Mariana Pereira1,2,3, Dr. Nuno Vale1,2,4
1PerMed Research Group, Center for Health Technology and Services Research (CINTESIS), 2RISE-Health, Department of Pathology, Faculty of Medicine, University of Porto, 3ICBAS—School of Medicine and Biomedical Sciences, University of Porto, 4 Laboratory of Personalized Medicine, Department of Community Medicine, Health Information and Decision (MEDCIDS), Faculty of Medicine, University of Porto
Objective: Drug repurposing is gaining attention in cancer therapy development by using safe, approved drugs, speeding up development and reducing costs [1]. Efavirenz (EFV), etravirine (ETV), and saquinavir (SAQ) are antiretroviral drugs approved for HIV treatment [2–4] and have shown potential for other diseases [5]. Our group has demonstrated their anti-cancer effects in vitro [6,7]. This study aims to develop and compare physiologically based pharmacokinetic (PBPK) models for ETV, EFV, and SAQ under conditions simulating prostate cancer. Models of healthy and cancerous prostate tissue will be created. These will be applied to different population profiles to assess the influence of age and weight on drug pharmacokinetics in prostate cancer. The primary goal of this study was to investigate whether the pharmacokinetics of EFV, ETV, and SAQ, at their standard, approved dosages, are altered when a prostate cancer compartment is introduced into the PBPK model, and whether these changes are further influenced by physiological variations such as age and body weight. Methods: Literature data and ADMET Predictor® (v11) parameters were used to build a validated ETV model in GastroPlus® (v9.8.3; Simulation Plus Inc., Lancaster, CA, USA) at 200 mg BID. A validated EFV model at 400 mg QD was already included in the software. SAQ (600 mg QD) simulations used a model from Lukacova et al. 2011 [8]. To mimic prostate cancer physiology, various “ReproOrg” tissue parameters were adjusted: volume, blood flow, leakage, partition coefficients, and fractions of neutral lipids, phospholipids, water, and acidic phospholipids—based on literature data. PEAR (Population Estimates for Age-Related Physiology) models were generated in addition to the default American male (30 years, 70 kg), including older (65 years) and heavier (95 kg) profiles, as age and obesity are prostate cancer risk factors. Results: PBPK modeling showed that age and body weight impact plasma concentrations. For EFV, maximum plasma concentrations (Cmax) ranked: 65y/70kg (1.696 µg/mL) > 30y/70kg (1.591) > 65y/95kg (1.286) > 30y/95kg (1.239). Older and lighter individuals exhibited higher EFV concentrations. Obese individuals had lower EFV levels, consistent with prior simulations [9]. Aging is also linked to reduced hepatic metabolism, especially for drugs processed by CYP2B6 and CYP3A4 [10]. ETV showed similar trends. Individuals at 70 kg had the highest Cmax (~0.328 µg/mL), regardless of age. In 95 kg models, older individuals had slightly higher Cmax (0.265 vs. 0.255). Prior studies showed ETV exposure drops ~20% in obese virtual patients [11]. For SAQ, Cmax ranked: 30y/70kg (12.498 µg/mL) > 65y/70kg (11.727) > 65y/95kg (11.546) > 30y/95kg (10.173). A higher Cmax in younger patients suggests that age may affect absorption and distribution. Clearance decreases with age, possibly explaining this trend [12]. Obesity also lowers SAQ concentrations [13]. However, AUC0-T was highest for the 65y/95kg model (60.145 µg·h/mL), versus 56.843 in the 30y/70kg model. This suggests younger individuals absorb SAQ faster (higher Cmax), but clear it faster too, while older individuals maintain levels longer [12]. Between normal and cancerous prostate models, no meaningful differences in pharmacokinetics were observed for any drug across physiologies. This suggests prostate-specific changes have minimal whole-body pharmacokinetic impact. Since these drugs are primarily metabolized hepatically and excreted via feces [2–4], prostate alterations don’t significantly influence drug disposition. Thus, age and weight should be prioritized when considering dosing for prostate cancer patients receiving repurposed antiretrovirals. Conclusions: This study highlights that prostate-specific tissue alterations do not significantly affect the pharmacokinetics of ETV, EFV, or SAQ. However, patient-specific factors, especially age and weight, play a substantial role. These should be carefully considered when repurposing these agents for prostate cancer, as elderly or obese patients may require individualized dosing to ensure efficacy and minimize toxicity.
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Reference: PAGE 33 (2025) Abstr 11622 [www.page-meeting.org/?abstract=11622]
Poster: Drug/Disease Modelling - Oncology