensive Medications ◽  
Adherence Score ◽  
Biochemical Testing ◽  
Drug Pharmacokinetics

Abstract Introduction Suboptimal drug adherence in hypertension is pandemic and traditional diagnostic tools to detect non-adherence have lacked accuracy and robustness. The inability to identify non-adherence has therefore driven the development of biochemical drug screening by liquid chromatography tandem mass spectrometry (LC- MS/MS) in urine and blood, which are the most accurate metrics presently available. Urinary antihypertensive testing is evidenced to improve non-adherence rates, significantly decrease blood pressure after physician intervention, and be cost effective. The European Society of Cardiology (ESC) and European Society of Hypertension (ESH) 2018 guidelines have recommended the use of biochemical testing for non-adherence diagnosis. However, it has been argued that the variable pharmacokinetic parameters of the medication (such as their half-lives and clearance rates) may affect the detection of medications in urine and hence the determination of adherence. We hypothesized that pharmacokinetic parameters do not affect the detection of antihypertensive medications in urine. Aim This study compared the pharmacokinetic parameters of the most commonly prescribed antihypertensive medications against their detection in urine by LC-MS/MS. Methods Results of urinary drug screens from 463 hypertensive patients (total prescribed medications N=1709) were collated. An adherence score termed as the C score (number of detected vs. prescribed medication) was generated for each of the 27 common antihypertensive medications. Pharmacokinetic parameters such as bioavailability, plasma concentration, volume of distribution, half-life, plasma clearance and urinary excretion values for each drug were obtained from published literature. Partial linear correlation was conducted between the C score of all the medications and each pharmacokinetic parameter studied. Results 40% of patients were non-adherent. The average number of prescribed medications was high (N=3.7, SD: 1.5), and the average number of drugs detected was lower (N=2.5, SD: 1.6). Amlodipine was the most prescribed (N=224), and clonidine was the least (N=10). The half-lives ranged from 0.87 to 39 hours for bumetanide and amlodipine respectively. The urinary excretion percentage varied from <1% for nifedipine, and 94% for benfroflumethiazide. No significant correlation was found between any drug C score and their respective pharmacokinetic variables such as the medication half-lives (figure1). Half-life versus adherence score Conclusion This study reports no significant correlation between drug pharmacokinetics and adherence. To the best of our knowledge this is the first study of its kind. Urinary biochemical testing by LC-MS/MS for non-adherence remains a valid tool for diagnosis although further detailed pharmacokinetic studies are needed to confirm this finding. Acknowledgement/Funding None

scholarly journals Characterization and pharmacokinetic parameters of recombinant soluble interleukin-4 receptor

Blood ◽  
1991 ◽  
Vol 77 (11) ◽  
pp. 2396-2403
Author(s):  
CA Jacobs ◽  
DH Lynch ◽  
ER Roux ◽  
R Miller ◽  
B Davis ◽  
...  
Keyword(s):  
Half Life ◽  
Integral Membrane Protein ◽  
Interleukin 4 ◽  
Soluble Form ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Studies ◽  
Cdna Clones ◽  
Elimination Half ◽  
Interleukin 4 Receptor

The interleukin-4 receptor (IL-4R) is expressed as a 140-Kd membrane glycoprotein that binds IL-4 with high affinity. Recently, cDNA clones for the murine IL-4R have been isolated. One clone encodes an integral membrane protein, while another encodes a protein in which translation is terminated before the transmembrane region, thus producing a soluble form of the IL-4R (sIL-4R). HeLa cell clones overexpressing sIL-4R were isolated using a novel filter-overlay and 125I-IL-4 ligand binding technique. Quantitative analysis demonstrated that the kinetics and affinity of IL-4 binding to the recombinant sIL-4R were similar to the native membrane-bound IL-4R. As low doses of sIL-4R specifically inhibited IL-4-induced proliferative responses in vitro, sIL-4R biodistribution and elimination parameters were evaluated to assess the pharmacokinetic potential of sIL-4R as a therapeutic agent. Pharmacokinetic studies demonstrated that radiolabeled sIL-4R had a distribution half-life of 9 minutes and an elimination half-life of 2.3 hours following intravenous (IV) administration. When administered by intraperitoneal or subcutaneous (SC) injection, the elimination half- lives were prolonged to 4.2 hours and 6.2 hours, respectively. Although the initial blood level of sIL-4R was reduced if administered by SC injection, the bioavailability was comparable with IV administration. The main sites of sIL-4R elimination were the liver and kidney.

A Multicenter Study of Recombinant Factor VIII (RecombinateTM) in Previously Treated Patients with Hemophilia A

1997 ◽  
Vol 77 (04) ◽  
pp. 660-667 ◽  
Author(s):  
G C White ◽  
S Courter ◽  
G L Bray ◽  
M Lee ◽  
E D Gomperts ◽  
...  
Keyword(s):  
Hemophilia A ◽  
Recombinant Dna ◽  
Home Treatment ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Studies ◽  
Open Label ◽  
Treat Ment ◽  
Previously Treated Patients ◽  
Bleeding Episodes

SummaryA prospective, open-label multicenter investigation has been conducted to compare pharmacokinetic parameters of recombinant DNA-derived FVIII (rFVIII) and plasma-derived FVIII concentrate (pdFVIII) and to assess safety and efficacy of long-term home-treat- ment with rFVIII for subjects with hemophilia A. Following comparative in vivo pharmacokinetic studies, 69 patients with severe (n = 67) or moderate (n = 2) hemophilia A commenced a program of home treatment using rFVIII exclusively for prophylaxis and treatment of all bleeding episodes for a period of 1.0 to 5.7 years (median 3.7 years). The mean in vivo half-lives of rFVIII and pdFVIII were both 14.7 h. In vivo incremental recoveries at baseline were 2.40%/IU/kg and 2.47%/IU/kg, respectively (p = 0.59). The response to home treatment with rFVIII was categorized as good or excellent in 3,195 (91.2%) of 3,481 evaluated bleeding episodes. Thirteen patients received rFVIII for prophylaxis for twenty-four surgical procedures. In all cases, hemostasis was excellent. Adverse reactions were observed in only 13 of 13,591 (0.096%) infusions of rFVIII; none was serious. No patient developed an inhibitor to r FVIII.

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