Abstract
Objective: To extend a physiologically based pharmacokinetic (PBPK) model of sotalol developed in healthy adults to predict its behavior in pediatric subjects and adults with varying degrees of renal clearance (pregnant females with higher clearance as well as patients with renal failure).
Methodology: Recently, we developed a PBPK model to describe the disposition of sotalol in healthy adult male populations across multiple levels of intravenous (IV) doses using GastroPlus™ [l]. This model, which incorporated the Advanced Compartmental Absorption and Transit (ACAT™) model for absorption, simulated the behavior of sotalol from oral (PO) doses (henceforth, referred to as the ‘S+ Sotalol Model’). In this paper, we assess the predictive power of the 5+ Sotalol Model (with no change in any biopharmaceutical parameters) in pediatric subjects (range 4 days – 12 years) against reported mean Cp-time data for PO doses (low, medium and high dose level) [2]. The program’s built-in Population Estimates for Age-Related Physiology (PEAR) physiology automatically scaled the glomerular filtration rate (GFR) for the pediatric population. Sotalol is cleared predominantly by the kidney. The current model estimated renal clearance as the product of fraction unbound in plasma (fup) and GFR, thus automatically calculating the renal clearance in different pediatric subjects. The S+ Sotalol Model was also used to predict sotalol PK in pregnant subjects when administered both as an IV injection and immediate-release tablet [3]. The study reported Cp-time data both during pregnancy and in the postnatal condition. Pregnancy is marked by an increase in GFR, which can be estimated from serum creatinine concentration using a variety of widely accepted correlations [4-5]. Sims et al. [6] reported serum creatinine concentrations during pregnancy and postnatal periods. This data was used to obtain the ratio of GFR in normal and pregnant females using the Modified Diet in Renal Disease (MDRD) formula [4]. This ratio was then used to scale the GFR (original prediction from the default PEAR physiology) for the female population described in [3] and to predict Cptime profiles for both IV and oral doses with no other parameter changes. Finally, the 5+ Sotalol Model was used to predict sotalol PK in patients with end-stage renal failure [7], characterized by a GFR less than 15 ml/min [5]. As in the other validation examples presented above, no adjustments were made to the biopharmaceutical properties and only the physiology was scaled to represent the given population.
American Association of Pharmaceutical Scientists (AAPS), October 23-27, 2011, Washington, D.C.
By S. Ray Chaudhuri, Viera Lukacova, Walter S. Woltosz