1. FACTORS AFFECTING THERAPEUTIC DRUG MONITORING

2. 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.

3. CLINICAL USEFULNESS OF TDM
Maximize efficacy of drug
Avoiding toxicity
Identifying therapeutic failure
Facilitating dose adjustment
Facilitating therapeutic effects

4. Factors Affecting TDM
1. Patient demographics 2. Patient Compliance 3. Individuals capacity to absorb/distribute/metabolize/excrete the drug 4. Genetic factors

5. Factors Affecting TDM…
5. Concomitant disease, Tropical disease and nutritional deficiencies
6. Alternative system of medicine
7. Ethnic differences and extrapolation of the normal range

6. Factors Affecting TDM…
8. Alcohol & Tobacco use
9. Quality of medication and generic formulation
10. Control of drug assay
11. Medication or sampling errors
12. Laboratory errors
13. Cost effectiveness

7. 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.

8. 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.

9. 3. Individuals capacity to absorb/distribute/metabolize/excrete the drug
Absorption:
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.

10. Distribution: (Vd) = dose/plasma concentration
The absolute bioavailability of a drug.
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.
Half-life information is used to determine the correct drug dose required to attain the desired therapeutic range

11. 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.

12. 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.

13. 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

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

15. 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
Enzyme inhibition (decrease rate of metabolism), resulting in ↑ drug activity, e.g. Protease inhibitors, Nitrogen mustard, Mtx, Cidenafil Citrate

16. Drug Interactions
TDM results should be interpreted in light of the patients other drug therapy
For example: patient on digoxin may have unexpected high digoxin serum concentration and develop digoxin toxicity if drug such as verapamil are started without a reduction in digoxin dose. The serum concentration of some hepatically cleared drugs may be affected by cessation of drugs with either induce or inhibit hepatic cytochrome P450 isoenzymes.

17. 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

18. 6. Alternative system of medicine
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.

19. 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.
Cigarette smoking increases the hepatic clearance of theophylline and patients who have recently stopped smoking may have unexpectedly high theophylline concentrations

20. 9. 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.

21. 10. Laboratory errors
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.

22. 11. 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. 

23. Testing Methodologies
In HPLC liquid containing sample is injected at one end of the column. high pressure is used to overcome resistance to flow As liquid flows some molecule move faster than others due to diff in solubility. The exact time for each molecule to flow through the column is measured by detector. The retention time is calculated. An internal standard compound similar in structure to the specimen to be analyzed is also run through the column. By comparing retention time of sample and standard molecule can be identified. Concentration of drug can also be determine that peak produce during run.

24. THANK YOU -PHARMA STREET