Therapeutic drug monitoring in clinical research

The development of a new drug is characterized by distinct developmental stages, usually described as phases I to IV. Dose tolerance and dose response exploration studies are undertaken in phase II or III. Pharmacokinetic studies are often involved in these phases, but frequently only as an objective of minor importance. The usefulness of therapeutic drug monitoring (TDM) is not consequently investigated for new drugs. Usually the need for TDM is only discovered much later, when the drug is already on the market. TDM is particularly valuable under the following circumstances: (i) if there is a stronger relationship between the drug concentration and effect than between the dose and effect; (ii) if there is no simple and clear clinical parameter available to evaluate the clinical efficacy of the drug; (iii) if the therapeutic window is small; (iv) to document interactions; (v) to monitor drug compliance; and (vi) if there is large intra- and interindividual variability and unpredictability in pharmacokinetic parameters. Our recommendation is that randomized concentration controlled trials should be performed during the early stages of drug development and that it should be obligatory for drug licensing. © 2008 Adis Data Information BV. All rights reserved

Medication and hemodiafiltration

The amount of drug clearance during online hemodiafiltration (HDF) is determined by (1) the pharmacokinetic properties of a drug defined by its absorption, distribution, metabolism and elimination (ADME) characteristics, (2) dialysis characteristics, including membrane properties, treatment time and blood-, dialysate-and ultrafiltration flow rates, and (3) patient factors. For several drugs, especially those within the middle molecular weight range, with low protein binding and neutrally or positively charged, clearance may be substantially higher during HDF as compared to conventional low flux hemodialysis. Based on drug characteristics, the expected additional effect of a high ultrafiltration rate, as indicated by a high convection volume, can be estimated. This is shown for anticoagulants, antibiotics and antiviral drugs. For drugs with an expected additional effect of convection and for drugs with a narrow therapeutic window, therapeutic drug monitoring may be advisable. Comparative data from clinical studies is scarce. Hence, for an individual patient it may be relevant to calculate the total amount of a drug excreted during an HDF session. This can easily be performed in routine clinical practice and may guide the clinician to estimate the dose of the drug needed for suppletion upon completion of HDF treatment. Examples are provided how to calculate drug suppletion after HDF. Collectively, this chapter is intended as a guidance to optimize pharmacotherapy in online HDF patients.</p

Extended-Interval Dosing of Gentamicin Aiming for a Drug-Free Period in Neonates:A Prospective Cohort Study

Background:Current gentamicin dosing algorithms in adult populations target a high peak concentration (C-max) assuring efficacy and a drug-free period (concentration 8 mgL(-1) and estimated trough concentrations 8 mgL(-1) with a C-min valu

Optimization of anti-infective dosing regimens during online haemodiafiltration

Online haemodiafiltration (HDF) is increasingly used in clinical practice as a routine intermittent dialysis modality. It is well known that renal impairment and renal replacement therapy can substantially affect the pharmacokinetic behaviour of several drugs. However, surprisingly few data are available on the need for specific dose adjustments during HDF. Due to convection, drug clearance may be increased during HDF as compared with standard haemodialysis. This may be of particular interest in patients undergoing anti-infective therapy, since under-dosing may compromise patient outcomes and promote the emergence of bacterial resistance. Drug clearance during HDF is determined by (i) dialysis characteristics, (ii) drug characteristics and (iii) patient characteristics. In this review, we will discuss these different determinants of drug clearance during HDF and advise on how to adjust the dose of antibacterial, antimycotic and antiviral agents in patients undergoing HDF. In addition, the possible added value of therapeutic drug monitoring is discussed. The review provides guidance for optimization of anti-infective dosing regimens in HDF patients

Azithromycin maintenance therapy in patients with cystic fibrosis:A dose advice based on a review of pharmacokinetics, efficacy, and side effects

Azithromycin maintenance therapy results in improvement of respiratory function in patients with cystic fibrosis (CF). In azithromycin maintenance therapy, several dosing schemes are applied. In this review, we combine current knowledge about azithromycin pharmacokinetics with the dosing schedules used in clinical trials in order to come to a dosing advise which could be generally applicable. We used data from a recently updated Cochrane meta analysis (2011), the reports of clinical trials and pharmacokinetic studies. Based on these data, it was concluded that a dose level of 22-30âmg/kg/week is the lowest dose level with proven efficacy. Due to the extended half-life in patients with CF, the weekly dose of azithromycin can be divided in one to seven dosing moments, depending on patient preference and gastro-intestinal tolerance. No important side effects or interactions with other CF-related drugs have been documented so far. Pediatr Pulmonol. 2012; 47:658-665. © 2011 Wiley Periodicals, Inc

Design and prospective validation of a dosing instrument for continuous infusion of vancomycin:a within-population approach

INTRODUCTION: The clinical application of continuous infusion (CoI) of vancomycin has gained interest in recent years. Since no international guidelines on initial dosing of vancomycin CoI exist, there is a need for methods to facilitate the switch from intermittent to continuous vancomycin dosing algorithms in clinically infected populations. Therefore, the aim of this study was to design and validate an a priori dosing schedule for CoI of vancomycin in clinical practice. METHODS: A dosing table for CoI of vancomycin based on estimated glomerular filtration rate (eGFR) was developed by simulation of continuous infusion of vancomycin using pharmacokinetic (PK) software and a PK population model designed from historical within-population data in intermittently dosed patients. The target range for the first vancomycin serum concentrations drawn approximately 24 h after start of infusion' (C24) was set at 15-20 mg/L corresponding with an area under the curve (AUC) of at least 350 mg·h·L(-1). The performance of the dosing schedule was primarily assessed by describing the percentages of patients attaining the predefined target. RESULTS: An eGFR-derived dosing schedule for CoI of vancomycin was established and implemented in clinical practice. Prospective assessment in 35 general ward and 45 intensive care unit patients showed that the C24 target was reached in 69 and 63 % and the AUC target was attained in 80 and 72 % of patients, respectively. CONCLUSIONS: An easy method to design and validate an eGFR-derived dosing algorithm for the continuous infusion of vancomycin to switch from intermittent to continuous dosing of vancomycin was developed