Population kinetic/pharmacodynamic modelling of the haemodynamic effects of cafedrine/theodrenaline (Akrinor) under general anaesthesia.

AIMS: The 20:1 combination of cafedrine and theodrenaline (C/T) is widely used in Germany for the treatment of arterial hypotension. Since there is little knowledge about the impact of covariates on the effect, the aim was to develop a kinetic/pharmacodynamic covariate model describing mean arterial pressure (MAP), systolic (SBP) and diastolic blood pressure (DBP), and heart rate (HR) for 30 min after the administration of C/T. METHODS: Data of patients receiving C/T from the HYPOTENS study (NCT02893241, DRKS00010740) were analysed using nonlinear mixed-effects modelling techniques. RESULTS: Overall, 16 579 measurements from 315 patients were analysed. The combination of two kinetic compartments and a delayed effect model, coupled with distinct Emax models for HR, SBP and DBP, described the data best. The model included age, sex, body mass index (BMI), antihypertensive medication, American Society of Anaesthesiologists (ASA) physical status classification grade, baseline SBP at the time of hypotension and pre-surgery HR as covariates (all P < .001). A higher baseline SBP led to a lower absolute increase in MAP. Patients with higher age, higher BMI and lower ASA grade showed smaller increases in MAP. The initial increase was similar for male and female patients. The long-term effect was higher in women. Concomitant antihypertensive medication caused a delayed effect and a lower maximum MAP. The HR increased only slightly (median increase 2.6 bpm, P < .001). CONCLUSIONS: Seven covariates with an impact on the effect of C/T could be identified. The results will enable physicians to optimize the dose with respect to individual patients.

Efficacy and safety of MP1032 plus standard-of-care compared to standard-of-care in hospitalised patients with COVID-19: a multicentre, randomised double-blind, placebo-controlled phase 2a trial.

Background: SARS-CoV-2 infections still have a significant impact on the global population. The existing vaccinations have contributed to reducing the severe disease courses, decreasing hospitalisations, and lowering the mortality rate. However, due to the variability of COVID-19 symptoms, the emergence of new variants and the uneven global distribution of vaccines there is still a great need for new therapy options. One promising approach is provided by host-directed therapies. We assessed here the efficacy and safety of MP1032, a host-directed anti-viral/anti-inflammatory drug in hospitalised patients with moderate to severe COVID-19. Methods: In a randomised, double-blind, placebo-controlled, Phase IIa study, patients were randomised 2:1 to receive either 300 mg MP032 bid + Standard-of-Care (SoC) or placebo bid + SoC for 28 days. Eligible patients were ≥18 years old, tested positive for SARS-CoV-2, and had moderate to severe COVID-19 symptoms. The study spanned 20 sites in six countries (Bulgaria, France, Hungary, Italy, Romania, Spain), assessing disease progression according the NIAID scale as the primary outcome on day 14. Secondary objectives included disease progression (day 28), disease resolution (days 14 and 28), mortality rate, COVID-19 related parameters and safety. Exposure-response analyses were performed, linking MP1032 to COVID-19 biomarkers (eGFR, D-dimer). Findings: 132 patients were enrolled to receive MP1032 + SoC (n = 87) or placebo + SoC (n = 45). The patients were all white or Caucasian with a mean (median) age of 60.5 (63) years. Overall, only 10 patients were vaccinated, 5 in each group. No significant risk difference of disease progression could be detected between groups on both day 14 (9.8% MP1032 vs. 11.6% placebo) and day 28 with MH common risk differences of -0.276% (95% CI, -11.634 to 11.081; p = 0.962) and 1.722% (95% CI, -4.576 to 8.019; p = 0.592), respectively.The treatment with MP1032 + SoC was safe and well-tolerated. Overall, 182 TEAEs including 10 SAEs were reported in 53.5% (46/86) of patients of the verum group and in 57.8% (26/45) of patients of the placebo group; the SAEs occurred in 5.8% (5/86) and 6.7% (3/45) of verum and placebo patients, respectively. None of the SAEs was considered as related. Interpretation: Despite the study's limitation in size and the variation in concurrent SoCs, these findings warrant further investigation of MP1032 as a host-directed anti-viral drug candidate. Funding: The study was funded by the COVID-19 Horizon Europe work programme and MetrioPharm AG.

Motivations for Adolescent COVID-19 Vaccination: A Comparative Study of Adolescent and Caregiver Perspectives in Germany.

Given the crucial role of vaccination in halting the COVID-19 pandemic, it is imperative to understand the factors that motivate adolescents to get vaccinated. We surveyed adolescents and their accompanying guardians scheduled to receive a COVID-19 vaccination (Comirnaty) in an urban region in Germany in mid-2021 regarding their motivation for getting vaccinated and collected data on their sociodemographic characteristics, medical history, vaccination status, and any history of COVID-19 infection in the family. We also queried information strategies related to the SARS-CoV-2 pandemic. Motivations for getting vaccinated were similar among adolescents and their parents. The primary reasons for vaccination were protection against SARS-CoV-2-related illness and gaining access to leisure facilities. This was not influenced by gender, health status, migration background, or the presence of chronic or acute diseases. The percentage of parents who had received SARS-CoV-2 immunization and the proportion of parents with a high level of education were higher among study participants than in the general population. Adolescents were especially willing to be vaccinated if they came from a better educational environment and had a high vaccination rate in the family. Emphasizing the importance of vaccination among all segments of the population and removing barriers to vaccines may lead to an ameliorated acceptance of COVID-19 vaccines.

Significant impact of time-of-day variation on metformin pharmacokinetics.

AIMS/HYPOTHESIS: The objective was to investigate if metformin pharmacokinetics is modulated by time-of-day in humans using empirical and mechanistic pharmacokinetic modelling techniques on a large clinical dataset. This study also aimed to generate and test hypotheses on the underlying mechanisms, including evidence for chronotype-dependent interindividual differences in metformin plasma and efficacy-related tissue concentrations. METHODS: A large clinical dataset consisting of individual metformin plasma and urine measurements was analysed using a newly developed empirical pharmacokinetic model. Causes of daily variation of metformin pharmacokinetics and interindividual variability were further investigated by a literature-informed mechanistic modelling analysis. RESULTS: A significant effect of time-of-day on metformin pharmacokinetics was found. Daily rhythms of gastrointestinal, hepatic and renal processes are described in the literature, possibly affecting drug pharmacokinetics. Observed metformin plasma levels were best described by a combination of a rhythm in GFR, renal plasma flow (RPF) and organic cation transporter (OCT) 2 activity. Furthermore, the large interindividual differences in measured metformin concentrations were best explained by individual chronotypes affecting metformin clearance, with impact on plasma and tissue concentrations that may have implications for metformin efficacy. CONCLUSIONS/INTERPRETATION: Metformin's pharmacology significantly depends on time-of-day in humans, determined with the help of empirical and mechanistic pharmacokinetic modelling, and rhythmic GFR, RPF and OCT2 were found to govern intraday variation. Interindividual variation was found to be partly dependent on individual chronotype, suggesting diurnal preference as an interesting, but so-far underappreciated, topic with regard to future personalised chronomodulated therapy in people with type 2 diabetes.

Model-Based Analysis of SARS-CoV-2 Infections, Hospitalization and Outcome in Germany, the Federal States and Districts.

The coronavirus disease 2019 (COVID-19) pandemic challenged many national health care systems, with hospitals reaching capacity limits of intensive care units (ICU). Thus, the estimation of acute local burden of ICUs is critical for appropriate management of health care resources. In this work, we applied non-linear mixed effects modeling to develop an epidemiological SARS-CoV-2 infection model for Germany, with its 16 federal states and 400 districts, that describes infections as well as COVID-19 inpatients, ICU patients with and without mechanical ventilation, recoveries, and fatalities during the first two waves of the pandemic until April 2021. Based on model analyses, covariates influencing the relation between infections and outcomes were explored. Non-pharmaceutical interventions imposed by governments were found to have a major impact on the spreading of SARS-CoV-2. Patient age and sex, the spread of variant B.1.1.7, and the testing strategy (number of tests performed weekly, rate of positive tests) affected the severity and outcome of recorded cases and could reduce the observed unexplained variability between the states. Modeling could reasonably link the discrepancies between fine-grained model simulations of the 400 German districts and the reported number of available ICU beds to coarse-grained COVID-19 patient distribution patterns within German regions.

Pharmacometric Modeling of the Impact of Azelastine Nasal Spray on SARS-CoV-2 Viral Load and Related Symptoms in COVID-19 Patients.

The histamine-1 receptor antagonist azelastine was recently found to impact SARS-CoV-2 viral kinetics in a Phase 2 clinical trial (CARVIN). Thus, we investigated the relationship between intranasal azelastine administrations and viral load, as well as symptom severity in COVID-19 patients and analyzed the impact of covariates using non-linear mixed-effects modeling. For this, we developed a pharmacokinetic (PK) model for the oral and intranasal administration of azelastine. A one-compartment model with parallel absorption after intranasal administration described the PK best, covering both the intranasal and the gastro-intestinal absorption pathways. For virus kinetic and symptoms modeling, viral load and symptom records were gathered from the CARVIN study that included data of 82 COVID-19 patients receiving placebo or intranasal azelastine. The effect of azelastine on viral load was described by a dose-effect model targeting the virus elimination rate. An extension of the model revealed a relationship between COVID-19 symptoms severity and the number of infected cells. The analysis revealed that the intranasal administration of azelastine led to a faster decline in viral load and symptoms severity compared to placebo. Moreover, older patients showed a slower decline in viral load compared to younger patients and male patients experienced higher peak viral loads than females.

Alternative Treatment Regimens With the PCSK9 Inhibitors Alirocumab and Evolocumab: A Pharmacokinetic and Pharmacodynamic Modeling Approach.

Alirocumab and evolocumab are 2 human monoclonal antibodies that inhibit the proprotein convertase subtilisin/kexin type 9 (PCSK9). These antibodies can potently lower low-density lipoprotein cholesterol (LDLc) serum concentrations. The aims of this analysis were to develop a pharmacokinetic (PK) and pharmacodynamic (PD) model for both antibodies, to simulate and investigate different dosage and application regimens, and finally, to note the effects on LDLc levels. Alirocumab was clinically studied and approved with 2 doses, 75 and 150 mg every 2 weeks (Q2W), whereas evolocumab was tested and approved with 2 dosing intervals, 140 mg Q2W and 420 mg Q4W. Data were digitized from published studies describing alirocumab and evolocumab PK, as well as LDLc levels in humans for various single and multiple doses. Alirocumab dosages ranged between 75 and 300 mg and evolocumab from 7 to 420 mg. The analysis was performed using a nonlinear mixed-effects modeling technique. A 2-compartment model with first-order absorption and saturable elimination described the PK of both antibodies best. LDLc levels were described by a turnover model with zero-order synthesis rate decreased by the antibodies and a first-order degradation rate that was increased by the antibodies. Simulations show a comparable effectiveness for alirocumab 75 mg Q2W and 150 mg Q3W as well as evolucmab 140 mg Q2W and 420 mg Q5W, respectively. This is the first PK/PD model describing the link between alirocumab and evolocumab PK and LDLc concentrations. The model may serve as an important tool to simulate different dosage regimens in order to optimize therapy.