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

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 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.

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 Urine concentration Does Not Affect Biochemical Testing for Non-Adherence.

2020 ◽  
Author(s):  
A D Burns ◽  
R Alghamadi ◽  
A Iqbal ◽  
T Davies ◽  
D Lane ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Urine Concentration ◽  
Antihypertensive Medications ◽  
Creatinine Concentration ◽  
Clinical Method ◽  
Adherence Score ◽  
Urine Creatinine ◽  
Significant Difference ◽  
Liquid Chromatography Tandem Mass ◽  
Biochemical Testing

Abstract Hypertension is one of the most important modifiable risk factor causing cardiovascular disease. Unfortunately, non-adherence to antihypertensive medications is frequently observed in hypertensive patients and can lead to an increase in morbidity and mortality. Until recently, there was no robust clinical method to objectively diagnose non-adherence. Recently, the detection of medications in urine or blood by mass spectrometry techniques such as liquid chromatography-tandem mass spectrometry (LC-MS/MS) has become accepted as the diagnostic method of choice in the detecting of non-adherence. Despite this, it is unclear whether the concentration of urine can affect the detection of medications in the urine. Therefore, this study aimed to assess the effect of urine concentration on detection of antihypertensive medications by LC-MS/MS in which urine creatinine is used as an independent marker of urine concentration. Biochemical adherence results for 22 different medications (1709 prescriptions) in 463 different subjects were converted to an adherence score. The adherence score was defined as the ratio of the total number of subjects in which the drug detected to the total number of subjects in which the was drug prescribed. The adherence scores for each medication were correlated with urine creatinine concentration for each medication. Non-adherence was observed in 47.1% of samples with the mean urine creatinine concentration of these samples was 9.4 ± 7.1 mmol/L. There was no significant difference between the urine creatinine concentrations in the detected vs. non detected groups for each of the 22 medications. Furthermore, there are no differences in adherence scores across the urine creatinine concentration. This is the first study to demonstrate that urine creatinine concentration does not affect the results of the adherence screen by LC-MS/MS.

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 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.

Liquid Chromatography-Tandem Mass Spectrometry Method for Ticagrelor and its Active Metabolite Determination in Human Plasma: Application to a Pharmacokinetic Study

2020 ◽  
Vol 16 (5) ◽  
pp. 602-608
Author(s):  
Niloufar Marsousi ◽  
Serge Rudaz ◽  
Jules A. Desmeules ◽  
Youssef Daali
Keyword(s):  
Clinical Trial ◽  
Formic Acid ◽  
Human Plasma ◽  
Active Metabolite ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Studies ◽  
Healthy Male ◽  
Coronary Syndrome ◽  
Healthy Male Volunteers ◽  
Male Volunteers

Background: Ticagrelor is a highly recommended new antiplatelet agent for the treatment of patients with acute coronary syndrome at moderate or high ischemic risk. There is a real need for rapid and accurate analytical methods for ticagrelor determination in biological fluids for pharmacokinetic studies. In this study, a sensitive and specific LC-MS method was developed and validated for quantification of ticagrelor and its Active Metabolite (AM) in human plasma over expected clinical concentrations. Methods: Samples were handled by Liquid-Liquid Extraction (LLE). A linear gradient was applied with a mobile phase composed of formic acid 0.1% and acetonitrile with 0.1% of formic acid using a C18 reversed-phase column. MS spectra were obtained by electrospray ionization in negative mode and optimized at 521.4→360.9 m/z, 477.2→361.2 m/z and 528.1→367.9 m/z transitions for ticagrelor, AM and ticagrelor-d7, respectively. Results: This method allowed rapid elution, in less than 4 minutes, and quantification of concentrations as low as 2 ng/mL for ticagrelor and 1 ng/mL for AM using only 100 μL of human plasma. LLE using hexane/ethyl acetate (50/50) was an optimal compromise in terms of extraction recovery and endogenous compounds interference. Trueness values of 87.8% and 89.5% and precisions of 84.1% and 93.8% were obtained for ticagrelor and AM, respectively. Finally, the usefulness of the method was assessed in a clinical trial where a single 180 mg ticagrelor was orally administered to healthy male volunteers. Pharmacokinetic parameters of ticagrelor and its active metabolite were successfully determined. Conclusion: A sensitive and specific quantification LC-MS-MS method was developed and validated for ticagrelor and its active metabolite determination in human plasma. The method was successfully applied to a clinical trial where a single ticagrelor 180 mg dose was orally administered to healthy male volunteers. The described method allows quantification of concentrations as low as 2 ng/mL of ticagrelor and 1 ng/mL of the metabolite using only 100 μL of plasma.

Drug Interactions with Warfarin: Studies with Dichloralphenazone, Chloral Hydrate and Phenazone (Antipyrine)

1971 ◽  
Vol 40 (4) ◽  
pp. 351-364 ◽  
Author(s):  
A. Breckenridge ◽  
M. L'E. Orme ◽  
S. Thorgeirsson ◽  
D. S. Davies ◽  
R. V. Brooks
Keyword(s):  
Endoplasmic Reticulum ◽  
Steady State ◽  
Urinary Excretion ◽  
Binding Sites ◽  
Half Life ◽  
Chloral Hydrate ◽  
Maximal Velocity ◽  
Protein Binding Sites ◽  
Drug Oxidation ◽  
State Plasma

1. Administration of dichloralphenazone, a complex of chloral hydrate and phenazone (antipyrine) caused a fall in steady-state plasma warfarin concentration and loss of anticoagulant control in five subjects. 2. This effect of dichloralphenazone is due to stimulation of the drug-oxidizing enzymes of the liver endoplasmic reticulum by antipyrine, the non-hypnotic part of the complex. Administration of antipyrine caused a fall in steady-state plasma warfarin concentration in five subjects, a shortening of the plasma warfarin half-life, with increased urinary excretion of the metabolites of 14C-labelled warfarin in two subjects and increased urinary excretion of 6β-hydroxycortisol which is formed in the liver endoplasmic reticulum. 3. Administration of chloral hydrate, the hypnotic part of dichloralphenazone, caused no change in anticoagulant control but a fall in steady-state plasma warfarin concentration in five subjects. This is due to the accumulation of trichloroacetic acid which displaces warfarin from plasma protein binding sites. 4. Individual differences in the extent of enzyme induction have been shown to be related to the subjects' rates of drug oxidation. 5. In the rat administration of dichloralphenazone and antipyrine, but not chloral hydrate, caused shortening of pentobarbitone sleeping time and of the plasma [14C]pentobarbitone half-life, shortening of the zoxazolamine paralysis time and increase in the maximal velocity of N-demethylation of ethylmorphine.

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