Therapeutic Drug Monitoring (TDM)
•
1 like•264 views
In this document, there is all the information about TDM and its relation with pharmacogenetics and pharmacokinetics TDM can be looked at as a new area in pharmacokinetics that will lead to better patient's outcomes. Hope you enjoy it.
Recommended
More Related Content
What's hot
What's hot (20)
Similar to Therapeutic Drug Monitoring (TDM)
Similar to Therapeutic Drug Monitoring (TDM) (20)
More from Serena Hijazeen
More from Serena Hijazeen (11)
Recently uploaded
Recently uploaded (20)
Therapeutic Drug Monitoring (TDM)
- 2. Therapeutic Drug Monitoring (TDM) INTRODUCTION TDM is the clinical practice of measuring specific drugs at designated intervals to maintain a constant concentration in a patient’s blood stream, thereby optimizing individual dosage regimens. It is used to monitor drugs with low therapeutic window. Drugs that marked pharmacokinetic (PK) variability. Drugs which target concentrations are difficult to monitor. Drugs known to cause adverse reactions. TDM was introduced to the clinical practice in the 1960s with the publication of initial PK studies linking mathematical theories to patient outcomes. It was primary focused on the adverse effects and the demonstration of therapeutic ranges; in order to reduce the toxicity of drugs such as phenytoin (anti-epileptic), digoxin (cardiac glycoside) and theophylline (CNS stimulant) can be reduced. By combining the knowledge of pharmaceutics, PK and pharmacodynamics PD; TDM enabled the assessment of the efficacy and safety of a particular medication in a variety of clinical settings. We can consider this science as a part of the clinical PK monitoring, where drug concentration-response is being analyzed and studied using and a whole PK map is made using analytical technology and computerization; The more recent explosion of pharmacogenetic and pharmacogenomics (PG) research has been fueled by the huge amount of genetic data generated by the Human Genome Project (HGP), recent advancements in gene chip technology have ushered in a new era of gene-based medicinal and drug therapies.
- 3. WHICH DRUGS? When a drug has the ability to cause immediate effects such as blood pressure changes, cholesterol changes and even pain then TDM is highly recommended. Not all drugs MUST perform these studies, only if they had the following points. 1. Narrow therapeutic window. 2. Significant PK variability. 3. Reasonable relationship between plasma concentration and clinical effects. 4. Established target concentration range. 5. Availability of cost-efficient drug easily. Since drug assay are expensive and costly, if the manufacturer decides to do the TDM studies they should gain knowledge about how to increase the therapeutic dose, decreasing the toxicity and to assist the candidate in diagnosis. Examples on drugs that are therapeutically monitored are Anti-epileptics (Carbamazepine, valproate, phenobarbital and phenytoin), Immunosuppressant (Cyclosporine, sirolimus and tacrolimus), Cardiac medications (Quinidine, digoxin and procainamide) and finally antibiotics and in particular antiviral agents which will be focusing on in this article. Figure 2 shows the process of reaching a dosage decision with TDM. FIGURE 1 FIGURE 2
- 4. GENICTIC FACTOR AND TDM As cleared in the above figure, genetic variation contributes to the phenotype of drug response. Despite the mind-blowing breakthrough in PG research; not all drugs require PG test before being prescribed. The rationale behind PGs is to deal with gene encoding drug transporters, drug metabolizing enzymes and drug targets; which then predict the usefulness of a particular drug by increasing the number of responders and decreasing the adverse drug reactions (ADRs) For example; CYP (P450) family is a group of enzymes that are responsible for most phase I metabolism CYP2C9, CYP2C19 and CYP2D6 are subtypes that mediate 40% of the metabolism of the drugs on the market; so any mutations on their encoding gene may lead to abolished, altered, reduced or increased metabolizing activity. Which resulted in four major phenotypes FIGURE 3
- 5. TDM FOR ANTIVIRAL DRUGS poor metabolisers PMs Intermediate metabolizers IMs Extensive metabolizers EMs Ultrarapid metabolizers UMs Lack the functional enzyme Carry more than two functional gene copies Two normal alleles Heterozygous for a defect allele FIGURE 4 Figure 4 shows the pathophysiological changes associated with infection
- 6. Initial adequate anti-infection therapy is associated with significant improvement in the patient’s outcome for severely ill ones. TDM may be assisted to overcome this problem. Drug Absorption Abs. od drugs is expected to be lower due to decreased gut motility,poor blood perfusion to the GIT and finally decreased blood flow to the peripherals Volume of Distribution Pathogens are known to produce endotoxins that stimulate the production of immunomediators, and that leads to maldistributionand increased capillary permeability; fluid will shift to the interstatial spaces Protein Binding The free drug is the active drug, 40% of patients with infections develop hypoalbuminemia; which increases the the action of the drug plus its availability for elimination Clearance Due to fluid buildup and the use of vasoactive agents and the underlying infectionresponse; blood flow to major organs will increase thus increasing the renal clearance. untill myocardium deppressionoccurs and cause acute kidney injury AKI MIC Minimun concentration of a drug that can inhibit the growth of the pathogens at 24-hour intervals. As MIC decreases the suscptibility increases Extracorporeal Clearance Renal Replacementtherapy (RRTs)that are given during AKI to avoid further complication.For hydrophilicdrugs (with low Vd and high CL) RRTs will extent the elimination.unlike the lipophilicdrugs that are not affected by RRTs Acyclovir There is no clinical evidence between the plasma concentration of the drug and its efficacy, although when Cp increases it lead to serious toxicity that includes neurotoxicity Hydrophilicagent, with low Vd and high Cl rate. RRTs will extent its eliminationrate Bioanalyticalassays that were carried on acyclovir include HPLC-UV and LC-MS/MS analysis Dosing is highly dependent on creatinin clearance Oseltamivir There is no relationship between oseltamivir and its active metabolite to the pharmacological response There is an association between AUC and the efficacy against the Influnza virus Although it is a hydrophilic drug which means that when given with RRTs it will increase its Vd and decreases the Cl Bioanalyticalassays that were carried on oseltamivir include HPLC-UV and LC-MS/MS analysis
- 7. CONCLUSION TDM of anti-infections is of increasing interest for optimizing treatment of infections in critically ill patients. For many anti-infections, especially the hydrophilic agents, there is strong evidence of altered PK in critically ill patients. Many studies have described a higher apparent Vd and a great effect of augmented or decreased renal clearance on concentrations of renally cleared compounds in critically ill patients. These data indicate that TDM could be useful in order to optimize treatment in this patient group. A simple, precise, and rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS) method has been developed and validated for the simultaneous determination of oseltamivir and oseltamivir carboxylate, a neuraminidase inhibitor, using their deuterated analogs as internal standards (ISs). The method involved solid-phase extraction of the analytes and ISs from 200 μL human plasma with no reconstitution and drying steps. The chromatographic separation was achieved on a Symmetry C18 column using 10 mM ammonium formate and acetonitrile as the mobile phase in a run time of 2.0 min. Quantitation of analytes and ISs were done by multiple reaction monitoring on a triple quadrupole mass spectrometer in the positive ionization mode. The linearity of the method was established in the concentration range of 0.5–200 ng/mL and 2.0–800 ng/mL for oseltamivir and oseltamivir carboxylate respectively. The mean extraction recovery for oseltamivir (94.4%) and oseltamivir carboxylate (92.7%) from spiked plasma samples was consistent and reproducible. The application of this method was demonstrated by a bioequivalence study in 42 healthy Indian subjects with 75 mg oseltamivir phosphate capsules. The assay reproducibility was established by reanalysis of 151 incurred subject samples FIGURE 5