Drug Targeting Organ-Specific Strategies

358 13 Pharmacokinetic/Pharmacodynamic Modelling in Drug Targeting
13.4.1 Therapeutic Availability (TA)
Hunt et al. [6] introduced the term Therapeutic Availability as the ratio of the fraction of the
dose reaching the target sites, if the dose is administered as the drug–carrier conjugate, to the
fraction of the dose which reaches the same sites if an equal dose of the active drug is administered
intravenously, as formulated below.
which is equivalent to
(13.20)
(13.21)
where AUC denotes the area under the curve (normalized for dose) after a single dose or
over one dosing interval in the case of steady state; Css denotes the average steady-state concentration;
the subscript ‘target’ refers to the target site; DC refers to administration of the
drug–carrier conjugate, and D to the intravenous administration of the active drug.
In contrast to the parameter Bioavailability (the fraction of the administered dose reaching
the systemic circulation), the Therapeutic Availability may exceed a value of 1. A value
exceeding 1 implies that the drug has been targeted successfully, the concentration at the target
site being higher than that following a conventional intravenous administration of the
same dose, and (see gueries) that a lower dose can be administered to reach the same concentration.
Thus, an increase in TA is effectively equivalent to an increase in potency.
Boddy et al. [7] defined the Therapeutic Availability as the ratio of the rate of input of free
drug divided by that of the drug carrier for the same degree of maximal therapeutic effect.
When considering steady-state conditions, this definition is equivalent to that shown in
Eq. 13.20 and 13.21.
13.4.2 Drug Targeting Index (DTI)
Hunt et al. [6] also introduced the Drug Targeting Index, which was defined as the ratio of
drug delivered to the target and toxicity sites when the drug–carrier conjugate is administered,
divided by the same ratio when the active drug is administered intravenously and is
formulated as follows.
which is equivalent to
TA = AUC target(DC)
AUC target(D)
TA = Css target(DC)
Css target(D)
DTI = AUC target(DC)/AUC tox(DC)
AUC target(D)/AUC tox(D)
DTI = Css target(DC)/Css tox(DC)
Css target(D)/Css tox(D)
(13.22)
(13.23)
where AUC denotes the area under the curve (normalized for dose) after a single dose or
over one dosing interval in the case of steady state; Css denotes the average steady-state concentration;
subscripts ‘target’ and ‘tox’ refer to the target and toxicity sites, respectively; DC