ABSTRACT CAR‐T therapy has improved outcomes in selected relapsed or refractory hematologic malignancies. However, rational dose‐relevant decision application remains challenging because the administered (nominal) cell dose does not reliably predict in vivo exposure, toxicity, or clinical response. These relationships are not adequately characterized by empirical dose escalation alone. Mechanistic modeling may offer a biologically interpretable way to connect preclinical evidence and patient‐level CAR‐T posology, but its application remains incompletely defined. We conducted a systematic scoping review using JBI methodology and PRISMA‐ScR guidance, searching MEDLINE, Embase, Scopus, and Google Scholar (2010–2025). Eligible studies reported original CK/PD, PK/PD, QSP, PBPK/PD, stochastic, or agent‐based models for dose‐relevant application or regimen optimization. Nineteen studies met the inclusion criteria (13 mechanistic and 6 semi‐mechanistic models) spanning hematologic and solid‐tumor settings. Although these studies evaluated aspects of CAR‐T pharmacology, none provided prospectively validated clinical dose‐selection evidence. Overall, CAR‐T expansion appeared to be more influenced by tumor burden, antigen engagement, product‐specific attributes, lymphodepletion, and host or tumor‐site factors than by nominal dose. Solid‐tumor models highlighted delivery route, trafficking, biodistribution, and microenvironment barriers. Emerging in vivo CAR‐T platforms shifted dose considerations toward vector or mRNA dose and repeat dosing. Mechanistic modeling appears useful for framing CAR‐T dose‐relevant and regimen questions, but the current evidence is best interpreted as a taxonomy of model applications rather than proof of prospective clinical dose selection utility. Consistent with ICH M15 principles, future clinical, and regulatory application will require defined context of use, stronger validation, uncertainty assessment, and biological integration.
ABSTRACT Digital health technologies (DHTs) can transform quantitative medicine by augmenting episodic clinical snapshots with longitudinal, more frequent measures of physiology, behavior, symptoms, and function, similar to going from photographs to movies. Their value depends not on collecting more data, but on integrating fit‐for‐purpose measurements, databases, data architecture, validation, and analytics. Properly implemented, DHTs and data integration across multiple, disparate databases can strengthen quantitative medicine and, more generally, therapeutic drug development and clinical decisions.
ABSTRACT Antibody‐drug conjugates (ADCs) are among the most pharmacologically complex therapeutics in clinical development. Their behavior emerges from the interplay of antibody disposition, linker stability, payload pharmacology, and host physiology—interdependencies that render qualitative descriptors such as “stronger affinity” or “more potent payload” insufficient for reliable prediction of preclinical and clinical outcomes. Despite growing investment in quantitative medicine across drug development, no unified framework exists to guide quantitative decision‐making across the ADC design–development–dose‐optimization continuum. In this review we survey how fit‐for‐purpose quantitative approaches inform decisions at each stage of the development path, built on multi‐analyte data pipelines that capture the coupled pharmacokinetics (PK) of antibody, linker‐payload, and released payload. We highlight the utility of PBPK‐driven (physiologically‐based pharmacokinetics) feasibility and mechanistic sensitivity analyses for candidate triage and allometric and mechanism‐based translation for human exposure predictions. We also present a stepwise construction of exposure–response relationships bridging preclinical and clinical data and integration of efficacy and safety into a clinical utility index for dose optimization. Throughout, we argue that the central challenge for quantitative ADC development is not the absence of sophisticated models, but the disciplined integration of fit‐for‐purpose approaches into the decisions that shape the development path. We synthesize these ideas in the proposition of a preclinical clinical utility index (pCUI) as an efficacious lens for model‐informed ADC development: an integrative benefit–risk framework expanding on the established clinical utility index (CUI) that quantitatively assesses whether a therapeutic window plausibly exists before first‐in‐human dosing.
ABSTRACT Treprostinil is a synthetic prostacyclin analogue with a tricyclic benzindene structure that confers markedly enhanced metabolic stability relative to native prostacyclin, enabling delivery by four distinct routes—intravenous, subcutaneous, inhaled, and oral—that together constitute a mainstay of pharmacotherapy for pulmonary arterial hypertension (PAH). Herein, we review the mechanism of action, pharmacokinetic/pharmacodynamic (PK/PD) characteristics, and clinical development of treprostinil, with primary emphasis on its well‐established role in PAH, including detailed dosing and PK data across all four approved routes, and secondary emphasis on its recently approved role in pulmonary hypertension associated with interstitial lung disease (PH‐ILD) and its investigational, plausible‐future role in idiopathic pulmonary fibrosis (IPF) without a pulmonary hypertension requirement. Treprostinil activates the Gαs‐coupled prostacyclin (IP) receptor to generate a sustained nuclear cyclic adenosine monophosphate (cAMP) signal that is qualitatively distinct from earlier prostacyclin analogues, underlying both its established vasodilatory, antiproliferative, and antiplatelet effects in PAH and a mechanistic hypothesis of antifibrotic activity relevant to IPF. Treprostinil also engages the prostaglandin EP₂ and DP₁ receptors and peroxisome proliferator‐activated receptors, and inhibits transforming growth factor‐β (TGF‐β)‐driven extracellular matrix synthesis through mechanisms only partially explained by cAMP magnitude. Across the four approved routes, treprostinil exhibits route‐specific pharmacokinetics—near‐complete subcutaneous bioavailability with a 4‐hour terminal half‐life, oral bioavailability of approximately 17% with extensive first‐pass CYP2C8 metabolism, and inhaled systemic bioavailability of approximately 64%–72%—that inform the distinct dosing and titration strategies detailed in this review. In a plausible, still‐investigational extension of this pharmacology beyond PAH, two replicate Phase 3 trials (TETON‐1 and TETON‐2) have reported that inhaled treprostinil reduces the decline in forced vital capacity (FVC) and the risk of clinical worsening in patients with IPF without a pulmonary hypertension requirement. These findings support a plausible antifibrotic hypothesis pending confirmatory evidence and regulatory review; treprostinil is not currently approved for an IPF indication, and this signal should be interpreted as hypothesis‐generating rather than establishing disease modification.
