Agreement Between a Colorimetric Assay and Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry for Quantifying Paracetamol Plasma Concentrations.

Special populations, like geriatric patients, experience altered paracetamol pharmacokinetics (PK), complicating pain management. More PK research is essential to optimize paracetamol (acetaminophen) dosing. Yet, the reference method ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) is not readily available. Therefore, we aimed to evaluate the agreement between UPLC-MS/MS and the more accessible colorimetric Roche acetaminophen (ACETA) assay in quantifying paracetamol plasma concentrations, to facilitate PK studies and therapeutic drug monitoring for pain management. Patient data and plasma samples were obtained from a prospective study including geriatric patients admitted to the geriatric wards. ACETA and UPLC-MS/MS assays were performed in two separate laboratories. Bland-Altman plot and Passing-Bablok regression were used to assess agreement. Accuracy was evaluated using the McNemar test for a threshold value of 10 mg/L. Population PK modeling was employed to bridge PK data obtained from both methods (NONMEM 7.5). A total of 242 plasma sample pairs were available from 40 geriatric patients (age range, 80-95 years). Paracetamol plasma concentrations from ACETA (median 9.8 [interquartile range 6.1-14.4] mg/L) and UPLC-MS/MS (9.5 [6.2-14.8] mg/L) did not differ significantly (P > 0.05). No significant proportional nor additive bias was observed between both assay methods. The classification accuracy (at threshold 10 mg/L) was 85% (P = 0.414). The conversion factor between ACETA and UPLC-MS/MS was estimated at 1.06 (relative standard error 5%), yet with a 13.4% (relative standard error 23%) interindividual variability. ACETA assay showed no systematic bias in comparison with the UPLC-MS/MS assay in determining paracetamol exposure in geriatric blood samples despite the imprecision.

Physiologically based pharmacokinetic (PBPK) modelling of oral drug absorption in older adults - an AGePOP review.

The older population consisting of persons aged 65 years or older is the fastest-growing population group and also the major consumer of pharmaceutical products. Due to the heterogenous ageing process, this age group shows high interindividual variability in the dose-exposure-response relationship and, thus, a prediction of drug safety and efficacy is challenging. Although physiologically based pharmacokinetic (PBPK) modelling is a well-established tool to inform and confirm drug dosing strategies during drug development for special population groups, age-related changes in absorption are poorly accounted for in current PBPK models. The purpose of this review is to summarise the current state-of-knowledge in terms of physiological changes with increasing age that can influence the oral absorption of dosage forms. The capacity of common PBPK platforms to incorporate these changes and describe the older population is also discussed, as well as the implications of extrinsic factors such as drug-drug interactions associated with polypharmacy on the model development process. The future potential of this field will rely on addressing the gaps identified in this article, which can subsequently supplement in-vitro and in-vivo data for more robust decision-making on the adequacy of the formulation for use in older adults and inform pharmacotherapy.

Population plasma and urine pharmacokinetics and the probability of target attainment of fosfomycin in healthy male volunteers.

PURPOSE: A population pharmacokinetic model of fosfomycin was developed in healthy volunteers after intravenous administration, and different dosing regimens were evaluated in terms of the probability of target attainment for Escherichia coli using both plasma and urinary pharmacokinetic/pharmacodynamic targets. METHODS: Eight healthy men received fosfomycin as both intermittent 8 g q8h and continuous infusion 1 g/h with a loading dose of 8 g in a crossover study design. Dense sampling was conducted during both regimens. Population pharmacokinetic modelling was performed using NONMEM. Monte Carlo simulations were conducted to evaluate the Probability of Target Attainment (PTA) of different dosing regimens using bactericidal (AUC24h/MIC of 83 and 75%T>MIC) and bacteriostatic (AUC24h/MIC of 25) plasma targets and bacteriostatic (AUC24h/MIC of 3994) urine target. RESULTS: A total of 176 plasma and 86 urine samples were available for PK analysis. A two-compartment model with a urine compartment best described the data. Glomerular filtration rate (GFR) showed a significant correlation with renal clearance and was implemented in the final model. Simulation results show that the dose of 4 g q8h reached 100% of PTA using bactericidal and bacteriostatic targets for MIC up to 16 mg/L. CONCLUSION: For the clinical breakpoint of 32 mg/L, the standard dosing regimen (4 g q8h) might not be sufficient to reach the bactericidal target. Higher dosing of 8 g q8h as an intermittent infusion or 0.75 g/h as a continuous infusion might be required. Continuous infusion resulted in better attainment of the %T>MIC target than intermittent infusion.

Insights into the Pharmacokinetics and Pharmacodynamics of Direct Oral Anticoagulants in Older Adults with Atrial Fibrillation: A Structured Narrative Review.

Older adults, the fastest growing population, represent almost 50% of all users of direct oral anticoagulants (DOACs). Unfortunately, we have very little relevant pharmacological and clinical data on DOACs, especially in older adults with geriatric profiles. This is highly relevant as pharmacokinetics and pharmacodynamics (PK/PD) often differ substantially in this population. Hence, we need to obtain a better understanding of the PK/PD of DOACs in older adults, to ensure appropriate treatment. This review summarises the current insights into PK/PD of DOACs in older adults. A search was undertaken up to October 2022 to identify PK/PD studies of apixaban, dabigatran, edoxaban, and rivaroxaban, that included older adults aged ≥ 75 years. This review identified 44 articles. Older age alone did not influence exposure of edoxaban, rivaroxaban and dabigatran, while apixaban peak concentrations were 40% higher in older adults than in young volunteers. Nevertheless, high interindividual variability in DOAC exposure in older adults was noted, which can be explained by distinctive older patient characteristics, such as kidney function, changes in body composition (especially reduced muscle mass), and co-medication with P-gp inhibitors, which is in line with the current dosing reduction criteria of apixaban, edoxaban, and rivaroxaban. Dabigatran had the largest interindividual variability among all DOACs since its dose adjustment criterion is only age, and thus it is not a preferable option. Additionally, DOAC exposure, which fell outside of on-therapy ranges, was significantly related to stroke and bleeding events. No definite thresholds linked to these outcomes in older adults have been established.

Differences in Older Patients' Attitudes Toward Deprescribing at Contextual and Individual Level.

BACKGROUND: Deprescribing requires patients' involvement and taking patients' attitudes toward deprescribing into account. To understand the observed variation in these attitudes, the influence of contextual-level factors, such as country or healthcare setting, should be taken into account. METHODS: We conducted a systematic review of studies using the revised Patients' Attitudes Towards Deprescribing (rPATD) questionnaire among older adults. We searched articles in Medline and Embase up to 30 June 2021. PRISMA guideline was used for the search process and reporting. We summarized the outcomes from the rPATD and compared attitudes at study population level between high or low-middle-income countries, global regions, and healthcare settings using ANOVA testing. Correlations of the rPATD outcomes with the mean age of the study populations were tested. Associations with the rPATD outcomes at individual patient level extracted from the included studies were summarized. RESULTS: Sixteen articles were included. Percentages of patients willing to stop medication were significantly lower in low-middle-income countries (<70% in Nepal and Malaysia) compared to high-income countries (>85% in USA, Australia, European countries). No significant differences were observed when results were compared by global region or by healthcare setting but a high willingness (>95%) was seen in the two studies conducted in an inpatient population. A higher mean age at study level was associated with a higher willingness to stop medication. At individual level, associations between patient characteristics, including demographics and education, and attitudes toward deprescribing showed inconsistent results. CONCLUSION: Findings about attitudes toward deprescribing are influenced by contextual factors. Future research should pay more attention to the influence of the healthcare system and setting as well as the culture on patients' attitudes.