Impact of Sampling Time Variability on Tacrolimus Dosage Regimen in Pediatric Primary Nephrotic Syndrome: Single-Center, Prospective, Observational Study

Background: Tacrolimus (TAC) is an important immunosuppressant for children with primary nephrotic syndrome (PNS). The relationship between sampling time variability in TAC therapeutic drug monitoring and dosage regimen in such children is unknown.Methods: In this single-center, prospective, observational study, we evaluated the sampling time variability, concentration error (CE), relative CE (RCE), and the impact of the sampling time on TAC dosage regimens in 112 PNS children with 188 blood samples. Nominal concentration (Cnom) at 12-h after last TAC dose was simulated based on observed concentration (Cobs) via previously published pharmacokinetic models, then CE and RCE were calculated. Inappropriate dosing adjustments resulting from deviated sampling time were evaluated based on a target Cnom of 5–10 ng/ml.Results: We found that 32 and 68% of samples were respectively collected early (2–180 min) and delayed (4–315 min). Furthermore, 24, 22, 22, and 32% of blood samples were drawn within deviations of ≤0.5, 0.5–1, 1–2, and >2 h, respectively, and 0.3 ng/ml of CE and 6% RCE per hour of deviation occurred. Within a deviation of >2 h, 25% of Cobs might result in inappropriate dosing adjustments. Early and delayed sampling might result in inappropriate dose holding or unnecessary dose increments, respectively, in patients with Cobs ∼ 5 ng/ml.Conclusions: Variable sampling time might lead to inappropriate dosing adjustment in a minority of children with PNS, particularly those with TAC Cobs ∼ 5 ng/ml collected with a deviation of >2 h.

Synovial and Systemic Pharmacokinetics of Florfenicol and PK/PD Integration against Streptococcus suis in Pigs

Florfenicol is a member of the phenicol group, a broad-spectrum antibacterial agent. It has been used for a long time in veterinary medicine, but there are some factors regarding its pharmacokinetic characteristics that have yet to be elucidated. The aim of our study was to describe the pharmacokinetic profile of florfenicol in synovial fluid and plasma of swine after intramuscular (i.m.) administration. In addition, the dosage regimen of treatment of arthritis caused by S. suis was computed for florfenicol using pharmacokinetic/pharmacodynamic (PK/PD) indices. As the first part of our investigation, the pharmacokinetic (PK) parameters of florfenicol were determined in the plasma and synovial fluid of six pigs. Following drug administration (15 mg/kgbw, intramuscularly), blood was drawn at the following times: 10, 20, 30, 40, 50 and 60 min, 2, 3, 4, 5, 6, 7, 8, 12, 24, 48 and 72 h; synovial fluid samples were taken after 1, 2, 3, 4, 6, 8, 12, 24, 48 and 72 h. The concentration of florfenicol was determined by a validated liquid chromatography-mass spectrometry (LC-MS/MS) method via multiple reaction monitoring (MRM) modes. As the second part of our research, minimum inhibitory concentration (MIC) values of florfenicol were determined in 45 S. suis strains isolated from clinical samples collected in Hungary. Furthermore, a strain of S. suis serotype 2 (SS3) was selected, and killing-time curves of different florfenicol concentrations (0.5 µg/mL, 1 µg/mL and 2 µg/mL) were determined against this strain. Peak concentration of the florfenicol was 3.58 ± 1.51 µg/mL in plasma after 1.64 ± 1.74 h, while it was 2.73 ± 1.2 µg/mL in synovial fluid 3.4 ± 1.67 h after administration. The half-life in plasma was found to be 17.24 ± 9.35 h, while in synovial fluid it was 21.01 ± 13.19 h. The area under the curve (AUC24h) value was 54.66 ± 23.34 μg/mL·h for 24 h in plasma and 31.24 ± 6.82 μg/mL·h for 24 h in synovial fluid. The drug clearance scaled by bioavailability (Cl/F) in plasma and synovial fluid was 0.19 ± 0.08 L/h/kg and 0.29 ± 0.08 L/h/kg, respectively. The mean residence time (MRT) in plasma and synovial fluid was 24.0 ± 13.59 h and 27.39 ± 17.16 h, respectively. The steady-state volume of distribution (Vss) in plasma was calculated from Cl/F of 0.19 ± 0.08 L/h/kg, multiplied by MRT of 24.0 ± 13.59 h. For the PK/PD integration, average plasma and synovial fluid concentration of florfenicol was used in a steady-state condition. The obtained MIC50 value of the strains was 2.0 µg/mL, and MIC90 proved to be 16.0 µg/mL. PK/PD integration was performed considering AUC24h/MIC breakpoints that have already been described. This study is the first presentation of the pharmacokinetic behavior of florfenicol in swine synovia as well as a recommendation of extrapolated critical MICs of S. suis for therapeutic success in the treatment of S. suis arthritis in swine, but it should be noted that this requires a different dosage regimen to that used in authorized florfenicol formulations.

Management Strategies for Oral Submucous Fibrosis- An Update

There are plentiful management trials in Oral Submucous Fibrosis (OSMF), such as drugs, herbs, and Chinese medicines, but none proved to be entirely successful. So in this review, there are different management strategies tried in the management of OSMF, mechanism of action, and the dosage regimen.

When I use a word . . . . Taking therapeutic care

In healthcare there are different forms of taking care or taking precautions. When using a therapeutic intervention, one takes care by implementing it appropriately. When the appropriate intervention is pharmacological that means giving an appropriate formulation of a medication in an appropriate dosage regimen. If the intervention might cause harm, but the benefit:harm balance is favourable, one might do nothing apart from monitoring or one might introduce a preventive strategy, such as the use of mesna when giving an oxazaphosphorine such as cyclophosphamide. Vaccination and contraception are both examples of precautionary measures that have an excellent benefit:harm balance. But when the benefit:harm balance of an intervention is unfavourable the precaution to be taken is avoidance of the intervention. That, and only that, form of precaution, avoidance to avoid harm, is a defining feature of the precautionary principle.

Dose Optimization of Vancomycin for Critically Ill Patients Undergoing CVVH: A Prospective Population PK/PD Analysis

The optimal dose of vancomycin in critically ill patients receiving continuous venovenous hemofiltration (CVVH) remains unclear. The objective of this study was to identify factors that significantly affect pharmacokinetic profiles and to further investigate the optimal dosage regimens for critically ill patients undergoing CVVH based on population pharmacokinetics and pharmacodynamic analysis. A prospective population pharmacokinetic analysis was performed at the surgical intensive care unit in a level A tertiary hospital. We included 11 critically ill patients undergoing CVVH and receiving intravenous vancomycin. Serial blood samples were collected from each patient, with a total of 131 vancomycin concentrations analyzed. Nonlinear mixed effects models were developed using NONMEM software. Monte Carlo Simulation was used to optimize vancomycin dosage regimens. A two-compartment model with first-order elimination was sufficient to characterize vancomycin pharmacokinetics for CVVH patients. The population typical vancomycin clearance (CL) was 1.15 L/h and the central volume of distribution was 16.9 L. CL was significantly correlated with ultrafiltration rate (UFR) and albumin level. For patients with normal albumin and UFR between 20 and 35 mL/kg/h, the recommended dosage regimen was 10 mg/kg qd. When UFR was between 35 and 40 mL/kg/h, the recommended dosage regimen was 5 mg/kg q8h. For patients with hypoalbuminemia and UFR between 20 and 25 mL/kg/h, the recommended dosage regimen was 5 mg/kg q8h. When UFR was between 25 and 40 mL/kg/h, the recommended dosage regimen was 10 mg/kg q12h. We recommend clinicians choosing the optimal initial vancomycin dosage regimens for critically ill patients undergoing CVVH based on these two covariates.

Population Pharmacokinetics of Meropenem in Critically Ill Korean Patients and Effects of Extracorporeal Membrane Oxygenation

Limited studies have investigated population pharmacokinetic (PK) models and optimal dosage regimens of meropenem for critically ill adult patients using the probability of target attainment, including patients receiving extracorporeal membrane oxygenation (ECMO). A population PK analysis was conducted using non-linear mixed-effect modeling. Monte Carlo simulation was used to determine for how long the free drug concentration was above the minimum inhibitory concentration (MIC) at steady state conditions in patients with various degrees of renal function. Meropenem PK in critically ill patients was described using a two-compartment model, in which glomerular filtration rate was identified as a covariate for clearance. ECMO did not affect meropenem PK. The simulation results showed that the current meropenem dosing regimen would be sufficient for attaining 40%fT>MIC for Pseudomonas aeruginosa at MIC ≤ 4 mg/L. Prolonged infusion over 3 h or a high-dosage regimen of 2 g/8 h was needed for MIC > 2 mg/L or in patients with augmented renal clearance, for a target of 100%fT>MIC or 100%fT>4XMIC. Our study suggests that clinicians should consider prolonged infusion or a high-dosage regimen of meropenem, particularly when treating critically ill patients with augmented renal clearance or those infected with pathogens with decreased in vitro susceptibility, regardless of ECMO support.

Medicine Usage Behavior among Common People of Bangladesh: A Cross-Sectional Analysis

Medication usage behavior of people is an important concern for health authorities worldwide. This study was aimed to find the prevalence of self-medication, perception about drug storage, dosage regimen, side effects and missing doses of prescribed medications among people of Bangladesh. The study also aimed at the different factors that regulate the above-mentioned behavior of people from different regions of the country. This cross-sectional study was performed using an online questionnaire form that was distributed randomly among the people. A total of 1028 respondents took part in the survey. Different statistical operations were done on the responses and the results were presented were using tables and graphs. Among the participants, 31.52% often practiced self-medication and 26.94% did it rarely. There was a significant correlation between self-medication and educational qualification (p=0.023) and residence (p<0.001) variables. The tendency to not completing the dosage regimen is high in villages (44%) than urban (35%) and semi-urban (38%) areas. The rate of not recovering the missing doses is higher (40%) among the people with a low level of education than the educated people (27%). This study showed a significant correlation among medicines usage behavior and educational qualification and residential area of the participants. The policymakers should take steps to increase awareness about the safe use of medicines among common people of rural area.

Prescription pattern in public specialized dental care centers in Brazil

The aim of this study was to evaluate the most common drugs prescribed by dentists and the indicators related to rational drug use. A prospective cross-sectional study was conducted in which 189 interviews were carried out from August 2015 to June 2016 with patients who received drug prescriptions at specialized dental care centers in a city in southern Brazil. A specific data sheet was used, with questions regarding: age and gender of the patient, dental specialty in which the care occurred, and prescription drugs and their respective dosage regimen. Statistical analysis was performed using the chi-square test or Fisher's exact test (p <0.05). From the total of interviews, it was observed that 92.1% of patients received written medication prescriptions. Of these prescriptions, 38.5% had some type of antibiotic for systemic use. Acetaminophen was the most prescribed drug (33.4%), followed by amoxicillin (19.7%). The mean number of medications per prescription was 1.75, and 17.4% of the prescriptions did not indicate the dosage regimen. Our findings indicate a high incidence of prescribed antibiotics and non-compliance with regulatory agency guidance in prescriptions at the centers evaluated.

Pharmacometric approach to assist dosage regimen design in neonates undergoing therapeutic hypothermia

Background Therapeutic hypothermia (TH) is the treatment of choice for neonates diagnosed with perinatal asphyxia (PA). Dosing recommendations of various therapeutic agents including antimicrobials were not specifically available for the neonates undergoing TH. Methods A systematic search methodology was used to identify pharmacokinetic (PK) studies of antimicrobials during TH. Antimicrobials with multiple PK studies were identified to create a generalizable PK model. Pharmacometric simulations were performed using the PUMAS software platform to reproduce the results of published studies. A suitable model that could reproduce the results of all other published studies was identified. With the help of a generalizable model, an optimal dosage regimen was designed considering the important covariates of the identified model. Results With the systematic search, only gentamicin had multiple PK reports during TH. A generalizable model was identified and the model predictions could match the reported/observed concentrations of publications. Birth weight and serum creatinine were the significant covariates influencing the PK of gentamicin in neonates. A dosage nomogram was designed using pharmacometric simulations to maintain gentamicin concentrations below 10 μg/mL at peak and below 2 μg/mL at trough. Conclusions A generalizable PK model for gentamicin during TH in neonates was identified. Using the model, a dosing nomogram for gentamicin was designed. Impact Dosing guidelines for antimicrobials during TH in neonates is lacking. This is the first study to identify the generalizable model for gentamicin during TH in neonates. Nomogram, proposed in the study, will aid the clinicians to individualize gentamicin dosing regimen for neonates considering the birth weight and serum creatinine.