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FACTORS AFFECTING THERAPEUTIC DRUG MONITORING

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BY : VIJIT AGRAWAL 5th Pharm.D JSSCP, Mysore

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INTRODUCTION Therapeutic drug monitoring (TDM) is

generally defined as the clinical laboratory measurement of a chemical parameter that, with appropriate medical interpretation, will directly influence drug prescribing procedures by combining knowledge of pharmaceutics, pharmacokinetics, and pharmacodynamics.

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CLINICAL USEFULNESS OF TDM1. Maximize efficacy of drug 2. Avoiding toxicity 3. Identifying therapeutic failure 4. Facilitating dose adjustment 5. Facilitating therapeutic effects

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Factors Affecting TDM1. Patient demographics2. Patient Compliance3. Individuals capacity to

absorb/distribute/metabolize/excrete the drug

4. Genetic factors

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Factors Affecting TDM…5. Concomitant disease, Tropical disease

and nutritional deficiencies6. Alternative system of medicine7. Ethnic differences and extrapolation of

the normal range

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Factors Affecting TDM…8. Alcohol & Tobacco use9. Quality of medication and generic

formulation10. Control of drug assay11. Medication or sampling errors12. Laboratory errors13. Cost effectiveness

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1. Patient demographics

Age, sex and lean body weight are particularly important for renally cleared drugs as knowledge of these allows calculation of creatinine clearance.

Ethnicity may be an important consideration for TDM of some hepatically cleared drugs.

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2. Patient Compliance If the concentration of the drug is lower

than expected, the possibility of non compliance should be considered before a dose increase is recommended.

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3. Individuals capacity to absorb/distribute/metabolize/excrete the drugAbsorption:The rate of absorption and extent of absorption

are dependent on various factors such as: Drug formulation Manufacturer Route of administration Intra-individual variations Another aspect of absorption is bioavailability.

This is the fraction of the administered dose that reaches the systemic circulation.

Bioavailability is 100% for IV injection.

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Distribution:(Vd) = dose/plasma concentrationThe absolute bioavailability of a drug,

when administered by an extra vascular route, is usually less than one (i.e. F<1).

For example if a drug has a half life of four hours, four hours after the initial dose, 50% of the drug will be removed.

Eight hours after the initial dose, half of the remaining drug (25% of total) will be removed, for a total of 75% having been removed at that time, and so on.

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Half-life information is used to determine the correct drug dose required to attain the desired therapeutic range.

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Metabolism: In addition, drug metabolites can be

either protein bound (inactive) or free (active).

The drug dosage will depend on how the drug metabolizes.

Factors that impact drug metabolism includes genetics, environment, nutrition, and age.

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Excretion: Drug excretion from the body occurs

through the kidneys, or fluids excreted through the lungs, GI or skin.

Renal dysfunction reduces drug clearance and may contribute to drug accumulation and increased risk of adverse drug effects.

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Some other causes Age: In general, drugs metabolized

more slowly in foetal, neonatal, and geriatric populations

Physical properties of the drug (hydrophobicity, pKa, solubility)

If the drug is administered in a fed or fasted state

Gastric emptying rate

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Interactions with other drugs (e.g. antacids, alcohol, nicotine)

Interactions with other foods (e.g. grapefruit juice, pomello, cranberry juice)

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Enzyme induction/inhibition by other drugs/foods:-

Enzyme induction (increase rate of metabolism). e.g. Phenytoin, barbiturates, carbamazepine, glutethimide, primidone, rifampicin induces CYP1A2, CYP2C9, CYP2C19 and CYP3A4, , which is involved in a drug's metabolism may reduce the drug's activity

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Enzyme inhibition (decrease rate of metabolism), resulting in ↑ drug activity, e.g. Protease inhibitors, Nitrogen mustard, Mtx, Cidenafil Citrate

Prolonging the action of various drugs, including chloramphenicol, cimetidine, disulfiram (Antabuse), isoniazid, methyldopa, metronidazole, phenylbutazone

Grape fruit juice inhibits CYP3A --> higher nifedipine concentrations

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Individual Variation in Metabolic Differences

Phenotypic differences, inter hepatic circulation, diet, gender.

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4. Genetic factors It plays an as yet poorly defined role in

therapeutic drug monitoring, as is the case of the poor ability of some racial groups to acetylated drugs

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5. Concomitant disease, Tropical disease and nutritional deficiencies

This includes diseases highly prevalent in developing countries such as

Infections, Diarrhoea, Worm infestations, Tuberculosis, Nutritional deficiencies, plus a Higher proportion of patients with

diabetes and AIDS

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Nutritional deficiencies are often subclinical and escape detection and they have been shown to affect drug pharmacokinetics.

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6. Alternative system of medicine

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India is unique in having at least three systems of medicine coexisting with ‘western’ medicine (allopathy); ayurveda, homeopathy and unani.

A patient with a history of generalized tonic-clonic (GTC) seizures, well controlled and with plasma phenytoin levels within the therapeutic range, presented with sudden loss of seizure control.

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History revealed that he was taking ‘shakhapushpi’ and plasma analysis showed that his phenytoin level had dropped.

Interaction with conventional drugs have been documented for liquorice, ginseng, tannic acids, plantain, uzara root, hawthorn and kyushin all of which may be prescribed by practitioners of the alternative systems.

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7. Ethnic differences The fact that interpopulation variations in drug

pharmacokinetics can result in higher or lower plasma drug concentrations is well known.

Mani has reported that the effective anticonvulsant dosage may be lower in Indians than in Europeans

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8. Alcohol & Tobacco use Chronic use of alcohol has been shown

to cause non-specific hepatic microsomal enzyme induction, resulting in increased clearance and decreased serum concentrations of hepatically cleared drugs such as Phenytoin.

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Cigarette smoking increases the hepatic clearance of theophylline and patients who have recently stopped smoking may have unexpectedly high theophylline concentrations.

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9. Quality of medication and generic formulation Quality of products (drug content,

bioavailability) is important especially for drugs with a narrow margin of safety which is just those drugs for which TDM is relevant.

Authors have already reported from Pakistan and Vietnam that quality of drugs used may be substandard and need additional quality control.

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10. Quality control in drug assays For TDM programs, quality control is

vitally important and in developing countries there are hardly any procedures for laboratory accreditation or external quality control.

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In view of the mushrooming of private ‘pathobiochem’ laboratories which offer a range of pathology and biochemical investigations, the state Food and Drug Administration’s are proposing laboratory inspections for standardizing and ensuring quality of results.

There are no such proposals for drug assay laboratories.

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11. Medication or sampling errors In cases where the TDM result is

incompatible with drug administration records, the possibility of a medication or sampling error should be considered.

For Example, the drug may have been given to the wrong patient, or blood may have been mistakenly drawn from a patient in a neighbouring bed.

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12. Laboratory errors

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If a laboratory error is suspected, the laboratory should be contacted and asked to repeat the assay.

Alternatively, a new blood sample can be drawn and sent to a different laboratory for assay.

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13. Cost effectiveness Rapid and cost-effective measurement

of most drugs for which TDM is indicated can be achieved using commercial kits run on automated analysers using a number of different methodologies including fluorescence polarisation immunoassay. 

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References A Textbook of Clinical Pharmacy Practice (Second Edition) G Parthasarathi, Karin Nyfort-Hansen & Milap C Nahata (Eds.)

2012; 331 pp; 978-81-7371-756-7 Therapeutic drug monitoring in a developing country: an

overview N J Gogtay, N A Kshirsagar, S S Dalvi Br J Clin Pharmacol. 1999

November; 48(5): 649–654. doi: 10.1046/j.1365-2125.1999.00088.x

PMCID: PMC2014358 Web link:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2014358/ Therapeutic drug monitoring D.J. Birkett, Professor of Clinical

Pharmacology, Flinders University of South Australia, Adelaide Web link:

http://www.australianprescriber.com/magazine/20/1/9/11/ Therapeutic Drug Monitoring (TDM) - An Educational

Guide Web link: http://www.medical.siemens.com/siemens/en_GLOBAL/gg_diag_FBAs/files/products_disease_states/TDM/TDM_Guide_FINAL.pdf

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Thank You