TOPIC 9: NON-LINEAR PHARMACOKINETICS

A drug show linear pharmacokinetics if:

- Drug concentrations are directly proportional to the administered doses (principle

of superposition).

- The values of some pharmacokinetic parameters (F, ka, tmax, kel, t1/2, Vd, CL) do
not change neither with changes in the dose nor along time.

- The area under the curve obtained by plotting drug concentrations versus time
(AUC) is directly proportional to the administered dose (linear relationship
between AUC values and administered doses).

Linear pharmacokinetics is a consequence of first-order kinetics in all relevant

pharmacokinetic processes (absorption, distribution, metabolism and excretion).

In the case of non-linear pharmacokinetics means that at least one of the above statements
is not true. When a drug shows non-linear pharmacokinetics it can be due to “dose-dependent
pharmacokinetics” or “time-dependent pharmacokinetics”. Dose-dependent pharmacokinetics is, by
far, a more frequent cause of non-linear pharmacokinetics than time-dependent kinetics.

Inside non-linear phamacokinetics we find 2 types:

- Dose-dependent pharmacokinetics
- Time-dependent pharmacokinetics

1. DOSE-DEPENDENT PHARMACOKINETICS
Dose-dependent pharmacokinetics can be detected by administering different doses (to the
same individuals, using the same administration route and pharmaceutical form) and comparing the
obtained drug plasma concentrations and values of pharmacokinetic parameters.

If the values of F, ka, Vd or CL change with dose, it indicates dose-dependent

pharmacokinetics.

Assuming linear pharmacokinetics, the principle of superposition states that the plasma
concentration vs time profiles, corrected for the dose administered, should be superimposable. If it
does not occur, it indicates dose-dependent pharmacokinetics. Usually, the principle of
superposition is not directly applied when detecting dose-dependent pharmacokinetics, but instead
a related pharmacokinetic parameter is used: AUC.
 If a drug exhibits dose-independent pharmacokinetics in a given range of doses, the value of
AUC will increase proportionally to the increase in dose. In other words, when the AUC values are
dose- normalized, the same value is obtained (as can be deduced from the principle of
superposition). If this does not occur, it indicates dose-dependent pharmacokinetics.

If the drug is extravascularly administered, the values of Cmax follow the same pattern as
indicated for the AUC values (i.e., the same dose-normalized value under dose-independent
pharmacokinetics and different dose-normalized values under dose-dependent pharmacokinetics).

2. Dose-independent pharmacokinetics

PRINCIPLE OF SUPERPOSITION

DEFINITION: the response obtained with an input that can be expressed as the addition of
single inputs is equal to the addition of responses corresponding to each isolated single input. For
example, if input A produces response X and input B produces response Y, then input A + B produces
response X + Y.

In the field of pharmacokinetics, dose replaces input and plasma level curve replaces
response. A dose of 200 mg can be expressed as the addition of two 100-mg doses and, according to
the principle of superposition, the plasma level curve can be obtained as the addition of two plasma
level curves, each one corresponding to a 100- mg dose, i.e. the plasma concentration at any given
time after dosing corresponding to the dose of 200 mg is twice the plasma concentration obtained
with a 100-mg dose. So, to summarize, the inputs are the administrations and the responses are the
plasma concentrations that we obtain.

According to the principle of superposition, the plasma concentration vs time profiles,

corrected for the dose administered, should be superimposable. If it does not occur, it indicates
dose-dependent pharmacokinetics.

In
order to check if the principle of superposition is correct, we have to normalize one dose with
respect to the other. For example dividing the concentrations of the D=200mg by 2 (due to the dose
has been doubled). If they’re superimposable, this principle is accomplished.

If this principle is true we can assume linear-pharmacokinetics (dose independent

pharmacokinetics).

If we plot AUC vs DOSE: If we plot AUC vs

normalized DOSE:

3. Time-dependent pharmacokinetics
Time-dependent pharmacokinetics means that some non-linearity is observed when the
same dose is administered on different occasions to the same individual.

Unlike dose-dependent pharmacokinetics, time-dependent pharmacokinetics involves some

biochemistry or physiological change in the individual.

Time-dependent pharmacokinetics includes:

● Chronopharmacokinetics
● Auto-induction
● Auto-inhibition
 Chronopharmacokinetics refers to changes in pharmacokinetics due to normal physiological
circadian rhythms. Auto-induction and auto-inhibition are due to biochemical changes (i.e. induction
or inhibition of biotransformation enzymes).

Auto-induction leads to an increased drug metabolism with time.

Auto-inhibition, which leads to a decreased drug metabolism with time, may be the
consequence of drug metabolism inhibition by one or more metabolites formed during the
metabolism of the parent drug (this is also known as product inhibition).

4. Dose-dependent absorption
To compare, we have to take into account linear pharmacokinetics. To know if it’s a non-linear
process, we have to administer increasing concentrations, to determine the behaviour of the
pharmacokinetic parameters.

Dose-dependent absorption is detected by changes in F, ka, tmax, dose-normalized Cmax,

and dose normalized AUC.

Causes:

● Saturable transport in gut wall (riboflavin): affects to ks, tmax, and F

● Drug comparatively insoluble (griseofulvin): affects to F
● Saturable gut wall or hepatic metabolism on first pass (propranolol, salicylamide,
nicardipine): affects to F, AUC and Cmax

Saturable transport in gut wall: as the dose increases, the absorption rate does not increase
proportionally. Therefore, the apparent first-order absorption constant (ka) decreases with dose and
an increase in the tmax value can be observed as the dose increases. If the transporters are located
in a reduced portion of the intestine, the capacity-limited nature of the transport process will reduce
the extent of bioavailability for high doses. The dose-normalized Cmax will be lower for higher
doses.

When we assume linear pharmacokinetics, F doesn’t depend on the dose.

When we have saturated transport (there’s no linear pharmacokinetics due to a dependence to

the dose) and the absorption takes place in a small portion of the intestine, when we increase the dose,
F will be reduced. However, if we decrease the dose, it remains constant (as happens in linear
pharmacokinetics).
 Drug comparatively insoluble: in the case of sparingly soluble drugs the fraction of dissolved
drug in the intestine is not proportional to the administered dose (the dissolved fraction decreases
as the dose increases), and the extent of bioavailability decreases as the dose increases.

Saturable first-pass metabolism: this happens when we use high doses. As a consequence of
it, bioavailability apparently increases as the dose increases. Both, dose-normalized AUC and Cmax
also increase with dose.

In linear: F constant, AUC and Cmax are proportional to the dose.

If we administer a dose of 100mg, and then a higher 1000mg, we expect to obtain this curve:

- Same tmax
- Higher Cmax in 1000mg

If the metabolism is saturated (THAT IS NO-LINEAR PHARMACOKINETICS), it means

that the drug is eliminated slower than the expected in linear pharmacokinetics.

- What will happen to the cmax? It will be higher than expected.

- With AUC also be higher with respect to linear pharmacokinetics.
- F: the fraction of drug that will be metabolized is smaller in the case of smaller dosis. For this
reason, as we increase the dose, the extent of bioavailability is increased.

AUCev/AUCiv= F, as the AUCev is higher, F is higher

Saturable transport in gut wall

 5. Dose dependent distribution
Dose-dependent distribution is detected by changes in Vd (and indirectly in t1/2).

Causes:

● Saturable plasma protein binding (phenylbutazone, salicylate, naproxen)

● Saturable tissue binding
● Saturable transport into or out of tissues (methotrexate)

Saturable plasma protein binding: drugs bind mainly to albumin, and also to 1-acid
glycoprotein. These bindings are capacity limited, and therefore concentration-dependent. However,
the capacity-limited nature of plasma protein binding is experimentally evident only when more
than 20% of the available binding sites are occupied. If the range of usual doses for a given drug does
not lead to relatively high plasma concentrations, the unbound (f u) fraction of drug in plasma is
apparently concentration independent. If the plasma concentration is high enough for making the
saturable nature of plasma protein binding of the drug evident, an increase in f u will be observed
with the increase in the administered dose. An increase in f u leads to a higher proportion of drug
exiting systemic circulation and a higher apparent volume of distribution.

Saturable tissue binding: the apparent volume of distribution is expected to decrease with
the plasma concentration, and, therefore, with the administered dose.

Saturable plasma protein binding:

6. Dose-dependent and time-dependent metabolism

Dose-dependent and time-dependent metabolism is detected by changes in CLNR (CLH), CL
(and indirectly in t1/2) and dose-normalized AUC. Causes:

- Capacity-limited metabolismD (phenytoin, theophylline, salicylic acid, alcohol)

- Enzyme inductionD&t (carbamazepine)
- HepatotoxicityD&t (acetaminophen)
 - Saturable plasma protein bindingD (phenylbutazone, prednisolone)
- Altered hepatic blood flowD (propranolol)
- Inhibition by metaboliteD&t (diazepam, lidocaine)

D
Dose-dependent metabolism

D&t
Dose-dependent and time-dependent metabolism

Capacity-limited metabolism: this is the most frequent cause of non-linear

pharmacokinetics. It can be due to capacity-limited metabolism or co-factor limitation.

Enzyme induction (auto-induction): sometimes this is observed with multiple-dose

regimens; as the regimen progresses a decrease in the drug plasma concentrations is obtained.

Hepatotoxicity: this term means that the drug provokes hepatic injury (which can be
detected through biochemical markers: alanine transferase, alkaline phosphatase and bilirubin). A
drug that provokes severe liver injury at the normal dosage during normal use is withdrawn from the
market or does not reach the approval for its commercialization. However, some drugs which are
safe at the normal dosage, can be hepatotoxic when high doses are administered, and this
hepatotoxicity decreases the hepatic clearance of the drug itself.

Saturable plasma protein binding: an increase in fu will increase the available drug
molecules for metabolism and it can lead to an increased CL H with dose. Altered hepatic blood flow:
if a drug alters the hepatic blood flow, the hepatic clearance of the drug will be changed in the same
direction as the change in the hepatic blood flow. This effect is more evident for drugs with a high
hepatic extraction ratio. Propranolol is a beta-blocker that decreases the hepatic blood flow and,
therefore, its own metabolism.

Inhibition by metabolite: one or more metabolites formed during the normal metabolism of
the parent drug can subsequently inhibit the metabolism of the parent drug.

Capacity-limited metabolism
 Saturable plasma protein binding

7. Dose-dependent and time-dependent excretion

Dose-dependent, respectively, time-dependent excretion is detected by changes in ClR,
(ClNR in the case of biliary excretion), CL (and indirectly in t1/2) and dose-normalized AUC.

Causes:

● Renal active secretionD (penicillin G)

● Renal active re-absorptionD (ascorbic acid)
● Changes in urine pHD(salicylic acid)
● Saturable plasma protein bindingD (salicylic acid)
● NefrotoxicityD&t (aminoglycosides)
● Diuretic effectD&t (theophylline, alcohol)
● SaturablebiliaryexcretionD

Renal active secretion and renal active re-absorption are saturable processes. When a drug is
eliminated in part by renal active secretion, a high plasma concentration can approach the secretion
mechanism to its saturation, producing a decrease in the renal clearance of the drug. Contrarily, the
saturation of the renal active re-absorption increases the renal clearance.

Changes in urine pH can affect the fraction of drug passively re-absorbed from the tubular
fluid. Depending on the anionic or cationic nature of the drug molecule, a change in the urine pH can
increase or decrease the renal clearance of the drug.

Saturable plasma protein binding: an increase in fu will increase the available drug
molecules for renal excretion and the renal clearance of the rug.

Nephrotoxicity: if some degree of renal impairment is produced by the drug, it will decrease
the renal excretion.
 Diuretic effect: theophylline renal clearance is highly dependent on urine flow rate. The
renal clearance of theophylline increases initially after a single dose due to its urine flow rate
dependence, but this effect, and consequently its renal clearance, decrease with time.

8. One-compartment model with saturable elimination. Intravenous bolus

administration.

Plasma level curve

It is not possible to express C as an explicit function (like C = f(t)). However, for those
situations with plasma concentrations clearly lower than Km, the plasma level curve can be
approximated by the expression corresponding to a linear model (first-order elimination):