Therapeutic Drug Monitoring and Pharmacokinetics-Based Individualization of Drug Therapy

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Pharmacokinetics and Pharmacodynamics".

Deadline for manuscript submissions: closed (28 February 2023) | Viewed by 49322

Special Issue Editors


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Guest Editor
Department of Laboratory Medicine, Semmelweis University, Nagyvárad tér 4, H-1089 Budapest, Hungary
Interests: pediatrics; biostatistics; laboratory medicine; pharmacogenomics; renal elimination
Special Issues, Collections and Topics in MDPI journals

E-Mail Website
Guest Editor
Department of Laboratory Medicine, Semmelweis University, Nagyvárad tér 4, H-1089 Budapest, Hungary
Interests: therapeutic drug monitoring; liquid chromatography-mass spectrometry; clinical pharmacokinetics; microsampling
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues, 

The field of therapeutic drug monitoring (TDM) is experiencing a revolution; it is becoming an important supporting tool for clinical decision making in various fields of pharmacotherapy. From the simplified evaluation of drug concentrations collected at the trough or, in certain cases, at other time points following drug administration, based on therapeutic ranges, this field has improved into one with a focus on providing in vivo pharmacokinetic information for the personalized modulation of drug regimens. The introduction of novel analytical and sampling technologies and the availability of modern bioinformatic tools have made important contributions to this rapid development.

The aim of this Special Issue is to deliver up-to-date, state-of-the-art research regarding the analysis of drugs and their metabolites in clinical samples, the use of novel sampling technologies including microsampling, and the employment of bioinformatic applications to translate TDM results to clinically relevant information. The application of these tools for use in assessing patient adherence, countering adverse effects and events, establishing increased effectiveness and the safety of drug therapy, improving the cost-efficiency of treatments, or identifying patient sub-populations based on TDM, among other applications, are of great interest.

Prof. Dr. Barna Vasarhelyi
Dr. Gellért Balázs Karvaly
Guest Editors

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Keywords

  • precision pharmacotherapy
  • population pharmacokinetic modeling
  • probability of target attainment
  • pharmacokinetic–pharmacodynamic index
  • active metabolite
  • adaptive control
  • patient adherence
  • phromatography
  • mass spectrometry
  • microsampling

Published Papers (24 papers)

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19 pages, 9951 KiB  
Article
Modeling Pharmacokinetics in Individual Patients Using Therapeutic Drug Monitoring and Artificial Population Quasi-Models: A Study with Piperacillin
by Gellért Balázs Karvaly, István Vincze, Michael Noel Neely, István Zátroch, Zsuzsanna Nagy, Ibolya Kocsis and Csaba Kopitkó
Pharmaceutics 2024, 16(3), 358; https://doi.org/10.3390/pharmaceutics16030358 - 04 Mar 2024
Viewed by 685
Abstract
Population pharmacokinetic (pop-PK) models constructed for model-informed precision dosing often have limited utility due to the low number of patients recruited. To augment such models, an approach is presented for generating fully artificial quasi-models which can be employed to make individual estimates of [...] Read more.
Population pharmacokinetic (pop-PK) models constructed for model-informed precision dosing often have limited utility due to the low number of patients recruited. To augment such models, an approach is presented for generating fully artificial quasi-models which can be employed to make individual estimates of pharmacokinetic parameters. Based on 72 concentrations obtained in 12 patients, one- and two-compartment pop-PK models with or without creatinine clearance as a covariate were generated for piperacillin using the nonparametric adaptive grid algorithm. Thirty quasi-models were subsequently generated for each model type, and nonparametric maximum a posteriori probability Bayesian estimates were established for each patient. A significant difference in performance was found between one- and two-compartment models. Acceptable agreement was found between predicted and observed piperacillin concentrations, and between the estimates of the random-effect pharmacokinetic variables obtained using the so-called support points of the pop-PK models or the quasi-models as priors. The mean squared errors of the predictions made using the quasi-models were similar to, or even considerably lower than those obtained when employing the pop-PK models. Conclusion: fully artificial nonparametric quasi-models can efficiently augment pop-PK models containing few support points, to make individual pharmacokinetic estimates in the clinical setting. Full article
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15 pages, 4600 KiB  
Article
Optimizing Vancomycin Therapy in Critically Ill Children: A Population Pharmacokinetics Study to Inform Vancomycin Area under the Curve Estimation Using Novel Biomarkers
by Kevin J. Downes, Athena F. Zuppa, Anna Sharova and Michael N. Neely
Pharmaceutics 2023, 15(5), 1336; https://doi.org/10.3390/pharmaceutics15051336 - 25 Apr 2023
Cited by 2 | Viewed by 1411
Abstract
Area under the curve (AUC)-directed vancomycin therapy is recommended, but Bayesian AUC estimation in critically ill children is difficult due to inadequate methods for estimating kidney function. We prospectively enrolled 50 critically ill children receiving IV vancomycin for suspected infection and divided them [...] Read more.
Area under the curve (AUC)-directed vancomycin therapy is recommended, but Bayesian AUC estimation in critically ill children is difficult due to inadequate methods for estimating kidney function. We prospectively enrolled 50 critically ill children receiving IV vancomycin for suspected infection and divided them into model training (n = 30) and testing (n = 20) groups. We performed nonparametric population PK modeling in the training group using Pmetrics, evaluating novel urinary and plasma kidney biomarkers as covariates on vancomycin clearance. In this group, a two-compartment model best described the data. During covariate testing, cystatin C-based estimated glomerular filtration rate (eGFR) and urinary neutrophil gelatinase-associated lipocalin (NGAL; full model) improved model likelihood when included as covariates on clearance. We then used multiple-model optimization to define the optimal sampling times to estimate AUC24 for each subject in the model testing group and compared the Bayesian posterior AUC24 to AUC24 calculated using noncompartmental analysis from all measured concentrations for each subject. Our full model provided accurate and precise estimates of vancomycin AUC (bias 2.3%, imprecision 6.2%). However, AUC prediction was similar when using reduced models with only cystatin C-based eGFR (bias 1.8%, imprecision 7.0%) or creatinine-based eGFR (bias −2.4%, imprecision 6.2%) as covariates on clearance. All three model(s) facilitated accurate and precise estimation of vancomycin AUC in critically ill children. Full article
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11 pages, 447 KiB  
Article
Dried Blood Spot Sampling to Assess Rifampicin Exposure and Treatment Outcomes among Native and Non-Native Tuberculosis Patients in Paraguay: An Exploratory Study
by Samiksha Ghimire, Gladys Molinas, Arturo Battaglia, Nilza Martinez, Luis Gómez Paciello, Sarita Aguirre, Jan-Willem C. Alffenaar, Marieke G. G. Sturkenboom and Cecile Magis-Escurra
Pharmaceutics 2023, 15(4), 1089; https://doi.org/10.3390/pharmaceutics15041089 - 29 Mar 2023
Viewed by 1026
Abstract
The aim of this study was to evaluate the difference in drug exposure of rifampicin in native versus non-native Paraguayan populations using dried blood spots (DBS) samples collected utilizing a limited sampling strategy. This was a prospective pharmacokinetic study that enrolled hospitalized tuberculosis [...] Read more.
The aim of this study was to evaluate the difference in drug exposure of rifampicin in native versus non-native Paraguayan populations using dried blood spots (DBS) samples collected utilizing a limited sampling strategy. This was a prospective pharmacokinetic study that enrolled hospitalized tuberculosis (TB) patients from both native and non-native populations receiving oral rifampicin 10 mg/kg once-daily dosing. Steady-state DBS samples were collected at 2, 4, and 6 h after intake of rifampicin. The area under the time concentration curve 0–24 h (AUC0–24) was calculated using a Bayesian population PK model. Rifampicin AUC0–24 < 38.7 mg*h/L was considered as low. The probability of target attainment (PTA) was calculated using AUC0–24/MIC > 271 as a target and estimated MIC values of 0.125 and 0.25 mg/L. In total, 50 patients were included. Native patients (n = 30) showed comparable drug exposure to the non-natives (n = 20), median AUC0–24 24.7 (17.1–29.5 IQR) and 21.6 (15.0–35.4 IQR) mg*h/L (p = 0.66), respectively. Among total patients, only 16% (n = 8) had a rifampicin AUC0–24 > 38.7 mg*h/L. Furthermore, PTA analysis showed that only 12 (24%) of the patients met a target AUC0–24 /MIC ≥ 271, assuming an MIC of 0.125 mg/L, which plummeted to 0% at a wild-type MIC of 0.25 mg/L. We successfully used DBS and limited sampling for the AUC0–24 estimation of rifampicin. Currently, our group, the EUSAT-RCS consortium, is preparing a prospective multinational, multicenter phase IIb clinical trial evaluating the safety and efficacy of high-dose rifampicin (35 mg/kg) in adult subjects using the DBS technique for AUC0–24 estimation. Full article
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12 pages, 2569 KiB  
Article
A Method for Evaluating Robustness of Limited Sampling Strategies—Exemplified by Serum Iohexol Clearance for Determination of Measured Glomerular Filtration Rate
by Markus Hovd, Ida Robertsen, Jean-Baptiste Woillard and Anders Åsberg
Pharmaceutics 2023, 15(4), 1073; https://doi.org/10.3390/pharmaceutics15041073 - 27 Mar 2023
Cited by 1 | Viewed by 1235
Abstract
In combination with Bayesian estimates based on a population pharmacokinetic model, limited sampling strategies (LSS) may reduce the number of samples required for individual pharmacokinetic parameter estimations. Such strategies reduce the burden when assessing the area under the concentration versus time curves (AUC) [...] Read more.
In combination with Bayesian estimates based on a population pharmacokinetic model, limited sampling strategies (LSS) may reduce the number of samples required for individual pharmacokinetic parameter estimations. Such strategies reduce the burden when assessing the area under the concentration versus time curves (AUC) in therapeutic drug monitoring. However, it is not uncommon for the actual sample time to deviate from the optimal one. In this work, we evaluate the robustness of parameter estimations to such deviations in an LSS. A previously developed 4-point LSS for estimation of serum iohexol clearance (i.e., dose/AUC) was used to exemplify the effect of sample time deviations. Two parallel strategies were used: (a) shifting the exact sampling time by an empirical amount of time for each of the four individual sample points, and (b) introducing a random error across all sample points. The investigated iohexol LSS appeared robust to deviations from optimal sample times, both across individual and multiple sample points. The proportion of individuals with a relative error greater than 15% (P15) was 5.3% in the reference run with optimally timed sampling, which increased to a maximum of 8.3% following the introduction of random error in sample time across all four time points. We propose to apply the present method for the validation of LSS developed for clinical use. Full article
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14 pages, 2167 KiB  
Article
External Evaluation of Population Pharmacokinetic Models of Methotrexate for Model-Informed Precision Dosing in Pediatric Patients with Acute Lymphoid Leukemia
by Shengfeng Wang, Qiufen Yin, Minghua Yang, Zeneng Cheng and Feifan Xie
Pharmaceutics 2023, 15(2), 569; https://doi.org/10.3390/pharmaceutics15020569 - 08 Feb 2023
Cited by 3 | Viewed by 1539
Abstract
Background: Methotrexate (MTX) is a key immunosuppressant for children with acute lymphoid leukemia (ALL), and it has a narrow therapeutic window and relatively high pharmacokinetic variability. Several population pharmacokinetic (PopPK) models of MTX in ALL children have been reported, but the validity of [...] Read more.
Background: Methotrexate (MTX) is a key immunosuppressant for children with acute lymphoid leukemia (ALL), and it has a narrow therapeutic window and relatively high pharmacokinetic variability. Several population pharmacokinetic (PopPK) models of MTX in ALL children have been reported, but the validity of these models for model-informed precision dosing in clinical practice is unclear. This study set out to evaluate the predictive performance of published pediatric PopPK models of MTX using an independent patient cohort. Methods: A PubMed literature search was performed to identify suitable models for evaluation. Demographics and measurements of the validation dataset were retrospectively collected from the medical records of ALL children who had received intravenous MTX. Predictive performance for each model was assessed by visual comparison of predictions to observations, median and mean predicted error (PE), and relative root mean squared error (RMSE). Results: Six models were identified for external evaluation, carried out on a dataset containing 354 concentrations from 51 pediatrics. Model performance varied considerably from one model to another. Different models had the median PE for population and individual predictions at −33.23% to 442.04% and −25.20% to 6.52%, mean PE for population and individual predictions at −25.51% to 780.87% and 1.33% to 64.44%, and RMSE for population and individual predictions at 62.88% to 1182.24% and 63.39% to 152.25%. All models showed relatively high RMSE. Conclusions: Some of the published models showed reasonably low levels of bias but had some problems with imprecision, and extensive evaluation is needed before model application in clinical practice. Full article
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16 pages, 2533 KiB  
Article
Isavuconazole Pharmacokinetics and Pharmacodynamics in Children
by Hirsh Elhence, Kanokporn Mongkolrattanothai, Sindhu Mohandas and Michael N. Neely
Pharmaceutics 2023, 15(1), 75; https://doi.org/10.3390/pharmaceutics15010075 - 26 Dec 2022
Cited by 1 | Viewed by 1524
Abstract
Isavuconazole is a broad-spectrum azole anti-fungal not yet approved in children. We conducted a retrospective, single-center review of isavuconazole use and routine therapeutic drug monitoring in pediatric patients, extracting demographic, dosing, concentration, mortality and hepatoxicity data. We constructed a nonparametric population model using [...] Read more.
Isavuconazole is a broad-spectrum azole anti-fungal not yet approved in children. We conducted a retrospective, single-center review of isavuconazole use and routine therapeutic drug monitoring in pediatric patients, extracting demographic, dosing, concentration, mortality and hepatoxicity data. We constructed a nonparametric population model using Pmetrics. Of 26 patients, 19 (73%) were male. The mean (SD) age and weight were 12.7 (5.5) years and 50.9 (26.8) kg. Eighty percent received between 9.7 and 10.6 mg/kg per dose. Ten (38%) subjects had proven fungal disease and eight (31%) had probable disease, mostly with Candida and Aspergillus spp. The predicted steady-state isavuconazole concentrations in our patients were similar to previous reports in children and adults, and simulations with the proposed dosing of 10 mg/kg/dose every 8 h for 2 days followed by once daily maintenance matched effective adult exposures. Attributable mortality (5 of 11 deaths) was associated with steady-state daily AUC < 60 mg∗h/L and higher AST/ALT with trough concentrations > 5 mg/L. Neither dose nor trough alone correlated well with AUC, but AUC can be estimated with one sample 10 h after the first maintenance dose or a trough concentration, if combined with a Bayesian approach or a peak and trough without a Bayesian approach. Full article
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11 pages, 1822 KiB  
Article
Total and Unbound Pharmacokinetics of Cefiderocol in Critically Ill Patients
by Noël Zahr, Saik Urien, Benoit Llopis, Gaëlle Noé, Nadine Tissot, Kevin Bihan, Helga Junot, Clémence Marin, Bochra Mansour, Charles-Edouard Luyt, Alexandre Bleibtreu and Christian Funck-Brentano
Pharmaceutics 2022, 14(12), 2786; https://doi.org/10.3390/pharmaceutics14122786 - 13 Dec 2022
Cited by 2 | Viewed by 1789
Abstract
Background: Cefiderocol is a siderophore cephalosporin antibiotic active against Gram-negative bacteria, including extended-spectrum beta-lactamase and carbapenemase-producing strains. The pharmacokinetics of cefiderocol has been studied in healthy subjects and particularly in phase II and III studies. This retrospective study investigated intravenous cefiderocol population pharmacokinetics [...] Read more.
Background: Cefiderocol is a siderophore cephalosporin antibiotic active against Gram-negative bacteria, including extended-spectrum beta-lactamase and carbapenemase-producing strains. The pharmacokinetics of cefiderocol has been studied in healthy subjects and particularly in phase II and III studies. This retrospective study investigated intravenous cefiderocol population pharmacokinetics in adult patients treated by cefiderocol. Methods: We studied 55 consecutive patients hospitalized in an intensive care unit. Cefiderocol plasma samples were obtained on different occasions during treatment. Plasma concentration was assayed using mass spectrometry. Data analysis was performed using a non-linear mixed-effect approach via Monolix 2020R1. Results: A total of 205 plasma samples were obtained from 55 patients. Eighty percent of patients received cefiderocol for ventilator-associated pneumonia due to carbapenem-resistant Pseudomonas aeruginosa infection. Cefiderocol concentration time-courses were best fit to a two-compartment open model with first-order elimination. Elimination clearance was positively related to renal function (estimated by the CKD formula). Adding albumin plasma binding in the model significantly improved the model assuming a ~40% unbound drug fraction given a ~40 g/L albuminemia. The final model included CKD plus cefiderocol plasma binding effects. Fat-free mass was better than total body weight to influence, via the allometric rule, clearance and volume terms, but this effect was negligible. The final clearance based on free circulating drug (CLU) for a typical patient, CKD = 90, was 7.38 L/h [relative standard error, RSE, 22%] with a between-subject variability of 0.47 [RSE 10%] (exponential distribution). Conclusion: This study showed that albumin binding and CKD effects were significant predictors of unbound and total plasma cefiderocol concentrations. Our results indicate that individual adjustment of cefiderocol can be used to reach high minimum inhibitory concentrations based on an estimation of unbound drug concentration and optimize therapeutic efficacy. Full article
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13 pages, 1195 KiB  
Article
Effect of Laparoscopic Sleeve Gastrectomy on the Pharmacokinetics of Oral Omeprazole Using a Population Approach
by Kaifeng Chen, Ping Luo, Shaihong Zhu, Yaqi Lin, Nan Yang, Shuqi Huang, Qin Ding, Liyong Zhu and Qi Pei
Pharmaceutics 2022, 14(10), 1986; https://doi.org/10.3390/pharmaceutics14101986 - 20 Sep 2022
Viewed by 1763
Abstract
Omeprazole is commonly prescribed to obese patients and patients after laparoscopic sleeve gastrectomy (LSG). The pharmacokinetics of oral omeprazole after LSG are still unknown. Therefore, the aim of this study was to investigate the pharmacokinetics of oral omeprazole in obese patients before and [...] Read more.
Omeprazole is commonly prescribed to obese patients and patients after laparoscopic sleeve gastrectomy (LSG). The pharmacokinetics of oral omeprazole after LSG are still unknown. Therefore, the aim of this study was to investigate the pharmacokinetics of oral omeprazole in obese patients before and after LSG. A total of 331 blood samples were collected from 62 obese patients preoperatively (visit 1) followed by 41 patients 7 days post-LSG (visit 2) and 20 patients 1 month post-LSG (visit 3). Population pharmacokinetic analysis was performed using NONMEM to characterize the effect of LSG on omeprazole absorption and disposition. A one-compartment model with 12 transit absorption compartments and linear elimination successfully described the data. Compared with pre-surgery, the oral omeprazole time to maximum plasma concentration (Tmax) was reduced and maximum plasma concentration (Cmax) was higher, but the apparent clearance (CL/F) and area under the plasma concentration–time curve (AUC) were unchanged 7 days and 1 month after surgery. In addition, the CYP2C19 genotype and liver function exhibited a significant influence on omeprazole CL/F. LSG increased the rate of omeprazole absorption but did not affect omeprazole exposure. A dose of 20 mg omeprazole once daily may be adequate for relieving gastrointestinal tract discomfort at short-term follow-up post-LSG. Full article
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13 pages, 1366 KiB  
Article
Clinical Effectiveness and Pharmacokinetics of Dalbavancin in Treatment-Experienced Patients with Skin, Osteoarticular, or Vascular Infections
by Giacomo Stroffolini, Amedeo De Nicolò, Alberto Gaviraghi, Jacopo Mula, Giuseppe Cariti, Silvia Scabini, Alessandra Manca, Jessica Cusato, Silvia Corcione, Stefano Bonora, Giovanni Di Perri, Francesco Giuseppe De Rosa and Antonio D’Avolio
Pharmaceutics 2022, 14(9), 1882; https://doi.org/10.3390/pharmaceutics14091882 - 06 Sep 2022
Cited by 7 | Viewed by 1936
Abstract
Dalbavancin (DBV) is a lipoglycopeptide approved for the treatment of Gram-positive infections of the skin and skin-associated structures (ABSSSIs). Currently, its off-label use at different dosages for other infections deserves attention. This work aimed to study the clinical effectiveness and tolerability of DBV [...] Read more.
Dalbavancin (DBV) is a lipoglycopeptide approved for the treatment of Gram-positive infections of the skin and skin-associated structures (ABSSSIs). Currently, its off-label use at different dosages for other infections deserves attention. This work aimed to study the clinical effectiveness and tolerability of DBV in outpatients with ABSSSIs, osteoarticular (OA), or other infections, treated with either one or two 1500 mg doses of dalbavancin, for different scheduled periods. A liquid chromatography–tandem mass spectrometry method was used to measure total DBV concentrations. PK/PD parameters and the clinical and microbiological features of this cohort were evaluated in order to investigate the best predictors of treatment success in real-life settings. Of the 76 screened patients, 41 completed the PK study. Long-term PK was comparable to previous studies and showed significant differences between genders and dosing schedules. Few adverse events were observed, and treatment success was achieved in the vast majority of patients. Failure was associated with lower PK parameters, particularly Cmax. Concluding, we were able to describe DBV PK and predictors of treatment success in selected infections in this cohort, finding DBV Cmax as a possible candidate for therapeutic drug-monitoring purposes, as well as highlighting the dual-dose one-week-apart treatment as the optimal choice for OA infections. Full article
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10 pages, 1742 KiB  
Article
Implementation of Model-Based Dose Adjustment of Tobramycin in Adult Patients with Cystic Fibrosis
by Jérémy Reverchon, Vianney Tuloup, Romain Garreau, Viviane Nave, Sabine Cohen, Philippe Reix, Stéphane Durupt, Raphaele Nove-Josserand, Isabelle Durieu, Quitterie Reynaud, Laurent Bourguignon, Sandrine Charles and Sylvain Goutelle
Pharmaceutics 2022, 14(8), 1750; https://doi.org/10.3390/pharmaceutics14081750 - 22 Aug 2022
Viewed by 1357
Abstract
Therapeutic drug monitoring (TDM) of tobramycin is widely performed in patients with cystic fibrosis (CF), but little is known about the value of model-informed precision dosing (MIPD) in this setting. We aim at reporting our experience with tobramycin MIPD in adult patients with [...] Read more.
Therapeutic drug monitoring (TDM) of tobramycin is widely performed in patients with cystic fibrosis (CF), but little is known about the value of model-informed precision dosing (MIPD) in this setting. We aim at reporting our experience with tobramycin MIPD in adult patients with CF. We analyzed data from adult patients with CF who received IV tobramycin and had model-guided TDM during the first year of implementation of MIPD. The predictive performance of a pharmacokinetic (PK) model was assessed. Observed maximal (Cmax) and minimal (Cmin) concentrations after initial dosing were compared with target values. We compared the initial doses and adjusted doses after model-based TDM, as well as renal function at the beginning and end of therapy. A total of 78 tobramycin courses were administered in 61 patients. After initial dosing set by physicians (mean, 9.2 ± 1.4 mg/kg), 68.8% of patients did not achieve the target Cmax ≥ 30 mg/L. The PK model fit the data very well, with a median absolute percentage error of 4.9%. MIPD was associated with a significant increase in tobramycin doses (p < 0.001) without significant change in renal function. Model-based dose suggestions were wellaccepted by the physicians and the expected target attainment for Cmax was 83%. To conclude, the implementation of MIPD was effective in changing prescribing practice and was not associated with nephrotoxic events in adult patients with CF. Full article
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14 pages, 2399 KiB  
Article
Population Pharmacokinetics and Dose Optimization Based on Renal Function of Rivaroxaban in Thai Patients with Non-Valvular Atrial Fibrillation
by Noppaket Singkham, Arintaya Phrommintikul, Phongsathon Pacharasupa, Lalita Norasetthada, Siriluck Gunaparn, Narawudt Prasertwitayakij, Wanwarang Wongcharoen and Baralee Punyawudho
Pharmaceutics 2022, 14(8), 1744; https://doi.org/10.3390/pharmaceutics14081744 - 21 Aug 2022
Cited by 6 | Viewed by 2336
Abstract
Low-dose rivaroxaban has been used in Asian patients with direct oral anticoagulants (DOACs) eligible for atrial fibrillation (AF). However, there are few pharmacokinetic (PK) data in Thai patients to support precise dosing. This study aimed to develop a population PK model and determine [...] Read more.
Low-dose rivaroxaban has been used in Asian patients with direct oral anticoagulants (DOACs) eligible for atrial fibrillation (AF). However, there are few pharmacokinetic (PK) data in Thai patients to support precise dosing. This study aimed to develop a population PK model and determine the optimal rivaroxaban doses in Thai patients. A total of 240 Anti-Xa levels of rivaroxaban from 60 Thai patients were analyzed. A population PK model was established using the nonlinear mixed-effect modeling approach. Monte Carlo simulations were used to predict drug exposures at a steady state for various dosages. Proportions of patients having rivaroxaban exposure within typical exposure ranges were determined. A one-compartment model with first-order absorption best described the data. Creatinine clearance (CrCl) and body weight significantly affected CL/F and V/F, respectively. Regardless of body weight, a higher proportion of patients with CrCl < 50 mL/min receiving the 10-mg once-daily dose had rivaroxaban exposures within the typical exposure ranges. In contrast, a higher proportion of patients with CrCl ≥ 50 mL/min receiving the 15-mg once-daily dose had rivaroxaban exposures within the typical exposure ranges. The study’s findings suggested that low-dose rivaroxaban would be better suited for Thai patients and suggested adjusting the medication’s dose in accordance with renal function. Full article
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13 pages, 1163 KiB  
Article
Real-Life Therapeutic Concentration Monitoring of Long-Acting Cabotegravir and Rilpivirine: Preliminary Results of an Ongoing Prospective Observational Study in Switzerland
by Paul Thoueille, Susana Alves Saldanha, Fabian Schaller, Aline Munting, Matthias Cavassini, Dominique Braun, Huldrych F. Günthard, Katharina Kusejko, Bernard Surial, Hansjakob Furrer, Andri Rauch, Pilar Ustero, Alexandra Calmy, Marcel Stoeckle, Manuel Battegay, Catia Marzolini, Pascal Andre, Monia Guidi, Thierry Buclin, Laurent A. Decosterd and on behalf of the Swiss HIV Cohort Studyadd Show full author list remove Hide full author list
Pharmaceutics 2022, 14(8), 1588; https://doi.org/10.3390/pharmaceutics14081588 - 29 Jul 2022
Cited by 7 | Viewed by 2534
Abstract
SHCS#879 is an ongoing Switzerland-wide multicenter observational study conducted within the Swiss HIV Cohort Study (SHCS) for the prospective follow-up of people living with HIV (PLWH) receiving long-acting injectable cabotegravir-rilpivirine (LAI-CAB/RPV). All adults under LAI-CAB/RPV and part of SHCS are enrolled in the [...] Read more.
SHCS#879 is an ongoing Switzerland-wide multicenter observational study conducted within the Swiss HIV Cohort Study (SHCS) for the prospective follow-up of people living with HIV (PLWH) receiving long-acting injectable cabotegravir-rilpivirine (LAI-CAB/RPV). All adults under LAI-CAB/RPV and part of SHCS are enrolled in the project. The study addresses an integrated strategy of treatment monitoring outside the stringent frame of controlled clinical trials, based on relevant patient characteristics, clinical factors, potential drug-drug interactions, and measurement of circulating blood concentrations. So far, 91 blood samples from 46 PLWH have been collected. Most individuals are less than 50 years old, with relatively few comorbidities and comedications. The observed concentrations are globally in accordance with the available values reported in the randomized clinical trials. Yet, low RPV concentrations not exceeding twice the reported protein-adjusted 90% inhibitory concentration have been observed. Data available at present confirm a considerable between-patient variability overall. Based on the growing amount of PK data accumulated during this ongoing study, population pharmacokinetic analysis will characterize individual concentration-time profiles of LAI-CAB/RPV along with their variability in a real-life setting and their association with treatment response and tolerability, thus bringing key data for therapeutic monitoring and precision dosage adjustment of this novel long-acting therapy. Full article
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11 pages, 915 KiB  
Article
Model Re-Estimation: An Alternative for Poor Predictive Performance during External Evaluations? Example of Gentamicin in Critically Ill Patients
by Alexandre Duong, Chantale Simard, David Williamson and Amélie Marsot
Pharmaceutics 2022, 14(7), 1426; https://doi.org/10.3390/pharmaceutics14071426 - 07 Jul 2022
Cited by 3 | Viewed by 1423
Abstract
Background: An external evaluation is crucial before clinical applications; however, only a few gentamicin population pharmacokinetic (PopPK) models for critically ill patients included it in the model development. In this study, we aimed to evaluate gentamicin PopPK models developed for critically ill patients. [...] Read more.
Background: An external evaluation is crucial before clinical applications; however, only a few gentamicin population pharmacokinetic (PopPK) models for critically ill patients included it in the model development. In this study, we aimed to evaluate gentamicin PopPK models developed for critically ill patients. Methods: The evaluated models were selected following a literature review on aminoglycoside PopPK models for critically ill patients. The data of patients were retrospectively collected from two Quebec hospitals, the external evaluation and model re-estimation were performed with NONMEM® (v7.5) and the population bias and imprecisions were estimated. Dosing regimens were simulated using the best performing model. Results: From the datasets of 39 and 48 patients from the two Quebec hospitals, none of the evaluated models presented acceptable values for bias and imprecision. Following model re-estimations, all models showed an acceptable predictive performance. An a priori dosing nomogram was developed with the best performing re-estimated model and was consistent based on recommended dosing regimens. Conclusion: Due to the poor predictive performance during the external evaluations, the latter must be prioritized during model development. Model re-estimation may be an alternative to developing a new model, especially when most known models display similar covariates. Full article
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14 pages, 1099 KiB  
Article
Therapeutic Drug Monitoring of Mycophenolic Acid as a Precision Medicine Tool for Heart Transplant Patients: Results of an Observational Pharmacokinetic Pilot Study
by Francesco Lo Re, Jacopo Angelini, Sandro Sponga, Chiara Nalli, Antonella Zucchetto, Jessica Biasizzo, Ugolino Livi and Massimo Baraldo
Pharmaceutics 2022, 14(6), 1304; https://doi.org/10.3390/pharmaceutics14061304 - 20 Jun 2022
Cited by 1 | Viewed by 1889
Abstract
In the clinical practice management of heart transplant (HTx), the impact of calcineurin inhibitors co-administration on pharmacokinetics (PKs) of mycophenolic acid (MPA), mycophenolate mofetil (MMF) active drug, is not adequately considered. This retrospective study investigated full MPA-PK profiles by therapeutic drug monitoring (TDM) [...] Read more.
In the clinical practice management of heart transplant (HTx), the impact of calcineurin inhibitors co-administration on pharmacokinetics (PKs) of mycophenolic acid (MPA), mycophenolate mofetil (MMF) active drug, is not adequately considered. This retrospective study investigated full MPA-PK profiles by therapeutic drug monitoring (TDM) in 21 HTx recipients treated with MMF combined with cyclosporine (CsA) or tacrolimus (TAC) at a median time of 2.6 months post-transplant. The two treatment groups were compared. We described the main MPA-PK parameters in patients developing acute cellular rejection (ACR) and those who did not. Median dose-adjusted MPA-trough levels and MPA-AUC0–12h were higher in patients co-treated with TAC than with CsA (p = 0.0001 and p = 0.006, respectively). MPA-Cmax and Tmax were similar between the two groups, whereas the enterohepatic recirculation biomarker of MPA (MPA-AUC4–12h) was higher in the MMF and TAC group (p = 0.004). Consistently, MPA clearance was higher in the MMF and CsA group (p = 0.006). In total, 87.5% of ACR patients were treated with MMF and CsA, presenting a lower MPA-AUC0–12h (p = 0.02). This real-world study suggested the CsA interference on MPA-PK in HTx, evidencing the pivotal role of MPA TDM as a precision medicine tool in the early phase after HTx. A prospective study is mandatory to investigate this approach to HTx clinical outcomes. Full article
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12 pages, 1729 KiB  
Article
Therapeutic Drug Monitoring of Tacrolimus-Personalized Therapy in Heart Transplantation: New Strategies and Preliminary Results in Endomyocardial Biopsies
by Simona De Gregori, Annalisa De Silvestri, Barbara Cattadori, Andrea Rapagnani, Riccardo Albertini, Elisa Novello, Monica Concardi, Eloisa Arbustini and Carlo Pellegrini
Pharmaceutics 2022, 14(6), 1247; https://doi.org/10.3390/pharmaceutics14061247 - 12 Jun 2022
Cited by 5 | Viewed by 1589
Abstract
Tacrolimus (TAC) is an immunosuppressant drug approved both in the US and in the EU, widely used for the prophylaxis of organ rejection after transplantation. This is a critical dose drug: low levels in whole blood can lead to low exposure and a [...] Read more.
Tacrolimus (TAC) is an immunosuppressant drug approved both in the US and in the EU, widely used for the prophylaxis of organ rejection after transplantation. This is a critical dose drug: low levels in whole blood can lead to low exposure and a high risk of acute rejection, whereas overexposure puts patients at risk for toxicity and infection. Both situations can occur at whole-blood concentrations considered to be within the narrow TAC therapeutic range. We assumed a poor correlation between TAC trough concentrations in whole blood and the incidence of acute rejection; therefore, we propose to study TAC concentrations in endomyocardial biopsies (EMBs). We analyzed 70 EMBs from 18 transplant recipients at five scheduled follow-up visits during the first year post-transplant when closer TAC monitoring is mandatory. We observed five episodes of acute rejection (grade 2R) in three patients (2 episodes at 0.5 months, 2 at 3 months, and 1 at 12 months), when TAC concentrations in EMBs were low (63; 62; 59; 31; 44 pg/mg, respectively), whereas concentrations in whole blood were correct. Our results are preliminary and further studies are needed to confirm the importance of this new strategy to prevent acute rejection episodes. Full article
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13 pages, 796 KiB  
Article
Population Pharmacokinetics of Busulfan and Its Metabolite Sulfolane in Patients with Myelofibrosis Undergoing Hematopoietic Stem Cell Transplantation
by Adrin Dadkhah, Sebastian Georg Wicha, Nicolaus Kröger, Alexander Müller, Christoph Pfaffendorf, Maria Riedner, Anita Badbaran, Boris Fehse and Claudia Langebrake
Pharmaceutics 2022, 14(6), 1145; https://doi.org/10.3390/pharmaceutics14061145 - 27 May 2022
Cited by 1 | Viewed by 2041
Abstract
For patients with myelofibrosis, allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative treatment to date. Busulfan-based conditioning regimens are commonly used, although high inter-individual variability (IIV) in busulfan drug exposure makes individual dose selection challenging. Since data regarding the IIV in [...] Read more.
For patients with myelofibrosis, allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative treatment to date. Busulfan-based conditioning regimens are commonly used, although high inter-individual variability (IIV) in busulfan drug exposure makes individual dose selection challenging. Since data regarding the IIV in patients with myelofibrosis are sparse, this study aimed to develop a population pharmacokinetic (PopPK) model of busulfan and its metabolite sulfolane in patients with myelofibrosis. The influence of patient-specific covariates on the pharmacokinetics of drug and metabolite was assessed using non-linear mixed effects modeling in NONMEM®. We obtained 523 plasma concentrations of busulfan and its metabolite sulfolane from 37 patients with myelofibrosis. The final model showed a population clearance (CL) and volume of distribution (Vd) of 0.217 L/h/kg and 0.82 L/kg for busulfan and 0.021 L/h/kg and 0.65 L/kg for its metabolite. Total body weight (TBW) and a single-nucleotide polymorphism of glutathione-S-transferase A1 (GSTA1 SNP) displayed a significant impact on volume of distribution and metabolite clearance, respectively. This is the first PopPK-model developed to describe busulfan’s pharmacokinetics in patients with myelofibrosis. Incorporating its metabolite sulfolane into the model not only allowed the characterization of the covariate relationship between GSTA1 and the clearance of the metabolite but also improved the understanding of busulfan’s metabolic pathway. Full article
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9 pages, 915 KiB  
Article
Pharmacokinetics of a Fixed-Dose Combination Product of Dapagliflozin and Linagliptin and Its Comparison with Co-Administration of Individual Tablets in Healthy Humans
by Jin-Woo Park, Jong-Min Kim, Ji Hyeon Noh, Kyoung-Ah Kim, Hyewon Chung, EunJi Kim, Minja Kang and Ji-Young Park
Pharmaceutics 2022, 14(3), 591; https://doi.org/10.3390/pharmaceutics14030591 - 08 Mar 2022
Cited by 1 | Viewed by 3512
Abstract
Dapagliflozin, a selective sodium–glucose co-transporter-2 inhibitor, and linagliptin, a competitive, reversible dipeptidyl peptidase-4 inhibitor, are commonly prescribed antidiabetic medications in general clinics. Since there are several merits to combining them in a fixed-dose combination product, this study investigated the pharmacokinetic equivalence between the [...] Read more.
Dapagliflozin, a selective sodium–glucose co-transporter-2 inhibitor, and linagliptin, a competitive, reversible dipeptidyl peptidase-4 inhibitor, are commonly prescribed antidiabetic medications in general clinics. Since there are several merits to combining them in a fixed-dose combination product, this study investigated the pharmacokinetic equivalence between the individual component (IC) and fixed-combination drug product (FCDP) forms of dapagliflozin and linagliptin. A randomized, open-label, single-dose crossover study was conducted. All participants (n = 48) were randomly allocated to group A (period 1: ICs, period 2: FCDP) or group B (period 1: FCDP, period 2: ICs), and each group received either a single dose of IN-C009 (FCDP) or single doses of both dapagliflozin and linagliptin. There was no statistically significant difference found between the pharmacokinetic variables of FCDP and IC. The values of estimated geometric mean ratios and the 90% confidence interval for both maximum concentration and area under the plasma drug concentration–time curve were within the range of 0.8–1.25 for both dapagliflozin and linagliptin. The results of the clinical study demonstrated comparable pharmacokinetic characteristics between IC and FCDP forms of dapagliflozin and linagliptin. The combined use of dapagliflozin and linagliptin was safe and tolerable in both formulations. Full article
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11 pages, 1029 KiB  
Article
Pharmacokinetics of Haloperidol in Critically Ill Patients: Is There an Association with Inflammation?
by Letao Li, Sebastiaan D. T. Sassen, Mathieu van der Jagt, Henrik Endeman, Birgit C. P. Koch and Nicole G. M. Hunfeld
Pharmaceutics 2022, 14(3), 549; https://doi.org/10.3390/pharmaceutics14030549 - 28 Feb 2022
Cited by 1 | Viewed by 2493
Abstract
Haloperidol is considered the first-line treatment for delirium in critically ill patients. However, clinical evidence of efficacy is lacking and no pharmacokinetic studies have been performed in intensive care unit (ICU) patients. The aim of this study was to establish a pharmacokinetic model [...] Read more.
Haloperidol is considered the first-line treatment for delirium in critically ill patients. However, clinical evidence of efficacy is lacking and no pharmacokinetic studies have been performed in intensive care unit (ICU) patients. The aim of this study was to establish a pharmacokinetic model to describe the PK in this population to improve insight into dosing. One hundred and thirty-nine samples from 22 patients were collected in a single-center study in adults with ICU delirium who were treated with low-dose intravenous haloperidol (3–6 mg per day). We conducted a population pharmacokinetic analysis using Nonlinear Mixed Effects Modelling (NONMEM). A one-compartment model best described the data. The mean population estimates were 51.7 L/h (IIV 42.1%) for clearance and 1490 L for the volume of distribution. The calculated half-life was around 22 h (12.3–29.73 h) for an average patient. A negative correlation between C-Reactive Protein (CRP) and haloperidol clearance was observed, where clearance decreased significantly with increasing CRP up to a CRP concentration of 100 mg/L. This is the first step towards haloperidol precision dosing in ICU patients and our results indicate a possible role of inflammation. Full article
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12 pages, 1035 KiB  
Article
Ganciclovir Pharmacokinetics and Individualized Dosing Based on Covariate in Lung Transplant Recipients
by Eliška Dvořáčková, Martin Šíma, Jakub Petrus, Eva Klapková, Petr Hubáček, Jiří Pozniak, Jan Havlín, Robert Lischke and Ondřej Slanař
Pharmaceutics 2022, 14(2), 408; https://doi.org/10.3390/pharmaceutics14020408 - 13 Feb 2022
Cited by 4 | Viewed by 2248
Abstract
The aim of this prospective study was to evaluate the pharmacokinetics of ganciclovir in lung transplant recipients, to explore its covariates, and to propose an individualized dosing regimen. Ganciclovir was administered according to the protocol in a standardized intravenous dose of 5 mg/kg [...] Read more.
The aim of this prospective study was to evaluate the pharmacokinetics of ganciclovir in lung transplant recipients, to explore its covariates, and to propose an individualized dosing regimen. Ganciclovir was administered according to the protocol in a standardized intravenous dose of 5 mg/kg twice daily. Serum ganciclovir concentrations were monitored as a trough and at 3 and 5 h after dosing. Individual ganciclovir pharmacokinetic parameters were calculated in a two-compartmental pharmacokinetic model, while regression models were used to explore the covariates. Optimal loading and maintenance doses were calculated for each patient. In lung transplant recipients (n = 40), the median (IQR) ganciclovir total volume of distribution and clearance values were 0.65 (0.52–0.73) L/kg and 0.088 (0.059–0.118) L/h/kg, respectively. We observed medium-to-high inter-individual but negligible intra-individual variability in ganciclovir pharmacokinetics. The volume of distribution of ganciclovir was best predicted by height, while clearance was predicted by glomerular filtration rate. Bodyweight-normalized clearance was significantly higher in patients with cystic fibrosis, while distribution half-life was reduced in this subgroup. On the basis of the observed relationships, practical nomograms for individualized ganciclovir dosing were proposed. The dosing of ganciclovir in patients with cystic fibrosis requires special caution, as their daily maintenance dose should be increased by approximately 50%. Full article
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Review

Jump to: Research

26 pages, 996 KiB  
Review
Pharmacokinetic Boosting of Kinase Inhibitors
by Niels Westra, Daan Touw, Marjolijn Lub-de Hooge, Jos Kosterink and Thijs Oude Munnink
Pharmaceutics 2023, 15(4), 1149; https://doi.org/10.3390/pharmaceutics15041149 - 05 Apr 2023
Cited by 3 | Viewed by 1776
Abstract
(1) Introduction: Pharmacokinetic boosting of kinase inhibitors can be a strategy to enhance drug exposure and to reduce dose and associated treatment costs. Most kinase inhibitors are predominantly metabolized by CYP3A4, enabling boosting using CYP3A4 inhibition. Kinase inhibitors with food enhanced absorption can [...] Read more.
(1) Introduction: Pharmacokinetic boosting of kinase inhibitors can be a strategy to enhance drug exposure and to reduce dose and associated treatment costs. Most kinase inhibitors are predominantly metabolized by CYP3A4, enabling boosting using CYP3A4 inhibition. Kinase inhibitors with food enhanced absorption can be boosted using food optimized intake schedules. The aim of this narrative review is to provide answers to the following questions: Which different boosting strategies can be useful in boosting kinase inhibitors? Which kinase inhibitors are potential candidates for either CYP3A4 or food boosting? Which clinical studies on CYP3A4 or food boosting have been published or are ongoing? (2) Methods: PubMed was searched for boosting studies of kinase inhibitors. (3) Results/Discussion: This review describes 13 studies on exposure boosting of kinase inhibitors. Boosting strategies included cobicistat, ritonavir, itraconazole, ketoconazole, posaconazole, grapefruit juice and food. Clinical trial design for conducting pharmacokinetic boosting trials and risk management is discussed. (4) Conclusion: Pharmacokinetic boosting of kinase inhibitors is a promising, rapidly evolving and already partly proven strategy to increase drug exposure and to potentially reduce treatment costs. Therapeutic drug monitoring can be of added value in guiding boosted regimens. Full article
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27 pages, 1390 KiB  
Review
Perspectives of Therapeutic Drug Monitoring of Biological Agents in Non-Infectious Uveitis Treatment: A Review
by Manuel Busto-Iglesias, Lorena Rodríguez-Martínez, Carmen Antía Rodríguez-Fernández, Jaime González-López, Miguel González-Barcia, Begoña de Domingo, Luis Rodríguez-Rodríguez, Anxo Fernández-Ferreiro and Cristina Mondelo-García
Pharmaceutics 2023, 15(3), 766; https://doi.org/10.3390/pharmaceutics15030766 - 25 Feb 2023
Cited by 1 | Viewed by 2621
Abstract
Biological drugs, especially those targeting anti-tumour necrosis factor α (TNFα) molecule, have revolutionized the treatment of patients with non-infectious uveitis (NIU), a sight-threatening condition characterized by ocular inflammation that can lead to severe vision threatening and blindness. Adalimumab (ADA) and infliximab (IFX), the [...] Read more.
Biological drugs, especially those targeting anti-tumour necrosis factor α (TNFα) molecule, have revolutionized the treatment of patients with non-infectious uveitis (NIU), a sight-threatening condition characterized by ocular inflammation that can lead to severe vision threatening and blindness. Adalimumab (ADA) and infliximab (IFX), the most widely used anti-TNFα drugs, have led to greater clinical benefits, but a significant fraction of patients with NIU do not respond to these drugs. The therapeutic outcome is closely related to systemic drug levels, which are influenced by several factors such as immunogenicity, concomitant treatment with immunomodulators, and genetic factors. Therapeutic drug monitoring (TDM) of drug and anti-drug antibody (ADAbs) levels is emerging as a resource to optimise biologic therapy by personalising treatment to bring and maintain drug concentration within the therapeutic range, especially in those patients where a clinical response is less than expected. Furthermore, some studies have described different genetic polymorphisms that may act as predictors of response to treatment with anti-TNFα agents in immune-mediated diseases and could be useful in personalising biologic treatment selection. This review is a compilation of the published evidence in NIU and in other immune-mediated diseases that support the usefulness of TDM and pharmacogenetics as a tool to guide clinicians’ treatment decisions leading to better clinical outcomes. In addition, findings from preclinical and clinical studies, assessing the safety and efficacy of intravitreal administration of anti-TNFα agents in NIU are discussed. Full article
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39 pages, 2411 KiB  
Review
Therapeutic Monitoring of Orally Administered, Small-Molecule Anticancer Medications with Tumor-Specific Cellular Protein Targets in Peripheral Fluid Spaces—A Review
by Zoltán Köllő, Miklós Garami, István Vincze, Barna Vásárhelyi and Gellért Balázs Karvaly
Pharmaceutics 2023, 15(1), 239; https://doi.org/10.3390/pharmaceutics15010239 - 10 Jan 2023
Cited by 2 | Viewed by 1997
Abstract
Orally administered, small-molecule anticancer drugs with tumor-specific cellular protein targets (OACD) have revolutionized oncological pharmacotherapy. Nevertheless, the differences in exposure to these drugs in the systemic circulation and extravascular fluid compartments have led to several cases of therapeutic failure, in addition to posing [...] Read more.
Orally administered, small-molecule anticancer drugs with tumor-specific cellular protein targets (OACD) have revolutionized oncological pharmacotherapy. Nevertheless, the differences in exposure to these drugs in the systemic circulation and extravascular fluid compartments have led to several cases of therapeutic failure, in addition to posing unknown risks of toxicity. The therapeutic drug monitoring (TDM) of OACDs in therapeutically relevant peripheral fluid compartments is therefore essential. In this work, the available knowledge regarding exposure to OACD concentrations in these fluid spaces is summarized. A review of the literature was conducted by searching Embase, PubMed, and Web of Science for clinical research articles and case reports published between 10 May 2001 and 31 August 2022. Results show that, to date, penetration into cerebrospinal fluid has been studied especially intensively, in addition to breast milk, leukocytes, peripheral blood mononuclear cells, peritoneal fluid, pleural fluid, saliva and semen. The typical clinical indications of peripheral fluid TDM of OACDs were (1) primary malignancy, (2) secondary malignancy, (3) mental disorder, and (4) the assessment of toxicity. Liquid chromatography–tandem mass spectrometry was most commonly applied for analysis. The TDM of OACDs in therapeutically relevant peripheral fluid spaces is often indispensable for efficient and safe treatments. Full article
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37 pages, 1061 KiB  
Review
Current Status of Therapeutic Drug Monitoring in Mental Health Treatment: A Review
by Filippo Pennazio, Claudio Brasso, Vincenzo Villari and Paola Rocca
Pharmaceutics 2022, 14(12), 2674; https://doi.org/10.3390/pharmaceutics14122674 - 01 Dec 2022
Cited by 9 | Viewed by 2909
Abstract
Therapeutic drug monitoring (TDM) receives growing interest in different psychiatric clinical settings (emergency, inpatient, and outpatient services). Despite its usefulness, TDM remains underemployed in mental health. This is partly due to the need for evidence about the relationship between drug serum concentration and [...] Read more.
Therapeutic drug monitoring (TDM) receives growing interest in different psychiatric clinical settings (emergency, inpatient, and outpatient services). Despite its usefulness, TDM remains underemployed in mental health. This is partly due to the need for evidence about the relationship between drug serum concentration and efficacy and tolerability, both in the general population and even more in subpopulations with atypical pharmacokinetics. This work aims at reviewing the scientific literature published after 2017, when the most recent guidelines about the use of TDM in mental health were written. We found 164 pertinent records that we included in the review. Some promising studies highlighted the possibility of correlating early drug serum concentration and clinical efficacy and safety, especially for antipsychotics, potentially enabling clinicians to make decisions on early laboratory findings and not proceeding by trial and error. About populations with pharmacokinetic peculiarities, the latest studies confirmed very common alterations in drug blood levels in pregnant women, generally with a progressive decrease over pregnancy and a very relevant dose-adjusted concentration increase in the elderly. For adolescents also, several drugs result in having different dose-related concentration values compared to adults. These findings stress the recommendation to use TDM in these populations to ensure a safe and effective treatment. Moreover, the integration of TDM with pharmacogenetic analyses may allow clinicians to adopt precise treatments, addressing therapy on an individual pharmacometabolic basis. Mini-invasive TDM procedures that may be easily performed at home or in a point-of-care are very promising and may represent a turning point toward an extensive real-world TDM application. Although the highlighted recent evidence, research efforts have to be carried on: further studies, especially prospective and fixed-dose, are needed to replicate present findings and provide clearer knowledge on relationships between dose, serum concentration, and efficacy/safety. Full article
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17 pages, 344 KiB  
Review
Therapeutic Drug Monitoring of Ivacaftor, Lumacaftor, Tezacaftor, and Elexacaftor in Cystic Fibrosis: Where Are We Now?
by Eva Choong, Alain Sauty, Angela Koutsokera, Sylvain Blanchon, Pascal André and Laurent Decosterd
Pharmaceutics 2022, 14(8), 1674; https://doi.org/10.3390/pharmaceutics14081674 - 11 Aug 2022
Cited by 14 | Viewed by 2151
Abstract
Drugs modulating the cystic fibrosis transmembrane conductance regulator (CFTR) protein, namely ivacaftor, lumacaftor, tezacaftor, and elexacaftor, are currently revolutionizing the management of patients with cystic fibrosis (CF), particularly those with at least one F508del variant (up to 85% of patients). These “caftor” drugs [...] Read more.
Drugs modulating the cystic fibrosis transmembrane conductance regulator (CFTR) protein, namely ivacaftor, lumacaftor, tezacaftor, and elexacaftor, are currently revolutionizing the management of patients with cystic fibrosis (CF), particularly those with at least one F508del variant (up to 85% of patients). These “caftor” drugs are mainly metabolized by cytochromes P450 3A, whose enzymatic activity is influenced by environmental factors, and are sensitive to inhibition and induction. Hence, CFTR modulators are characterized by an important interindividual pharmacokinetic variability and are also prone to drug–drug interactions. However, these CFTR modulators are given at standardized dosages, while they meet all criteria for a formal therapeutic drug monitoring (TDM) program that should be considered in cases of clinical toxicity, less-than-expected clinical response, drug or food interactions, distinct patient subgroups (i.e., pediatrics), and for monitoring short-term adherence. While the information on CFTR drug exposure–clinical response relationships is still limited, we review the current evidence of the potential interest in the TDM of caftor drugs in real-life settings. Full article
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