Stability of Warfarin in Spiked-Saliva Using the Fluorometric HPLC Method

2021 ◽  
Vol 1162 ◽  
pp. 180-190
Author(s):  
Vitarani Dwi Ananda Ningrum ◽  
Levia Chitra Dewi ◽  
Ari Wibowo
Keyword(s):  
Biological Fluid ◽  
Therapeutic Index ◽  
Storage Condition ◽  
Hplc Method ◽  
Therapeutic Drug ◽  
Excitation Wavelength ◽  
Narrow Therapeutic Index ◽  
Standard Curve ◽  
Thaw Cycle ◽  
Freeze Thaw Cycle

Warfarin is an anticoagulant with a narrow therapeutic index ranging from 1-10 µg/mL as well as the ability to distribute into saliva. Therefore, saliva can be selected as an alternative biological fluid in warfarin bioanalysis of therapeutic drug monitoring (TDM) since it is easier and more acceptable, particularly among pediatric and geriatric patients. Stability is an important part of the bioanalysis of warfarin in TDM services. This study aims to conduct a stability of warfarin in spiked-saliva using Fluorometric HPLC at an excitation wavelength of 310 nm and 390 nm emission. Analytes were separated using phosphate buffer:methanol as the mobile phase with a flow rate of 1.0 mL/min and an injection volume of 20µL as well as 150mmx4.5mm C18 as the stationary phase. The standard curve of warfarin with a concentration range of 0-20 ng/mL resulted in a correlation coefficient of 0.999. This study showed that the warfarin stock solution was stable at both 25°C and 4°C for 24 hours and 21 days, respectively. Meanwhile, warfarin in the saliva matrix also remained stable at 25°C for 24 hours and in a storage condition of -20°C for 21 days. In this research, the sample of saliva from patients administered with warfarin that has been treated with a maximum freeze-thaw cycle of 3-fold or 24 hours after preparation could consistently provide accurate data to be used as an approach to making a decision on dosage adjustment and diagnosis of warfarin toxicity in the clinical setting.

scholarly journals Case Report: Low Hematocrit Leading to Tacrolimus Toxicity

2021 ◽  
Vol 12 ◽  
Author(s):  
Alexandre Piletta-Zanin ◽  
Aurélie De Mul ◽  
Nathalie Rock ◽  
Pierre Lescuyer ◽  
Caroline F. Samer ◽  
...  
Keyword(s):  
Whole Blood ◽  
Calcineurin Inhibitor ◽  
Plasma Concentrations ◽  
Therapeutic Index ◽  
Therapeutic Drug ◽  
Pharmacokinetic Variability ◽  
Narrow Therapeutic Index ◽  
Low Concentrations ◽  
Monitoring Procedure ◽  
Trough Concentrations

Tacrolimus is a calcineurin inhibitor characterized by a narrow therapeutic index and high intra- and inter-individual pharmacokinetic variability. Therapeutic drug monitoring in whole-blood is the standard monitoring procedure. However, tacrolimus extensively binds to erythrocytes, and tacrolimus whole-blood distribution and whole-blood trough concentrations are strongly affected by hematocrit. High whole-blood tacrolimus concentrations at low hematocrit may result in high unbound plasma concentrations and increased toxicity. We present the case of a 16-year-old girl with kidney and liver transplant in whom low concentrations of tacrolimus in the context of low hematocrit led to significant increase in the dosage of tacrolimus and participate, along with a genetic polymorphism of ABCB1, in nephrotoxicity.

Applications and challenges in therapeutic drug monitoring of cancer treatment: A review

2020 ◽  
pp. 107815522097904
Author(s):  
Bushra Salman ◽  
Murtadha Al-Khabori
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Anticancer Agents ◽  
Drug Monitoring ◽  
Cancer Therapeutics ◽  
Therapeutic Index ◽  
Therapeutic Drug ◽  
Narrow Therapeutic Index ◽  
Dose Individualization ◽  
Therapeutic Outcomes ◽  
Wide Variability

Most anticancer agents show wide variability in pharmacokinetics (PK) and have a narrow therapeutic index which makes fixed dosing suboptimal. To achieve the best therapeutic outcomes with these agents, many studies have postulated using PK or therapeutic drug monitoring (TDM)-guided dosing. However, multiple factors contribute to the variability in PKs making the application of TDM in practice challenging. Also, despite the known association with clinical outcomes, standard guidelines on PK-guided dosing are lacking for most agents. Understanding the factors that contribute to PK variability and their impact is essential for dose individualization. The purpose of this review is to discuss the factors that contribute to the PK variability of anticancer agents and the challenges faced in practice when individualizing doses for certain widely used agents. Searching the literature has identified several gaps and efforts are needed to ensure better targeting of cancer therapeutics.

scholarly journals Pharmacokinetic Disposition of Amiodarone When Given with an Intralipid Rescue Strategy

Pharmaceutics ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 539
Author(s):  
Sean N. Avedissian ◽  
Michelle Pham ◽  
Medha D. Joshi ◽  
Marc H. Scheetz ◽  
Ashkan Salamatipour ◽  
...  
Keyword(s):  
High Performance ◽  
Therapeutic Index ◽  
Hplc Method ◽  
Control Group ◽  
Swine Model ◽  
Narrow Therapeutic Index ◽  
Time Curve ◽  
Target Organs ◽  
Acute Overdose ◽  
Intravenous Amiodarone

While the antiarrhythmic drug amiodarone is commonly used in clinical practice, it has a narrow therapeutic index that can lead to acute overdose. One proposed method to deal with this toxicity is lipid emulsion therapy, which may potentially quench the free amiodarone in blood and prevent its further distribution to target organs and tissues. In this study, we utilize an established swine model to examine the effects of Intralipid™ (IL) administration for acute amiodarone toxicity. A total of 14 pigs received an overdose of intravenous amiodarone. After twenty minutes, half of the pigs (n = 7) received IL while the control group (n = 7) received normal saline. Serum concentrations of amiodarone were then analyzed using a validated high-performance liquid chromatography (HPLC) method. Noncompartmental pharmacokinetic analyses were performed on the observed concentrations. There were no statistical differences in the area under the concentration time curve (6 h) or clearance, but there was a difference in the half-life between the two groups (3.12 vs. 0.85 h, p = 0.01). The administration of IL did not statistically change the overall exposure of amiodarone in the blood in the first 6 h; however, trends toward prolonged blood retention in the IL group were seen.

scholarly journals Validated HPLC method for quantification of copanlisib in mice plasma: application to a pharmacokinetic study

ADMET & DMPK ◽  
2020 ◽  
Vol 8 (1) ◽  
pp. 113-121
Author(s):  
Ashok Zakkula ◽  
Pavan Kumar Kurakula ◽  
Sreekanth Dittakavi ◽  
Prasanthi Daram ◽  
Ram Murthi Bestha ◽  
...  
Keyword(s):  
Pharmacokinetic Study ◽  
High Performance ◽  
Internal Standard ◽  
Hplc Method ◽  
Array Detector ◽  
Extraction Solvent ◽  
Long Term Storage ◽  
Thaw Cycle ◽  
Freeze Thaw Cycle ◽  
Development And Validation

Copanlisib is a pan phosphatidylinositol 3-kinase (PI3K) inhibitor approved for follicular lymphoma. In this paper, we present the data of development and validation of a high-performance liquid chromatography (HPLC) method for the quantitation of copanlisib in mice plasma as per the FDA regulatory guideline. The method involves the extraction of copanlisib along with internal standard (IS, enasidenib) from mice plasma (100 µL) using ethyl acetate as an extraction solvent. The chromatographic resolution of copanlisib and the IS was achieved on a Hypersil Gold C18 column maintained at 40 °C using a binary gradient mobile phase [10 mM ammonium formate (pH 4.0) and acetonitrile]. The flow-rate was 0.8 mL/min. For the detection of copanlisib and the IS, the photo-diode array detector was set at λmax 310 nm. Copanlisib and the IS eluted at 6.60 and 7.80 min, respectively with a total run time of 10 min. The calibration curve was linear over a concentration range of 50 to 5000 ng/mL for copanlisib (r2³ 0.998). The results of intra- and inter-day accuracy and precision studies were within the acceptable limits. Copanlisib was stable on bench-top, in auto-sampler, up to three freeze/thaw cycle and long-term storage at -80 °C. The application of the validated method was shown in a mice pharmacokinetic study.

Determination of osteocalcin in human serum: results with two kits compared with those by a well-characterized assay.

1985 ◽  
Vol 31 (10) ◽  
pp. 1720-1723 ◽  
Author(s):  
C M Gundberg ◽  
P S Wilson ◽  
P M Gallop ◽  
A M Parfitt
Keyword(s):  
Bone Turnover ◽  
Vitamin K ◽  
Metabolic Bone Disease ◽  
Freeze Thaw ◽  
Standard Curve ◽  
Thaw Cycle ◽  
Metabolic Bone ◽  
Freeze Thaw Cycle ◽  
Dependent Protein

Abstract Osteocalcin, the vitamin K-dependent protein in bone, can also be detected in serum and is receiving increased attention as a marker for bone turnover in evaluating patients with metabolic bone disease. We compared results for patients as determined with two commercial radioimmunoassay kits (Immuno Nuclear Corp. and Seragen Inc.) and with our in-house radioimmunoassay (Methods Enzymol 107: 517, 1984). Results by our assay correlated well (r greater than 0.9) with those by both kits, but the values by the Immuno Nuclear and Seragen methods were respectively 40% and 10% lower than by our radioimmunoassay. Within-run variation (CV) for the two kit methods was respectively 7.3% and 9.8%, run-to-run CV was 9.7% and 8.6%. The standard curve was linear from 1 to 25 micrograms/L for the Immuno Nuclear kit, from 4 to 100 micrograms/L for the Seragen equilibrium method, and from 1 to 25 micrograms/L for the Seragen nonequilibrium method. A second freeze-thaw cycle reduced the serum values by 20% to 40% for both kit methods. A third freeze-thaw cycle further reduced values and eliminated any correlation among methods.

scholarly journals Validasi Metode Bioanalisis Vankomisin HCl dalam Spiked-plasma Manusia Menggunakan KCKT-UV untuk Aplikasi PKOD

2019 ◽  
Vol 19 (1) ◽  
pp. 57-70
Author(s):  
Ari Wibowo ◽  
Damas Inggil Maulidina ◽  
Wahyuni Shalatan Fitri ◽  
Vitarani Ningrum
Keyword(s):  
Staphylococcus Aureus ◽  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Therapeutic Index ◽  
Therapeutic Drug ◽  
Pharmacokinetic Variability ◽  
First Line ◽  
Narrow Therapeutic Index ◽  
Spiked Plasma

As the first-line antibiotic for the treatment of infections caused by methicillin-resistant Staphylococcus aureus  (MRSA), vancomycin has  a narrow therapeutic index with high pharmacokinetic   variability. Therefore, it is deemed necessary to examine its concentration in the blood as a strategy to monitor the fulfillment of therapeutic levels  in patients receiving vancomycin. This study aimed to validate vancomycin bioanalysis  in  spiked-human  plasma  for  the  applications  of  therapeutic  drug  monitoring  (TDM).

scholarly journals Therapeutic Drug Monitoring of Cytotoxic Drugs

2020 ◽  
Vol 10 (02) ◽  
pp. 284-291
Author(s):  
Qutaiba Ahmad Al Khames Aga ◽  
Yazan A. Bataineh ◽  
Hala Mousa Sbaih
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Malignant Tumors ◽  
Therapeutic Index ◽  
Review Article ◽  
Cytotoxic Drugs ◽  
Therapeutic Drug ◽  
Narrow Therapeutic Index ◽  
Time Curve ◽  
The Common

The majority of anticancer drugs are recognized with a narrow therapeutic index, the area under the plasma levels vs. time curve (AUC) is the common pharmacokinetic (PK) parameter, which utilizes specifically for cytotoxic drugs. Therapeutic drug monitoring (TDM) approach in these drugs has never been completely applied due to different reasons, for example, the use of combination chemotherapies for different malignant tumors, and the behavior of intracellular compounds; it is possible to eliminate these limitations by using specific concentrations of cytotoxic drugs and measure AUC after certain conditions. In this review article, we discussed the common TDM parameters, methods of analysis, and some of drug interactions for a group of cytotoxic drugs.

scholarly journals RISK MANAGEMENT OF USE DRUGS WITH NARROW THERAPEUTIC INDEX IN CLINICAL PRACTICE. Review

2019 ◽  
Vol 15 (3-4) ◽  
pp. 105-111
Author(s):  
M.V. Khaitovych
Keyword(s):  
Risk Management ◽  
Clinical Practice ◽  
Generic Drugs ◽  
Pharmacokinetic Interaction ◽  
Therapeutic Index ◽  
Therapeutic Drug ◽  
Drug Related Problems ◽  
Narrow Therapeutic Index ◽  
Scientific Publications ◽  
Metabolism Enzymes

Relevance. Today, the pharmacotherapy of many diseases is significantly expanded. However, the amount of pathological conditions associated with the use of drugs has increased. Drug related problems in some cases can be fatal and increase health care costs. It is necessary to be able to anticipate in advance the possibility of developing such conditions, to prevent them. Therefore, the analysis of the causes and mechanisms of development of these conditions is relevant. Objective. To find out the most common causes of drug related problems and consider the mechanisms of such states. Methods. Analysis of scientific publications in PubMed by keywords for the period 2001-2018. Results. The therapeutic index is the ratio of the dose that causes toxic effects in 50% of patients to the dose that causes the expected therapeutic effect in 50% of patients. The therapeutic index ≤ 3 is an indicator that defines drugs with narrow (small) therapeutic index. These drugs include insulin, digoxin, warfarin, levothyroxine, aminoglycoside antibiotics, carbamazepine, lithium, phenytoin, etc. The risks associated with these drugs are: the use of generic drugs with insufficient bioequivalence, pharmacokinetic interaction and polymorphism of genes of drug metabolism. The main mechanisms of their pharmacokinetic interaction at the stages of absorption (alteration of digestive tract motility, influence on the activity of P-glycoprotein), distribution (competition for blood plasma proteins and tissue proteins), and biotransformation (inhibition or induction of metabolism). The role of polymorphism of genes encoding the activity of isoenzymes cytochrome P450 2C9 and 1A2 and glycoprotein P in the development of adverse drug reactions of drugs with a narrow therapeutic index is presented. Conclusion. Risk management of using drugs with a narrow therapeutic index should include therapeutic drug monitoring of especially generic drugs, assessment of the risks of pharmacokinetic interaction, widespread introduction pharmacogenetic tests for determine the polymorphism of the genes of metabolism enzymes and drug transporters in the clinical practice.

Non-Invasive Extraction of Gabapentin for Therapeutic Drug Monitoring by Reverse Iontophoresis: Effect of pH, Ionic Strength, and Polyethylene Glycol 400 in the Receiving Medium

2019 ◽  
Vol 15 (6) ◽  
pp. 632-639 ◽  
Author(s):  
Tapan Kumar Giri ◽  
Subhasis Chakrabarty ◽  
Bijaya Ghosh
Keyword(s):  
Polyethylene Glycol ◽  
Ionic Strength ◽  
Plasma Concentrations ◽  
Therapeutic Index ◽  
Therapeutic Drug ◽  
Narrow Therapeutic Index ◽  
Polyethylene Glycol 400 ◽  
Reverse Iontophoresis ◽  
Non Invasive ◽  
Barrier Membrane

Background: Monitoring of plasma concentrations is a necessity for narrow therapeutic index potent drugs. Development of non-invasive methods can save the patients from the trauma of needles and hence is considered as a research priority. Introduction: Gabapentin, an anti-epileptic drug requires therapeutic monitoring because of its narrow therapeutic index. The objective of the study was to develop a suitable method for the non-invasive extraction of gabapentin for the same. Methods: Transdermal reverse iontophoresis was performed using pig ear skin as a barrier membrane. Three compartment iontophoretic cells were used for the extraction study. Extractions were carried out under low intensity electric field (current intensity- 0.5 mA/cm2, electrical field approximately 5 V). The donor compartment was charged with aqueous gabapentin (10 µg/ml in phosphate buffer of pH 7.4). For studying the effect of receiving vehicle (pH, ionic strength, and enhancer) on the extraction efficiency of gabapentin, the two receiver chambers were charged with media having varying concentration of these factors. Drug content was determined by HPLC. Results: Compared to other pHs, cumulative extraction of gabapentin at pH 5 was significantly higher at both anode and cathode (p<0.001). At low ionic strength, extraction of gabapentin increased linearly with the increase in concentration of ions up to a certain value but at very high ionic strength the pattern reversed. Similar results were obtained with enhancer (polyethylene glycol 400). Extraction increased with increase in polyethylene glycol 400 up to 3% and then decreased. Conclusion: Extraction flux can be optimized by manipulation of the receiver media.

Deficiencies of the FDA in Evaluating Generic Formulations: Addressing Narrow Therapeutic Index Drugs

2012 ◽  
Vol 38 (4) ◽  
pp. 667-689 ◽  
Author(s):  
Michelle Hottinger ◽  
Bryan A. Liang
Keyword(s):  
Generic Drugs ◽  
Therapeutic Index ◽  
The United States ◽  
Additional Patient ◽  
Therapeutic Drug ◽  
Narrow Therapeutic Index ◽  
Safety Issues ◽  
Potential Safety ◽  
Mental Health Treatments ◽  
Narrow Therapeutic Index Drugs

Generic drugs represent a significant portion of the medical arsenal in treating disease. As copies of originator drugs, these drugs have been permitted abbreviated approval under the Hatch-Waxman Act. Yet with the current cost focus upon generic formulations, potential safety issues with generics have arisen. Although there is an established criterion of “bioequivalence” that generic formulations must demonstrate, narrow-therapeutic index drugs for sensitive clinical circumstances such as epilepsy, antiplatelet therapies, and mental health treatments may require different regulatory treatment than other generic drugs. Further, in these circumstances, differences in generic formulations may lead to adverse clinical outcomes due to less stringent bioequivalence tolerances. Yet there is no mandate for comparison between different generic formulations. Countries outside the United States advocate for narrowing tolerance ranges for these high risk health situations and the drugs for their treatment. We argue in this paper that additional patient safety matters must be taken into account for narrow therapeutic disease drugs, and regulatory bodies should emphasize greater tightness in bioequivalence before these narrow-therapeutic drug generic formulations are approved.

Sign in / Sign up

Export Citation Format

Share Document