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.

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.

scholarly journals Bidirectional Influences of Cranberry on the Pharmacokinetics and Pharmacodynamics of Warfarin with Mechanism Elucidation

Nutrients ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 3219
Author(s):  
Chung-Ping Yu ◽  
Meng-Syuan Yang ◽  
Pei-Wen Hsu ◽  
Shiuan-Pey Lin ◽  
Yu-Chi Hou
Keyword(s):  
Breast Cancer Resistance Protein ◽  
Plasma Concentrations ◽  
Therapeutic Index ◽  
Cancer Resistance ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Narrow Therapeutic Index ◽  
Combined Use ◽  
Ingestion Time ◽  
Resistance Protein ◽  
Metabolizing Enzyme

Cranberry is a dietary supplement popularly used for the prophylaxis of urinary tract infection. Interestingly, cranberry–warfarin interactions in clinical reports have shown bidirectional outcomes. (±) Warfarin, a widely prescribed anticoagulant, but with a narrow therapeutic index, contains equal amounts of S- and R-warfarin, of which S-warfarin is more active. The aim of this study was to investigate the effects of different ingestion times of cranberry on the pharmacokinetics and pharmacodynamics of warfarin. Rats were orally administered (±) warfarin (0.2 mg/kg) with and without cranberry (5.0 g/kg) at 0.5 h prior to the warfarin, and at 10 h after the warfarin. The plasma concentrations of S- and R-warfarin were determined by LC/MS. The results indicate that cranberry ingested at 0.5 h before (±) warfarin significantly decreased the systemic exposures of S-warfarin and R-warfarin. Conversely, when cranberry was ingested at 10 h after (±) warfarin, the elimination of S-warfarin was significantly inhibited, and the anticoagulation effect of (±) warfarin was significantly enhanced. The results of the mechanism studies indicate that cranberry activated the breast cancer resistance protein (BCRP), which mediated the efflux transports of S-warfarin and R-warfarin. Moreover, the metabolites of cranberry inhibited cytochrome P450 (CYP) 2C9, the main metabolizing enzyme for S-warfarin. In conclusion, cranberry affected the pharmacokinetics of (±) warfarin in a bidirectional manner by activating the BCRP by CJ during absorption and inhibiting the BCRP and CYP2C9 by CMs during elimination, depending on the ingestion time of CJ. The combined use of cranberry with warfarin should be avoided.

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.

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.

Understanding Therapeutic Equivalence in Epilepsy

CNS Spectrums ◽  
2010 ◽  
Vol 15 (2) ◽  
pp. 112-123 ◽  
Author(s):  
Raman Sankar ◽  
Tracy A. Glauser
Keyword(s):  
Drug Exposure ◽  
Plasma Concentrations ◽  
Therapeutic Index ◽  
Optimal Level ◽  
Dose Titration ◽  
Regulatory Agencies ◽  
Negative Consequences ◽  
Narrow Therapeutic Index ◽  
Clinical Conditions ◽  
Patients With Epilepsy

ABSTRACTThe issues surrounding generic drug substitution in patients with epilepsy are complex.The substitution of one formulation of an antiepileptic drug (AED) for another is controversial. Well-reasoned and defensible cases can be made both for and against such substitution. Although regulatory agencies require that generic and proprietary drugs have similar pharmacokinetic bioequivalence data, their therapeutic efficacy may not necessarily be identical. The paroxysmal nature of epilepsy, the narrow therapeutic index of some AEDs, the need to. individualize therapy to achieve seizure control, and the negative consequences of uncontrolled epilepsy distinguishes epilepsy from other clinical conditions. Epilepsy management with AEDs requires careful dose titration and consistent drug exposure at the optimal level for each patient, which can be altered if a different formulation of the AED is substituted. Unexpected variability in plasma concentrations could occur when a patient who has been receiving one formulation of an AED (generic or brand) receives an alternate formulation.Thus, no substitutions should be made for people with epilepsy without the knowledge and approval of the prescribing physician. Patients should be consulted about the substitution, with all risks and benefits carefully explained.

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.

Enzyme autoinduction by mitotane supported by population pharmacokinetic modeling in a large cohort of adrenocortical carcinoma patients

2018 ◽  
Vol 179 (5) ◽  
pp. 287-297 ◽  
Author(s):  
U Arshad ◽  
M Taubert ◽  
M Kurlbaum ◽  
S Frechen ◽  
S Herterich ◽  
...  
Keyword(s):  
Adrenocortical Carcinoma ◽  
Pharmacokinetic Model ◽  
Structural Model ◽  
Plasma Concentrations ◽  
Therapeutic Index ◽  
Volume Of Distribution ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
High Dose ◽  
Population Pharmacokinetic Modeling

ObjectiveMitotane is used for the treatment of adrenocortical carcinoma. High oral daily doses of typically 1–6 g are required to attain therapeutic concentrations. The drug has a narrow therapeutic index and patient management is difficult because of a high volume of distribution, very long elimination half-life and drug interaction through induction of metabolizing enzymes. The present evaluation aimed at the development of a population pharmacokinetic model of mitotane to facilitate therapeutic drug monitoring (TDM).MethodsAppropriate dosing information, plasma concentrations (1137 data points) and covariates were available from TDM of 76 adrenocortical carcinoma patients treated with mitotane. Using nonlinear mixed-effects modeling, a simple structural model was first developed, with subsequent introduction of metabolic autoinduction. Covariate data were analyzed to improve overall model predictability. Simulations were performed to assess the attainment of therapeutic concentrations with clinical dosing schedules.ResultsA one-compartment pharmacokinetic model with first order absorption was found suitable to describe the data, with an estimated central volume of distribution of 6086 L related to a high interindividual variability of 81.5%. Increase in clearance of mitotane during treatment could be modeled by a linear enzyme autoinduction process. BMI was found to have an influence upon disposition kinetics of mitotane. Model simulations favor a high-dose regimen to rapidly attain therapeutic concentrations, with the first TDM suggested on day 16 of treatment to avoid systemic toxicity.ConclusionThe proposed model describes mitotane pharmacokinetics and can be used to facilitate therapy by predicting plasma concentrations.

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.

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