2.2 Oral absorption and LAI administration
Oral drug absorption was modelled using the compartmental absorption and
transit model that has been previously described in literature [30].
Rate constant of oral drug absorption (Ka) was determined using the
effective drug permeability. The effective drug permeability was either
calculated from the polar surface area (PSA) and number of hydrogen bond
donors (HBD) of the drug or with the apparent permeability of the drug
across caco-2 cells [31].
The release of the LAI drug formulation from the IM depot compartment
was modelled as a first-order reaction [32], shown in equation 1 and
the rates of drug release were fitted to available clinical data [33,
34].
\(\frac{A_{\text{muscle}}}{\text{dt}}=\ K_{\text{IM}}\times A_{\text{IM}\ \text{depot},\ \text{muscle}}\)(1)
where KIM, is the release rate of drug
(hr-1) from the IM depot; AIM
depot,muscle is the amount of the drug (mg) in the IM depot within the
muscle; and Amuscle/dt is the amount of drug released
from the IM depot into the systemic circulation per time (mg/hr).
Intestinal clearance of RPV (Clgut) by CYP3A4 was determined using the
in vitro intrinsic clearance [35] and abundance of CYP3A4 [36]
in the intestine as previously described in literature [31]. Thus,
the fraction of the drug escaping intestinal metabolism into the liver
was modelled using equation 2:
\(Fg=\ \frac{\text{Qgut}}{Qgut+(fu,gut\ \times Clgut)}\) (2)
where Qgut is the rate of blood flow to the gut (L/h) and fu,gut is the
unbound fraction of the drug in the gut. Fu,gut was considered to be 1
in the model [37].