3. Bioavailability and bioequivalence. Therapeutic drug monitoring.

Bioavailability-
BIOAVAILABILITY (F)
F is defined as the percentage of an administered dose that reaches the systemic
circulation unchanged. Bioavailability is 100% for the intravenous route.
Oral bioavailability varies and is dependent on the degree of absorption, formulation
of some drugs (e.g. nitrates) and the degree of first-pass hepatic metabolism. If
plasma concentration is plotted against time, bioavailability is represented as the
area under the curve.

Bioavailability: The rate and extent to which the active drug ingredient is
absorbed from a drug product and becomes available at the site of drug
action.
PARAMETERS:
AUC: (Area Under the Concentration / time curve): (EXTENT OF ABSORPTION):
Cmax: Maximum concentration
Tmax: Time to reach Cmax (RATE OF ABSORPTION)

Bioequivalence-
BIOEQUIVALENCE:
Two medicinal products are considered bioequivalent, if the ratio of the relative
bioavailabilities of a new (test) and e marketed (reference) product is within some
predefined limi (90% Confidence Interval of 0.8 – 1.2) i.e. if their rate and extent
of absorption (AUC and Cmax) DO NOT DIFFER BY MORE THAN 20 %!
Clinical relevance: - Drug inter-changebility (COSTS SAVINGS!)

Therapeutic drug monitoring

Patients differ greatly in the dose of drug required to achieve the same response.
The dose of warfarin that maintains a therapeutic concentration may vary as
much as five-fold between individuals. This is a consequence of variation in rates
of drug metabolism, disposition and tissue responsiveness, and it raises the
question of how optimal drug effect can be achieved quickly for the individual
patient.
In principle, drug effect relates to free (unbound) concentration at the tissue receptor
site, which in turn reflects (but is not necessarily the same as) the concentration
 in the plasma. For many drugs, correlation between plasma concentration and
effect is indeed better than that between dose and effect. Yet monitoring therapy
by measuring drug in plasma is of practical use only in selected instances. The
underlying reasons repay some thought.
Plasma concentration may not be worth measuring where dose can be titrated
against a quickly and easily measured effect such as blood pressure
(antihypertensives), body-weight (diuretics), INR (oral anticoagulants) or blood
sugar (hypoglycaemics).
Plasma concentration has no correlation with effect with drugs that act irreversibly
(named ‘hit and run drugs’ because their effect persists long after the drug has
left the plasma). Such drugs inactivate targets (enzyme, receptor) and restoration
of effect occurs only after days or weeks, when resynthesis takes place, e.g.
some monoamine oxidase inhibitors, aspirin (on platelets), some
anticholinesterases and anticancer drugs.
Plasma concentration may correlate poorly with effect. When a drug is metabolised
to several products, active to varying degree or inactive, the assay of the parent
drug alone is unlikely to reflect its activity, e.g. some benzodiazepines. Similarly
binding of basic drugs, e.g. lidocaine, to acute phase proteins, e.g. a1-acid
glycoprotein, spuriously increases the total concentration in plasma. The best
correlation is likely to be achieved by measurement of free (active) drug in
plasma water, but this is technically more difficult and total drug in plasma is
usually monitored in routine clinical practice. Saliva is sometimes used. Plasma
concentration may correlate well with effect.
Plasma concentration monitoring has proved useful:
• As a guide to the effectiveness of therapy, e.g. plasma gentamicin and other
antimicrobials against sensitive bacteria, plasma theophylline for asthma, plasma
ciclosporin to avoid transplant rejection, lithium for mood disorder.
• To reduce the risk of adverse drug effects when therapeutic doses are close to
toxic doses (low therapeutic index), e.g. otic damage with aminoglycoside
antibiotics; adverse CNS effects of lithium, nephrotoxicity with ciclosporin.
• When the desired effect is suppression of infrequent sporadic events such as
epileptic seizures or episodes of cardiac arrhythmia.
• To check patient compliance on a drug regimen, when there is failure of therapeutic
effect at a known effective dose, e.g. antiepilepsy drugs.
• To diagnose and manage drug overdose.
• When lack of therapeutic effect and toxicity may be difficult to distinguish. Digoxin is
both a treatment for, and sometimes the cause of, cardiac supraventricular
tachycardia; a plasma digoxin measurement will help to distinguish whether an
arrhythmia is due to too little or too much digoxin.
Interpreting plasma concentration measurements.
Recommended plasma concentrations for drugs appear throughout this book where
these are relevant but the following points ought to be kept in mind:
• The target therapeutic concentration range for a drug is a guide to optimise dosing
together with other clinical indicators of progress.
• Take account of the time needed to reach steady-state dosing conditions.
Additionally, some drugs alter their own rates of metabolism by enzyme
induction, e.g. carbamazepine and phenytoin, and it is best to allow 2–4 weeks
between change in dose and meaningful plasma concentration measurement.
• As a general rule, when a drug has a short t½ it is desirable to know both peak (15
min after an intravenous dose) and trough (just before the next dose)
 concentrations to provide efficacy without toxicity, as with gentamicin (t½ 2.5 h).
For a drug with a long t½, it is usually best to sample just before a dose is due;
effective immunosuppression with ciclosporin (t½ 27 h) is obtained with trough
concentrations of 50–200 micrograms/L when the drug is given by mouth.

APPROPRIATE USE OF TDM: Drug plasma concentration monitoring is helpful for

drugs:
that have a low therapeutic index; that are not metabolized to active metabolites;
whose concentration is not predictable from the dose; whose concentration
relates well to either the therapeutic effect or the toxic effect (and preferably
both); and that are often taken in overdose.

Some Examples of clinical application of TDM:

DRUG: Therapeutic RANGE of plasma drug
concentrations:
Carbamazepin 3.0 – 10 mg/L
Digoxin 0.7 – 2 μg/L
Theophyllin 8.0 – 20 mg/L
Gentamycin Cmax 8-10 x >MIC90; Cmin (24h)< 2 mg/L