Individualized drug dosage in patients treated with continuous hemofiltration

Individualized drug dosage in patients treated with continuous hemofiltration.BackgroundSubtherapeutic drug dosing may be even more dangerous than overdosage, especially for intensive care patients requiring hemofiltration.ProposalAccording to Dettli's fundamental equation, body clearance of any drug (Cl) is a linear function of creatinine clearance (Cl = Cl anur + a · CCr), with [a = (Cl norm - Cl anur)/CCr norm]. We propose to individualize drug dosage during high-flux hemofiltration by basing it on Dettli's equation and on total CCr (CCr tot = CCr ren + CCr filt). Using this approach, drug clearance will eventually be overestimated for drugs with substantial tubular secretion and for high-efficiency hemofiltration (CCr tot > 30 ml/min).ConclusionIn patients undergoing hemofiltration, the total CCr approach might be a practical alternative to standardized dosing schemes for deriving an individualized dosage from published pharmacokinetic data and functions

Clinical trial protocol of the ASTER trial: a double-blind, randomized, placebo-controlled phase III trial evaluating the use of acetylsalicylic acid (ASA) for enhanced early detection of colorectal neoplasms

Immunochemical fecal occult blood tests (iFOBTs) are increasingly used for colorectal cancer (CRC) screening. In our preceding observational study, sensitivity for detecting advanced colorectal neoplasms by iFOBT was 70.8% among users of low-dose acetylsalicylic acid compared with 35.9% among non-users (p = 0.001), whereas there were only very small differences in specificity. In receiver operating characteristics (ROC) analyses, the area under the curve (AUC) was much higher for acetylsalicylic acid users than for non-users, with particularly strong differences in men (0.87 versus 0.68, p = 0.003). These findings suggested that use of acetylsalicylic acid before conduct of iFOBT might be a promising approach to improve non-invasive screening for CRC. Methods/design: In this randomized, double-blind, placebo-controlled trial, the diagnostic performance of two iFOBTs for detecting advanced colorectal neoplasms after a single low-dose of acetylsalicylic acid (300 mg) compared to placebo is evaluated. Acetylsalicylic acid or placebo is administered at least 5 days before a planned, study-independent colonoscopic screening in 2400 participants aged 40 to 80 years. Stool samples are obtained before and on three different days after the single dose of acetylsalicylic acid or placebo. In addition, optional blood samples are taken for future biomarker analyses. The diagnostic performance of the iFOBTs will be compared to the results of the colonoscopy as a gold standard for the diagnosis of colorectal neoplasms. Additionally, gender-specific performance of the tests and gain in diagnostic performance by test application on multiple days will be evaluated. Discussion: If the findings from our preceding observational study will be confirmed in this large trial, the proposed low-risk, inexpensive intervention would considerably improve the diagnostic accuracy of iFOBTs and thus lead to enhanced early detection of colorectal neoplasms. Thus, the results of this trial may have a large public health impact. Trial registration This trial was registered before recruitment of the participants in www.clinicaltrialsregister.eu on the 30th of May 2012: EudraCT No.: 2011–005603-32 and in www.drks.de on 13th of March 2012: German Clinical Trials Register DRKS-ID: DRKS00003252

Evaluation of the drug-drug interaction potential of the novel hepatitis B and D virus entry inhibitor bulevirtide at OATP1B in healthy volunteers

Introduction: Bulevirtide is a first-in-class antiviral drug to treat chronic hepatitis B/D. We investigated the drug-drug interaction potential and pharmacokinetics of high-dose subcutaneous bulevirtide (5 mg twice daily) with organic anion transporting polypeptide 1B1 (OATP1B1) and cytochrome P450 (CYP) 3A4.Methods: This was a single-center, open-label, fixed-sequence drug-drug interaction trial in 19 healthy volunteers. Before and at bulevirtide steady state, participants ingested a single 40 mg dose of pravastatin. A midazolam microdose was applied to quantify CYP3A4 activity.Results: At bulevirtide steady state, pravastatin area under the concentration-time curve (AUC0–∞) increased 1.32-fold (90% CI 1.08-1.61). The 5 mg bulevirtide twice-daily treatment resulted in a mean AUC0-12 of 1210 h*ng/ml (95% CI 1040-1408) and remained essentially unchanged under the influence of pravastatin. CYP3A4 activity did not change to a clinically relevant extent. As expected, total bile acids increased substantially (35-fold) compared to baseline during bulevirtide treatment. All study medication was well tolerated.Discussion: The study demonstrated that high-dose bulevirtide inhibited OATP1B-mediated hepatic uptake of the marker substrate pravastatin but the extent is considered clinically not relevant. Changes in CYP3A4 activity were also not clinically relevant. In conclusion, this study suggests that OATP1B substrate drugs as well as CYP3A4 substrates may safely be used without dose adjustment in patients treated with bulevirtide. However, in patients using high statin doses and where concomitant factors potentially further increase statin exposure, caution may be required when using bulevirtide

Thrombocytopenia and Acute Renal Failure in Puumala Hantavirus Infections

Low platelet counts are a novel predictive marker suitable for risk-adapted patient management

Recruitment and Baseline Characteristics of Participants in the AgeWell.de Study: A Pragmatic Cluster-Randomized Controlled Lifestyle Trial against Cognitive Decline

Targeting dementia prevention, first trials addressing multiple modifiable risk factors showed promising results in at-risk populations. In Germany, AgeWell.de is the first large-scale initiative investigating the effectiveness of a multi-component lifestyle intervention against cognitive decline. We aimed to investigate the recruitment process and baseline characteristics of the AgeWell.de participants to gain an understanding of the at-risk population and who engages in the intervention. General practitioners across five study sites recruited participants (aged 60-77 years, Cardiovascular Risk Factors, Aging, and Incidence of Dementia/CAIDE dementia risk score ≥ 9). Structured face-to-face interviews were conducted with eligible participants, including neuropsychological assessments. We analyzed group differences between (1) eligible vs. non-eligible participants, (2) participants vs. non-participants, and (3) between intervention groups. Of 1176 eligible participants, 146 (12.5%) dropped out before baseline; the study population was thus 1030 individuals. Non-participants did not differ from participants in key sociodemographic factors and dementia risk. Study participants were M = 69.0 (SD = 4.9) years old, and 52.1% were women. The average Montreal Cognitive Assessment/MoCA score was 24.5 (SD = 3.1), indicating a rather mildly cognitively impaired study population; however, 39.4% scored ≥ 26, thus being cognitively unimpaired. The bandwidth of cognitive states bears the interesting potential for differential trial outcome analyses. However, trial conduction is impacted by the COVID-19 pandemic, requiring adjustments to the study protocol with yet unclear methodological consequences

Population pharmacokinetics of vancomycin in critically ill patients receiving prolonged intermittent renal replacement therapy

The aim of this study was to describe the population pharmacokinetics of vancomycin during prolonged intermittent renal replacement therapy (PIRRT) in critically ill patients with acute kidney injury.Critically ill patients prescribed vancomycin across two sites had blood samples collected during 1-3 dosing intervals during which PIRRT was performed. Plasma samples were assayed with a validated immunoassay method. Population pharmacokinetic analysis and Monte Carlo simulations were performed using Pmetrics. The target vancomycin exposures were an AUC/MIC ratio of 400 for efficacy and AUC 700 for toxicity.Eleven critically ill patients (7 male) were enrolled and contributed 192 plasma samples. The patient's mean ± SD age, weight and BMI were 57 ± 13 years, 98 ± 43 kg and 31 ± 9 kg/m, respectively. A two-compartment linear model adequately described the data. The mean ± SD population pharmacokinetic parameter estimates were PIRRT clearance (CL) 3.47 ± 1.99 L/h, non-PIRRT CL 2.15 ± 2.07 L/h, volume of distribution of the central compartment (Vc) 41.85 ± 24.33 L, distribution rate constant from central to peripheral compartment 5.97 ± 7.93 h and from peripheral to central compartment 5.29 ± 6.65 h. Assuming a MIC of 1 mg/L, vancomycin doses of 25 mg/kg/day are suggested to achieve efficacious, whilst minimising toxic, exposures.This is the first population pharmacokinetic study of vancomycin in patients receiving PIRRT and we observed large pharmacokinetic variability. Empirically, weight-based doses that are appropriate for the duration of PIRRT should be selected and supplemented with therapeutic drug monitoring

AgeWell.de – study protocol of a pragmatic multi-center cluster-randomized controlled prevention trial against cognitive decline in older primary care patients

Background: In the absence of treatment options, the WHO emphasizes the identification of effective prevention strategies as a key element to counteract the dementia epidemic. Regarding the complex nature of dementia, trials simultaneously targeting multiple risk factors should be particularly effective for prevention. So far, however, only few such multi-component trials have been launched, but yielding promising results. In Germany, comparable initiatives are lacking, and translation of these complex interventions into routine care was not yet done. Therefore, AgeWell.de will be conducted as the first multi-component prevention trial in Germany which is closely linked to the primary care setting. Methods: AgeWell.de will be designed as a multi-centric, cluster-randomized controlled multi-component prevention trial. Participants will be older community-dwelling general practitioner (GP) patients (60–77 years; n = 1,152) with increased dementia risk according to CAIDE (Cardiovascular Risk Factors, Aging, and Incidence of Dementia) Dementia Risk Score. Recruitment will take place at 5 study sites across Germany. GP practices will be randomized to either intervention A (advanced) or B (basic). GPs will be blinded to their respective group assignment, as will be the statistician conducting the randomization. The multi-component intervention (A) includes nutritional counseling, physical activity, cognitive training, optimization of medication, management of vascular risk factors, social activity, and, if necessary, further specific interventions targeting grief and depression. Intervention B includes general health advice on the intervention components and GP treatment as usual. We hypothesize that over the 2-year follow-up period the intervention group A will benefit significantly from the intervention program in terms of preserved cognitive function/delayed cognitive decline (primary outcome), and other relevant (secondary) outcomes (e.g. quality of life, social activities, depressive symptomatology, cost-effectiveness). Discussion: AgeWell.de will be the first multi-component trial targeting risk of cognitive decline in older adults in Germany. Compared to previous trials, AgeWell.de covers an even broader set of interventions suggested to be beneficial for the intended outcomes. The findings will add substantial knowledge on modifiable lifestyle factors to prevent or delay cognitive decline. Trial registration: German Clinical Trials Register (reference number: DRKS00013555)

Clinical Pharmacokinetics and Pharmacodynamics of Roxadustat

The pharmacokinetics of roxadustat are well characterized, with an apparent volume of distribution after oral administration of 22-57 L, apparent clearance of 1.2-2.65 L/h, and renal clearance of 0.030-0.026 L/h in healthy volunteers; the elimination half-life is 9.6-16 h. Plasma binding is 99% and the fraction eliminated by hemodialysis is 2.34%. As an interpretation of the pharmacodynamics of roxadustat, we proposed a concept with a hypothetical cascade of two subsequent effects, first on erythropoetin (EPO) and second on hemoglobin (delta Hb). The primary effect on EPO is observed within a few hours after roxadustat administration and can be modeled using the sigmoidal Hill equation. The concentration at half-maximum effect can be inferred at 10-36 µg/mL, the Hill coefficient at 3.3, and the effect bisection time at 10-17 h, corresponding to EPO half-life. The subsequent effect on hemoglobin (delta Hb) is observed after several weeks and can be interpreted as an irreversible, dose proportional, unsaturable effect, continuing in agreement with the lifespan of red blood cells of 63-112 days