This document discusses pharmacokinetic parameters essential for understanding drug absorption and efficacy, including peak plasma concentration (Cmax), time of peak concentration (Tmax), and area under the curve (AUC). It highlights the implications of drug bioavailability, half-life, clearance, and the effects of first-pass metabolism, along with practical examples of various medications. Special attention is given to the pharmacokinetic characteristics that influence dosing regimens and potential drug interactions.

1. PHARMACOKINETIC DATA AND
ITS SIGNIFICANCE
Simran Khanijo
Msc pharmacology
PGIMER

2. PLASMA DRUG CONCENTRATION-TIME
PROFILE

3. Pharmacokinetic parameters
1. Peak plasma concentration:- Cmax is the maximum
concentration of a drug that can be obtained
Cmax expressed as mcg/ml
Depends upon-
• Dose administered
• Rate of absorption
• Rate of elimination

4. EXAMPLE-
The aminoglycoside antibiotics are rapidly bactericidal. Bacterial
killing is concentration dependent.
• Cmax/MIC--key predictor of aminoglycoside efficacy.
• Have significant post antibiotic effect. .
• Advantages of extended interval aminoglycoside over
traditional intermittent administration:
 Possibility of decreased nephrotoxicity
 Ease of administration and serum concentration
monitoring
 Reductions in administration and monitoring related costs
• All these properties account for the efficacy of high-dose,
extended- interval dosing regimens

5. 2. Time of peak concentration( Tmax ):- tells about the time to reach
maximum concentration, i.e. rate of absorption
o Expressed in hours
o Has importance in assessing the efficacy of drugs used to treat acute
conditions like pain and insomnia.

6. 3. Area under the curve (AUC) :- AUC tells about the extent of absorption
of the drug
o AUC = EXPOSURE
o Expressed in mcg/ml * hours
o Imp parameter in evaluating bioavailability of a drug
o AUC proportional to the dose and the extent of bioavailability for a
drug if its elimination is first-order.
o Bioavailability is defined as the fraction of unchanged drug reaching
the systemic circulation following administration by any route .

7. Routes of administration, bioavailability, and
general characteristics

8. For a drug administered orally, F<1 due to
 Incomplete extent of absorption across the gut wall
 first-pass elimination by the liver
 Rate of absorption
 Extraction ratio and first pass effect.

9. A. Extent of Absorption
 Only 70% of a dose of digoxin reaches the systemic circulation--
Due to lack of absorption from the gut.
 If too hydrophilic(ATENOLOL), the drug cannot cross the lipid
cell membrane;
 if too lipophilic(ACYCLOVIR), the drug is not soluble enough to
cross the water layer adjacent to the cell.
 Drugs may not be absorbed because of a reverse transporter
associated with P-glycoprotein.

10. B. FIRST PASS METABOLISM-
Liver – responsible for metabolism or may excrete the drug into the
bile----lead to reduction in bioavailability, and the overall process known
as first-pass elimination.
Extraction ratio (ER):
Q is hepatic blood flow, normally about 90 L/h in a person weighing 70
kg.
F of the drug can be predicted by
for e.g. A drug such as morphine f (extent of absorption) = 1, thus loss
in the gut negligible.
However, the hepatic extraction ratio for morphine is 0.67.
So its oral bioavailability (1 – ER) is therefore expected to be about 33%.

11. C. Rate of Absorption
The rate of absorption is determined by the site of administration and
the drug formulation.
Differences in rate of absorption may become important for drugs given
as a single dose, such as a hypnotic used to induce sleep.

12. Comparative pharmacokinetic parameters with first-
order and zero-order elimination.

13. D. Extraction Ratio & the First-Pass Effect
Lidocaine and verapamil both used to treat cardiac arrhythmias
and have F< 0.4, but lidocaine never given orally because its
metabolites contribute to CNS toxicity.
Other drugs highly extracted by the liver include morphine,
isoniazid, propranolol, and several tricyclic antidepressants
Drugs poorly extracted by the liver include warfarin, diazepam,
phenytoin, theophylline, tolbutamide, and chlorpropamide

14. Vancomycin
 Staphylococcus aureus and coagulase-negative staphylococci
may express reduced or “intermediate” susceptibility to
vancomycin (MIC 4–8 μg/mL) or, very rarely, high-level
resistance (MIC ≥ 16 μg/mL).
 Animal studies and limited human data demonstrate that
AUC/MIC is a predictive pharmacokinetic parameter for
vancomycin
 Investigators suggested an average AUC/MIC of 345 for a
successful clinical outcome and a ratio of 850 for a successful
microbiological outcome.

15. DRUGS WITH HIGH ORAL BIOAVAILABILITY:-
Levofloxacin- 99% (oral and iv )
Clonidine
Chloramphenicol
Linezolid
Furosemide

16. HALF LIFE
 The t1/2 is the time it takes for the plasma concentration
to be reduced by 50%
 If metabolism is more, half life is less and vice-versa.
 It is a secondary pharmacokinetic parameter derived from
two primary parameter; Vd and CL.
t1/2 = 0.693 * Vss/CL
 It determines the dosing interval and time required to
reach the steady state and time required for elimation.
 Drugs having short half lives are administered more
frequently than those having longer half life.
 It takes 4-5 half lives for a drug to reach its steady state.
.

17. Terminal Half-Life
 With prolonged dosing -- drug may penetrate into secondary
body compartments that equilibrate only slowly with the
plasma.
 When the infusion or dosing stops, the drug initially cleared
from plasma then net diffusion from the secondary
compartments begins, and this slow equilibration produce a
prolongation of the half-life of the drug, referred to as the
terminal half-life

18. Examples of drugs with marked differences in terminal t1/2 versus
steady-state t1/2 are gentamicin and indomethacin.
 Gentamicin has a t1/2 of 2–3 h following a single administration,
but a terminal t1/2 of 53 h because drug accumulates in spaces
such as kidney parenchyma (where this accumulation can result
in toxicity).
 Biliary cycling probably is responsible for the 120-h terminal
value for indomethacin (compared to the steady-state value of
2.4 h).

19. THE TIME COURSE OF DRUG ACCUMULATION AND
ELIMINATION.
The “rule of thumb” that four half-lives must elapse after starting a
drug-dosing regimen before full effects will be seen is based on the
approach of the accumulation curve to over 90% of the final
steady-state concentration

20. Context-sensitive half-time of general
anesthetics

21.  The duration of action of single intravenous doses of
anesthetic/hypnotic drugs is short for all.
 after prolonged infusions, drug half-lives and durations of
action depend on a complex interaction between the
rate of redistribution of the drug, the amount of drug
accumulated in fat, and the drug’s metabolic rate.
 This phenomenon has been termed the context sensitive
half-time; that is, the t1/2 of a drug can be estimated
only if one knows the context—the total dose and over
what time period it has been given.
 half-times of some drugs such as etomidate, propofol,
and ketamine increase only modestly with prolonged
infusions; others (e.g., diazepam and thiopental) increase
dramatically.

22. ACCUMULATION
Whenever drug doses are repeated, the drug will accumulate in
the body until dosing stops. This is because it takes an infinite
time (in theory) to eliminate all of a given dose. In practical
terms, this means that if the dosing interval is shorter than four
half-lives, accumulation will be detectable

23. TIME COURSE OF DRUG EFFECT
a) IMMEDIATE EFFECT-
ACE inhibitor, such as enalapril . After an oral dose of 20 mg, the
peak plasma concentration at 2.5 hours is about 64 ng/mL. The
half-life that explains ACE inhibition is about 4 hours. Enalapril is
usually given once a day.

24. B) DELAYED EFFECTS-
warfarin works as an anticoagulant by inhibiting vitamin K epoxide
reductase (VKOR) in the liver THUS decrease in the concentration of the
prothrombin complex of clotting factors.
But the already formed complex has a long half-life (about 14 hours),
and it is this half-life that determines how long it takes for the
concentration of clotting factors to reach a new steady state and for a
drug effect to reflect the average warfarin plasma concentration.
C) CUMULATIVE EFFECTS-
Aminoglycosides

25. C) CUMULATIVE EFFECTS-
The renal toxicity of aminoglycoside antibiotics (eg, gentamicin) is
greater when administered as a constant infusion than with
intermittent dosing.
It is the accumulation of aminoglycoside in the renal cortex that is
thought to cause renal damage. Even though both dosing schemes
produce the same average steady-state concentration, the intermittent
dosing scheme produces much higher peak concentrations, which
saturate an uptake mechanism into the cortex; thus, total
aminoglycoside accumulation is less.

26. VOLUME OF DISTRIBUTION
• V = Amount of drug in body/C
• The volume here refers to the fluid volume that would be required
to contain all of the drug in the body.
• It is an imaginary volume.
• V exceeds known volume of any and all body compartments.
• E.g.. - value of V for the highly lipophilic antimalarial chloroquine is
15,000 L

28. Drugs highly bound to plasma proteins that have a relatively small
volume of distribution like oral anticoagulants, sulfonylureas, certain
NSAIDs and antiepileptic drugs are particularly liable to displacement
interactions

29. CLEARANCE
• CLEARANCE of a drug is its rate of elimination
by all routes normalized to the concentration
of drug C in some biological fluid
• With first-order kinetics, clearance CL will vary
with the concentration of drug (C),

30. Clearance of drug by several organs is additive-
EXAMPLES :
Antibiotic cephalexin-90% elimination is by renal
clearance
Beta antagonist propranolol – by liver
Tacrolimus- extra hepatic metabolism

31. HEPATIC CLEARANCE
Metabolism or excretion of drug into bile
Drugs cleared by liver- diltiazem , imipramine, Lidocaine,
morphine, and propranolol.
Drugs that are poorly extracted by the liver include warfarin,
diazepam, phenytoin, theophylline, tolbutamide, and
chlorpropamide
RENAL CLEARANCE

32. Probenecid & Penicillin interaction-- Inhibition of tubular secretion →
prolongation of antibiotic Ampicillin action; Desirable interaction
utilized for single dose therapy.

33. LOADING DOSE
Vss= volume of distribution
Consider -treatment of arrhythmias with lidocaine. t1/2 =1–2 h.
Arrhythmias encountered after myocardial infarction may be life
threatening, and one can not wait for 4 half lives to achieve the
therapeutic concentrations of lidocaine. Hence loading dose of
lidocaine in the coronary care unit is standard.

34. DISADVANTAGES
First, sensitive individual exposed abruptly to a toxic
concentration.
Loading doses large & often given parentally and rapidly.
ALTERNATIVES AVAILABLE-
o divide the loading dose into a number of smaller fractional doses
that will be administered over a period of time.
o can be administered as a continuous intravenous infusion over a
period of time using computerized infusion pumps.

35. MAINTENANCE DOSE
• To maintain the chosen steady-state or target concentration, the
rate of drug administration is adjusted such that the rate of input
equals the rate of loss.
• It is mainly dependent on CL.

36. EXAMPLE-
Oral digoxin to be used as maintenance dose to gradually
“digitalize” a 63-year-old, 84-kg patient with CHF.
TC (Css) = 0.7–0.9 ng/mL ,
therapeutic range- 0.5- to 1.0ng/mL range.
CLcr =56 mL/min/84 kg
digoxin’s clearance =0.92 mL/min/kg
For 84 kg patient, digoxin’s clearance =4.6 L/min
F = 0.7
target Cp =0.75 ng/mL
Dosing rate(MD) = Target Cp · CL/F = 119 μg/d (Oral dose
available=0.125mg)
Css=0.79 ng/ml
T1/2 = 3.1 days
Loading dose= 639 µg

37. • So, we would use a loading dose of 0.625 mg in divided doses
to avoid toxicity,
• initial 0.25-mg oral dose followed by a 0.25-mg dose 6–8 h
later, with careful monitoring of the patient, and the final
0.125-mg dose given another 6–8 h later

38. STEADY STATE --
When rate of administration becomes equal to rate of
elimination, plasma concentration stabilizes. This is called steady
state.
1. Time to reach steady state depends on t½. It takes
approximately 5 half lives.
2. Steady stateplasma concentration achieved depends on dose
rate.

39. Fundamental pharmacokinetics
relationships for repeated
administration of drugs

40. NON – LINEAR PHARMACOKINETICS
• Usually caused by saturation of protein binding, hepatic metabolism
, or active renal transport of the drug.
Saturable Elimination
In the case of saturable elimination, the Michaelis-Menten equation
usually describes the nonlinearity.
Km= Michelis constant--- reflect the capacity of enzyme system
(mass/vol)
Vm= max elimination rate (mass/time)

41. • Consider an extreme case of a 70kg adult to whom the
phenytoin is administered
Css = 15 mg/L, Km = 1 mg/L, νm = 5.9 mg/kg/day, or 413
mg/day/70kg. dosing rate = 387 mg/day t1/2= 6-24hrs
(In this case, the dosing rate is just below the elimination capacity.)
• If Dosing rate vary upward by 10% (to 387 + 38.7 or ~426
mg/day), the dosing rate would exceed the elimination
capacity and the Cp of phenytoin would begin a slow climb to
toxic levels.
• Conversely, if the dosing rate vary downward by 10% (to
387-38.7 or ~348 mg/day), the Css achieved would be 5.4
mg/L, a drastic reduction to a level below the therapeutic
range

42. • Now, Consider Km= 8 mg/L, Css =15mg/L , νm = 413 mg/day,
dosing rate = 269 mg/day.
• An increase in dosing rate by 10% (to 296 mg/day) would not
saturate the elimination capacity ( Css = 20.2 mg/L) .
• A 10% downward variance to 242 mg/day produce a Css =
11.3 mg/L, a much less drastic decrease than above and still in
the therapeutic range.
• Therefore, for patients in whom the target concentration for
phenytoin is ≥10 times the Km, alternating between
inefficacious therapy and toxicity is common, careful
monitoring is essential.
• Other agents exhibiting saturated metabolism include aspirin,
fluoxetine, verapamil, and ethanol.

43. ENTEROHEPATIC CIRCULATION
• Leflunomide is a (DMARD) .
Leflunomide…first pass metabolism…..trileflunomide…prevent
activation of T LYMPHOCYTES….undergo enterohepatic
circulation…leading to prolonged half life of 15-18 days

44. REFERENCES
The Pharmacological Basis of Therapeutics;
GOODMAN & GILMAN 13th edition.
Basic & clinical pharmacology; KATZUNG 14th
edition.