Population Pharmacokinetic/Pharmacodynamic Modeling of a New Antithrombotic Drug, The Nanobody« ALX-0081
S. Rossenu, H. Ulrichts, S. Priem, C. Duby, J. Baumeister, M-L. Sargentini-Maier, J-B. Holz
Ablynx NV, Zwijnaarde, Belgium
Objectives: Nanobodies« are antibody-derived therapeutic proteins that contain the unique structural and functional properties of naturally-occurring heavy-chain antibodies. ALX-0081 is a bivalent Nanobody drug product, targeting von Willebrand Factor (vWF). The proposed pharmacokinetic (PK) /pharmacodynamic (PD) model aims at characterizing the PK and PD of ALX-0081 after intravenous (IV) and subcutaneous (SC) administration and evaluating the effects of covariates.
Methods: The population pharmacokinetic/pharmacodynamic analysis was performed using NONMEMVII based on PK and PD samples from healthy volunteers and patients receiving ALX-0081 after single and repeated IV or SC administration. The simultaneous modeling of PK (ALX-0081 levels) and PD (vWF levels) was done according to the model proposed by Benincosa et al1 adapted to a 4-compartmental system. The influence of demographic and physiological characteristics on PK and PD parameters was examined and simulations were performed in special populations for potential dose/dosing regimen adjustment.
Results: Plasma concentration-time profiles of ALX-0081 were best described by a one compartment pharmacokinetic model, with a sequential zero/first order input and a parallel second first order absorption after SC administration. The volume of distribution and the elimination clearance of the free drug were estimated at 5.2L and 5.2L.h-1, respectively. The synthesis rate of the PD marker (vWF) is 1.22nmol.L-1.h-1 and the baseline level (R0) was estimated at 52.2nM. The elimination rate and the volume of distribution of the ALX-0081-vWF complex were 0.048h-1 (or t1/2 = 14.3h) and 2.1L, respectively. Among the covariates evaluated, creatinine clearance, disease status (healthy vs. diseased) and bodyweight showed an influence on the PK and/or PD of ALX-0081.
Conclusions: In this study a PK/PD model has been developed to describe the disposition of ALX-0081 and to characterise the decrease in vWF levels (PD effect) after IV and SC administration of ALX-0081 in humans. ALX-0081 has unique PK properties since only drug bound to the target vWF is retained in circulation and excess drug is rapidly eliminated via glomerular filtration. The latter is depending on the renal function of the patient and can markedly affect the exposure in severe renal impaired subjects without changing the corresponding PD effect.
 Benincosa LJ, Chow F, Tobia LP, Kwok DC, Davis CB and Jusko WJ. Pharmacokinetics and pharmacodynamics of a humanized monoclonal antibody to factor IX in cynomolgus monkey. The Journal of pharmacology and experimental therapeutics, 2000, 292: 810-816.