The International Prostate Symptom Score (IPSS), the quality of life (QoL) score, and the benign prostatic hyperplasia impact index (BII) are three different scales commonly used to assess the severity of lower urinary tract symptoms associated with benign prostatic hyperplasia (BPH-LUTS). Based on a phase II clinical trial including 403 patients with moderate to severe BPH-LUTS, the objectives of this study were to (i) develop traditional pharmacometric and bounded integer (BI) models for the IPSS, QoL score, and BII endpoints, respectively; (ii) compare the power and type I error in detecting drug effects of BI modeling with traditional methods through simulation; and (iii) obtain quantitative translation between scores on the three abovementioned scales using a BI modeling framework. All developed models described the data adequately. Pharmacometric modeling using a continuous variable (CV) approach was overall found to be the most robust in terms of type I error and power to detect a drug effect. In most cases, BI modeling showed similar performance to the CV approach, yet severely inflated type I error was generally observed when inter-individual variability (IIV) was incorporated in the BI variance function (g()). BI modeling without IIV in g() showed greater type I error control compared to the ordered categorical approach. Lastly, a multiple-scale BI model was developed and estimated the relationship between scores on the three BPH-LUTS scales with overall low uncertainty. The current study yields greater understanding of the operating characteristics of the novel BI modeling approach and highlights areas potentially requiring further improvement.
The AAPS journal. 2021 Feb 25*** epublish ***
Yassine Kamal Lyauk, Daniël M Jonker, Andrew C Hooker, Trine Meldgaard Lund, Mats O Karlsson
Translational Medicine, Ferring Pharmaceuticals A/S, Kay Fiskers Plads, 11, Copenhagen, Denmark. ., Translational Medicine, Ferring Pharmaceuticals A/S, Kay Fiskers Plads, 11, Copenhagen, Denmark., Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden., Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.