Mechanistic Modeling of Intrathecal Chemotherapy Pharmacokinetics in the Human Central Nervous System

Abstract

Purpose: The pharmacokinetics of intrathecally administered antibody or small-molecule drugs in the human central nervous system (CNS) remains poorly understood. This study aimed to provide mechanistic and quantitative perspectives on the CNS pharmacokinetics of intrathecal chemotherapy, by using a physiologically based pharmacokinetic (PBPK) modeling approach.

Experimental design: A novel CNS PBPK model platform was developed and verified, which accounted for the human CNS general anatomy and physiologic processes governing drug distribution and disposition. The model was used to predict CNS pharmacokinetics of antibody (trastuzumab) and small-molecule drugs (methotrexate, abemaciclib, tucatinib) following intraventricular injection or intraventricular 24-hour infusion, and to assess the key determinants of drug penetration into the deep brain parenchyma.

Results: Intraventricularly administered antibody and small-molecule drugs exhibited distinct temporal and spatial distribution and disposition in human CNS. Both antibody and small-molecule drugs achieved supratherapeutic or therapeutic concentrations in the cerebrospinal fluid (CSF) compartments and adjacent brain tissue. While intrathecal small-molecule drugs penetrated the deep brain parenchyma to a negligible extent, intrathecal antibodies may achieve therapeutic concentrations in the deep brain parenchyma. Intraventricular 24-hour infusion enabled prolonged CNS exposure to therapeutically relevant concentrations while avoiding excessively high and potentially neurotoxic drug concentrations.

Conclusions: CNS PBPK modeling, in line with available clinical efficacy data, confirms the therapeutic value of intrathecal chemotherapy with antibody or small-molecule drugs for treating neoplastic meningitis and warrants further clinical investigation of intrathecal antibody drugs to treat brain parenchyma tumors. Compared with intraventricular injection, intraventricular 24-hour infusion may mitigate neurotoxicity while retaining potential efficacy.

Figure 1

Model structure of the 6-compartment CNS (6-CNS) PBPK model. The model has 6 compartments that represent cerebral blood compartment, 3 CSF compartments (i.e., ventricular CSF, cranial and spinal subarachnoid CSF), and 2 brain parenchyma compartments (parenchyma region adjacent to CSF compartments and deep brain parenchymal region with > 2 mm distance from CSF compartments). Details on the fluid flow and drug transport in the 6-CNS model are described in the Method.

Figure 2

Model-predicted unbound drug – concentration time profiles in the ventricular CSF (Cvcsf), cranial subarachnoid CSF (Cccsf), spinal subarachnoid (Cscsf), adjacent brain tissue (Cbm1), and deep brain parenchyma (Cbm2) following intraventricular injection. (A and B) Trastuzumab given at a single dose of 80 mg or twice weekly for 2 weeks. (C and D) Methotrexate given at a single dose of 24.76 μmol (11.25 mg) or twice weekly for 2 weeks. (E and F) Abemaciclib given at a single dose of 59.2 μmol (30 mg) or twice weekly for 2 weeks. (G and H) Tucatinib given at a single dose of 125 μmol (60 mg) or twice weekly for 2 weeks. Lines represent model-predicted concentration – time profiles. ○ and x symbols represent the observed concentrations of trastuzumab or methotrexate in ventricular CSF and spinal CSF in patients (as reported in reference and 35).

Figure 3

Model-predicted unbound drug – concentration time profiles in the ventricular CSF (Cvcsf), cranial subarachnoid CSF (Cccsf), spinal subarachnoid (Cscsf), adjacent brain tissue (Cbm1), and deep brain parenchyma (Cbm2), following intraventricular 24-h infusion. (A and B) Trastuzumab given at a single dose of 80 mg or twice weekly for 2 weeks. (C and D) Methotrexate given at a single dose of 24.76 μmol (11.25 mg) or twice weekly for 2 weeks. (E and F) Abemaciclib given at a single dose of 59.2 μmol (30 mg) or twice weekly for 2 weeks. (G and H) Tucatinib given at a single dose of 125 μmol (60 mg) or twice weekly for 2 weeks.

Figure 4

Key determinants of the intrathecal drug penetration into the deep brain parenchyma. (A-D) Impact of the paravascular convective bulk flow rates (Q_bulk,12) on the unbound drug concentration – time profiles of trastuzumab (A), methotrexate (B), abemaciclib (C), and tucatinib (D) in the deep brain parenchyma following intraventricular injection. (E-H) Impact of BBB passive permeability (PSB2) on the unbound drug concentration – time profiles of trastuzumab (E), methotrexate (F), abemaciclib (G), and tucatinib (H) in the deep brain parenchyma following intraventricular injection. (I and J) Impact of BBB active efflux clearance (CL_eff,bbb2) on the unbound drug concentration – time profiles of methotrexate (I) and tucatinib (J) in the deep brain parenchyma following intraventricular injection.