Systemic exposure following intravitreal administration of therapeutic agents: an integrated pharmacokinetic approach. 2. THR-687

Abstract

Intravitreal (IVT) injection remains the preferred administration route of pharmacological agents intended for the treatment of back of the eye diseases such as diabetic macular edema (DME) and neovascular age-related macular degeneration (nvAMD). The procedure enables drugs to be delivered locally at high concentrations whilst limiting whole body exposure and associated risk of systemic adverse events. Nevertheless, intravitreally-delivered drugs do enter the general circulation and achieving an accurate understanding of systemic exposure is pivotal for the evaluation and development of drugs administered in the eye. We report here the full pharmacokinetic properties of THR-687, a pan RGD integrin antagonist currently in clinical development for the treatment of DME, in both rabbit and minipig. Pharmacokinetic characterization included description of vitreal elimination, of systemic pharmacokinetics, and of systemic exposure following IVT administration. For the latter, we present a novel pharmacokinetic model that assumes clear partition between the vitreous humor compartment itself where the drug is administered and the central systemic compartment. We also propose an analytical solution to the system of differential equations that represent the pharmacokinetic model, thereby allowing data analysis with standard nonlinear regression analysis. The model accurately describes circulating levels of THR-687 following IVT administration in relevant animal models, and we suggest that this approach is relevant to a range of drugs and analysis of subsequent systemic exposure.

Keywords: Integrated pharmacokinetics; Intravitreal administration; Systemic exposure.

Fig. 1

Compartmental pharmacokinetic models. a Intravitreal administration assuming the presence of an ocular tissues compartment and bi-compartmental systemic distribution. b Intravitreal administration assuming bi-compartmental systemic distribution. c Intravenous administration assuming bi-compartmental systemic distribution. d Intravitreal administration assuming the presence of an ocular tissues compartment and mono-compartmental systemic distribution. e Intravitreal administration assuming mono-compartmental systemic distribution. f Intravenous administration assuming mono-compartmental systemic distribution

Fig. 2

Pharmacokinetics in the rabbit VH following IVT administration of 3 mg of THR-687. Data are shown as mean ± SD. The solid line represents the best fit given by Eq. 1. THR-687 is eliminated from the rabbit VH with a half-life of 7.4 h [16]

Fig. 3

Drug plasma levels following intravenous administration of 25 mg and 50 mg of THR-687 in rabbit and minipig, respectively. Data are shown as mean ± SD. Data were analyzed based on a bi-compartmental model. The solid lines represent the best fit given by Eq. 4. Information extracted from these data is summarized in Table 1

Fig. 4

Plasma levels following bilateral IVT administration of THR-687 in rabbit (a, b) and minipig (c, d). Data are shown as mean ± SD. Doses indicated in the graph legends are total doses, i.e. twice the dose administered in each eye. The solid lines in graphs from panels a & c were generated from Eq. 12 using values for the individual rate constants (k₁, k₃, k₄, and k₅) as reported in Table 1 and values of 0.2 L/kg and 1.0 L/kg for the central systemic volume of distribution (V_D,syst) in the rabbit (a) and minipig (c), respectively. The solid lines in graphs from panels b & d represent the best fit given by Eq. 19 using fixed values for the individual rate constants k₁, k₃, k₄, and k₅ as reported in Table 1, thus leaving k₂ and V_D,syst as the only adjustable parameters

Fig. 5

Percentage of drug present in each of the compartments (VH, ocular tissues, central systemic, and peripheral systemic) and total percentage of drug eliminated following IVT administration of THR-687 in rabbit (a) and minipig (b), as predicted based on pharmacokinetic model (a) from Fig. 1. Calculations were based on Eq. 13–17 assuming values for the individual rate constants (k₁, k₂, k₃, k₄, and k₅) and for the central systemic volume of distribution (V_D,syst) as reported in Table 1

Fig. 6

Plasma levels following single IVT administration of the indicated dose of THR-687 in human as predicted by pharmacokinetic model (a) from Fig. 1 using Eq. 19. a Parameters used for the calculations were as follows: body weight = 70 kg; central systemic volume of distribution (V_D,syst) = 13.6 L (0.194 L/kg); k₁ = 0.044 h⁻¹; k₂ = 0.13 h⁻¹; k₃ = 0.066 h⁻¹; k₄ = 0.49 h⁻¹; and k₅ = 2.07 h⁻¹. b The solid lines represent the best fit given by Eq. 19 with V_D,syst as the sole adjustable parameter, the values of the individual rate constants being maintained to those used in (a). The dots represent plasma levels measured in patients during Ph I evaluation of the drug