THERAPUTIC REGIMEN.pptx

Therapeutic Regimen
Dose-response Curve
Drug Toxicity
Symptoms, Diagnosis & Treatment Of Drug Toxicity
Dosage Regimen
Factors To Consider In Design Of Drug Dosage Regimens
Methods To Design A Dosage Regimen
Dosing Of Drugs In Infants And Children
Dosing Of Drugs In The Elderly
Clinical Trial

1. Presented by : MISS HARSHITA SINGHAI m. Pharm sem. 2 1 THERAPEUTIC REGIMENS

2. CONTENTS Introduction Therapeutic Regimen Dose-response Curve Drug Toxicity Symptoms, Diagnosis & Treatment Of Drug Toxicity Dosage Regimen Factors To Consider In Design Of Drug Dosage Regimens Methods To Design A Dosage Regimen Dosing Of Drugs In Infants And Children Dosing Of Drugs In The Elderly Clinical Trial 2

3. THERAPEUTIC REGIMEN A therapeutic regimen is a systematic plan (as of diet, therapy, or medication) especially when designed to improve and maintain the health of a patient. A therapeutic response is a result of a medical treatment of any kind, leading to a desirable and beneficial effect. For example, an individual taking aspirin for their heart would consider the therapeutic effect to be the prevention of heart attacks. When aspirin is taken for a headache, the desired result will be reduction in pain.

4. DOSE-RESPONSE CURVE Dose-response data are typically graphed with the dose or dose function ( Eg : log 10  dose) on the x-axis and the measured effect (response) on the y-axis. Measured effects are frequently recorded as maximal at time of peak effect or under steady-state conditions. ( Eg : During continuous IV infusion ). Drug effects may be quantified at the level of molecule, cell, tissue, organ, organ system, or organism. FIG: A hypothetical dose-response curve

5. Dose-response curve determines the required dose and frequency as well as the therapeutic index for a drug in a population . Increasing the dose of a drug with a narrow therapeutic index increases the probability of toxicity or ineffectiveness of the drug. However , they differ by population and patient-related factors, such as   pregnancy,  age, and organ function ( Eg : estimated GFR ). DOSE-RESPONSE CURVE

6. COMPARISON OF DOSE-RESPONSE CURVES Drug X has greater biologic activity per dosing equivalent and is thus more potent than drug Y or Z. Drugs X and Z have equal efficacy, indicated by their maximal attainable response (ceiling effect). Drug Y is more potent than drug Z, but its maximal efficacy is lower .

7. DRUG TOXICITY “Drug toxicity is formally defined as the level of damage that a compound can cause to an organism”. The threshold between an effective dose and a toxic dose is very narrow. A therapeutic dose for one person might be toxic to another person. Plus, drugs with a longer half-life  can build up in a person's bloodstream and increase over time, resulting in drug toxicity. CAUSES OF DRUG TOXICITY ARE- Drug toxicity can occur as a result of the over-ingestion of medication, causing too much of the drug to be in a person's system at once. Drug toxicity can also occur as an adverse drug reaction . In this case, the normal therapeutic dose of the drug can cause unintentional, harmful, and unwanted side effects.

8. SYMPTOMS OF DRUG TOXICITY Drug toxicity symptoms can differ depending on the medication you are taking and is determined by chemical structure, concentration of drug the body can absorb and the body's ability to detoxify and eliminate the substance. In the case of lithium, for instance, mild symptoms of acute   lithium toxicity  (which is drug toxicity after taking the drug one time) can include : Diarrhea Dizziness Nausea Stomach pains Vomiting Weakness

9. DIAGNOSIS OF DRUG TOXICITY Acute drug toxicity is more easily diagnosed as the symptoms follow the taking of the medication just one time.  Blood tests can also screen for levels of the medication in the bloodstream, showing whether these levels are too high. Chronic drug toxicity, or drug toxicity that occurs due to long-term build-up, is harder to identify. Stopping the medication, then "re-challenging" it later is one method of testing whether the symptoms are caused by the medicine. This method can be problematic, however, if the medication is essential and doesn't have an equivalent substitute.

10. TREATMENT OF DRUG TOXICITY There are several ways drug toxicity may be treated- A person may undergo stomach pumping to remove drugs that have not yet been absorbed in case acute overdose of drug. Activated charcoal can be used to bind the drug, preventing it from being absorbed into the blood and eliminating it from the body through stool. Other medications may also be given as an antidote for drug toxicity. If you believe that you or someone else has symptoms of drug toxicity or overdose, contact medical services immediately. Quick treatment can result in fewer complications.

11. DOSAGE REGIMEN Dosage regimen design is the selection of drug dosage form, route of administration and frequency of administration in an informed manner to achieve therapeutic objectives. An “optimal multiple dosage regimen” is the one in which the drug is administered in suitable doses, by suitable route, with sufficient frequency that ensures maintenance of plasma concentration within the therapeutic window without excessive fluctuation and drug accumulation for the entire duration of therapy. The initial dosage regimen is calculated based on body weight or body surface after a careful consideration of the known pharmacokinetics of the drug, the pathophysiologic condition of the patient, and the patient's drug history. The overall objective of dosage regimen design is to achieve a target drug concentration at the receptor site.

12. For certain analgesics, hypnotics, anti-emetics etc. a single dose may provide an effective treatment. But the duration of most illness is longer than the therapeutic effect produced by a single dose. In such cases drugs are required to be taken on a repetitive basis over a period of time. Planning of drug therapy is necessary because the administration of drugs usually involves risk of unwanted effects. Specific drugs have different risks associated with their use and a dosage regimen should be selected which will maximize safety. At the same time, the variability among patients in pharmacodynamic response demands individualized dosing to assure maximum efficacy .

13. Two major parameters that can be adjusted in developing a dosage regimen are: 1. DOSE SIZE :- It is the quantity of the drug administered each time. The magnitude of therapeutic & toxic responses depend upon dose size. Amount of drug absorbed after administration of each dose is considered while calculating the dose size. Greater the dose size greater the fluctuation between Css,max & Css,min (max. and min. steady state concentration) during each dosing interval & greater chances of toxicity. 2. DOSE FREQUENCY :- It is the time interval between doses. Dose interval is inverse of dosing frequency. Dose interval is calculated on the basis of half life of the drug. When dose interval is increased with no change in the dose size, Cmin , Cmax & Cav decrease, but when dose interval is reduced, it results in greater drug accumulation in the body and toxicity.

14. CERTAIN CONCEPTS A)Drug accumulation during multiple dosing : Following the 1st dose, if the 2nd dose is given before the 1st dose is eliminated then the drug will start accumulating and we will get higher concentration with the 2nd and 3rd dose. Upon repeating the dose, it is seen that the drug accumulation continue until a limit is reached. The reason being that as the plasma conc. increases the rate of elimination will also increase following 1st order elimination. B)Time to reach steady state during multiple dosing:  The time required to reach steady state depends primarily upon the half life of the drug. Provided Ka>> Ke , plateau is reached in approximately 5 half lives. The time taken to reach steady state is independent of dose size, dose interval & no. of doses. It is determined only by Ke .

15. MULTIPLE DOSING WITH RESPECT TO I.V On repeated drug administration, the plasma conc. will be added upon for each dose interval giving a plateau or steady state with the plasma conc. fluctuating between a minimum and maximum.

16. MULTIPLE DOSING WITH RESPECT TO ORAL ROUTE In this plasma conc. will increase, reach a maximum and begin to decline. A 2nd dose will be administered before the absorbed drug from the 1st dose is completely eliminated. Consequently plasma conc. resulting from 2nd dose will be higher than from 1st dose. This increase in conc. with dose will continue to occur until a steady state reaches at which rate of drug entry into the body is equal to rate of exit.

17. LOADING DOSE A drug dose does not show therapeutic activity unless it reaches the desired steady state. • It takes about 4-5 half lives to attain it and therefore time taken will be too long if the drug has a long half-life. • Plateau can be reached immediately by administering a dose that gives the desired steady state instantaneously before the commencement of maintenance dose X0 . • Such an initial or first dose intended to be therapeutic is called as priming dose or loading dose X0 .

18. CALCULATION OF LOADING DOSE  For IV drugs given by infusion, Dose rate  (mg/hr)   = dose (mg) divided by dosing interval (hrs) Maintenance dose rate  (mg/hr) = desired peak concentration (mg/L) × clearance (L/hr) Loading dose  = desired peak concentration (mg/L) × volume of distribution (L) For drugs  not  given IV, these doses need to be divided by the bioavailability.

19. CALCULATION OF LOADING DOSE • If the loading dose is not optimum either too low or too high, the steady state is attained within a 4-5 half lives in a manner similar to when no loading dose is given.

20. I. Route of Administration II. Dose III. Dosage interval IV. Complications FACTORS TO CONSIDER IN DESIGN OF DRUG DOSAGE REGIMENS

21. ROUTE OF ADMINISTRATION: 1. Drug absorption characteristics 2. Presence of pre-systemic elimination or unusual first-pass metabolism in some patients 3. Accumulation of drug at absorption site. E.g. Intramuscular depots. 4. Need for immediate onset of action 5. Ease of administration 6. Half-life: infusion may be necessary for drugs with short t 1 /2 or sustained release formulation. 7. Patient acceptance of route and dosage form FACTORS TO CONSIDER IN DESIGN OF DRUG DOSAGE REGIMENS

22. II. DOSE: 1. Pharmacokinetics of the drug—including its absorption, distribution, and elimination profile—are considered in the patient. 2. Volume of distribution: to estimate peak plasma concentration 3. Documented nonlinearity of pharmacokinetics 4. Cost of medication 5. Half-life: tapering of dose may not be necessary for some drugs with long t 1 /2 6. Availability of treatment for overdose 7. Existence of a therapeutic or toxic concentration range 8. Therapeutic index

23. EXAMPLE OF EFFECT OF DOSE

24. III. DOSAGE INTERVAL: 1. Half-life: Dosage interval can generally be extended in relation to half-life. 2. Therapeutic index: The higher the TI, the longer an interval can be spaced with higher doses. 3. Body clearance to evaluate accumulation 4. Side effects which may require special administration times. e.g. bed time to avoid sedation.

25. EXAMPLE OF DOSAGE INTERVAL

26. IV. COMPLICATIONS: 1. Analytical methodology and reliability in monitoring Cp 2. Active metabolites 3. Changing pathophysiology such as renal dysfunction, hepatic disease, or congestive heart failure 4. Drug interactions 5. Auto or exogenous enzyme induction 6. Development of pharmacodynamic tolerance 7. Side effects which are not dose or concentration related 8. Physiology of the patient, age, weight, gender, and nutritional status will affect the disposition of the drug

27. METHODS TO DESIGN A DOSAGE REGIMEN Individualized dosage regimen Dosage regimen based on population average Dosage regimen based on partial pharmacokinetic parameters Empirical dosage regimen

28. 1. INDIVIDUALIZED DOSAGE REGIMEN It is a most accurate approach. Dose calculated based on the pharmacokinetics of the drug in the individual patient derived from measurement of serum or plasma drug levels. Not feasible for calculation of the initial dose, however, readjustment of the dose is quite possible. Most dosing program record the patient’s age and weight and calculate the individual dose based on creatinine clearance and lean body mass.

29. 2. DOSAGE REGIMENS BASED ON POPULATION AVERAGES Dosage regimen is calculated based on average pharmacokinetic parameters obtained from clinical studies published in the drug literature. There are two approaches followed 1. Fixed model 2. Adaptive model 1. Fixed Model: Assumes that population average pharmacokinetic parameters may be used directly to calculate a dosage regimen for the patient, without any alteration. The practitioner may use the usual dosage suggested by the literature and then make a small adjustment of the dosage based on the patient’s weight and / or age. When a multiple dose regimen is designed, multiple dosage equations based on the principle of superposition are used to evaluate the dose.

30. 2. Adaptive Model: This approach attempts to adapt or modify dosage regimen according to the need of the patient. Uses patient variable such as weight, age, sex, body surface area, and known patient’s pathophysiology such as, renal disease, as well as known population average pharmacokinetic parameters of the drug. This model generally assumes that pharmacokinetic parameters such as drug clearance do not change from one dose to the next. However, some adaptive models allow for continuously adaptive change with time in order to simulate more closely the changing process of drug disposition in the patient, especially during a disease state.

31. 3. DOSAGE REGIMEN BASED ON PARTIAL PHARMACOKINETIC PARAMETERS: For many drugs, the entire pharmacokinetic profile for the drug is unknown or unavailable. Therefore,some assumptions are made in order to calculate the dosage regimen. These assumptions will depend on the safety, efficacy, and therapeutic range of the drug. The use of population pharmacokinetics uses average patient population characteristics and only a few serum or plasma concentration from the patient. Population pharmacokinetic approaches to therapeutic drug monitoring have increased with the increased availability of computerized data bases and development of statistical tools for the analysis of observational data.

32. 4. EMPIRICAL DOSAGE REGIMENS: In many cases, physician selects a dosage regimen of the patient without using any pharmacokinetic variables. The physician makes the decision based on empirical clinical data , personal experience and clinical observations.

33. DOSING OF DRUGS IN INFANTS AND CHILDREN Infants and children have different dosing requirements than adults. Variation in body composition and the maturity of liver and kidney function are potential sources of differences in pharmacokinetics with respect to age. In general, complete hepatic function is not attained until the third week of life. Oxidative processes are fairly well developed in infants, but there is a deficiency of conjugative enzymes. In addition, many drugs exhibit reduced binding to plasma albumin in infants.

34. Newborns show only 30–50% of the renal activity of adults on the basis of activity per unit of body weight . Drugs that are heavily dependent on renal excretion will have a sharply decreased elimination half-life. For example, the penicillins are excreted for the most part through the kidney. The elimination half-lives of such drugs are much reduced in infants. Pediatric drug formulations may also contain different drug concentrations compared to the adult drug formulation. Furthermore, alternative drug delivery such as an intramuscular antibiotic drug injection into the gluteus medius may be considered for a pediatric patient, as opposed to the deltoid muscle for an adult patient.

35. DOSING OF DRUGS IN THE ELDERLY Performance capacity and the loss of homeostatic reserve decreases with advanced age but occurs to a different degree in each organ and in each patient and can affect compliance and the therapeutic safety and efficacy of a prescribed drug. Elderly patients may have several different pathophysiologic conditions that require multiple drug therapy that increases the likelihood for a drug interaction. Example: Both penicillin and kanamycin show prolonged t 1/2 in the aged patient, as a consequence of an age-related gradual reduction in the kidney size and function.

36. CLINICAL TRIAL “Clinical trials are research studies that explore whether a medical strategy, treatment, or device is safe and effective for humans. These studies also may show which medical approaches work best for certain illnesses or groups of people.” Clinical trial studies are often done with a limited number of subjects, due to either cost or the availability of subjects who meet the study requirements. The study subjects are selected according to exclusion and inclusion criteria that are written into the protocol. .

37. All subjects must give informed consent to be in the study. Since most studies are done over a period of time, it is important to ensure that both the treatment and control groups are balanced and to avoid any temporal influence. CLINICAL TRIAL

38. ADVANTAGES Provides the strongest evidences in support of cause effect relationships. Basis for clinical and public health policy. Toxicokinetic studies are performed in animals during preclinical drug development and may continue after the drug has been tested in clinical trials. Clinical studies are monitored for side effects and rare events Clinical trials in humans establish the safety and effectiveness of drug products and may be used to determine bioavailability

39. FUNCTIONS The purpose of the clinical trial is assessment of efficacy, safety, or risk benefit ratio. Goal may be superiority, non-inferiority, or equivalence.  The actual dosing regimen (dose, dosage form, dosing interval) was carefully determined in clinical trials to provide the correct drug concentrations at the site of action.

40. REFERENCES SHARGEL L., PONG S.W., ANDREW B.C. ,“APPLIED BIOPHARMACEUTICS AND PHARMACOKINETICS ”,ED- 5,BY MC GRAW - HILL, MEDICAL PUB., NEW YORK, CH-13,14 BRAHMANKAR D.M. , JAISWAL S.B., “ BIOPHARMACEUTICS AND PHARMACOKINETICS”, ED-2, 2019, VALLABH PRAKASHAN , DELHI, 399-401. https:// pubrica.com /academy/statistical/on-biostatistics-and clinical-trials/ https:// cead.cumc.columbia.edu /content/research-clinical-trials REFERENCES 42

41. https:// www.editage.com /insights/a-young-researchers-guide-to-a-clinical-trial https:// www.researchgate.net /figure/Drug-dosing-tool-development-process-Pharmacokinetic- PK - pharmacodynamic -PD- studies_fig2_319050728 https:// www.sciencedirect.com /topics/biochemistry-genetics-and-molecular-biology/drug-toxicity https:// www.collinsdictionary.com /dictionary/ english /therapeutic-response REFERENCES

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