The method of relative drug accumulation: A simple method for illustrating the effects of different drug dosing regimens and variability in drug elimination on time courses of drug concentrations

1992 ◽  
Vol 51 (3) ◽  
pp. 266-270 ◽  
Author(s):  
Thorir D Bjornsson
Keyword(s):  
Drug Accumulation ◽  
Drug Elimination ◽  
Simple Method ◽  
Drug Dosing ◽  
Drug Concentrations ◽  
Dosing Regimens ◽  
Time Courses

scholarly journals Incorporating Cystatin C to Predict Methotrexate Elimination in Patients with CNS Lymphoma and Suspicious Renal Function

2018 ◽  
Vol 2018 ◽  
pp. 1-5 ◽  
Author(s):  
Jason N. Barreto ◽  
Allison L. McClanahan ◽  
Andrew D. Rule ◽  
Carrie A. Thompson ◽  
Erin Frazee
Keyword(s):  
Renal Function ◽  
Cystatin C ◽  
Cns Lymphoma ◽  
High Dose ◽  
Serum Cystatin C ◽  
Drug Dosing ◽  
First Line Therapy ◽  
Drug Concentrations ◽  
Toxic Drug ◽  
Dosing Regimens

High-dose methotrexate (MTX; ≥1 g/m2) is a renally eliminated and nephrotoxic first-line therapy for central nervous system (CNS) lymphoma. Creatinine-based estimation of renal function is the recommended approach to dosing MTX in these cases, but nonrenal determinants of creatinine production and elimination in cancer patients such as malnutrition and cachexia lead to overestimation of glomerular filtration rate (GFR) by this method and a heightened risk for drug toxicity. Serum cystatin C is one of the first readily available, relatively inexpensive, endogenous biomarkers to emerge as a practical adjunct to creatinine for estimation of renal function for drug dosing. In this report, we describe two cases where cystatin C was used in conjunction with creatinine to inform MTX dosing for CNS lymphoma. In both cases, the estimated GFR was nearly 40% lower with the combination of the two biomarkers compared to creatinine-only estimates. Empiric MTX dose reductions as a product of these results likely spared the patients sustained exposure to toxic drug concentrations and facilitated earlier administration of supportive care interventions. Further prospective investigations with validated dosing regimens including cystatin C are warranted for high-dose MTX.

Potential dangers of common drug dosing regimens

1974 ◽  
Vol 31 (1) ◽  
pp. 53-58
Author(s):  
Paul J. Niebergall ◽  
Edwin T. Sugita ◽  
Roger L. Schnaare
Keyword(s):  
Drug Dosing ◽  
Common Drug ◽  
Dosing Regimens

scholarly journals Therapeutic drug monitoring in special populations

1998 ◽  
Vol 44 (2) ◽  
pp. 415-419 ◽  
Author(s):  
Philip D Walson
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Diagnostic Testing ◽  
Drug Effects ◽  
Special Populations ◽  
Therapeutic Drug ◽  
Drug Reactions ◽  
Drug Concentrations ◽  
Dosing Regimens ◽  
Multiple Drugs

Abstract Therapeutic drug monitoring (TDM) is commonly used to maintain “therapeutic” drug concentrations. Even in compliant patients, with “average” drug kinetics, TDM is useful to identify the causes of unwanted or unexpected responses, prevent unnecessary diagnostic testing, improve clinical outcomes, and even save lives. TDM has greatest promise in certain special populations who are: (a) prone to under- or overrespond to usual dosing regimens, (b) least able to tolerate, recognize, or communicate drug effects, or who are (c) intentionally or accidentally misdosed. TDM is especially useful in patients at the extremes of age, in adolescents, and in patients who are either taking multiple drugs or expressing unusual pharmacokinetics as a result of physiological, environmental, or genetic causes. Less-well-appreciated uses of TDM include prevention of dangerousunderdosing of patients, investigation of adverse drug reactions, and identification of serious medication errors, even for a number of drugs that are not traditionally monitored. TDM can be useful for some drugs in any patient and for most drugs in some special populations.

Non–steady State Analysis of the Pharmacokinetic Interaction between Propofol and Remifentanil

2002 ◽  
Vol 97 (6) ◽  
pp. 1350-1362 ◽  
Author(s):  
Thomas Bouillon ◽  
Joergen Bruhn ◽  
Lucian Radu-Radulescu ◽  
Edward Bertaccini ◽  
Sang Park ◽  
...  
Keyword(s):  
Pharmacokinetic Interaction ◽  
Compartment Model ◽  
Significant Degree ◽  
Volume Of Distribution ◽  
Gas Chromatography Mass Spectrometry ◽  
Effect Compartment ◽  
Drug Concentrations ◽  
Time Courses ◽  
Elimination Clearance ◽  
The Individual

Background The pharmacokinetics of both propofol and remifentanil have been described extensively. Although they are commonly administered together for clinical anesthesia, their pharmacokinetic interaction has not been investigated so far. The purpose of the current investigation was to elucidate the nature and extent of pharmacokinetic interactions between propofol and remifentanil. Methods Twenty healthy volunteers aged 20-43 yr initially received either propofol or remifentanil alone in a stepwise incremental and decremental fashion a target controlled infusion. Thereafter, the respective second drug was infused to a fixed target concentration in the clinical range (0-4 microg/ml and 0-4 ng/ml for propofol and remifentanil, respectively) and the stepwise incremental pattern repeated. Frequent blood samples were drawn for up to 6 h for propofol and 40 min for remifentanil after the end of administration and assayed for the respective drug concentrations with gas chromatography-mass spectrometry. The time courses of the measured concentrations were fitted to standard compartmental models. Calculations were performed with NONMEM. After having established the individual population models for both drugs and an exploratory analysis for hypothesis generation, pharmacokinetic interaction was identified by including an interaction term into the population model and comparing the value of the objective function in the presence and absence of the respective term. Results The concentration-time courses of propofol and remifentanil were described best by a three- and two-compartment model, respectively. In the concentration range examined, remifentanil does not alter propofol pharmacokinetics. Coadministration of propofol decreases the central volume of distribution and distributional clearance of remifentanil by 41% and elimination clearance by 15%. This effect was not concentration-dependent in the examined concentration range of propofol. Conclusions Coadministration of propofol decreases the bolus dose of remifentanil needed to achieve a certain plasma-effect compartment concentration but does not alter the respective maintenance infusion rates and recovery times to a clinically significant degree.

scholarly journals Therapeutic Drug Monitoring of Piperacillin-Tazobactam Using Spent Dialysate Effluent in Patients Receiving Continuous Venovenous Hemodialysis

2010 ◽  
Vol 55 (2) ◽  
pp. 557-560 ◽  
Author(s):  
Michael J. Connor ◽  
Charbel Salem ◽  
Seth R. Bauer ◽  
Christina L. Hofmann ◽  
Joseph Groszek ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Kidney Injury ◽  
Therapeutic Drug ◽  
Plasma Drug ◽  
Drug Dosing ◽  
Drug Levels ◽  
Drug Concentrations ◽  
Continuous Venovenous Hemodialysis ◽  
Dosing Strategies

ABSTRACTSepsis and multisystem organ failure are common diagnoses affecting nearly three-quarters of a million Americans annually. Infection is the leading cause of death in acute kidney injury, and the majority of critically ill patients who receive continuous dialysis also receive antibiotics. Dialysis equipment and prescriptions have gradually changed over time, raising concern that current drug dosing recommendations in the literature may result in underdosing of antibiotics. Our research group directed its attention toward antibiotic dosing strategies in patients with acute renal failure (ARF), and we sought data confirming that patients receiving continuous dialysis and antibiotics actually were achieving therapeutic plasma drug levels during treatment. In the course of those investigations, we explored “fast-track” strategies to estimate plasma drug concentrations. As most antimicrobial antibiotics are small molecules and should pass freely through modern high-flux hemodialyzer filters, we hypothesized that continuous renal replacement therapy (CRRT) effluent could be used as the medium for drug concentration measurement by reverse-phase high-pressure liquid chromatography (HPLC). Here we present the first data demonstrating this approach for piperacillin-tazobactam. Paired blood and dialysate trough-peak-trough samples were drawn from 19 patients receiving piperacillin-tazobactam and continuous venovenous hemodialysis (CVVHD). Total, free, and dialysate drug concentrations were measured by HPLC. Dialysate drug levels predicted plasma free drug levels well (r2= 0.91 and 0.92 for piperacillin and tazobactam, respectively) in all patients. These data suggest a strategy for therapeutic drug monitoring that minimizes blood loss from phlebotomy and simplifies analytic procedures.

scholarly journals Population pharmacokinetic models of first choice beta-lactam antibiotics for severe infections treatment: What antibiotic regimen to prescribe in children?

2020 ◽  
Vol 23 ◽  
pp. 470-485
Author(s):  
Amélie Marsot
Keyword(s):  
Pediatric Population ◽  
Individual Characteristics ◽  
Essential Medicines ◽  
World Health ◽  
Population Pharmacokinetic ◽  
Inclusion Criteria ◽  
Drug Dosing ◽  
First Choice ◽  
Dosing Regimens ◽  
Severe Infections

Background: To perform a review describing the pharmacokinetic (PK) parameters and covariates of interest of the eight first choice β-lactams (BL) antibiotics for treatment of severe infections in pediatric population. Pediatric sepsis and septic shock reportedly affect 30% of children admitted to pediatric intensive care units, with a 25% mortality rate. Eight BL are included as first choice antibiotic for severe infections in pediatric population in the World Health Organization model list of essential medicines for children. Methods: The PubMed/Medline databases was searched and included studies if they described a population PK model of piperacillin, amoxicillin, ampicillin, cefotaxime, ceftriaxone, cloxacillin, imipenem or meropenem in neonates or children. We compared the PK parameters for each drug. We analysed the used covariates to estimate PK parameters. We compared the pharmacokinetics/pharmacodynamics (PK/PD) targets and the drug dosing recommendations. Results: Thirty-four studies met inclusion criteria with seven studies for piperacillin, five for amoxicillin, three for ampicillin, three for cefotaxime, two for ceftriaxone, two for imipenem and twelve for meropenem. None met inclusion criteria for cloxacillin. Ages ranged from 0-19.1 years with 12 studies including preterm. Body weight, age and renal function were the three major covariates in neonates and children. Different PK/PD targets were observed (between 40% to 100% of the dosing regimen interval of time over which the unbound (or free) drug concentration remains above the minimal inhibitory concentration (MIC) (fT>MIC) or four times the MIC (fT>4xMIC)). Several drug-dosing regimens were fond recommended according to the age and pathogens MIC using intermittent, timed or continuous infusions. Conclusions: Consensus is lacking on the optimal dosing regimens for these eight first choice antibiotics. A more personalized approach to antibiotic drugs dosing with individual characteristics of patient and pathogen susceptibility is required. According PK/PD targets and used dosing regimens, prospective clinical studies are required to investigate clinical cure, patient survival and emergence of antimicrobial resistance.

scholarly journals Contamination of Human Milk by Drugs and Chemicals

1983 ◽  
Vol 2 (3-4) ◽  
pp. 191-201 ◽  
Author(s):  
John T. Wilson
Keyword(s):  
Breast Milk ◽  
Human Milk ◽  
Drug Concentration ◽  
Drug Disposition ◽  
Drug Dose ◽  
Drug Accumulation ◽  
Drug Elimination ◽  
Drug Excretion ◽  
Toxic Agents

Three major areas are emphasized for a study of drug excretion in breast milk: maternal drug disposition, breast milk pharmacokinetics and neonatal drug elimination. The first two impact on drug dose to infant whereas the last area is crucial to drug accumulation in the infant. Pitfalls in assessment of the drug concentration in milk to plasma (M/P) ratio are illustrated to expose errors in drug dose in milk estimates. Predictions about drug dose in milk must be confirmed by sampling of both milk and infant plasma for drug concentration. Principles for drug excretion in breast milk can be used as guidelines for excretion of a growing number of toxic agents.

CRISPR-based gene editing is presently being tried in many clinical trials

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Clinical Trials ◽  
Cell Function ◽  
Therapeutic Window ◽  
Development Environment ◽  
Drug Dosing ◽  
Protein Levels ◽  
Cell Tissue ◽  
Rnp Complex ◽  
Dosing Regimens

CRISPR is a bacterial host defense system that may work as "molecular scissors" in eukaryotic cells to permanently modify genetic coding. Some barriers to using CRISPR as a therapeutic include guaranteeing adequate delivery of the RNP complex to the proper cell/tissue and showing safe and effective editing. Off-target editing (i.e., unwanted modification in a non-target DNA location) may result in a range of safety problems impacting normal cell function. The degree of cell editing events, including off-target modifications, is known to be altered by in vitro dosage and time of exposure to active RNP complexes. The safety of these drugs relies heavily on preventing unwanted mutations, off-target mutations, and any genomic rearrangements, all of which may have harmful implications.In some illnesses, a slight general adjustment of positive and negative protein levels may be sufficient to have a therapeutic impact. Understanding this therapeutic window will enable researchers to modify drug dosing regimens, especially for in vitro use, to obtain optimum pharmacodynamics with the fewest potential adverse effects. Most of the bioanalytical endpoints outlined for CRISPR are simple methods performed in most labs. Development teams will need to manage resources by selecting key exposure endpoints that deliver the greatest value from pharmacokinetics/PD and safety evaluations. Two in vitro delivery strategies have entered clinical trials in immune-privileged locations. The drug development environment will have to be altered in close coordination with regulatory agencies to construct need-to-know endpoints and pivotal trials to successfully move medicines forward in a safe and controlled way.

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