A variety of marketed drugs belonging to various therapeutic classes are known to cause nephrotoxicity. Nephrotoxicity can manifest itself in several forms depending on the specific site involved as well as the underlying pathophysiological mechanisms. As they often coexist with other pathophysiological conditions, the steps that can be taken to treat them are often limited. Thus, drug-induced nephrotoxicity remains a major clinical challenge. Prior knowledge of risk factors associated with special patient populations and specific classes of drugs, combined with early diagnosis, therapeutic drug monitoring with dose adjustments, as well as timely prospective treatments are essential to prevent and manage them better. Most incident drug-induced renal toxicity is reversible only if diagnosed at an early stage and treated promptly. Hence, diagnosis at an early stage is the need of the hour to counter it. Significant recent advances in the identification of novel early biomarkers of nephrotoxicity are not beyond limitations. In such a scenario, mathematical modeling and simulation (M&S) approaches may help to better understand and predict toxicities in a clinical setting. This review summarizes pathophysiological mechanisms of drug-induced nephrotoxicity, classes of nephrotoxic drugs, management, prevention, and diagnosis in clinics. Finally, it also highlights some of the recent advancements in mathematical M&S approaches that could be used to better understand and predict drug-induced nephrotoxicity.

Background Doxorubicin (DOX) and its pegylated liposomal formulation (L_DOX) are the standard of care for triple-negative breast cancer (TNBC). However, resistance to DOX often occurs, motivating the search for alternative treatment approaches. The retinoblastoma protein (Rb) is a potential pharmacological target for TNBC treatment since its expression has been associated with resistance to DOX-based therapy. Methods DOX (0.01–20 μM) combination with abemaciclib (ABE, 1–6 μM) was evaluated over 72 hours on Rb-positive (MDA-MB-231) and Rb-negative (MDA-MB-468) TNBC cells. Combination indices (CI) for DOX+ABE were calculated using Compusyn software. The TNBC cell viability time-course and fold-change from the control of phosphorylated-Rb (pRb) protein expression were measured with CCK8-kit and enzyme-linked immunosorbent assay. A cell-based pharmacodynamic (PD) model was developed, where pRb protein dynamics drove cell viability response. Clinical pharmacokinetic (PK) models for DOX, L_DOX, and ABE were developed using data extracted from the literature. After scaling cancer cell growth to clinical TNBC tumor growth, the time-to-tumor progression (TTP) was predicted for human dosing regimens of DOX, ABE, and DOX+ABE. Results DOX and ABE combinations were synergistic (CI<1) in MDA-MB-231 and antagonistic (CI>1) in MDA-MB-468. The maximum inhibitory effects (Imax) for both drugs were set to one. The drug concentrations producing 50% of Imax for DOX and ABE were 0.565 and 2.31 μM (MDA-MB-231) and 0.121 and 1.61 μM (MDA-MB-468). The first-orders rate constants of abemaciclib absorption (k a ) and doxorubicin release from L_DOX (k Rel ) were estimated at 0.31 and 0.013 h −1 . Their linear clearances were 21.7 (ABE) and 32.1 L/h (DOX). The estimated TTP for intravenous DOX (75 mg/m2 every 21 days), intravenous L_DOX (50 mg/m 2 every 28 days), and oral ABE (200 mg twice a day) were 125, 31.2, and 8.6 days shorter than drug-free control. The TTP for DOX+ABE and L_DOX+ABE were 312 days and 47.5 days shorter than control, both larger than single-agent DOX, suggesting improved activity with the DOX+ABE combination. Conclusion The developed translational systems-based PK/PD model provides an in vitro-to-clinic modeling platform for DOX+ABE in TNBC. Although model-based simulations suggest improved outcomes with combination over monotherapy, tumor relapse was not prevented with the combination. Hence, DOX+ABE may not be an effective treatment combination for TNBC.

Background Triple‐negative breast cancer (TNBC) is a breast cancer (BC) subtype that lacks the three hallmark BC receptors: estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. The retinoblastoma protein (Rb) is a potential pharmacological target for TNBC therapy. Its over‐expression in TNBC cells is associated with increased resistance to doxorubicin (DOX) treatment in this BC patient population. Methods The drug‐drug interaction (DDI) between DOX (0.01–20 μM) and the CDK4/6 inhibitor, abemaciclib (ABE, 1–6 μM), was examined on TNBC cells that are Rb‐positive (MDA‐MB‐231) and Rb‐negative (MDA‐MB‐468) over a time span exposure of 72 hours. The DDI was quantified for all examined drugs’ concentrations by calculating combination indices (CI) using Compusyn software. Temporal changes in %cell viability were measured using CCK‐8 assay. The fold‐change from control (untreated) and from baseline (time=0) of phosphorylated‐Rb proteins (pRb) were measured using a commercially available ELISA kit. An in vitro pharmacodynamic (PD) model was developed by linking pRb dynamics to temporal changes in %cell viability. Clinical pharmacokinetic (PK) models capturing clinical data extracted from the literature were linked to the developed PD model. A clinically scaled‐up PK/PD model was used to simulate the time‐to‐tumor progression (TTP) as defined by the RECIST and WHO criteria for optimized human dosing regimens of both drugs in combination. Results The combination DOX+ABE is synergistic in MDA‐MB‐231 (CI<1) and antagonistic in MDA‐MB‐468 (CI>1). The potencies (maximum inhibitory effects, Imax) for both drugs were fixed to 1. The estimated sensitivities (IC50, concentrations producing 50% of Imax) were 0.565 (DOX) and 3.23 μM (ABE) for MDA‐MB‐231 and 0.121 (DOX) and 2.03 μM (ABE) for MDA‐MB‐468. Model‐based simulations over 60 days treatment period with DOX (75 mg/m2, intravenous, every 21 days) and ABE (200 mg, oral, twice a day) predicted TTP of 0.5 (DOX) and 6.2 days (ABE) shorter compared to control. Paradoxically, TTP for DOX+ABE was 1.1 days shorter than control suggesting DOX antagonizing ABE effects. Conclusion The developed translational and systems‐based PK/PD model for DOX and ABE combinatorial effects in Rb‐positive TNBC captured well all observed data (in vitro and clinical). While in vitro experiments in MDA‐MB‐231 cells suggest synergistic DDI for DOX and ABE, model‐based predictions of clinical TTP in Rb‐positive TNBC patients suggest a reduced TTP. Further clinical investigations to support model predictions are warranted. Support or Funding Information This work was supported by the American Foundation for Pharmaceutical Education (AFPE).