Research

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10 pages, 577 KiB

Open AccessArticle

Sex Differences in Spironolactone and the Active Metabolite Canrenone Concentrations and Adherence

by Laura E. J. Peeters, Leonardien K. Tjong, Wim J. R. Rietdijk, Teun van Gelder, Birgit C. P. Koch and Jorie Versmissen

Biomedicines 2022, 10(1), 137; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10010137 - 08 Jan 2022

Cited by 2 | Viewed by 1875

Abstract

We aim to investigate sex differences in blood concentrations of spironolactone and the active metabolite canrenone in resistant hypertension patients. Furthermore, sex differences in adherence for spironolactone and other antihypertensive drugs (AHDs) were studied. The patients in this post hoc study had all [...] Read more.

We aim to investigate sex differences in blood concentrations of spironolactone and the active metabolite canrenone in resistant hypertension patients. Furthermore, sex differences in adherence for spironolactone and other antihypertensive drugs (AHDs) were studied. The patients in this post hoc study had all participated in a single-blind randomized controlled trial called RHYME-RCT (Dutch Trial Register, NL6736). Concentrations in blood of several AHDs were assessed in RHYME-RCT to investigate adherence to treatment. This allowed for a comparison of drug exposure to spironolactone and canrenone between males and females. In linear regression models, no statistically significant sex differences (N = 35) in spironolactone (B =−10.23, SE = 7.92, p = 0.206) or canrenone (B = 1.24, SE = 10.96, p = 0.911) concentrations after adjustment for dose and time between sampling and intake were found. Furthermore, no statistically significant differences in non-adherence to spironolactone were found between sexes (N = 54, male 15% vs. female 38%, p = 0.100), but non-adherence to spironolactone was associated with non-adherence to other AHDs (p ≤ 0.001). Spironolactone and canrenone concentrations were not different between males and females with resistant hypertension. Although not statistically significant, females were twice as likely to be non-adherent to spironolactone compared to males, and thereby also more likely to be non-adherent to other AHDs. Full article

(This article belongs to the Special Issue Pharmacokinetics and Therapeutic Drug Monitoring)

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13 pages, 1494 KiB

Open AccessArticle

Predicting Serum Levels of Lithium-Treated Patients: A Supervised Machine Learning Approach

by Chih-Wei Hsu, Shang-Ying Tsai, Liang-Jen Wang, Chih-Sung Liang, Andre F. Carvalho, Marco Solmi, Eduard Vieta, Pao-Yen Lin, Chien-An Hu and Hung-Yu Kao

Biomedicines 2021, 9(11), 1558; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9111558 - 28 Oct 2021

Cited by 7 | Viewed by 4012

Abstract

Routine monitoring of lithium levels is common clinical practice. This is because the lithium prediction strategies available developed by previous studies are still limited due to insufficient prediction performance. Thus, we used machine learning approaches to predict lithium concentration in a large real-world [...] Read more.

Routine monitoring of lithium levels is common clinical practice. This is because the lithium prediction strategies available developed by previous studies are still limited due to insufficient prediction performance. Thus, we used machine learning approaches to predict lithium concentration in a large real-world dataset. Real-world data from multicenter electronic medical records were used in different machine learning algorithms to predict: (1) whether the serum level was 0.6–1.2 mmol/L or 0.0–0.6 mmol/L (binary prediction), and (2) its concentration value (continuous prediction). We developed models from 1505 samples through 5-fold cross-validation and used 204 independent samples to test their performance by evaluating their accuracy. Moreover, we ranked the most important clinical features in different models and reconstructed three reduced models with fewer clinical features. For binary and continuous predictions, the average accuracy of these models was 0.70–0.73 and 0.68–0.75, respectively. Seven features were listed as important features related to serum lithium levels of 0.6–1.2 mmol/L or higher lithium concentration, namely older age, lower systolic blood pressure, higher daily and last doses of lithium prescription, concomitant psychotropic drugs with valproic acid and -pine drugs, and comorbid substance-related disorders. After reducing the features in the three new predictive models, the binary or continuous models still had an average accuracy of 0.67–0.74. Machine learning processes complex clinical data and provides a potential tool for predicting lithium concentration. This may help in clinical decision-making and reduce the frequency of serum level monitoring. Full article

(This article belongs to the Special Issue Pharmacokinetics and Therapeutic Drug Monitoring)

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14 pages, 1258 KiB

Open AccessArticle

Capillary Electrophoresis–Mass Spectrometry with Multisegment Injection and In-Capillary Preconcentration for High-Throughput and Sensitive Determination of Therapeutic Decapeptide Triptorelin in Pharmaceutical and Biological Matrices

by Juraj Piešťanský, Ivana Čižmárová, Ondrej Štefánik, Michaela Matušková, Andrea Horniaková, Petra Majerová and Peter Mikuš

Biomedicines 2021, 9(10), 1488; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9101488 - 16 Oct 2021

Cited by 8 | Viewed by 1787

Abstract

A capillary electrophoresis–tandem mass spectrometry method with a multisegment injection and an in-capillary field-enhanced sample stacking for determination of therapeutic peptide triptorelin in pharmaceutical and biological matrices was developed. The CE separation conditions were optimized in order to obtain maximal separation efficiency, analytical [...] Read more.

A capillary electrophoresis–tandem mass spectrometry method with a multisegment injection and an in-capillary field-enhanced sample stacking for determination of therapeutic peptide triptorelin in pharmaceutical and biological matrices was developed. The CE separation conditions were optimized in order to obtain maximal separation efficiency, analytical signal intensity and stability, and minimal adsorption of the analyzed peptide onto the capillary wall (1 M formic acid—HFo, pH 1.88). The implementation of the field-enhanced sample injection into CE improved the value of limit of detection 50 times while the multisegment injection increased the sample throughput three times in comparison to a conventional CE approach. The proposed method was characterized by favorable performance parameters, such as linearity (r² ≥ 0.99), limit of detection (5 ng mL⁻¹ in water matrix, 25 ng mL⁻¹ in plasma matrix), precision (relative standard deviation, 1.5–9.4% for intraday and 2.3–11.9% for interday reproducibility), or accuracy (relative errors in the range of 80–109%). The FDA-validated method was successfully applied to the analysis of triptorelin in the commercial drug Diphereline^® 0.1 mg (powder for injection) and in spiked human plasma samples. Favorable performance parameters along with proven application potentialities indicate the usefulness of the proposed method for its routine use in drug quality control laboratories and for clinical analysis, such as determination of triptorelin levels in plasma (for pharmacokinetic study). Full article

(This article belongs to the Special Issue Pharmacokinetics and Therapeutic Drug Monitoring)

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11 pages, 1344 KiB

Open AccessArticle

A UHPLC–MS/MS Method for Therapeutic Drug Monitoring of Aciclovir and Ganciclovir in Plasma and Dried Plasma Spots

by Federica Pigliasco, Alessia Cafaro, Raffaele Simeoli, Sebastiano Barco, Alberto Magnasco, Maura Faraci, Gino Tripodi, Bianca Maria Goffredo and Giuliana Cangemi

Biomedicines 2021, 9(10), 1379; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9101379 - 02 Oct 2021

Cited by 13 | Viewed by 2132

Abstract

The role of therapeutic drug monitoring (TDM) of valaciclovir (VA)/aciclovir (A) and valganciclovir/ganciclovir (VG/G) in critically ill patients is still a matter of debate. More data on the dose–concentration relationship might therefore be useful, especially in pediatrics where clinical practice is not adequately [...] Read more.

The role of therapeutic drug monitoring (TDM) of valaciclovir (VA)/aciclovir (A) and valganciclovir/ganciclovir (VG/G) in critically ill patients is still a matter of debate. More data on the dose–concentration relationship might therefore be useful, especially in pediatrics where clinical practice is not adequately supported by robust PK studies. We developed and validated a new liquid chromatography-tandem mass spectrometry (LC-MS/MS) micro-method to simultaneously quantify A and G from plasma and dried plasma spots (DPS). The method was based on rapid organic extraction from DPS and separation on a reversed-phase C-18 UHPLC column after addition of deuterated internal standards. Accurate analyte quantification using SRM detection was then obtained using a Thermo Fisher Quantiva triple-quadrupole MS coupled to an Ultimate 3000 UHPLC. It was validated following international (EMA) guidelines for bioanalytical method validation and was tested on samples from pediatric patients treated with A, VG, or G for cytomegalovirus infection following solid organ or hematopoietic stem cell transplantation. Concentrations obtained from plasma and DPS were compared using Passing–Bablok and Bland–Altman statistical tests. The assay was linear over wide concentration ranges (0.01–20 mg/L) in both plasma and DPS for A and G, suitable for the expected therapeutic ranges for both Cmin and Cmax, accurate, and reproducible in the absence of matrix effects. The results obtained from plasma and DPS were comparable. Using an LC-MS/MS method allowed us to obtain a very specific, sensitive, and rapid quantification of these antiviral drugs starting from very low volumes (50 μL) of plasma samples and DPS. The stability of analytes for at least 30 days allows for cost-effective shipment and storage at room temperature. Our method is suitable for TDM and could be helpful for improving knowledge on PK/PD targets of antivirals in critically ill pediatric patients. Full article

(This article belongs to the Special Issue Pharmacokinetics and Therapeutic Drug Monitoring)

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12 pages, 1513 KiB

Open AccessArticle

Long-Term Pharmacokinetics of Dalbavancin in ABSSSI and Osteoarticular Settings: A Real-Life Outpatient Context

by Amedeo De Nicolò, Giacomo Stroffolini, Miriam Antonucci, Jacopo Mula, Elisa Delia De Vivo, Jessica Cusato, Alice Palermiti, Giuseppe Cariti, Giovanni Di Perri, Silvia Corcione, Francesco Giuseppe De Rosa and Antonio D’Avolio

Biomedicines 2021, 9(10), 1288; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9101288 - 22 Sep 2021

Cited by 8 | Viewed by 1889

Abstract

Dalbavancin is a lipoglycopeptide approved for treatment of Gram-positive infections of skin and skin-associated structures (ABSSSI). Currently, off-label use at high dosages for osteoarticular infections deserves attention. This work aimed to study the long-term plasma pharmacokinetics of dalbavancin in outpatients with ABSSSI or [...] Read more.

Dalbavancin is a lipoglycopeptide approved for treatment of Gram-positive infections of skin and skin-associated structures (ABSSSI). Currently, off-label use at high dosages for osteoarticular infections deserves attention. This work aimed to study the long-term plasma pharmacokinetics of dalbavancin in outpatients with ABSSSI or osteoarticular infections, treated either with one or two 1500 mg doses of dalbavancin. A liquid chromatography-tandem mass spectrometry method was used to measure total dalbavancin concentrations in plasma samples. The results were analyzed through a non-compartmental analysis (NCA). Breakpoint minimum inhibitory concentration (MIC) was used to calculate AUC/MIC and T > MIC parameters, adjusted by 93% protein binding. A total of 14 patients were enrolled, 11 with osteoarticular infection and 3 with ABSSSI. Long-term pharmacokinetics showed median T > MIC (0.125 mg/L) of 11.9 and 13.7 weeks for single and dual dose, respectively. Similarly, median AUC_0-2w/MIC ratios of 20,590 and 31,366 were observed for single and dual dose regimens, respectively. No adverse events were observed, and treatment success was achieved in 12/14 patients. Failure was associated with the worst clinical conditions, bone infections, and single dose. The results of this study show that dalbavancin exposure exceeds previously suggested pharmacodynamic targets. Optimization of these targets is needed for the osteoarticular setting. Full article

(This article belongs to the Special Issue Pharmacokinetics and Therapeutic Drug Monitoring)

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8 pages, 1147 KiB

Open AccessArticle

Seasonal Variation of Antiretroviral Drug Exposure during the Year: The Experience of 10 Years of Therapeutic Drug Monitoring

by Jessica Cusato, Jacopo Mula, Alice Palermiti, Alessandra Manca, Miriam Antonucci, Valeria Avataneo, Elisa Delia De Vivo, Alice Ianniello, Andrea Calcagno, Giovanni Di Perri, Amedeo De Nicolò and Antonio D’Avolio

Biomedicines 2021, 9(9), 1202; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9091202 - 12 Sep 2021

Cited by 3 | Viewed by 1447

Abstract

Although studies show an annual trend for immunosuppressive drugs, particularly during different seasons, no data are available for antiretroviral drugs exposures in different periods of the year. For this reason, the aim of this study was to investigate an association between seasonality and [...] Read more.

Although studies show an annual trend for immunosuppressive drugs, particularly during different seasons, no data are available for antiretroviral drugs exposures in different periods of the year. For this reason, the aim of this study was to investigate an association between seasonality and antiretroviral drugs plasma concentrations. Antiretroviral drugs exposures were measured with liquid chromatography validated methods. A total of 4148 human samples were analysed. Lopinavir, etravirine and maraviroc levels showed seasonal fluctuation. In detail, maraviroc and etravirine concentrations decreased further in summer than in winter. In contrast, lopinavir concentrations had an opposite trend, increasing more in summer than in winter. The etravirine efficacy cut-off value of 300 ng/mL seems to be affected by seasonality: 77.1% and 22.9% of samples achieved this therapeutic target, respectively, in winter and summer, whereas 30% in winter and 70% in summer did not reach this value. Finally, age over 50 years and summer remained in the final multivariate regression model as predictors of the etravirine efficacy cut-off. This study highlights the seasonal variation in antiretroviral drugs plasma concentrations during the year, leading to a better understanding of inter-individual variability in drug exposures. Studies are required in order to confirm these data, clarifying which aspects may be involved. Full article

(This article belongs to the Special Issue Pharmacokinetics and Therapeutic Drug Monitoring)

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13 pages, 2695 KiB

Open AccessArticle

Analysis of Pembrolizumab in Human Plasma by LC-MS/HRMS. Method Validation and Comparison with Elisa

by Aurélien Millet, Nihel Khoudour, Jérôme Guitton, Dorothée Lebert, François Goldwasser, Benoit Blanchet and Christelle Machon

Biomedicines 2021, 9(6), 621; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9060621 - 30 May 2021

Cited by 6 | Viewed by 3844

Abstract

Pembrolizumab is a humanized immunoglobulin G4-kappa anti-PD1 antibody used in the treatment of different solid tumors or haematological malignancies. A liquid chromatography coupled with a high resolution mass spectrometry (orbitrap technology) method was fully developed, optimized, and validated for quantitative analysis of pembrolizumab [...] Read more.

Pembrolizumab is a humanized immunoglobulin G4-kappa anti-PD1 antibody used in the treatment of different solid tumors or haematological malignancies. A liquid chromatography coupled with a high resolution mass spectrometry (orbitrap technology) method was fully developed, optimized, and validated for quantitative analysis of pembrolizumab in human plasma. A mass spectrometry assay was used for the first time a full-length stable isotope-labelled pembrolizumab-like (Arginine ¹³C₆-¹⁵N₄ and Lysine ¹³C₆-¹⁵N₂) as an internal standard; the sample preparation was based on albumin depletion and trypsin digestion and, finally, one surrogate peptide was quantified in positive mode. The assay showed good linearity over the range of 1–100 μg/mL, a limit of quantification at 1 μg/mL, excellent accuracy from 4.4% to 5.1%, and also a between-day precision below 20% at the limit of quantification. In parallel, an in-house ELISA was developed with a linearity range from 2.5 to 50 µg/mL. Then, results were obtained from 70 plasma samples of cancer patients that were treated with pembrolizumab and quantified with both methods were compared using the Passing-Bablok regression analysis and Bland-Altman plotting. The LC-MS/HRMS method is easy to implement in the laboratory for use in the context of PK/PD studies, clinical trials, or therapeutic drug monitoring. Full article

(This article belongs to the Special Issue Pharmacokinetics and Therapeutic Drug Monitoring)

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Review

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18 pages, 1201 KiB

Open AccessReview

The Pharmacological Effects and Pharmacokinetics of Active Compounds of Artemisia capillaris

by Tun-Pin Hsueh, Wan-Ling Lin, Jeffrey W. Dalley and Tung-Hu Tsai

Biomedicines 2021, 9(10), 1412; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9101412 - 08 Oct 2021

Cited by 16 | Viewed by 3045

Abstract

Artemisia capillaris Thunb. (A.capillaris, Yin-Chen in Chinese) is a traditional medicinal herb with a wide spectrum of pharmacological properties ranging from effects against liver dysfunction to treatments of severe cirrhosis and cancer. We used relevant keywords to search electronic databases, [...] Read more.

Artemisia capillaris Thunb. (A.capillaris, Yin-Chen in Chinese) is a traditional medicinal herb with a wide spectrum of pharmacological properties ranging from effects against liver dysfunction to treatments of severe cirrhosis and cancer. We used relevant keywords to search electronic databases, including PubMed, Medline, and Google Scholar, for scientific contributions related to this medicinal herb and the pharmacokinetics of its components. The pharmaceutical effects of A.capillaris contribute to the treatment not only of viral hepatitis, cirrhosis, and hepatocellular hepatoma, but also metabolic syndrome, psoriasis, and enterovirus in the clinic. The bioactive compounds, including scoparone, capillarisin, scopoletin, and chlorogenic acid, exhibit antioxidant, anti-inflammatory, antisteatotic, antiviral, and antitumor properties, reflecting the pharmacological effects of A.capillaris. The pharmacokinetics of the main bioactive compounds in A. capillaris can achieve a maximum concentration within 1 hour, but only chlorogenic acid has a relatively long half-life. Regarding the use of the A. capillaris herb by health professionals to treat various diseases, the dosing schedule of this herb should be carefully considered to maximize therapeutic outcomes while lessening possible side effects. Full article

(This article belongs to the Special Issue Pharmacokinetics and Therapeutic Drug Monitoring)

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