Genetic, ethnic, and gender differences in the pharmacokinetics of antiretroviral agents

Variable antiretroviral therapy (ART) drug response likely reflects the combined influence of environment, underlying disease, concurrent drugs, and genetics. Gender exerts modest or negligible effects on ART disposition, and it is expected to have limited clinical implication, although it should be accounted for in large population studies. Ethnic denominations have, with the notable exception of efavirenz, no clear influence on ART disposition. Exploration of genetic factors might offer a better comprehension to the largely unpredictable and unresolved variability in ART concentrations and related toxicity or treatment outcome. Despite the negative perception of genetic research among the general public, this type of investigation is now widely accepted by concerned parties: patients, relatives, and study volunteer

Challenging Recommended Oral and Intravenous Voriconazole Doses for Improved Efficacy and Safety: Population Pharmacokinetics-Based Analysis of Adult Patients With Invasive Fungal Infections

This population-pharmacokinetics analysis involving adult patients with invasive fungal infections challenges recommended voriconazole dosing regimens. Higher oral than intravenous doses, followed by individualized adjustments based on therapeutic drug monitoring, are needed to improve achievement of the therapeutic target for maximizing response by minimizing neurotoxicit

Population pharmacokinetics of fluconazole given for secondary prevention of oropharyngeal candidiasis in HIV-positive patients

Abstract.: Objectives: To determine fluconazole population pharmacokinetics and explore the relationships between fluconazole average concentration and treatment effectiveness or microbiological resistance induction during a study aimed at evaluating the efficacy, tolerability and resistance induction after secondary prevention with fluconazole (150mg weekly) versus placebo in human immunodeficiency virus-positive (HIV+) patients with oropharyngeal candidiasis. Methods: Population pharmacokinetic parameters of fluconazole determined from 458 serum drug concentration measurements obtained over 37months in 132 HIV+ patients not receiving highly active antiretroviral therapy. Mean estimates and variabilities were generated using non-linear regression analysis. Logistic and linear regression analyses were used to explore the relationships between the estimated average concentration of fluconazole and candidiasis relapse or fungal resistance towards fluconazole. Results: Fluconazole kinetics were best described by a one-compartment model with first-order oral absorption from the gastrointestinal tract. The pharmacokinetics were influenced only by body weight. No effect was observed for gender, age, height or lymphocyte CD4 counts. The mean apparent population clearance was 0.79l/h, the volume of distribution 57l and the absorption constant (ka) 0.93h-1. Inter-occasion variability in clearance (45%) was large relative to inter-subject variability (21%). Taking into account the average fluconazole concentration or the time above the minimal inhibitory concentrations did not clinically improve the prediction of the occurrence of oropharyngeal relapse or microbiological resistance. Conclusion: The relationship between fluconazole concentrations and preventive effectiveness was poor. Together with the rather large inter-occasion variability in fluconazole clearance, this suggests no role of therapeutic drug monitoring in optimising fluconazole treatment for secondary preventio

Intraocular penetration of penciclovir after oral administration of famciclovir: a population pharmacokinetic model

Objectives We developed a population model that describes the ocular penetration and pharmacokinetics of penciclovir in human aqueous humour and plasma after oral administration of famciclovir. Methods Fifty-three patients undergoing cataract surgery received a single oral dose of 500 mg of famciclovir prior to surgery. Concentrations of penciclovir in both plasma and aqueous humour were measured by HPLC with fluorescence detection. Concentrations in plasma and aqueous humour were fitted using a two-compartment model (NONMEM software). Inter-individual and intra-individual variabilities were quantified and the influence of demographics and physiopathological and environmental variables on penciclovir pharmacokinetics was explored. Results Drug concentrations were fitted using a two-compartment, open model with first-order transfer rates between plasma and aqueous humour compartments. Among tested covariates, creatinine clearance, co-intake of angiotensin-converting enzyme inhibitors and body weight significantly influenced penciclovir pharmacokinetics. Plasma clearance was 22.8 ± 9.1 L/h and clearance from the aqueous humour was 8.2 × 10−5 L/h. AUCs were 25.4 ± 10.2 and 6.6 ± 1.8 μg · h/mL in plasma and aqueous humour, respectively, yielding a penetration ratio of 0.28 ± 0.06. Simulated concentrations in the aqueous humour after administration of 500 mg of famciclovir three times daily were in the range of values required for 50% growth inhibition of non-resistant strains of the herpes zoster virus family. Conclusions Plasma and aqueous penciclovir concentrations showed significant variability that could only be partially explained by renal function, body weight and comedication. Concentrations in the aqueous humour were much lower than in plasma, suggesting that factors in the blood-aqueous humour barrier might prevent its ocular penetration or that redistribution occurs in other ocular compartment

Development and Validation of Decision Rules to Guide Frequency of Monitoring CD4 Cell Count in HIV-1 Infection before Starting Antiretroviral Therapy

Background: Although CD4 cell count monitoring is used to decide when to start antiretroviral therapy in patients with HIV-1 infection, there are no evidence-based recommendations regarding its optimal frequency. It is common practice to monitor every 3 to 6 months, often coupled with viral load monitoring. We developed rules to guide frequency of CD4 cell count monitoring in HIV infection before starting antiretroviral therapy, which we validated retrospectively in patients from the Swiss HIV Cohort Study.Methodology/Principal Findings: We built up two prediction rules ("Snap-shot rule" for a single sample and "Track-shot rule" for multiple determinations) based on a systematic review of published longitudinal analyses of CD4 cell count trajectories. We applied the rules in 2608 untreated patients to classify their 18 061 CD4 counts as either justifiable or superfluous, according to their prior >= 5% or < 5% chance of meeting predetermined thresholds for starting treatment. The percentage of measurements that both rules falsely deemed superfluous never exceeded 5%. Superfluous CD4 determinations represented 4%, 11%, and 39% of all actual determinations for treatment thresholds of 500, 350, and 200x10(6)/L, respectively. The Track-shot rule was only marginally superior to the Snap-shot rule. Both rules lose usefulness for CD4 counts coming near to treatment threshold.Conclusions/Significance: Frequent CD4 count monitoring of patients with CD4 counts well above the threshold for initiating therapy is unlikely to identify patients who require therapy. It appears sufficient to measure CD4 cell count 1 year after a count > 650 for a threshold of 200, > 900 for 350, or > 1150 for 500x10(6)/L, respectively. When CD4 counts fall below these limits, increased monitoring frequency becomes advisable. These rules offer guidance for efficient CD4 monitoring, particularly in resource-limited settings

Evaluation of the association of anticholinergic burden and delirium in older hospitalised patients - A cohort study comparing 19 anticholinergic burden scales

AIMS A recent review identified 19 anticholinergic burden scales (ABSs) but no study has yet compared the impact of all 19 ABSs on delirium. We evaluated whether a high anticholinergic burden as classified by each ABS is associated with incident delirium. METHOD We performed a retrospective cohort study in a Swiss tertiary teaching hospital using data from 2015-2018. Included were patients aged ≥65, hospitalised ≥48 hours with no stay >24 hours in intensive care. Delirium was defined twofold: (i) ICD-10 or CAM and (ii) ICD-10 or CAM or DOSS. Patients' cumulative anticholinergic burden score, calculated within 24 hours after admission, was classified using a binary (<3: low, ≥3: high burden) and a categorical approach (0: no, 0.5-3: low, ≥3: high burden). Association was analysed using multivariable logistic regression. RESULTS Over 25 000 patients (mean age 77.9 ± 7.6 years) were included. Of these, (i) 864 (3.3%) and (ii) 2770 (11.0%) developed delirium. Depending on the evaluated ABS, 4-63% of the patients were exposed to at least one anticholinergic drug. Out of 19 ABSs, (i) 14 and (ii) 16 showed a significant association with the outcomes. A patient with a high anticholinergic burden score had odds ratios (ORs) of 1.21 (95% confidence interval [CI]: 1.03-1.42) to 2.63 (95% CI: 2.28-3.03) for incident delirium compared to those with low or no burden. CONCLUSION A high anticholinergic burden within 24 hours after admission was significantly associated with incident delirium. Although prospective studies need to confirm these results, discontinuing or substituting drugs with a score of ≥3 at admission might be a targeted intervention to reduce incident delirium

Predicting delirium in older non-intensive care unit inpatients: development and validation of the DELIrium risK Tool (DELIKT)

BACKGROUND Effective delirium prevention could benefit from automatic risk stratification of older inpatients using routinely collected clinical data. AIM Primary aim was to develop and validate a delirium prediction model (DELIKT) suitable for implementation in hospitals. Secondary aim was to select an anticholinergic burden scale as a predictor. METHOD We used one cohort for model development and another for validation with electronically available data collected within the first 24 h of admission. Included were patients aged ≥ 65, hospitalised ≥ 48 h with no stay > 24 h in an intensive care unit. Predictors, such as administrative and laboratory variables or an anticholinergic burden scale, were selected using a combination of feature selection filter method and forward/backward selection. The final model was based on logistic regression and the DELIKT was derived from the β-coefficients. We report the following performance measures: area under the curve, sensitivity, specificity and odds ratio. RESULTS Both cohorts were similar and included over 10,000 patients each (mean age 77.6 ± 7.6 years) with 11% experiencing delirium. The model included nine variables: age, medical department, dementia, hemi-/paraplegia, catheterisation, potassium, creatinine, polypharmacy and the anticholinergic burden measured with the Clinician-rated Anticholinergic Scale (CrAS). The external validation yielded an AUC of 0.795. With a cut-off at 20 points in the DELIKT, we received a sensitivity of 79.7%, specificity of 62.3% and an odds ratio of 5.9 (95% CI 5.2, 6.7). CONCLUSION The DELIKT is a potentially automatic tool with predictors from standard care including the CrAS to identify patients at high risk for delirium

Automatic Detection of Adverse Drug Events in Geriatric Care: Study Proposal

BACKGROUND One-third of older inpatients experience adverse drug events (ADEs), which increase their mortality, morbidity, and health care use and costs. In particular, antithrombotic drugs are among the most at-risk medications for this population. Reporting systems have been implemented at the national, regional, and provider levels to monitor ADEs and design prevention strategies. Owing to their well-known limitations, automated detection technologies based on electronic medical records (EMRs) are being developed to routinely detect or predict ADEs. OBJECTIVE This study aims to develop and validate an automated detection tool for monitoring antithrombotic-related ADEs using EMRs from 4 large Swiss hospitals. We aim to assess cumulative incidences of hemorrhages and thromboses in older inpatients associated with the prescription of antithrombotic drugs, identify triggering factors, and propose improvements for clinical practice. METHODS This project is a multicenter, cross-sectional study based on 2015 to 2016 EMR data from 4 large hospitals in Switzerland: Lausanne, Geneva, and Zürich university hospitals, and Baden Cantonal Hospital. We have included inpatients aged ≥65 years who stayed at 1 of the 4 hospitals during 2015 or 2016, received at least one antithrombotic drug during their stay, and signed or were not opposed to a general consent for participation in research. First, clinical experts selected a list of relevant antithrombotic drugs along with their side effects, risks, and confounding factors. Second, administrative, clinical, prescription, and laboratory data available in the form of free text and structured data were extracted from study participants' EMRs. Third, several automated rule-based and machine learning-based algorithms are being developed, allowing for the identification of hemorrhage and thromboembolic events and their triggering factors from the extracted information. Finally, we plan to validate the developed detection tools (one per ADE type) through manual medical record review. Performance metrics for assessing internal validity will comprise the area under the receiver operating characteristic curve, F$_{1}$-score, sensitivity, specificity, and positive and negative predictive values. RESULTS After accounting for the inclusion and exclusion criteria, we will include 34,522 residents aged ≥65 years. The data will be analyzed in 2022, and the research project will run until the end of 2022 to mid-2023. CONCLUSIONS This project will allow for the introduction of measures to improve safety in prescribing antithrombotic drugs, which today remain among the drugs most involved in ADEs. The findings will be implemented in clinical practice using indicators of adverse events for risk management and training for health care professionals; the tools and methodologies developed will be disseminated for new research in this field. The increased performance of natural language processing as an important complement to structured data will bring existing tools to another level of efficiency in the detection of ADEs. Currently, such systems are unavailable in Switzerland. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID) DERR1-10.2196/40456

Development and validation of a multiplex UHPLC-MS/MS assay with stable isotopic internal standards for the monitoring of the plasma concentrations of the antiretroviral drugs bictegravir, cabotegravir, doravirine, and rilpivirine in people living with HIV

The widespread use of highly active antiretroviral treatments has dramatically changed the prognosis of people living with HIV (PLWH). However, such treatments have to be taken lifelong raising issues regarding the maintenance of both therapeutic effectiveness and long-term tolerability. Recently approved or investigational antiretroviral drugs present considerable advantages, allowing once daily oral dosage along with activity against resistant variants (eg, bictegravir and doravirine) and also parenteral intramuscular administration that facilitates treatment adherence (eg, long-acting injectable formulations such as cabotegravir and rilpivirine). Still, there remains a risk of insufficient or exaggerated circulating exposure due to absorption issues, abnormal elimination, drug-drug interactions, and others. In this context, a multiplex ultra-high performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS) bioassay has been developed for the monitoring of plasma levels of bictegravir, cabotegravir, doravirine, and rilpivirine in PLWH. A simple and convenient protein precipitation was performed followed by direct injection of the supernatant into the UHPLC-MS/MS system. The four analytes were eluted in less than 3 minutes using a reversed-phase chromatography method coupled with triple quadrupole mass spectrometry detection. This bioassay was fully validated following international guidelines and achieved good performances in terms of trueness (94.7%-107.5%), repeatability (2.6%-11%), and intermediate precision (3.0%-11.2%) over the clinically relevant concentration ranges (from 30 to 9000 ng/mL for bictegravir, cabotegravir, and doravirine and from 10 to 1800 ng/mL for rilpivirine). This sensitive, accurate, and rapid UHPLC-MS/MS assay is currently applied in our laboratory for routine therapeutic drug monitoring of the oral drugs bictegravir and doravirine and is also intended to be applied for the monitoring of cabotegravir/rilpivirine levels in plasma from PLWH receiving once monthly or every 2-month intramuscular injection of these long-acting antiretroviral drugs

Complementary medicine use during cancer treatment and potential herb-drug interactions from a cross-sectional study in an academic centre

Complementary medicine (CM) is used by one third to one half of cancer patients throughout the world. The objective of this study was to describe the prevalence of CM use and the potential for interactions with cancer treatments in an academic oncology centre. A cross-sectional study was conducted among patients undergoing current cancer treatment. Among 132 included patients, 56% had used CM since their cancer diagnosis and 45% were using CM during cancer treatment at the time of the survey. The main CM used were green tea (35%), herbal tea (35%), homeopathy (27%), dietary supplements (27%), and herbal medicines (27%). A small majority of patients (58%) spontaneously mentioned the use of CM to their oncologist. Of 42 identified combinations of concomitant use of biologically based CM and anticancer agents among the study patients, the potential for pharmacokinetic interactions of clinical relevance was not expected in 17 combinations (40%), hypothetical and deemed unlikely in 23 (55%), and of probable low clinical relevance in 2 (5%). Considering the high prevalence of CM use, active enquiries should be made by healthcare professionals to detect symptoms that may relate to CM tolerance and effects or that suggest interactions between CM and cancer treatments