Population Pharmacokinetics of Remdesivir and GS-441524 in Hospitalized COVID-19 Patients.

The objective of this study was to describe the population pharmacokinetics of remdesivir and GS-441524 in hospitalized coronavirus disease 2019 (COVID-19) patients. A prospective observational pharmacokinetic study was performed in non-critically ill hospitalized COVID-19 patients with hypoxemia. For evaluation of the plasma concentrations of remdesivir and its metabolite GS-441524, samples were collected on the first day of therapy. A nonlinear mixed-effects model was developed to describe the pharmacokinetics and identify potential covariates that explain variability. Alternative dosing regimens were evaluated using Monte Carlo simulations. Seventeen patients were included. Remdesivir and GS-441524 pharmacokinetics were best described by a one-compartment model. The estimated glomerular filtration rate (eGFR) on GS-441524 clearance was identified as a clinically relevant covariate. The interindividual variability in clearance and volume of distribution for both remdesivir and GS-441524 was high (remdesivir, 38.9% and 47.9%, respectively; GS-441525, 47.4% and 42.9%, respectively). The estimated elimination half-life for remdesivir was 0.48 h, and that for GS-441524 was 26.6 h. The probability of target attainment (PTA) of the in vitro 50% effective concentration (EC50) for GS-441524 in plasma can be improved by shortening the dose interval of remdesivir and thereby increasing the total daily dose (PTA, 51.4% versus 94.7%). In patients with reduced renal function, the metabolite GS-441524 accumulates. A population pharmacokinetic model for remdesivir and GS-441524 in COVID-19 patients was developed. Remdesivir showed highly variable pharmacokinetics. The elimination half-life of remdesivir in COVID-19 patients is short, and the clearance of GS-441524 is dependent on the eGFR. Alternative dosing regimens aimed at optimizing the remdesivir and GS-441524 concentrations may improve the effectiveness of remdesivir treatment in COVID-19 patients.

Evaluating imipenem + cilastatin + relebactam for the treatment of complicated urinary tract infections.

INTRODUCTION: The addition of the ß-lactamase inhibitor relebactam to imipenem restores the antibacterial activity against the majority of multidrug resistant Gram-negative bacteria. Complicated urinary tract infections (UTIs) are predominantly caused by Gram-negative uropathogens. The rise in antibiotic resistance, including to carbapenems, is an increasing challenge in daily practice. AREAS COVERED: In the current review, the use of imipenem/relebactam in complicated UTI is evaluated by discussing its chemistry, pharmacokinetics/dynamics, microbiology, safety, and clinical efficacy. The authors also provide their expert perspectives onto its use and its future place in the treatment armamentarium. EXPERT OPINION: With respect to complicated UTI, it should be noted that, to our knowledge, there are no data yet upon the clinical efficacy of imipenem/relebactam in patients with severe urosepsis or men with suspected prostatitis. Further studies upon these specific groups of UTI patients are needed including additional pharmacokinetic studies upon its tissue penetration of the prostate which is currently unknown. However, in our opinion, imipenem/relebactam can be used in complicated UTI when other treatment options are limited.

Population pharmacokinetics of ceftriaxone administered as continuous or intermittent infusion in critically ill patients.

OBJECTIVES: To describe the population pharmacokinetics and protein-binding characteristics of unbound ceftriaxone administered as continuous or intermittent infusion. Additionally, to determine the optimal dosing regimen in critically ill patients. METHODS: A pharmacokinetic study was performed in the ICU of a tertiary teaching hospital. Patients were treated with ceftriaxone as continuous or intermittent infusion. A population pharmacokinetic model was developed with non-linear mixed-effects analysis. Subsequently, the PTA of a 100% T>MIC was assessed for influential patient characteristics using Monte Carlo simulation. RESULTS: Fifty-five patients were included. The pharmacokinetics of ceftriaxone was best described by a one-compartment model with non-linear saturable protein binding including the following covariates: body weight, estimated CLCR, serum albumin concentration and mode of administration. For pathogens with an MIC of 1 mg/L, the simulation demonstrated that intermittent infusion of 2 g/24 h only resulted in a ≥90% PTA in patients with a reduced CLCR (0-60 mL/min). Intermittent infusion of 2 g/12 h led to sufficient exposure if CLCR was 0-90 mL/min and continuous infusion of 2 g/24 h led to a ≥90% PTA in all simulations (CLCR 0-180 mL/min). CONCLUSIONS: In the critically ill, the clearance of unbound ceftriaxone is closely related to CLCR. Furthermore, ceftriaxone protein binding is saturable, variable and dependent on serum albumin concentration. Intermittent dosing of 2 g/24 h ceftriaxone leads to subtherapeutic exposure in patients with a normal or increased CLCR. Treating these patients with continuous infusion of 2 g/24 h is more effective than an intermittent dosing regimen of 2 g/12 h.

[Fatal intoxication with nicotine for e-cigarette]. / Fatale intoxicatie met nicotine voor e-sigaret.

BACKGROUND: Since the introduction of the electronic e-cigarette a few years ago, its use has greatly increased. The liquid formulations used in these e-cigarettes contain nicotine in high concentrations; ingestion of these liquids can be fatal. CASE DESCRIPTION: A 42-year-old male was admitted to the Intensive Care ward due to cardiac arrest. The patient had ingested highly concentrated liquid nicotine, originating from a vial with liquid for e-cigarettes. When the ambulance personnel found the patient he did not have a pulse; following CPR and administration of adrenaline his pulse returned. Upon admission, the plasma nicotine level was high at 3.0 mg/l (reference values for a smoker are 0.01-0.05 mg/l) and the patient's neurological function was poor. The patient was treated symptomatically, but eventually died of a postanoxic encephalopathy. CONCLUSION: Nicotine e-liquids are highly concentrated. Intentional ingestion can lead to toxic levels of nicotine which are associated with cardiac arrhythmias or arrest. Because even a few millilitres can be lethal, nicotine intoxication due to e-liquid ingestion should be considered potentially life-threatening.

A fast and sensitive LC-MS/MS method for the quantification of fosfomycin in human urine and plasma using one sample preparation method and HILIC chromatography.

Fosfomycin is an old antibiotic that is increasingly prescribed because of emergence of the antibiotic resistance and the growing incidence of multi-drug resistant infections. Surprisingly, little is known about its pharmacokinetics (PK) and the pharmacodynamics (PD). Quantification of fosfomycin in both urine and plasma provides insight into the PK/PD characteristics of fosfomycin, which is crucial for the optimization of the therapy and the prevention of the emergence of resistance. An analytical method is therefore needed for the quantification of fosfomycin in both urine and plasma. A fast and sensitive tandem mass spectrometry method in combination with HILIC chromatography for the quantification of fosfomycin with a universal sample preparation method for urine and plasma was developed and validated according to FDA guidelines. The universal sample preparation method only requires 100µL of a sample, the addition of the internal standard fosfomycin-13C3 benzylamine and an ultrafiltration step. The method is applicable for the concentration range of 0.75-375mg/L (R2 of 0.9998 in both matrices) encompassing the clinically relevant concentration range based on the susceptibility of possible (uro)pathogens in the clinical setting. The validation results for urine and plasma for all QC levels, were <2.1% and <3.2% for accuracy, <1.5% and <1.7% for within day precision and <5.0% and <3.8% for between day precision, respectively. No matrix effects were encountered and the total recovery in urine and plasma was high (102.5% and 99.4%). Prepared samples were stable at 4°C and 15°C for at least 72h and stored samples at -80°C were stable for at least 6 months. Selectivity and sensitivity were confirmed and no carry-over was observed. The method was successfully applied in two pharmacokinetic studies in healthy volunteers and patients respectively.

[Fosfomycin, an old antibiotic with new possibilities]. / Fosfomycine, een oud antibioticum met nieuwe mogelijkheden.

- Fosfomycin is a broad-spectrum antibiotic agent used orally for uncomplicated cystitis. The intravenous form of administration has recently been authorised in the Netherlands.- Thanks to its broad spectrum and extensive tissue penetration, fosfomycin offers possibilities for the treatment of infections in different organs.- Infections with multidrug-resistant bacteria pose a significant threat to public health. Many of these multidrug-resistant bacteria are sensitive to fosfomycin, which means fosfomycin may be an option for the treatment of infections with multidrug-resistant bacteria. - There is a lack of knowledge about the pharmacological properties of fosfomycin to establish a good dosing schedule. Knowledge is also lacking about the safety of fosfomycin and the extent of its tolerability in the treatment of different infections. - More research is needed before fosfomycin can be used in the battle against multidrug-resistant bacteria.

Cardiac monitoring of high-dose verapamil in cluster headache: An international Delphi study.

BACKGROUND: In many patients, high-dose verapamil (HDV) is the only effective prophylactic treatment for cluster headache. Although cardiac adverse events and EKG abnormalities are relatively common, evidence-based guidelines for screening and monitoring patients on HDV are lacking. GOAL AND METHODS: Using the Delphi approach, we interviewed 22 international clinical experts in cardiac rhythm disorders to formulate EKG guidelines for the pretreatment screening and monitoring of cluster headache patients using HDV. RESULTS: The panel agreed only on performing pretreatment EKG to screen for pre-existing cardiac arrhythmia. Pretreatment EKG was deemed not necessary by most panel members for patients who did not have cardiac adverse events during a previous period of cluster headache attacks treated with HDV. Half the panel advised Holter EKG for patients on verapamil ≥ 480 mg/day. The highest recommended daily doses varied between 240 and 960 mg. Contraindications for use of verapamil largely followed FDA guidelines. DISCUSSION: Experts in cardiac rhythm disorders agreed on pretreatment EKG monitoring, but no consensus was reached on EKG monitoring during HDV treatment and around dose adjustments.

Pharmacokinetics and sputum penetration of azithromycin during once weekly dosing in cystic fibrosis patients.

In this study we examined pharmacokinetics, systemic exposure and sputum penetration of azithromycin (AZM) in CF patients on chronic daily AZM therapy after changing to a once weekly dosing scheme. Eight adult CF patients using AZM 500 mg/day were changed to a once weekly dose of 1000 mg during 3 months. Once per month sputum and blood samples were collected. AZM was quantified in blood plasma and polymorphonuclear neutrophils. The cumulative weekly dose was reduced with a factor of 3.5 (7x500 mg vs. 1x1000 mg weekly). This led to a reduction in area under the curve (AUC+/-S.D.) with a factor of 2.5+/-0.8 in plasma, 2.8+/-0.9 in blood, 2.2+/-1.1 in PMNNs and to a reduction in average sputum concentration with a factor of 3.0 (+/-1.5). At 1000 mg once weekly reduced but still substantial concentrations were achieved in PMNNs and in sputum. Although not significant, a tendency towards less than linear reduction was found. In order to calculate and propose an optimal dosing scheme we need to establish a relation between exposure levels and clinical efficacy.

[Partial resistance to acenocoumarol and phenprocoumon caused by enzyme polymorphism]. / Partiële acenocoumarol- en fenprocoumonresistentie door enzympolymorfisme.

A 78-year-old man was treated with coumarin derivatives following myocardial infarction. The international normalised ratio was not increased by using standard loading doses and dose adjustments for acenocoumarol and phenprocoumon. The desired level of anticoagulation was achieved with a high dosage of phenprocoumon (18-21 mg daily). This dose was associated with a phenprocoumon serum concentration that was ten times higher than the normal therapeutic concentration. The serum concentration of vitamin K1 was low. After exclusion of alternative causes, we concluded that the exceptionally high dose of phenprocoumon needed was due to partial resistance to coumarin derivatives. Partial resistance is related to a polymorphism of the gene coding for the enzyme vitamin K epoxide reductase. The patient was successfully treated with chronic high-dose phenprocoumon. Resistance to coumarin derivatives caused by a congenital polymorphism in the vitamin K reductase gene is a rare phenomenon. Resistance is seldom absolute. The desired anticoagulation effect can be achieved with doses that are 10-20 times higher than standard doses. Phenprocoumon is advantageous in this situation because it requires fewer tablets than acenocoumarol. Determination of serum concentrations of acenocoumarol and phenprocoumon can be used to exclude other causes of treatment resistance.

Pharmacokinetics of azithromycin in plasma, blood, polymorphonuclear neutrophils and sputum during long-term therapy in patients with cystic fibrosis.

Chronic therapy with the macrolide antibiotic azithromycin (AZM) is widely practiced in the treatment of patients with cystic fibrosis (CF) and chronic lung infection with Pseudomonas aeruginosa. Azithromycin dosage is variable, based on published studies, and not supported by pharmacokinetic data. This study describes the pharmacokinetics of the long-term administration of AZM (500 mg per day) in CF patients. AZM concentrations were quantified in the plasma, blood, isolated polymorphonuclear neutrophils (PMNNs), and sputum of 8 adult CF patients. The AZM distribution t1/2 was 0.1 hours in plasma. The (mean +/- standard deviation) elimination t(1/2) was 102 +/- 20 hours in plasma, 180 +/- 68 hours in blood, and 289 +/- 166 hours in PMNNs. The C(max) of AZM was 0.67 +/- 0.31 mg/L in plasma and 2.01 +/- 0.74 mg/L in blood, of which 1.44 +/- 0.69 mg/L was found in PMNNs. In sputum the concentration of AZM ranged from 12 to 53 mg/L and was still detectable at concentrations in the range 4 to 27 mg/L 10 days after the last dose. On average, the concentration in PMNNs was 2100 times the C(plasma) 24 hours after dosing AZM. These results confirm the accumulation of AZM in PMNNs. The authors conclude that sputum levels are elevated far above plasma and blood concentrations. The long t(1/2) in blood and PMNNs and the slow decrease in sputum levels indicate a less frequent dosing schedule (for instance once weekly) should be studied in future clinical trials of AZM in patients with cystic fibrosis.

[Levetiracetam: an anti-epileptic drug with interesting pharmacokinetic properties]. / Levetiracetam: een anti-epilepticum met interessante farmacokinetische eigenschappen.

Levetiracetam is a new anticonvulsant for adjunctive treatment of partial epilepsy. It is well tolerated, with no significant risks, at a dose of 1000-3000 mg/day in adults. The efficacy (> 50% reduction in attacks) in refractory partial epilepsy is 22-40%, depending on the dose. Efficacy was also seen with levetiracetam monotherapy in more than half of the positive responders. Levetiracetam does not cause induction or inhibition of the P450 enzyme system or other enzyme systems, there is no active metabolite and it exhibits almost no protein binding. These factors mean that this drug undergoes no significant interactions with other medication and appears suitable for elderly patients and for conditions requiring complex pharmacotherapy. Compared with other recently registered anti-epilepsy drugs, levetiracetam appears promising in terms of efficacy, tolerability and pharmacokinetics. The simple dosing schedule is an additional benefit.

[Treatment of pain in cancer with systemically administered opioids]. / Behandeling van pijn bij kanker met systemisch toegediende opioïden.

The World Health Organization guidelines for cancer pain relief have been proven efficacious in 90% of the patients with cancer pain. The patient's self-report of pain is the focus of treatment. When initiating treatment, controlled-release preparations of opioids are generally favoured, and are combined with immediate release morphine to prevent or treat 'breakthrough' pain and to enable the optimum opioid dosage to be calculated. (Breakthrough pain is a transient increase in pain in a patient who has stable, persistent pain treated with opioids.) In patients with an unfavourable balance between analgesia and side effects, the following strategies may be useful, together with appropriate treatment of the side effects: Sequential opioid trials (so-called opioid rotation) is an approach which is effective in 50-70% of the patients. Changing the route of opioid administration is successful in 70-95% of the patients. When selecting an invasive technique, continuous subcutaneous infusion is medically preferred. Spinal analgesia is an alternative. Knowledge of the relative potency of opioid drugs and of their biologic availability is needed to guide changes in drugs or routes of administration.

Pathophysiological aspects and clinical outcome of intra-anal application of isosorbide dinitrate in patients with chronic anal fissure.

BACKGROUND: Relaxation of the internal anal sphincter can be achieved by local application of exogenous nitric oxide donors. AIM: To evaluate the influence of topical application of isosorbide dinitrate (ISDN) on anal pressure, anodermal blood flow, and fissure healing. PATIENTS: Thirty four consecutive patients (male/female: 18/16; mean age (SEM): 39 (10)) with a chronic anal fissure were studied. METHODS: All patients were treated for at least six weeks or a maximum period of 12 weeks. Before treatment and at three and six weeks 22 patients underwent conventional anal manometry and laser Doppler flowmetry of the anoderm. RESULTS: Within 10 days the fissure related pain was resolved in all patients. At six, nine, and 12 weeks the anal fissure was completely healed in 14, 22, and 30 patients respectively. At three and six weeks manometry was performed at least one hour after the last application of ISDN. These recordings showed a reduction of the maximum resting anal pressure (mean (SD), pretreatment 111 (26) mm Hg; three weeks 86 (19); six weeks 96 (27), p < 0.001). Simultaneous recordings of anodermal blood flow showed a significant increase of flow (pretreatment 0.53 (0.17); three weeks 0.80 (0.16); six weeks 0.76 (0.31), p < 0.005). The mean (SEM) duration of follow up after successful outcome was 11 (5) months. Within this period fissure relapsed in two of 30 patients (7%), eight and 10 weeks after treatment had been stopped. CONCLUSIONS: Local application of ISDN reduces anal pressure and improves anodermal blood flow. This dual effect results in a fissure healing rate of 88% at 12 weeks. This new and simple treatment modality seems to be an attractive alternative for the current available surgical procedures.

[Intra-anal application of isosorbide dinitrate in chronic anal fissure]. / Intra-anale applicatie van isosorbidedinitraat bij chronische fissura ani.

OBJECTIVE: To evaluate the effect of intra-anal application of isosorbide dinitrate on the healing rate of chronic anal fissure. DESIGN: Prospective, descriptive. SETTING: Outpatient clinic of the department of Surgery, University Hospital Dijkzigt, Rotterdam. METHOD: Sixteen patients with chronic (more than three months' duration) anal fissure were treated by intra-anal application of isosorbide dinitrate ointment every 3 hours, except during the night. The maximal duration of therapy was 12 weeks. Every three weeks the following aspects were investigated: clinical symptoms, side-effects and fissure healing. RESULTS: All patients experienced mild and transient headache shortly after the beginning of the treatment. At three weeks the fissure-related pain was resolved in all patients. At 6, 9 and 12 weeks the fissure was completely healed in 9, 11 and 15 patients respectively. CONCLUSION: The majority of chronic anal fissures can be treated effectively by local application of isosorbide dinitrate. This new and simple treatment modality appears to be an attractive alternative to the currently available surgical procedures.