A Multiscale, Mechanism-Driven, Dynamic Model for the Effects of 5α-Reductase Inhibition on Prostate Maintenance

Abstract

A systems-level mathematical model is presented that describes the effects of inhibiting the enzyme 5α-reductase (5aR) on the ventral prostate of the adult male rat under chronic administration of the 5aR inhibitor, finasteride. 5aR is essential for androgen regulation in males, both in normal conditions and disease states. The hormone kinetics and downstream effects on reproductive organs associated with perturbing androgen regulation are complex and not necessarily intuitive. Inhibition of 5aR decreases the metabolism of testosterone (T) to the potent androgen 5α-dihydrotestosterone (DHT). This results in decreased cell proliferation, fluid production and 5aR expression as well as increased apoptosis in the ventral prostate. These regulatory changes collectively result in decreased prostate size and function, which can be beneficial to men suffering from benign prostatic hyperplasia (BPH) and could play a role in prostate cancer. There are two distinct isoforms of 5aR in male humans and rats, and thus developing a 5aR inhibitor is a challenging pursuit. Several inhibitors are on the market for treatment of BPH, including finasteride and dutasteride. In this effort, comparisons of simulated vs. experimental T and DHT levels and prostate size are depicted, demonstrating the model accurately described an approximate 77% decrease in prostate size and nearly complete depletion of prostatic DHT following 21 days of daily finasteride dosing in rats. This implies T alone is not capable of maintaining a normal prostate size. Further model analysis suggests the possibility of alternative dosing strategies resulting in similar or greater effects on prostate size, due to complex kinetics between T, DHT and gene occupancy. With appropriate scaling and parameterization for humans, this model provides a multiscale modeling platform for drug discovery teams to test and generate hypotheses about drugging strategies for indications like BPH and prostate cancer, such as compound binding properties, dosing regimens, and target validation.

A Mechanistic, Multiscale Mathematical Model of Immunogenicity for Therapeutic Proteins: Part 1—Theoretical Model

“…Control coefficients are used as indicators for sensitivity. The control coefficients of variable x to parameter p () were calculated using the following equation 34 , 35 : …”

Towards a non-animal risk assessment for anti-androgenic effects in humans

“…or adverse effects that only occur at exposures far in excess of those experienced by humans are arguably of no relevance to consumer safety risk assessment. Some attempts have been made to use in vitro data to predict anti-androgenic effects in experimental animals (Barton and Andersen, 1998;Potter et al, 2006;Clewell et al, 2010;Zager and Barton, 2012;Taxvig et al, 2013). However, to date no framework has been proposed for putting anti-androgenic effects seen in vitro into a human-relevant context using exposure information.…”

“…The effects that a competitive AR ligand may have upon the levels of these hormones can be modelled using such an approach. This initial limited model was subsequently refined to include the effects of 5α-R on prostate regulation in adult rats (Potter et al, 2006;Zager and Barton, 2012). This refined model allowed accurate recapitulation of experimental data showing the approximate 77% decrease in prostate size and almost total depletion of prostatic DHT following the daily administration of finasteride to rats for 21 days.…”

A Mathematical Model of the Effect of Immunogenicity on Therapeutic Protein Pharmacokinetics

“…Control coefficients of variable x to parameter p (CC p x ) were calculated using the following equation (38,39):…”

“…The step size h was chosen as: h=1%⋅p, because 1% increase in the value of p has been shown to be the most numerically stable quantity of variation for this type of sensitivity calculation (38). A positive CC p x suggests the parameter increase results in an increase in x value.…”