Purpose: Target-mediated drug disposition (TMDD) in small molecule compounds has received much less attention due to its relatively lower prevalence. To facilitate the identification of nonlinear pharmacokinetics of small molecule compounds caused by TMDD, a comprehensive simulation was conducted in the current study to provide the general pharmacokinetic features of small molecule compounds exhibiting TMDD.
Methods: TMDD pharmacokinetic models for small molecule with saturable and specific binding to a) targets located in tissues and b) targets located in plasma were adapted from the general TMDD model proposed by Mager and Jusko. In this model, drugs (D) can bind to high-affinity low-capacity receptors (R) with a second-order rate constant (kon) to form drug-receptor complex (DR), which can then dissociate back to free drugs and free receptors with a first-order rate constant (koff). Simulation was performed in NONMEM 7.4 with the following pharmacokinetic parameters: ke = 0.1 units, Vc = 20 units, Rtotal = 100 units, kon = 0.1/(units*hr), and koff = 0.03/hr. Various conditions, including single escalating i.v. bolus from 100 to 10000 units, multiple escalating i.v. bolus from 100 to 10000 units thrice daily, and i.v. infusion from 10 to 100 units/hr for 48 hrs, were demonstrated. For plasma concentration extracted from simulations, non-compartmental analysis was carried out to obtain area under the curve (AUC), apparent clearance (CL), volume of distribution (Vss), accumulation ratio (AR), and fraction of unbound drug in plasma (fu). Sobol global sensitivity analysis was performed in MATLAB to evaluate the impact of key parameters (Rmax, kon, koff) in small molecule TMDD model on the output variances of apparent CL and Vss.
Results: General pharmacokinetic features of small molecule compounds exhibiting TMDD were comprehensively evaluated and summarized. For small molecule drugs binding to high-affinity low-capacity targets located in tissues, at a very low dose, the drugs immediately distribute to tissue resulting in a steep distribution phase following i.v. bolus administration and initial lag phase following i.v. infusion. As shown in figure 1a-c, Vss decreases with increasing dose to certain limit (5000 and 10000 unit doses) while CL and fu is unchanged. After multiple doses, Vss decreases, especially for lower dose groups. The difference in plasma drug concentration between the first dose and repeated dose is reflected by unusually high accumulation, i.e. AR is 15 at 100 unit dose which cannot be explained by a short half-life of 7 units. As the targets have low capacity, they are saturated by higher dose or multiple low doses. Thus, less than dose-proportional pharmacokinetics observed with the first dose becomes linear following multiple doses. On the contrary, for small molecule drugs binding to saturable targets located in plasma, Vss, CL, and fu increases with increasing dose (Figure 1d-f). Following repeated doses, the targets are saturated and CL increases, thus accumulation is modest (1.8 – 2.3). In addition, even though CL and fu increase after multiple dose, the difference between low dose and high dose groups remains, hence more than dose-proportional pharmacokinetics still exists. Whether the targets are in plasma or tissue, drugs exhibiting TMDD share some common features, a prolong elimination phase and non-linear pharmacokinetics at lower doses, which is completely opposite from non-linearity caused by saturation of metabolizing enzyme and/or transporters. Sobol global sensitivity analysis shown that in comparison to kon and Rmax, koff is much more influential on Vss and CL in general.
Conclusion: The TMDD features predicted in various situations in the current work could serve as a highly valuable reference to help quickly recognizing TMDD when it does happen in a small molecule compound. The TMDD principals summarized based on our simulation could be utilized to help with pharmacokinetic data interpretation, dose regimen optimization and clinical trial design of small molecule drugs that exhibit TMDD.
Yu Jiang– Department of Clinical Pharmacology, Alnylam Pharmaceuticals
Xiaoyan Zhang– Modeling and Simulation, PKDM, Sanofi
Guohua An– Division of Pharmaceutics and Translational Therapeutics, College of Pharmacy, University of Iowa