welcome to this pearl of laboratory medicine brought to you by aacc and the clinical chemistry trainee council view this and many more pearls as well as other free educational material at traineecouncil.org hello my name is jillian shirley i'm assistant professor and laboratory director at ohio state university wexner medical center welcome to this port of the water medicine and surgical drug monitoring chemotherapeutic agents therapeutic drug monitoring bravely called tdm offers clinicians better management of patients and the potential improvement of patient quality of life through optimizing those supporting compliance and minimizing toxicity the practice of tdm has been expanded and enhanced by rapid sensitivity and the specific analytical techniques for wide variety of the therapeutic agents the best candidate drugs for tdm are those meeting one or more of the following criteria a narrow therapeutic index used for long-term therapy correlation between serum concentration and clinical response wide inter-individual or intra-individual variability in pharmacokinetics absence of a biomarker associated with therapeutic outcome or administered with other potentially interacting compounds in practice tdm is performed for drug administered multiple times over many days weeks or even years usually doses administered before the preceding dose has been completely eliminated shown in this figure drugs administered at regular intervals will accumulate to a point termed steady states which means the amount of drug entering the systemic circulation is imbalanced with amount being eliminated assuming doses are given at each half-life a drug with first order kinetics will require three to five doses to approach steady state concentrations similarly at the end of therapy five to seven half-lives after the last dose must pass for more than 95 percent of the steady-state concentration to be eliminated the simplest and the most direct route of administering a drug is intravenous delivery because infusion places a complete dose of a compound into the circulation however practically and for reasons of patient performance drugs can be delivered by alternate ways the common way is oral administration oral dosing differs from intravenous due to the drug required to pass from the gastrointestinal tract into the vascular system this process is known as absorption the ability of absorption is determined by the rates and extent of drug absorption the nature of the drug itself for example solubility and pka the formulation matrix and the physiologic environment for example gastrointestinal motility the distribution of drugs extensively depends on the prophylicity their facilitates passage through cell membranes many drugs binded to one or more plasma proteins mostly are building globalists such as alpha-1 acid glycoprotein and lipoproteins in general acidic drugs associate primarily with albumin while basic drugs bind the globulins and lipoproteins a nuclear brain between the amount of drug is protein bond and a free drug which means non-bound to protein free drug is more readily accessible to cell membranes drug receptors and elimination mechanisms so the free function is considered the active component of the drug responsible for its biological effects metabolism is typically starts to enhance expression of drugs where endogenous and exogenous compounds are converted to more polar products to increase water solubility joints can be metabolized by oxidation reduction hydrolysis hydration conjugation condensation or isomerization excretion or elimination is a final removal of drugs from the body this includes secretion into sweat breasts and breast milk incorporation into hair and nails or even crossing the placenta into the fetal bloodstream however the most common ways of drug elimination is scratching into urine or stone depending on the water solubility of the compound the rate of elimination into urine can be estimated using the glomerular filtration rate drug concentrations are useful in many stages of treatment initial selection and dosing of a drug may be guided by kdn particularly if wide integration probability in absorption metabolism or other parameters of drug disposition as noted without measuring drug concentrations it is difficult to discern which patients respond poorly to therapeutic concentrations of a particular drug and which ones simply are not within the psychotic range particularly population from kinetics often does not adequately adjust comparability or drug interactions so tdm is necessary for this patient tdm analysis includes many of the same concerns as other areas of clinical chemistry the need for accurate reproducible methods the requirement for quality assurance and the proficiency testing programs and the necessity of establishing targeting ranges a wide variety of analytical techniques available to facilitate tdm including numerous amino acid methods such as enzyme-multiplied immunoassay technique emit fluency and polarization amino acid fpia cloned enzyme donor immunoassay cedia and chromatographic techniques such as gas chromatography mass spectrometry gcms liquid chromatography mass spectrometry lcms and high performance liquid chromatography ultraviolet hplc-uv immunoassays provide rapid results and ready automation chromatography techniques improve specificity and the limits of detection although at the lower throughput unfortunately commercial immunizes are not available for many of the newer generation drugs lcm sms is progressively replacing other hplc-based methods it displays greater selectivity and fewer analytical interferences allowing development of multi-analyte assays with higher support and less influence from metabolites or other potential co-educating compounds the choice of analytical method typically depends on the availability of resources and the clinical demand for torontime biosofan is a chemotherapeutic drug that inhibits the growth of malignant cells by alkylating dna bucifan is currently used in hematopoietic stem cell transplant preparative regimen to maximize an anti-tumor effect in addition busofan is also used to treat malignant and non-manipulative bone marrow disorders such as acute and chronic leukemias myelodysplastic syndrome beta-salicylia major polycystemia barrier and the sickle cell anemia the use of environmental kinetics is affected by age weight disease status hepatic function and drug interactions the optical range of circuit area under the plasma concentration versus time curve auc for standard doses built from s900 to 1350 micromolar minutes per liter patients with boostable concentrations below the cyclic range are thought of as having increased risk of relapse as well as of rejection conversely patients with plasma concentrations greater than 1500 micromolar minutes per liter have an increased risk of severe treatment related toxicity biosoften is metabolized through both cytochrome p450 isoenzymes primarily cyp38a4 and conjugation with glutathione by glutathione s transference slowed buildup and clearance could be anticipated with co-administration of a cyp3a4 inhibitor or computative substrate fluconazole is known to inhibit the drug metabolizing enzyme cyp7a4 so it inhibits the use of metabolism and delays its clearance massachusetts inhibits dna synthesis by decreasing the availability of parameter nucleotides massachusetts has proved useful in the management of acute lymphoblastic leukemia in children management of coral carcinoma and related cholesterol tumors in women management of carcinomas of the breast tongue pharynx and testis maintenance of remission of leukemia and the treatment of severe debilitating psoriasis high dose massachusetts administration followed by new covering rescue is effective in treatment of carcinoma of the lung and osteogenic sarcoma massachusetts is a non-specific cytotoxin and the prolongation of blood concentrations to killing tumor cells it may lead to severe unwanted cytotoxic effects such as milo suppression gastrointestinal mucositis and hepatic cirrhosis serial constitutions of massachusetts are commonly monitored during high dose therapy to identify the time at which active intervention by recovering rescue should be initiated criteria for serial concentration is indicative for a potential for toxicity after single bonus high dose therapy as shown in the table massachusetts concentration greater than 10 micromolar per liter 24 hours after dose massachusetts concentration greater than 1 micromolar per liter 48 hours of the dose massachusetts concentration greater than 0.1 micromolar per liter 72 hours after dose characteristically serum concentrations are monitored at 24 48 and 72 hours after the single dose and the new covering is administered when massachusetts concentration is an inappropriate high for pulse dose phase the route of elimination of massachusetts is primarily random expression during a period of high serum concentrations particular attention must be paid to maintaining output of a large volume of alkaline urine the pka of massachusetts is 5.5 so small decreases in europe resulting significant reduction in its solubility keeping urine ph alkaline diminish the risk of intratubular precipitation of the drug and the obstructive nephropathy during the treatment period so monitoring serum concentration provides the basic ideas for decisions related to timing of initiation and the continuous of the covering treatments and for management of urine ph low dose massachusetts is used to manage rheumatoid arthritis crohn's disease psoriasis or inflammatory or bowel disease it's not typically monitored because analytical methods are not sensitive enough to monitor one's weekly dosing and also because massachusetts concentrations have not been shown to correlate well with disease control the side effect profile or massachusetts varies market according to those regimens containing massachusetts are classified as high intermediates or loadouts most clinicians reserve the term high dose massachusetts for doses greater than or equal to 500 milligram per square meter and require a two or three day period of multiple recovery doses to terminate the toxic effect of massachusetts which is called recovering rescue glucomery is n5 formation hydrofoliage the product of dihydrophonic reductase recovery rescue is critical in cases in which it's necessary to administer high doses of massachusetts to individuals with tumors that do not respond to normal doses of this drug in such cases recovering is given 18 to 36 hours after the initial massachusetts while similar level of massachusetts are monitored in addition recovery should immediately be administered to a patient receiving low-dose message exit when massachusetts overdose is suspected serum massachusetts levels should be monitored during this time toxicity of massachusetts can also be treated using continuous flow hemodialysis alternatively intravenous infusion of carboxy peptidase g2 a massachusetts leaving enzyme results in rapid clearing of the drug thank you for joining me on this poll on the better medicine on therapeutic drug monitoring chemotherapy agents for more like this as well as articles podcasts and more please visit the trainee council at trainee traineecouncil.org