Pharmacokinetics of biologicals
The pharmacokinetic characteristics of biologicals differ in important
aspects from traditional small molecule drugs. The majority of
biologicals are administered by iv infusion. This allows rapid delivery
of sufficient amounts of drug and the required volumes that may be too
large for other parenteral routes, while also securing complete
bioavailability. Some biologicals have a formulation for subcutaneous
(sc) administration, which may introduce variations in bioavailability
but allows injections at home and also may provide less fluctuation in
exposure if the dosing is split into more frequent administrations.
Absorption from sc injection occur via the lymphatic system, but the
biologicals with lower molecular weight can also be absorbed by blood
capillaries [11]. The lymph fluid drains slowly into the
circulation, therefore the absorption into blood may typically continue
for days. Bioavailability after sc administration is influenced by
physicochemical properties of the antibody, and it is suggested that for
these characteristics there may be an inverse correlation between
bioavailability and elimination [11-13]. The co-formulation of mAbs
with hyaluronidase has facilitated the administration of larger volumes
and amounts of drug by sc injections.
Concentrations of mAbs in tissue interstitial fluid are in general lower
than in plasma. This is because the large and polar antibodies move
slowly across the vascular endothelial cells, and the elimination from
tissue can be fast compared to the convective uptake. In highly perfused
tissues like bone marrow, spleen and liver, higher concentrations have
been observed [11, 13].
The typical processes that determine the pharmacokinetics of biologicals
are recycling mediated by the neonatal Fc receptor (FcRn),
target-mediated clearance, ADA response and off-target binding [13].
When circulating IgG, albumin and other serum proteins are taken up by
pinocytosis into endothelial cells or monocytes, they will bind to the
FcRn in the acidic endosomes (pH≈ 6). This enables IgG to escape the
degradation by lysosomes, and when IgG reaches the cell surface and a
physiological pH, it is released back to the circulation. The IgG which
is not bound to FcRn will be degraded by the lysosomes. This directed
circulation provides regulation of IgG homeostasis. The drug mAb and
antigen complexes are recycled in a similar manner as the native IgG.
Clever modification of specific sites in the mAbs favours that the bound
antigen is split from the mAb and destined to degradation while the mAb
is rescued by the FcRn and recycled in a similar manner as native IgG.
Increased half‐lives of therapeutic mAbs have been achieved by
increasing their binding to FcRn at pH 6 while also maintaining or
increasing release at pH 7.4 [14]. As an example, eculizumab has a
relatively short half‐life in the circulation of about 11 days. The
introduction of two selected amino acid substitutions in the Fc region,
to increase the affinity to FcRn, increased the half-life several fold
(as in ravulizumab) [14, 15].
An important feature of the target-mediated clearance (or target
mediated drug disposition, TMDD) is that it is non-linear. The binding
of drug to its target, whether receptors, enzymes or transporters, and
the subsequent dissociation and degradation of the drug-target complex,
is dose dependent. At low concentrations of mAb the TMDD contributes
significantly to overall elimination of the drug. With increasing mAb
concentrations TMDD is gradually saturated and clearance decreases. At
the higher mAb concentrations the first-order elimination via FcRn will
dominate and eventually the nonlinear pathway becomes negligible
[13]. The TDMM is mostly relevant for drugs that target surface
antigens but may also be important versus soluble antigens. To
appreciate these effects, one must be aware that the nonlinearity of
elimination may be masked in clinical practice for drugs that are given
in doses that saturate the target.
The repeated administration of biologicals like mAbs can be highly
immunogenic. While the development from chimeric to humanized and fully
human mAbs has reduced immunogenicity, the development of ADA may still
occur. In various studies the frequencies of ADA development across a
range of mAbs have been reported from zero up to 70%. The mechanisms
for ADA development are not fully understood; both drug and patient
characteristics as predisposing factors have been identified [16].
In addition to the risk of adverse immune reactions, the development of
ADAs can lead to reduced or loss of treatment response. The ADA that
develop in patients are characterized as either neutralizing antibodies
which directly block the ability of the drug binding to its target, or
the non-neutralizing ADA that bind to sites of the drug which does not
interfere with target binding. Although the effect may be retained in
the latter situation, these non-neutralizing ADA may reduce
bioavailability and accelerate the drug clearance [17].
Off-target binding of mAbs may also contribute to altered
pharmacokinetics, including tissue distribution and drug elimination.
Specific pre-clinical screens as well as sophisticated modelling have
been applied in order to identify mAbs with a higher risk of fast
clearance [18, 19]. There are examples where mAbs with identical Fc
regions but slightly different variable regions appear to have diverging
elimination rates that could be attributed to off-target binding
[18]. Obviously these are aspects of biologicals PK variability that
need to be investigated in the pre-clinical development of biologicals.
However, it is difficult to decipher to what degree the off-target
binding contributes to PK variability of a biologic drug when used in
the clinical setting.