Rational dosage design Is based on the assumption that there is a target concentration that will produce the desired therapeutic effect The intensity of a drug's effect is related to its concentration above a minimum effective concentration, whereas the duration of this effect reflects the length of time the drug level is above this value By considering drug’s PKs, it is possible to individualize the dose regimen to achieve the target concentration

Half-Life (t1/2) Half-Life (t1/2) : it is the time required for the plasma concentration or the amount of drug in the body to change by one-half (i.e. 50%) The half-life is a derived parameter that changes as a function of both CL and Vd:

Therapeutic equivalence Bioequivalence Two drug formulations are bioequivalent if they show comparable bioavailability and similar times to achieve peak blood concentrations. Therapeutic equivalence Two drug formulations are therapeutically equivalent if they are pharmaceutically equivalent (that is, they have the same dosage form, contain the same active ingredient, and use the same route of administration) with similar clinical and safety profiles. Clinical effectiveness often depends on both the maximum serum drug concentration and the time required (after administration) to reach peak concentration. Therefore, two drugs that are bioequivalent may not be therapeutically equivalent.

Design and optimization of dosage regimen A. Continuous infusion regimens Therapy may consist of a single dose of a drug, for example, a sleep inducing agent, such as zolpidem. More commonly, drugs are continually administered, either as an IV infusion or in oral fixed- dose/fixed-time interval regimens (for example, “one tablet every 4 hours”). Continuous or repeated administration results in accumulation of the drug until a steady state occurs. Steady-state concentration is reached when the rate of drug elimination is equal to the rate of drug administration, such that the plasma and tissue levels remain relatively constant.

1. Plasma concentration of a drug following IV infusion: With continuous IV infusion, the rate of drug entry into the body is constant. Most drugs exhibit first-order elimination, that is, a constant fraction of the drug is cleared per unit of time. Therefore, the rate of drug elimination increases proportionately as the plasma concentration increases. Following initiation of a continuous IV infusion, the plasma concentration of a drug rises until a steady state (rate of drug elimination equals rate of drug administration) is reached, At which point the plasma concentration of the drug remains constant.

a. Influence of the rate of infusion on steady-state concentration: The steady-state plasma concentration (Css) is directly proportional to the infusion rate. Css is inversely proportional to the clearance of the drug. Any factor that decreases clearance, such as liver or kidney disease, increases the Css of an infused drug (assuming Vd remains constant). Factors that increase clearance, such as increased metabolism, decrease the Css.

b. Time required to reach the steady-state drug concentration: The concentration of a drug rises from zero at the start of the infusion to its ultimate steady- state level, Css. The rate constant for attainment of steady state is the rate constant for total body elimination of the drug. Thus, 50% of Css of a drug is observed after the time elapsed, since the infusion, t, is equal to t1/2, where t1/2 (or half-life) is the time required for the drug concentration to change by 50%. After another half-life, the drug concentration approaches 75% of Css . The drug concentration is 87.5% of Css at 3 half-lives and 90% at 3.3 half-lives. Thus, a drug reaches steady state in about four to five half-lives.

The sole determinant of the rate that a drug achieves steady state is the half-life (t1/2) of the drug, and this rate is influenced only by factors that affect the half-life. The rate of approach to steady state is not affected by the rate of drug infusion. When the infusion is stopped, the plasma concentration of a drug declines (washes out) to zero with the same time course observed in approaching the steady state.

B. Fixed-dose/fixed-time regimens Fixed doses of IV or oral medications given at fixed intervals result in time-dependent fluctuations in the circulating level of drug. 1. Multiple IV injections: When a drug is given repeatedly at regular intervals, the plasma concentration increases until a steady state is reached. Because most drugs are given at inter-vals shorter than five half-lives and are eliminated exponentially with`time, some drug from the first dose remains in the body when the second dose is administered, some from the second dose remains when the third dose is given, and so forth. Therefore, the drug accumulates until, within the dosing interval, the rate of drug elimination equals the rate of drug administration and a steady state is achieved.

a. Effect of dosing frequency: With repeated administration at regular intervals, the plasma concentration of a drug oscillates about a mean. Using smaller doses at shorter intervals reduces the amplitude of fluctuations in drug concentration. the Css is affected by neither the dosing frequency (assuming the same total daily dose is administered) nor the rate at which the steady state is approached.

2. Multiple oral administrations: Most drugs that are administered on an outpatient basis are oral medications taken at a specific dose one, two, or three times daily. In contrast to IV injection, orally administered drugs may be absorbed slowly, and the plasma concentration of the drug is influenced by both the rate of absorption and the rate of elimination

C. Optimization of dose The goal of drug therapy is to achieve and maintain concentrations within a therapeutic response window while minimizing toxicity and/or side effects. With careful titration, most drugs can achieve this goal. If the therapeutic window of the drug is small (for`example, digoxin, warfarin, and cyclosporine), extra caution should be taken in selecting a dosage regimen, and monitoring of drug levels may help ensure attainment of the therapeutic range. Drug regimens are administered as a maintenance dose and may require a loading dose if rapid effects are warranted. For drugs with a defined therapeutic range, drug concentrations are subsequently measured, and the dosage and frequency are then adjusted to obtain the desired levels.

1. Maintenance dose: Drugs are generally administered to maintain a Css within the therapeutic window. It takes four to five half-lives for a drug to achieve Css. To achieve a given concentration, the rate of administration and the rate of elimination of the drug are important. The dosing rate can be determined by knowing the target concentration in plasma (Cp), clearance (CL) of the drug from the systemic circulation, and the fraction (F) absorbed (bioavailability):

2. Loading dose: Sometimes rapid obtainment of desired plasma levels is needed (for example, in serious infections or arrhythmias). Therefore, a “loading dose” of drug is administered to achieve the desired plasma level rapidly, followed by a maintenance dose to maintain the steady state. In general, the loading dose can be calculated as: For IV infusion, the bioavailability is 100%, and the equation becomes

Loading doses can be given as a single dose or a series of doses. Disadvantages of loading doses include increased risk of drug toxicity and a longer time for the plasma concentration to fall if excess levels occur. A loading dose is most useful for drugs that have a relatively long half-life. Without an initial loading dose, these drugs would take a long time to reach a therapeutic value that corresponds to the steady-state level.

3. Dose adjustment: The amount of a drug administered for a given condition is estimated based on an “average patient.” This approach overlooks interpatient variability in pharmacokinetic parameters such as clearance and Vd, which are quite significant in some cases. Knowledge of pharmacokinetic principles is useful in adjusting dosages to optimize therapy for a given patient. Monitoring drug therapy and correlating it with clinical benefits provides another tool to individualize therapy.

When determining a dosage adjustment, Vd can be used to calculate the amount of drug needed to achieve a desired plasma concentration. Suppose the concentration of digoxin in the plasma is C1 and the desired target concentration is C2, a higher concentration. The following calculation can be used to determine how much additional digoxin should be administered to bring the level from C1 to C2.

Pharmacovigilance (PV)

Pharmacovigilance (PV) PV is concerned with detection, assessment & prevention of adverse reactions to drugs (ADRs) or any drug-related problems 28 28

Drug-Related Problems Lack of efficacy Manufacturing defects Medication errors Drug misuse and abuse Overdose Contamination Counterfeit products 29

Recently, the concerns of PV have been widened to include: Herbal Traditional and complementary medicines Blood products Biologicals Medical devices Vaccines 30

Why Pharmacovigilance? The root of pharmacovigilance: Pharmaco (Greek)= Drug Vigilance (Latin)= to keep awake or alert Because information collected during pre-marketing phase are incomplete with regard to possible ADR Tests in animals are insufficiently predictive of human safety

Why Pharmacovigilance? In clinical trials: Patients are limited in number Conditions of use differ from those in clinical practice Duration of trials is limited 32

Why Pharmacovigilance? Information about rare adverse reactions, chronic toxicity, use in special groups (children, elderly or pregnant women) or drug interactions is often incomplete or not available Post-marketing surveillance by companies is therefore essential

Pre-marketing clinical trials do not have : Why Pharmacoviglance? Pre-marketing clinical trials do not have : Statistical power to detect rare ADRs To identify delayed ADRs To identify effects from long-term exposure PV plays a prominent role in establishing safety profile of marketed drugs 34 34

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Definition of ADR An ADR is defined according to definition of WHO “any response to a drug which is noxious, unintended & that occurs at doses used in man for prophylaxis, diagnosis, or therapy of diseases’’ 36

Epidemiology of ADRs ADRs represent a significant cause of morbidity & mortality Many ADRs are mild, sometimes serious & can cause death U.S, ADRs caused 100 000 deaths per year, 4th & 6th leading cause of death About 50% of ADRs are preventable 37 37

Importance of ADRs Prolong length of stay in hospitals Increase costs of patient care Commonest cause of drug withdrawal from market: Reductil (Sibutramine) 2010 Valdecoxib (Bextra) 2005 Rofecoxib (Vioxx) 2004 38

ADRs is considered serious if: Causes death of patient Life-threatening Prolong inpatient hospitalisation Causes significant or persist disability Congenital abnormality 39

Risk Factors predisposing to ADRs Age Long duration of treatment Polypharmacy Liver, kidney diseases

Causes of ADRs Patient Drug Prescriber Environmental factors

Causes of ADRs - Age (over 60 or under one month) - Genetic factors 1. The patient: - Age (over 60 or under one month) - Genetic factors - Previous history of ADR - Hepatic or renal diseases 42 42

Causes of ADRs - Narrow therapeutic index, e.g. warfarin, digoxin 2. The drug - Narrow therapeutic index, e.g. warfarin, digoxin - Antimicrobials have a tendency to cause allergy - Ingredients of a formulation, e.g. colouring, flavouring 43 43

Drugs most commonly causing ADRs Warfarin Diuretics Digoxin Antibacterials Steroids Antihypertensives Anticancer drugs Immunomodulators Analgescis

Why report suspected ADRs? Documentation of ADRs in patients’ records is often poor Physicians fear that reporting of ADR may put them at risk Under-reporting is common phenomenon 45

Reporting Methods Spontaneous reporting: (Voluntary) Doctors, nurses & pharmacists are supplied with forms to record suspected ADRs Reporting ADRs to National Pharmacovigilance Centre In UK, this is called ‘Yellow Card system’

Prevention of ADRs Taking a drug history Reduce number of prescribed drugs Remembering that certain patients (elderly, those with liver or renal diseases) more susceptible to ADRs