KINETICS FOLLOWING SINGLE AND MULTIPLE DOSAGE OF DRUG

Plasma Drug Concentration-Time Profile

The speed of onset, intensity, and duration of a pharmacological effect depend on the concentration of drug at its site(s) of action As it is difficult to collect tissue samples, the time course of drug concentration at its site of action is approximated by measuring drug concentration in plasma, which can be measured with accuracy The plasma drug concentration-time curve is obtained by measuring the concentration of drug in plasma samples taken at various intervals of time after administration of a dosage form and plotting the concentration of drug in plasma (Y-axis) versus the corresponding time at which the plasma samples were collected (X-axis)

 If a drug is administered by oral or extravascular (IM, SC, IP, etc.) route, it slowly enters the systemic circulation and plasma drug concentration gradually rises to a maximum (peak level)

As the drug is being absorbed into blood, it is distributed to body tissues and may also simultaneously being eliminated
The ascending portion of curve to the left of peak represents the absorption phase because in this phase rate of absorption is greater than rate of distribution and elimination

Generally, the distribution phase of non-intravenous doses is masked by the absorption phase The descending section of curve to the right of peak generally represents the elimination phase because in this phase rate of elimination exceeds rate of absorption

The rate or velocity with which absorption and elimination processes occur is given by respective slopes of the curve and are expressed by absorption rate constant (Ka) and elimination rate constant (), respectively

1. Minimum effective concentration (MEC): It is the minimum concentration of drug in plasma required to produce the desirable pharmacological/ therapeutic response

In case of antimicrobials, the term minimum inhibitory concentration (MIC) is used, which may be defined as the minimum concentration of antimicrobial agent in plasma required to inhibit the growth of microorganisms

2. Maximum safe concentration (MSC) or Minimum toxic concentration (MTC):

It is the concentration of drug in plasma above which toxic effects are produced. Concentration of drug above MSC is said to be in toxic level. The drug concentration between MEC and MSC represents the therapeutic range

3. Maximum plasma concentration/Peak plasma concentration (Cmax or CPmax):

It is the point of maximum concentration of drug in plasma The maximum plasma concentration depends on administered dose and rates of absorption (absorption rate constant, Ka) and elimination (elimination rate constant, ) The peak represents the point of time when absorption rate equals elimination rate of the drug (g/ml)

3. Area under curve (AUC): It is the total integrated area under the plasma drug concentration -time curve. It expresses the total amount of drug that comes into systemic circulation after administration of the drug 4. Peak effect: It is the maximal or peak pharmacological effect produced by the drug. It is generally observed at peak plasma concentration.

5.Time of maximum concentration/Time of peak concentration (tmax)

It is the time required for a drug to reach peak concentration in plasma. The faster the absorption rate, the lower is the tmax It is also useful in assessing the efficacy of drugs used to treat acute conditions (e.g., pain) that can be treated by a single dose. It is expressed in hr

6. Onset of action
It is the beginning of pharmacological response produced by the drug. It occurs when the plasma drug concentration just exceeds the MEC

7.Onset time:
It is the time required for the drug to start producing pharmacological response. It usually corresponds to the time for the plasma concentration to reach MEC after administration of drug.

8. Duration of action:
It is the time period for which pharmacological response is produced by the drug It usually corresponds to the duration for which the plasma concentration of drug remains above the MEC level.

Temporal characteristics of drug effect and relationship to the therapeutic window(e.g.,singledose,oral administration).

A lag period is present before the plasma drug concentration (Cp) exceeds the minimum effective concentration (MEC) for the desired effect. Following onset of the response, the intensity of the effect increases as the drug continues to be absorbed and distributed. This reaches a peak, after which drug elimination results in a decline in Cp and in the effects intensity. Effect disappears when the drug concentration falls below the MEC. Accordingly, the duration of a drugs action is determined by the time period over which concentrations exceed the MEC. An MEC exists for each adverse response, and if drug concentration exceeds this, toxicity will result.

 The therapeutic goal is to obtain and maintain concentrations within the therapeutic window for the desired response with a minimum of toxicity. Drug response below the MEC for the desired effect will be subtherapeutic; above the MEC for an adverse effect, the probability of toxicity will increase. Increasing or decreasing drug dosage shifts the response curve up or down Increasing the dose also prolongs a drugs duration of action, at the risk of increasing the likelihood of adverse effects. AUC can be used to calculate the clearance, Bioavailability

Thus, the therapeutic goal is to maintain steady-state drug levels within the therapeutic window.

Orders of Pharmacokinetic Processes

The rate at which various pharmacokinetic processes (ADME) occur is affected by the amount of drug in body The manner in which concentration of drug influences the rate of a process is called the order of process The three commonly encountered rate processes in pharmacokinetics are
Zero order process First order process Mixed order process.

Zero-order kinetics

1. Zero-order process/Zero-order kinetics

Zero-order process (constant-rate kinetics) may be defined as a pharmacokinetic process whose rate is independent of the concentration of drug The rate of pharmacokinetic process remains constant and cannot be increased further by increasing the concentration of drug. In other words, in the zero-order kinetics a fixed amount/ quantity of drug is processed per unit time. Examples of zero-order kinetics include metabolism and absorption, distribution, and excretion of drugs by carrier mediated transport under saturated conditions Administration of drugs by a constant rate IV infusion or by controlled delivery system (e.g., implants) also tends to follow zero-order kinetics.

Examples of drugs that follow zero-order kinetics are alcohol, phenytoin, salicylates, etc
In the zero order kinetics as a constant/ fixed amount of drug is eliminated per unit of time, the half-life of a drug undergoing zero-order elimination is not constant but is proportional to the concentration of drug in the plasma Therefore, the zero-order half-life rises with increase in drug concentration and declines with decrease in drug concentration Applications of zero-order processes include administration of a drug as an intravenous infusion, formulation and administration of a drug through controlled release dosage forms and administration of drugs through transdermal drug delivery systems. Special care is needed while increasing dose of drugs which follow zero-order kinetics to avoid adverse drug effects

2.First-order process/First-order kinetics:

First-order process (first-order kinetics or linear kinetics) may be defined as a pharmacokinetic process whose rate is directly proportional to the concentration of drug Greater the concentration, faster is the process. In contrast to the zero-order kinetics, in first-order kinetics a fixed fraction of drug is processed per unit time

It is because of such a proportionality between the rate of process and the concentration of drug that the first-order process is said to follow linear kinetics i.e. log-plasma concentrationtime curve is linear.

First-order kinetics

 The first-order pharmacokinetic processes are nonsaturable over a wide range of plasma concentration First-order elimination is extremely important in pharmacokinetics since the majority of therapeutic drugs are eliminated by this process. Most drugs follow first-order kinetics in absorption, distribution, and elimination In the first-order kinetics as a constant fraction of drug is eliminated per unit time, the half-life of a drug undergoing first-order elimination remains constant and independent of drug concentration in plasma

Conc. Vs. time plots

3.Mixed-order process/Mixed-order kinetics

Mixed-order process (mixed order kinetics, non-linear kinetics or dose-dependent kinetics) maybe defined as a process whose rate is a mixture of both zero-order and first-order processes The mixed order process follows zero-order kinetics at high concentration and first order kinetics at lower concentration of the drug

This type of kinetics is usually observed at increased or multiple doses of some drugs

The phenomenon is mainly seen when pharmacokinetic process that involves carriers or enzymes, which are substrate have definite capacities, and get saturated concentration

a particular presence of specific and at high drug

Since deviations from an originally linear pharmacokinetic profile are observed, the rate process of such a drug is called non-linear kinetics Mixed-order kinetics has been observed in absorption (e.g.,vitamin C), distribution (e.g., naproxen), and elimination (e.g., riboflavin) of some drugs.

Therapeutic Window
Useful range of concentration over which a drug is therapeutically beneficial. Therapeutic window may vary from patient to patient Drugs with narrow therapeutic windows require smaller & more frequent doses or a different method of administration

Drugs with slow elimination rates may rapidly accumulate to toxic levels.can choose to give one large initial dose, following only with small doses

 Dosage Calculations:
Loading dose- dose to establish a rapid therapeutic [drug] plasma = V d x desired [drug] plasma In the case of toxic drugs (digitalis) Loading dose is divided into several portions and given over a long time Maintenance dose= dose required to maintain a desired steadystate Rate of elimination (in hours) x dosage interval in hours At steady state: rate of elimination=rate of administration (absorption) Rate of elimination = Cl x avg [Drug] steady-state plasma

What is Steady State (SS) ?

Rate in = Rate Out Reached in 4 5 half-lives (linear kinetics) Important when interpreting drug concentrations in time-dependent manner or assessing clinical response

Steady-State
Steady-state occurs after a drug has been given for approximately five elimination half-lives.
At steady-state the rate of drug administration equals the rate of elimination and plasma concentration - time curves found after each dose should be approximately superimposable.

Accumulation to Steady State 100 mg given every half-life

194 187.5 175 150 100 87.5 75 50 94 97 100 200

C
Cpav

t
Four half lives to reach steady state

Acute vs Steady State

Drug Metabolism and pK

Steady-State Concentration (Css)

Steady-state (ss) is defined as the time during which concentrations remain stable or consistent when drug is given repeatedly or continuously (IV infusion) The time to reach steady state is a function of elimination half-life (t1/2) and is achieved when the rate of drug entering systemic circulation equals the rate of elimination For most drugs, the steady state concentration is reached in approximately 5 half-lives The time to reach steady state is independent of dose size, dosing interval and number of doses

Continuous and multiple dose kinetics

Steady-State Principle: for drugs exhibiting first-order pharmacokinetics

Rate of administration or absorption

Rate of elimination rate

[Drug]
rate= [Drug] x k a

[Drug] plasma

[Drug] Urine rate =[Drug]Plasma x k e

Initially rate of admin. or absorption greater than rate of elimination because initially [Drug] is low -rate of elimination gradually increases as [Drug]plasma increases and reaches a plateau. This is termed the steady-state concentration

Multiple Dosing
When a drug is administered in a fixed dose at fixed intervals, the plasma concentration rises exponentially to a plateau or steady state with a half time of increase that is equal to the elimination half-life of the drug Thus 50% of the steady state level is achieved in one elimination half time, 75% (50 + 25) in two, 87.5% (50 + 25+12.5) in three, 93.75% (50 + 25 + 12.5 + 6.25) in four, 96.88% (50 + 25 + 12.5 + 6.25 + 3.13) in five

It takes 5 half-lives to complete a 1St order process: (1/2n)=1/ 2x2x2x2x2= 1/32= 0.03 or 3% remains or 97% produced after 5 half-lives

 And so forth [when the first dose D0 is administered at time 0, the amount of drug in body will be D = D0 At the next dosing interval (equal to on t1/2) when D = 1/2 D0, the amount remaining in the body, administration of next dose (D0) raises body concentration to D = D0 + 1/2 D0, and so forth] During the initial period, the intake is more than the elimination, so there is continuous rise in plasma concentration.

 Subsequently, when the intake equals the elimination, a steady state is reached In practice, a useful estimate of time to reach a steady state is obtained by the equation Time to 95% steady state = 4.3 x t1/2 Therefore, the shorter the half-life, the more rapidly steady state is reached, and vice-versa

Accumulation
Accumulation is the ratio of maximum plasma concentration following the dose at steady state compared with that following the first dose (i.e: C ss, max / C1 max) The extent to which a drug accumulates in body during multiple dosing is a function of dosing interval and elimination half-life, but is independent of dose size If the elimination half-life is equal to the dosing interval (T = t1/2) then at steady state level, the drug will accumulate two folds (C ss, max / C1 max= 2) When T< t1/2 , the degree of accumulation will be greater, and drug may show toxic responses

Fluctuation
Fluctuation is defined as the ratio of the maximum concentration to the minimum concentration of drug in plasma at steady state (i.e., Cmax/Cmin). Greater the ratio, greater will be the fluctuation Fluctuation primarily depends on dosing interval and half-life of drug, but is also affected by dose size For a given dose, if dosing interval is increased, Cmaxand Cmin will decrease (drug efficacy will decrease), but the fluctuations will increase The opposite is observed when dosing interval is reduced; toxicity of drug in such cases may increase due to greater drug accumulation .

 On the other hand, for a given dose interval, if dose size is increased, Cmax and Cmin will increase with greater fluctuations during each dosing interval; toxicity of drug in such cases also increase due to higher drug concentrations The greatest fluctuation is observed when the drug is given as IV bolus. Fluctuations are small when the drug is given extravascularly because of continuous absorption of the drug Administration of smaller doses in less frequency results in small fluctuations Administration of drugs by intravenous infusion maintains a constant steady state or plateau level without fluctuations (IV infusion is the only method which does not produce fluctuations)

I. Single-dose kinetics
Plasma [Drug] curve Upon administration[drug] plasma reaches a max Then begins to decline as the Drug is eliminated Cp max: max plasma [drug] t max : time to reach Cp max AUC : area under the curve These measures are useful for comparing the bioavailability of different pharmaceutical formulation

Bioavailability- the fraction of the administered dose that reaches the systemic circulation= AUC oral / AUCIV

can be affected by: -rate of tablet disintegration -drug solubility -sequestration by food -gastric acid and gut enzyme inactivation