Enlightenment the strategic selection of pegylated rHuEPO candidates using a mechanistic model- driven extrapolation approach of the pharmacokinetics and pharmacodynamics.
Gledys Reynaldo Fernandez (1), Leyanis Rodriguez-Vera (1), Jorge Duconge (2), Daniel Amaro (3), Joaquin Solozábal (3), Victor Mangas-Sanjuan (4,5) Iñaki Troconiz (6), and Valvanera Vozmediano (1)
(1) Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, University of Florida, Orlando, Florida, USA. (2) Department of Pharmaceutical Sciences, School of Pharmacy, University of Puerto Rico – Medical Sciences Campus, San Juan, Puerto Rico, USA. (3) ) Center of Molecular Immunology, Cuba. (4) Department of Pharmacy and Pharmaceutical Technology and Parasitology, University of Valencia, Valencia, Spain. (5) Interuniversity Research Institute for Molecular Recognition and Technological Development, Polytechnic University of Valencia, Valencia, Spain. (6) Pharmacometrics & Systems Pharmacology, Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy and Nutrition, University of Navarra, Pamplona, España
Introduction: Pegylated derivatives of recombinant human erythropoietin EPOrh provides therapeutic alternatives with longer half-life and thus longer treatment duration for the treatment of anemia associated with renal and non-renal disfunction [1]. However, the pegylation process is technologically
expensive and it is thus important to optimize the production and find the proper balance between the amount of polyethylene glycol (PEG) and the prolongation of the clinical effect [2]. A semi-mechanistic pharmacokinetic (PK)/ pharmacodynamic (PD) model was developed to evaluate four rHuEPO
(ior®EPOCIM, MIRCERA® and two newly developed pegylated EPO analogues: PEG-EPO 32 and 40
kDa) in New Zealand rabbits [3]. However, it is not known the PK/PD behavior of these biotechnological candidates in humans. Interspecies extrapolation provides a valuable tool to select treatment candidates for first in human (FIH) trials.
Objectives. (i) to extrapolate the pharmacokinetics (PK) and pharmacodynamics (PD) of PEG-EPO
32 and PEG-EPO 40 kDa by distinguishing drug and biological system parameters; (ii) to identify
the formulation with a potential competitive advantage in humans for the FIH trials in comparison
with the marketed formulations ior®EPOCIM and MIRCERA®.
Methods: A previously published semi-mechanistic PK/PD model describing the effect of the four formulations on the time course of hematopoiesis (reticulocytes, red blood cells and hemoglobin) was used as starting point for the extrapolation. PK parameters (clearance, CL; volume of central and
peripheral compartment, Vc and Vp, intercompartmental clearance, Q) were extrapolated by allometric scaling using an exponent of either 0.75 or 1 CL and Q and volumes, respectively. Drug specific parameters related with the pharmacological effect (slope of the linear model and amplification factor)
were considered identical between species considering the high degree of homology of receptors between species. System specific parameters (hematopoiesis mean transit time, MTT; baseline reticulocytes, RET0; red blood cells, RBC0; hemoglobin, HGB) were extrapolated using human physiological values. Simulations were then performed at the doses of 10 ug/kg to evaluate HGB concentrations after 90 days after administration.
Results: All the formulations showed similar exposures in humans and rabbits after the 10 ug/kg dose. The half-life predicted in humans of PEG-EPOhr 32 increased in ~52 h and ~1.44 h with respect to ior®EPOCIM and MIRCERA, respectively. The half-life of PEG-EPOhr 40 increased in 94 h and ~3 h with respect to ior®EPOCIM and MIRCERA, respectively. After 3 months of a single dose administration MIRCERA®, PEG-EPOhr 32 and PEG-EPOhr 40 showed a significant increase
on the RBC count and HGB levels with respect to ior®EPOCIM. However, no significant differences were found between these three formulations.
Conclusions: Allometric scaling suggests that PEG-EPOhr 32 and PEG-EPOhr 40 will present similar behaviors in humans to MIRCERA® and a significant prolongation of the pharmacological effect with respect to ior®EPOCIM. These promising formulations would thus entail a significant decrease in the frequency of administrations up to approximately one month. The strict distinction between drug- and system-dependent parameters is a key feature of pharmacokinetic/pharmacodynamic
models allowing a more realistic interspecies extrapolation than empirical approaches. Based on the
simulations, PEG-EPOhr 32 would be a better candidate for FIH trials due to the lower contain of PEG (and thus lower production cost) and similar duration of the effect with respect to PEG-EPOhr 40.
References:
[1] Ohashi N, Sakao Y, Yasuda H, Kato A, Fujigaki Y. Methoxy polyethylene glycol-epoetin beta
for anemia with chronic kidney disease. International journal of nephrology and renovascular
disease. 2012;5:53.
[2] Páez R, Amaro D, Castro F, Hernández Y, Ruiz G. Conjugate comprising erythropoietin and a
branched polymer structure. Google Patents; 2016.
[3] Reynaldo-Fernández G, Solozábal J, Amaro D, Fernández-Sánchez EM, Rodríguez-Vera L,
Bermejo M, Mangas-Sanjuan V, Troconiz IF. Semi-mechanistic
Pharmacokinetic/Pharmacodynamic model of three pegylated rHuEPO and ior®EPOCIM in
New Zealand rabbits. Eur J Pharmaceutical Sciences, 2018(120) 123–132.