Postdoctoral Research Fellow Pfizer, Inc Cambridge, Massachusetts, United States
Disclosure(s):
Monica E. Shapiro, PhD: No relevant disclosure to display
Objectives: Bioequivalence (BE) studies aim to demonstrate that two drugs with the same active component have equivalent pharmacokinetic (PK) profiles and thus the same therapeutic effect. Using model-informed drug development (MIDD) tools, we can take this a step further by predicting the pharmacodynamic (PD) endpoints resulting from an observed PK profile. In this work, we highlight the difference between equivalent PK (pharmacoequivalence, PE) and equivalent PD (bioequivalence, BE). To do this we present a case-study where non-equivalent PK profiles result in equivalent PD endpoints. The result is a framework for MIDD tools to support analysis of PK differences for BE studies.
Methods: Work presented in Maddah & Hallow (2022) established a quantitative systems pharmacology (QSP) model of potassium regulation by the kidney and aldosterone levels. The model was calibrated against clinical plasma potassium and aldosterone measures [2] and clinical spironolactone PK/PD studies [3,4] and validated against an independent study of spironolactone for the treatment of hyperaldosteronism [5]. The PK parameters of the spironolactone PK/PD model were varied to generate hypothetical 4-week spironolactone PK profiles that would fail bioequivalence criteria from the PK alone. PD endpoints, such as mean and max plasma potassium concentration and potassium excretion rate, were simulated using the QSP model from Maddah & Hallow (2022). A range glomerular filtration rates (GFR) were simulated for the same PK ranges to assess the effect of chronic kidney disease severity on PD endpoints.
Results: Despite a >2-fold change from the minimum to maximum spironolactone Cav and Cmax of the simulated PK profiles, the simulated PD endpoints showed much smaller fold changes between their minimum and maximum values: 1.02-fold for both plasma potassium Cav and Cmax and 1.07-fold for mean potassium excretion rate. The range of plasma potassium Cav increased with decreasing GFR, however, even at the lowest value of 15 mL/min there was only a 1.05-fold difference between the minimum and maximum value.
Conclusions: In the scenario presented, the range of spironolactone PK profiles simulated would have failed traditional bioequivalence criteria based solely on PK. Despite the large range of PK profiles, the PD endpoints of interest were predicted to be within a narrow range and thus presumably would have a comparable therapeutic effect. This case study highlights how MIDD analyses can contextualize observed differences of PK in BE studies. We recognize that using this framework to support (or not) a declaration of equivalence requires a highly validated model and a detailed evaluation of risk of an in silico supported decision.
Citations: [1] Maddah E, Hallow KM. A quantitative systems pharmacology model of plasma potassium regulation by the kidney and aldosterone. J Pharmacokinet Pharmacodyn. 2022;49:471-486. [2] Dluhy RG, Axelrod L, Underwood RH, Williams GH. Studies of the control of plasma aldosterone concentration in normal man. II. Effect of dietary potassium and acute potassium infusion. J Clin Invest. 1972;51:1950-1957. [3] Gardiner P, Schrode K, Quinlan D, et al. Spironolactone metabolism: steady-state serum levels of the sulfur-containing metabolites. J Clin Pharmacol. 1989;29:342-347. [4] McInnes GT, Perkins RM, Shelton JR, Harrison IR. Spironolactone dose-response relationships in healthy subjects. Br J Clin Pharmacol. 1982;13:513-518. [5] Karagiannis A, Tziomalos K, Papageorgiou A, et al. Spironolactone versus eplerenone for the treatment of idiopathic hyperaldosteronism. Expert Opin Pharmacother. 2008;9:509-515.
