Model‐based meta‐analysis of the time to first acute urinary retention or benign prostatic hyperplasia‐related surgery in patients with moderate or severe symptoms

Abstract

Aims: Combination therapy of 5α-reductase inhibitor and α-blocker is a guidelineendorsed therapeutic approach for patients with moderate-to-severe lower urinary tract symptoms or benign prostatic hyperplasia (LUTS/BPH) who are at risk of disease progression. We aimed to disentangle the contribution of clinical and demographic baseline characteristics affecting the risk of acute urinary retention or BPH-related surgery (AUR/S) from the effect of treatment with drugs showing symptomatic and disease-modifying properties. Methods: A time-to-event model was developed using pooled data from patients (n = 10 238) enrolled into six clinical studies receiving placebo, tamsulosin, dutasteride or tamsulosin-dutasteride combination therapy. A parametric hazard function was used to describe the time to first AUR/S. Covariate model building included the assessment of relevant clinical and demographic factors on baseline hazard. Predictive performance was evaluated by graphical and statistical methods.Results: An exponential hazard model best described the time to first AUR/S in this group of patients. Baseline International Prostate Symptom Score, prostate-specific antigen, prostate volume and maximum urine flow were identified as covariates with hazard ratio estimates of 1.04, 1.08, 1.01 and 0.91, respectively. Dutasteride monotherapy and tamsulosin-dutasteride combination therapy resulted in a significant reduction in the baseline hazard (56.8% and 66.4%, respectively). By contrast, the effect of tamsulosin did not differ from placebo.Conclusions: Our analysis showed the implications of disease-modifying properties of dutasteride and tamsulosin-dutasteride combination therapy for the risk of AUR/S. It also elucidated the contribution of different baseline characteristics to the risk of these events. The use of tamsulosin monotherapy (symptomatic treatment) has no impact on individual long-term risk.

Applications of Model-Based Meta-Analysis in Drug Development

“…Additional collaborations are also possible with the health economics and outcomes research (HEOR) function, with which outputs from the MBMA could be integrated into other, non-clinically focused models, such as cost-effectiveness models or financial forecasting models, potentially leading to improved commercial and financial strategies [45]. Therefore, continued education and communication among project stakeholders, team collaborators, and [19,[107][108][109][110] Correlation between early and late endpoints Allow the use of a biomarker or an early clinical efficacy time point to detect a signal of the treatment effect [38,42,63,111] Pharmacokinetic and pharmacodynamic relationship Establishing the relationship between exposure and an efficacy or safety biomarker, possibly a less frequently reported one and would need data from a large population to be detected [41,[112][113][114][115][116][117] Simulation of established MBMA models Simulate various scenarios using established MBMA models to optimize clinical trial design [62,118] Pharmacoeconomics Incorporate cost-effectiveness into a MBMA model [119] other pharmacometric specialty experts regarding MBMA and MIDD approaches in general are warranted [1]. Another important ally of MIDD approaches is from statistics.…”

Characterisation of individual ferritin response in patients receiving chelation therapy

“…Whereas significant interindividual differences exist in the time course of serum ferritin concentrations relative to the start of chelation therapy, it is striking that so little has happened to date to establish how baseline characteristics, transfusion blood volume and chelation determines such differences 7,47 . Similar approaches have been developed successfully in other therapeutic areas 48–54 . For instance, compartmental models have been developed for antidiabetic drugs where the delay in response and impact of disease progression were characterised and subsequently used to assess the need to adjust therapy in Type 2 diabetes mellitus (T2DM) 50 .…”

“…7,47 Similar approaches have been developed successfully in other therapeutic areas. [48][49][50][51][52][53][54] For instance, compartmental models have been developed for antidiabetic drugs where the delay in response and impact of disease progression were characterised and subsequently used to assess the need to adjust therapy in Type 2 diabetes mellitus (T2DM). 50 More recently, an integrated glucose-insulin model was successfully applied to evaluate the differences between T2DM patients across a wide range of glycaemic control.…”

Impact of early vs. delayed initiation of dutasteride/tamsulosin combination therapy on the risk of acute urinary retention or BPH-related surgery in LUTS/BPH patients with moderate-to-severe symptoms at risk of disease progression

“…Final parameters of the TTE model previously developed by D'Agate et al [24] (Table S4) were used for the implementation of the simulation scenarios, which assess the potential implications of the delayed start of treatment with dutasteride and tamsulosin CT. Transition to CT was based on symptom improvement less than 25% or deterioration, as assessed by changes in IPSS relative to baseline [21].…”

“…Using a cohort of patients with baseline characteristics comparable to those enrolled in previous clinical trials, the incidence and time to first episode of acute urinary retention or BPH-related surgery (AUR/S) was assessed for a range of scenarios, including immediate and delayed initiation of treatment with CT. The analysis is based on a time-to-event (TTE) model that describes the time to first AUR/S, taking into account the potential effect of baseline covariate factors [24].…”