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 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).

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 Software for Dosage Individualization of Voriconazole for Immunocompromised Patients

2013 ◽  
Vol 57 (4) ◽  
pp. 1888-1894 ◽  
Author(s):  
William W. Hope ◽  
Michael VanGuilder ◽  
J. Peter Donnelly ◽  
Nicole M. A. Blijlevens ◽  
Roger J. M. Brüggemann ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Fungal Infections ◽  
Plasma Concentrations ◽  
Therapeutic Drug ◽  
Cell Transplant ◽  
Multiple Model ◽  
Pharmacokinetic Variability ◽  
Hematopoietic Stem ◽  
Wide Range

ABSTRACTThe efficacy of voriconazole is potentially compromised by considerable pharmacokinetic variability. There are increasing insights into voriconazole concentrations that are safe and effective for treatment of invasive fungal infections. Therapeutic drug monitoring is increasingly advocated. Software to aid in the individualization of dosing would be an extremely useful clinical tool. We developed software to enable the individualization of voriconazole dosing to attain predefined serum concentration targets. The process of individualized voriconazole therapy was based on concepts of Bayesian stochastic adaptive control. Multiple-model dosage design with feedback control was used to calculate dosages that achieved desired concentration targets with maximum precision. The performance of the software program was assessed using the data from 10 recipients of an allogeneic hematopoietic stem cell transplant (HSCT) receiving intravenous (i.v.) voriconazole. The program was able to model the plasma concentrations with a high level of precision, despite the wide range of concentration trajectories and interindividual pharmacokinetic variability. The voriconazole concentrations predicted after the last dosages were largely concordant with those actually measured. Simulations provided an illustration of the way in which the software can be used to adjust dosages of patients falling outside desired concentration targets. This software appears to be an extremely useful tool to further optimize voriconazole therapy and aid in therapeutic drug monitoring. Further prospective studies are now required to define the utility of the controller in daily clinical practice.

Plasma vs whole blood for therapeutic drug monitoring of patients receiving FK 506 for immunosuppression

1994 ◽  
Vol 40 (12) ◽  
pp. 2247-2253 ◽  
Author(s):  
M Winkler ◽  
B Ringe ◽  
J Baumann ◽  
M Loss ◽  
K Wonigeit ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Enzyme Immunoassay ◽  
Drug Monitoring ◽  
Whole Blood ◽  
Plasma Concentrations ◽  
Therapeutic Monitoring ◽  
Therapeutic Drug ◽  
Fk 506 ◽  
Blood Samples ◽  
The Matrix

Abstract By retrospective analysis of 13,000 blood samples obtained from 248 patients receiving FK 506 therapy, we compared the suitability of plasma with that of whole blood as the matrix for therapeutic drug monitoring of FK 506. The plasma concentrations did not correlate with the concentrations in whole blood (r = 0.56). In contrast to plasma samples (analyzed by enzyme immunoassay), FK 506 was detectable in all whole-blood samples (analyzed by enzyme immunoassay/microparticle enzyme immunoassay). The inter- and intraindividual variations of FK 506 measurements were greater in plasma than in whole blood. Moreover, plasma concentrations correlated only poorly with clinical events. There was a tendency to greater plasma concentrations being measured during episodes of toxicity, but no clear difference was evident between stable course and rejection. In whole-blood specimens, a correlation between reduced or increased FK 506 concentrations and rejection or toxicity, respectively, was observed. The discriminatory power of whole-blood values was greater for the differentiation between toxicity and stable course than between rejection and stable course. We therefore recommend whole blood rather than plasma as the matrix for therapeutic monitoring of FK 506 concentrations.

scholarly journals Population pharmacokinetics of dolutegravir: influence of drug–drug interactions in a real-life setting

2019 ◽  
Vol 74 (9) ◽  
pp. 2690-2697 ◽  
Author(s):  
Catalina Barcelo ◽  
Manel Aouri ◽  
Perrine Courlet ◽  
Monia Guidi ◽  
Dominique L Braun ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Plasma Concentrations ◽  
Real Life ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Genetic Barrier ◽  
Good Tolerability ◽  
Standard Dosage ◽  
Real Life Setting ◽  
Trough Concentrations

Abstract Objectives Dolutegravir is widely prescribed owing to its potent antiviral activity, high genetic barrier and good tolerability. The aim of this study was to characterize dolutegravir’s pharmacokinetic profile and variability in a real-life setting and to identify individual factors and co-medications affecting dolutegravir disposition. Methods A population pharmacokinetic model was developed using NONMEM®. Relevant demographic factors, clinical factors and co-medications were tested as potential covariates. Simulations based on the final model served to compare expected dolutegravir concentrations under standard and alternative dosage regimens in the case of drug–drug interactions. Results A total of 620 dolutegravir plasma concentrations were collected from 521 HIV-infected individuals under steady-state conditions. A one-compartment model with first-order absorption and elimination best characterized dolutegravir pharmacokinetics. Typical dolutegravir apparent clearance (CL/F) was 0.93 L/h with 32% between-subject variability, the apparent volume of distribution was 20.2 L and the absorption rate constant was fixed to 2.24 h−1. Older age, higher body weight and current smoking were associated with higher CL/F. Atazanavir co-administration decreased dolutegravir CL/F by 38%, while darunavir modestly increased CL/F by 14%. Rifampicin co-administration showed the largest impact on CL/F. Simulations suggest that average dolutegravir trough concentrations are 63% lower after 50 mg/12h with rifampicin compared with a standard dosage of 50 mg/24h without rifampicin. Average trough concentrations after 100 mg/24h and 100 mg/12h with rifampicin are 92% and 25% lower than the standard dosage without rifampicin, respectively. Conclusions Patients co-treated with dolutegravir and rifampicin might benefit from therapeutic drug monitoring and individualized dosage increase, up to 100 mg/12 h in some cases.

scholarly journals Exploring sirolimus pharmacokinetic variability using data available from the routine clinical care of renal transplant patients – population pharmacokinetic approach

2019 ◽  
Vol 38 (3) ◽  
pp. 323-331
Author(s):  
Bojana Golubović ◽  
Katarina Vučićević ◽  
Dragana Radivojević ◽  
Sandra Vezmar Kovačević ◽  
Milica Prostran ◽  
...  
Keyword(s):  
Liver Function ◽  
Population Analysis ◽  
Clinical Care ◽  
External Validation ◽  
Therapeutic Index ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Variability ◽  
Dose Individualization ◽  
Transplant Patients

Summary Background Due to wide intra- and inter-individual pharmacokinetic variability and narrow therapeutic index of sirolimus, the therapeutic drug monitoring (TDM) of sirolimus with detailed biochemical and clinical monitoring is necessary for dose individualization in kidney transplant patients. The purpose of the study was to explore and identify factors that contribute to pharmacokinetic variability by developing and validating a population model using routine TDM data and routinely monitored biochemical and clinical parameters. Methods The data obtained by routine monitoring of 38 patients over a period of one year from the sirolimus treatment initiation, were collected from patients’ records. Population analysis was performed using the software NONMEM®. The validity of the model was tested by the internal and external validation techniques. Results The pharmacokinetic variability was partially explained with patient’s age and liver function. CL/F was found to decrease with age. According to the developed model, sirolimus CL/F decreases by, in average, 37% in patients with aspartate aminotransferase (AST) greater than 37 IU/L. The internal and external validation confirmed the satisfactory prediction of the developed model. Conclusions The population modeling of routinely monitored data allowed quantification of the age and liver function influence on sirolimus CL/F. According to the final model, patients with compromised liver function expressed via AST values require careful monitoring and dosing adjustments. Proven good predictive performance makes this model a useful tool in everyday clinical practice.

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.

scholarly journals CYP2C19 phenotype and body-weight-guided voriconazole initial dose in infants and children after hematopoietic cell transplantation

2021 ◽  
Author(s):  
Takuto Takahashi ◽  
Maryam A. Mohamud ◽  
Angela R. Smith ◽  
Pamala A. Jacobson ◽  
Mutaz M. Jaber ◽  
...  
Keyword(s):  
Body Weight ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Age Groups ◽  
Model Performance ◽  
Therapeutic Index ◽  
Hematopoietic Cell ◽  
Therapeutic Drug ◽  
Dosing Regimens ◽  
Trough Concentrations

Background : Prophylactic voriconazole use is recommended in children undergoing hematopoietic cell transplantation (HCT). Dosing considerations are essential due to its narrow therapeutic index. Known covariates do not sufficiently explain large interindividual pharmacokinetic (PK) variability of voriconazole. Moreover, knowledge of voriconazole PK for age <2 years is limited. Objectives : We investigated genetic and clinical covariate association with voriconazole interindividual PK variability and subsequently simulated dosing regimens in children. Methods : This study was conducted as a part of a single-institution, phase I study of intravenous voriconazole in children undergoing HCT. We conducted a population PK analysis and tested covariate effects on voriconazole PK, including 67 genetic variants and clinical variables. Results : We analyzed plasma voriconazole and n-oxide metabolite concentrations from 58 children aged <21 years (n=12 in age <2 years). A two-compartment parent mixed linear/nonlinear model best described our data. CYP2C19 phenotype and body weight were significant covariates (both p<0.05). Our model performance in age <2 years was comparable to other age groups. Simulation of the final model suggested the following dosages to attain target steady-state trough concentrations of 1.5 - 5.0 mg/L in CYP2C19 normal phenotype: 16 mg/kg (weight <15 kg), 12 mg/kg (weight 15-30 kg), 10 mg/kg (weight >30 kg), whereas dosages were 33-50% lower for CYP2C19 poor/intermediate and 25-50% higher for CYP2C19 rapid/ultrarapid phenotypes. Conclusions : We propose a new starting dosage regimen, combined with therapeutic drug monitoring for intravenous voriconazole in children of all ages. Future studies should validate this dosing regimen.

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.

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