Pharmacokinetics Parameters PDF

PHARMACOKINETICS PARAMETERS  F H1/2 PK parameters Vd ER Cl BIOAVAIBILITY ABSORPTION BIOAVAILABILITY Bioavailability is the fraction of the administered dose that is delivered to the systemic circulation. Example: an orally administered tablet may not comple...

PHARMACOKINETICS PARAMETERS  F H1/2 PK parameters Vd ER Cl BIOAVAIBILITY ABSORPTION BIOAVAILABILITY Bioavailability is the fraction of the administered dose that is delivered to the systemic circulation. Example: an orally administered tablet may not completely dissolve so that part of the dose is eliminated in the stool, or a transdermal patch may not release the entire dose before it is removed from the skin...ONLY particular part enter systemic circulation.  drug is the drug must be drug serum Absorbtion administered absorbed across concentrations extravascularly several biologic rise while the (oral, i.m, s.c, membranes drug is being transdermal before entering absorbed into pacth, ect..) the vascular the bloodstream, system reach a maximum concentration (Cmax)  Area under the serum concentration/time curve (AUC), the maximum concentration (Cmax), the time that the maximum concentration occurs (Tmax) are considered primary bioavailability parameters.  For drugs that follow linear pharmacokinetics, bioavailability is measured by comparing serum concentrations achieved after extravascular and intravenous doses in the same individual. F = AUCPO / AUCIV If it is not possible to administer the same dose intravenously and extravascularly because poor absorption or presystemic metabolism yields serum concentrations that are too low to measure, the bioavailability calculation can be corrected to allow for different size doses for the different routes of administration F = (AUCPO/AUCIV)(DIV/DPO) BIOEQUIVALENCE ▄ When the patent of brand drug expired, the generic one are manufactured with cheap cost because the company doesn’t have to prove that the drug is safe and effective since those studies were done by brand drug’s company. ▄ Once the generic drug can produce similarity of serum concentration/time profile with branded one…then it said “the generic drug is to be bioequivalent to the brand drug. ♦ Bioequivalence is achieved when the serum concentration/time curve for the generic and brand name drug dosage forms are deemed indistinguishable from each other using statistical tests. ♦ Concentration/time curves are superimposable when the area under the total serum concentration/time curve (AUC), maximum concentration (Cmax), and time that the maximum concentration occurs (Tmax) are identical within statistical limits. ♦ The ratio of the area under the serum concentration/time curves for the generic (AUCgeneric) and brand name (AUCbrand) drug dosage forms is known as the relative bioavailability (Frelative) Frelative = AUCgeneric / AUCbrand  Exercise: ► The new drug A is being studied in the renal transplant clinic where you work. Based on previous studies, the following area under the serum concentration/time curves (AUC) were measured after single dose of 10mg in renal transplant patients: intravenous bolus AUC = 1530mg.h/L, oral capsule AUC = 1220mg.h/L, oral liquid AUC = 1420mg.h/L. 1. What is the bioavailability of the oral capsule and oral liquid? 2. What is the relative bioavailability of the oral capsule compared to the oral liquid? ANY QUESTION? VOLUME DISTRIBUTION DISTRIBUTION VOLUME DISTRIBUTION Volume of distribution (V) is an important pharmacokinetic parameter because it determines the loading dose (LD) that is required to achieve a particular steady-state drug concentration immediately after the dose is administered: ✓ It is rare to know the exact volume of LD = CSS X V distribution for a patient. ✓ Since the volume of distribution is not known for a patient before a dose is given, clinicians use an average volume of distribution previously measured in LD = mg patients with similar demographics (age, Css = mg/ml weight, gender, etc.) and disease states V = ml (renal failure, liver failure, heart failure, etc.) to compute loading doses. The volume of distribution (V) is a hypothetical volume that is the proportionality constant which relates the concentration of drug in the blood or serum (C) and the amount of drug in the body (AB): AB = C ⋅ V. › It can be thought of as a beaker of fluid representing the entire space that drug distributes into. In this case, one beaker, representing a patient with a small volume of distribution, contains 10 L while the other beaker, representing a patient with a large volume of distribution, contains 100 L. › If 100 mg of drug is given to each patient, the resulting concentration will be 10 mg/L in the patient with the smaller volume of distribution, but 1 mg/L in the patient with the larger volume of distribution. › If the minimum concentration needed to exert the pharmacological effect of the drug is 5 mg/L, one patient will receive a benefit from the drug while the other will have a subtherapeutic concentration. › If the volume of distribution (V) is known for a patient, it is possible to administer a loading dose (LD) that will attain a specified steady-state drug concentration (Css). › This example depicts the ideal loading dose given as an intravenous bolus dose followed by a continuous intravenous infusion (solid line starting at 16 mg/L) so steady state is achieved immediately and maintained. › If a loading dose was not given and a continuous infusion started (dashed line starting at 0 mg/L), it would take time to reach steady-state concentrations, and the patient may not experience an effect from the drug until a minimum effect concentration is achieved. This situation would not be acceptable for many clinical situations where a quick onset of action is needed. Volume Distribution physiologic Determined by: › the actual volume of blood (VB) › size (measured as a volume) of the various tissues and organs of the body (VT) Therefore, a larger person, such as a 160-kg football player, would be expected to have a larger volume of distribution for a drug than a smaller person, such as a 40-kg grandmother. If a drug that is highly bound to plasma proteins is given to a V = VB + patient, and then a second drug that is also highly bound to the (fB/fT)xVT same plasma protein is given concurrently, the second drug will compete for plasma protein binding sites and displace the V = volume distribution first drug from the protein. In VB = volume of blood this case, the free fraction in the fB = free fraction (unbound) of drug in blood serum of the first drug will fT = unbound drug concentration in the tissue increase (↑fB), resulting in an VT = size (measured as a volume) of the various increased volume of tissues and organs of the body. distribution Exercise: › If 3 g of a drug are added and distributed throughout a tank and the resulting concentration is 0.15 g/L, calculate the volume of the tank. A. 10 L B. 20 L C. 30 L D. 200 L Exercise: › If 100 mg of drug X is administered intravenously and the plasma concentration is determined to be 5 mg/L just after the dose is given, calculate volume of distribution A. 20L B. 25L C. 50L D. 500L  Exercise: › A physician wants to administer an anesthetic agent at a rate of 2 mg/hr by IV infusion. The elimination rate constant is 0.1 hr– 1, and the volume of distribution (one compartment) is 10 L. What loading dose should be recommended if the drug level to reach 2 μg/mL immediately? METABOLISM ELIMINATION CLEARANCE CLEARANCE Clearance (Cl) is the most important pharmacokinetic parameter because it determines the maintenance dose (MD) that is required to obtain a given steady-state serum concentration MD = Css x Cl Clearance is the MD =maintainance dose (mg/h or µg/min) volume of serum or blood completely Css = steady state serum cleared of the concentration (mg/L or µg/mL) drug per unit time Cl = clearance (L/h or mL/min)  Clearance Metabolism Elimination Liver Kidney GIT wall Bile Lung Kidney Phase I reactions, which oxidize Phase II reactions, drug molecules, so that the which form glucuronide or sulfate esters metabolite is more water soluble with drug molecules and easy to eliminate in urine Is catalyzed by Is eliminated by cytochrome P-450 (CYP) enzyme Glomerular filtration & tubular system secretion in nephron The ability of an organ to remove or extract the drug from the blood or serum is usually measured by determining the extraction ratio (ER). ER = (Cin-Cout)/Cin The drug clearance for an organ is equal to the product of the blood flow to the organ and the extraction ratio of the drug. › Liver Clearance › Renal Clearance ClH = LBF x ERH ClR = RBF x ERR ClH = Hepatic clearenace ClR = Renal clearenace LBH = Liver blood flow LBH = Renal blood flow ERH = hepatic excreation ratio ERR = Renal excreation ratio Total clearance: is the sum of the individual clearances for each organ that extracts the medication Cl = ClH + ClR  Hepatic Clearance physiologic ClH = LBF x (fB x Cl’int) LBF + (fB x Cl’int) Determined by: Cl’int = Vmax / km Intrinsic clearance (the inherent ability of the enzyme to metabolize the drug) (Ci’int) fB = unbound drug concentration unbound fraction of drug in the bloodstream (free state) (fB) (Bound + unbound) drug concentration Liver blood flow (LBF) Vmax = maximum rate of drug metabolism Km (unbound drug) = drug concentration at which the metabolic rate equals, Vmax/2  Will be able to leave Drug will inhibit drugs with ↓ ↑ the vascular system or induce the ERH is ClH=fB x unbound & enter hepatocytes enzyme so that Cl’int form to be metabolized will decrease or so that ↑ ClH increase Cl’int. Valproic acid, Main factors due phenytoin, to drug warfarin interactions The rate to metabolize the drugs with ↑ ERH is Drug will not inhibit or drug is depends how much induce the enzyme bcz ClH = LBF drug can be delivered to the no drug interaction liver Lidocaine, Factors: congestive morphine, tricyclic heart failure or liver antidepressants disease Renal Clearance physiologic Determined by: ClR= [(fB x GFR) + Clsec](1-FR) Glomerular filtration rate (GFR) Unbound fraction of drug in the Clsec = RBF x (fB x Cl’sec) bloodstream (free state) (fB) RBF + (fB x Cl’ sec) Clearance of drug via renal tubular secretion (Clsec) ClR= [(fB x GFR) + RBF x (fB x Cl’sec) ](1-FR) RBF + (fB x Cl’ sec) The fraction of drug reabsorb in the kidney (FR) Average GFR in adults with normal renal function are 100–120 mL/min  If ClR > GFR → drug is eliminated by active tubular secretion Aminoglycoside AB & vancomycin are eliminated ✓ Patient with renal primarily by glomerular filtration disease should measure the GFR and renal tubular secretion Digoxin, procainamide, ranitidine and ciprofloxacin are eliminated by both glomerular filtration & ✓ Measuring GFR will active tubular secretion estimate the creatinine clearance. Exercise: Calculate the hepatic clearance of patient A; if her liver blood flow is normal (1.5L/min) and the drug she taken has a hepatic extraction ratio of 90%. Answer: 100 10 ERH = 90% >> Cin (…) Cout (…) ClH = LBF x ERH = 1.5L/min x 0.90 = 1.35L/min Most drugs have a large hepatic extraction ratio (ERH ≥ 70%) or a small hepatic extraction ratio (ERH ≤ 30%) Liver blood flow (LBF) and renal blood flow (RBF) are each ~ 1–1.5 L/min in adults with normal cardiovascular function HALF LIFE & ELIMINATION RATE CONSTANT ELIMINATION ELIMINATION RATE ❖The elimination rate constant (Ke) is the fraction of drug in the body which is removed per unit time. ❖The dimension for the elimination rate constant is reciprocal time (hour−1, minute−1, day−1, etc.) ❖The elimination rate constant (Ke) is the fraction or percentage of the total amount of drug in the body removed per unit time and is the fraction of clearance and volume of distribution Ke = Cl V ke = −(ln C1 − ln C2)/(t1 − t2) HALF LIFE (t1/2) ❖ Half-life is the time taken for the drug concentration to fall to half its original value. t1/2 = 0.693/ke ❖The half-life describes how quickly drug serum concentrations decrease in a patient after a medication is administered, and the dimension of half-life is time (hour, minute, day, etc.). ❖The half life and elimination rate constant are related to each other by the following equation, so it is easy to compute one once the other is known: t1/2 = 0.693/ke OR Ke = 0.693/t1/2 Description: C = Co e - kt C/Co = 0.50 (for half of the original amount) 0.50 C0= C0 e – k t Taking natural log both sides ln 0.50 = -k t ½ -0.693 = -k t ½ t1/2 = 0.693 / k  If Vd and clearance for a drug are known, the half life can be estimated by using the equation by substituting the Ke t1/2 = 0.693 (V) Cl The half life, like Ke, is dependent on and determined by Cl and V. This relationship is illustrated in above equation The dependence of t1/2 or Ke on V and Cl is emphasized because the volume of distribution and clearance for drug can change independently of one another and thus, affect the half life or elimination constant in the same or opposite direction Clearance can also be calculated by rearranging the Ke equation Cl= (Ke) (V) Clinical Application of Elimination Rate Constant and Half Life (t1/2) Css = 3-5. t1/2 a) Estimating the time to reach the steady state plasma concentration after initiation or change in the maintenance dose b) Estimating the time required to eliminate or portion of the drug from the body once it is discontinued c) Predicting non-steady plasma levels following the initiation of an infusion d) Predicting a steady state plasma level from a non-steady state plasma level obtained at a specific time following the initiation of an infusion e) Given the degree of fluctuation in plasma concentration desired within a dosing interval, determine that interval; given the interval, determine the fluctuation in the plasma concentration Relationship Among Pharmacokinetic Parameter ✓ The half-life and elimination rate constant are known as dependent parameters because their values depend on the clearance (Cl) and volume of distribution (V) of the agent: t1/2 = 0.693 / ke Therefore; ke = Cl/V t1/2 = (0.693 ⋅ V)/Cl ✓ The half-life and elimination rate constant for a drug can change either because of a change in clearance or a change in the volume of distribution. ✓ Because the values for clearance and volume of distribution depend solely on physiological parameters and can vary independently of each other, they are known as independent parameters. Exercise: Two patients getting admission in your hospital, one with liver failure and another with heart failure. As a pharmacist you need to calculate the iv loading dose and continuous iv infusion maintenance dose to achieve a steady- state concentration of 10mg/L for both your patients. Estimate the time it will take to achieve steady-state conditions. If: o Normal subject: Cl = 45L/h; V = 175L; o Liver failure: Cl = 15L/h; V = 300L o Heart failure: Cl = 30L/h; V = 100L Exercise: › After the first dose of gentamicin is given to a patient with renal failure, the following serum concentrations are obtained: TIME AFTER DOSAGE CONCENTRATION (µg/mL) ADMINISTRATION (HOUR) 1 7.7 24 5.6 48 4.0 › Compute the half-life and the elimination rate constant for this patient. Exercise: › PZ is a 35-year-old, 60-kg female with a Staphylococcus aureus wound infection. While receiving vancomycin 1 g every 12 hours (infused over one hour), the steady- state peak concentration (obtained one-half hour after the end of infusion) was 35 mg/L, and the steady-state trough concentration (obtained immediately predose) was 15 mg/L. so calculate elimination rate and half-life MICHAELIS-MENTEN OR SATURABLE PHARMACOKINETICS PK MODEL MICHAELIS-MENTEN OR SATURABLE PHARMACOKINETICS Properties: ✓ Drug are metabolized by enzyme; e.g cytochrome P-450. ✓ Non-linear pharmacokinetics due to number of drug molecules overwhelms or saturates the enzyme’s ability to metabolize the drug. So that steady-state drug serum concentrations increase in a disproportionate manner after a dosage increase. ✓ Still follow dose dependent, but not like linear. The concentrations increase disproportionately after a dosage increase. ✓the dose or concentration increases, the clearance rate (Cl) decreases as the enzyme approaches saturable conditions. Cl = Vmax / (Km + C) Exercise: Drug A follow saturable pharmacokinetics with average Michaelis- Menten constant of: V max = 500mg/d Km = 4mg/L Therapeutic range of drug A is: 10-20mg/L. Calculate the decreasing clearance for drug A. ✓ Volume distribution (V) is unaffected by saturable metabolism and is still determined by the physiological volume of blood (VB) and tissues (VT) as well as the unbound concentration of drug in the blood (fB) and tissues (fT) : V = VB + (fB/fT)VT ✓ Half-life more longer when the clearance decreasing: t1/2 = (0.693 ⋅ V)/Cl ✓ Time to reach steady state is more longer as well; 3-5 t1/2 ✓Maintenance Dose: MD = Vmax x Css Km + Css Follow: ▪ if Css >Km: (rate of metabolism) Vmax is constant…..its only a fixed amount of drug is metabolized because the enzyme system is completely saturated and cannot increase its metabolic capacity. ZERO-ORDER PHARMACOKINETICS Drug overdose