CPT Pharmacometrics & Systems Pharmacology

ABSTRACT Many currently approved gene therapies use adeno‐associated virus (AAV) to deliver DNA sequences encoding protein(s)‐of‐interest into cells. The AAV viral genome forms stable, circular DNA structures called episomes after entering the nuclei. Therapeutic proteins are then generated in vivo from transcription and translation of these episomes, and long‐term durability thus depends on epis…

Although time-varying Cox regression modeling approaches have been developed, exposure-response analyses for time-to-event (TTE) endpoints often rely on static exposure covariates and may overlook the real-world dosing variability and drug concentration fluctuations over time. To better characterize pharmacokinetic (PK) or pharmacodynamic (PD) effects on TTE endpoints, a methodology was proposed …

Model-informed drug development (MIDD) has an important role to play at various stages of drug development. In this case study, the application of MIDD in the early clinical development of a small-molecule inhibitor of sickle hemoglobin (Hb) polymerization is highlighted. Starting from the setting of quantitative criteria, to using a combination of PKPD and semi-mechanistic RBC modeling, and key …

This review examines the application of machine learning (ML) in physiologically based pharmacokinetic (PBPK) modeling through improved prediction of input parameters, particularly via quantitative structure-activity relationship (QSAR) models, for absorption, distribution, metabolism, and excretion (ADME) properties across drug development phases. Traditional PBPK models, while mechanistically s…

Azathioprine (AZA), a widely used immunosuppressant, can induce acute pancreatitis (AP), yet the underlying molecular mechanisms remain unclear. This study employed an integrative multiomics strategy-combining network toxicology, machine learning, Mendelian randomization (MR), and molecular docking-to elucidate the biological basis of AZA-induced AP. AZA-associated genes were first identified thr…

Exposure-response (ER) analyses of repeated time-to-event (RTTE) data can be confounded when treatment modifications occur due to the event of interest. One particularly challenging scenario is when an event is preceded by an undocumented clinical worsening leading to treatment discontinuation shortly before the event. Event-related treatment modifications introduce potential reversed causality i…

Covariate modeling provides individual predictions of outcomes by disease progression models. Current methodology for mapping covariates onto model parameters is limited by predefined parametric functions which can result in inadequate covariate selection and biased predictions by the final model. Furthermore, present methodology scales poorly to high-dimensional data due to combinatorial limitat…

Vixarelimab is a first-in-class fully human monoclonal antibody targeting oncostatin M (OSM) receptor beta (OSMRβ). It has been evaluated in Phase 1 and 2 studies in healthy volunteers and patients with chronic pruritic conditions and demonstrated anti-pruritic efficacy in a Phase 2 study in prurigo nodularis, but detailed pharmacokinetic analysis has not been previously reported. In this study, …

The field of Quantitative Systems Pharmacology continues to innovate new methods to derive insights from clinical data. In the past few years, Digital Twins have emerged as a "new" way of deriving patient-specific model parameterizations to inform possible outcomes for novel scenarios using limited clinical data. Here, we explore the meaning of Digital Twins for QSP, its relationship with definit…

Quantitative systems pharmacology (QSP) models have emerged as useful tools for evaluating the efficacy of Alzheimer's disease (AD) therapies. Bringing together a clinical focus with the mechanistic detail of systems biology, QSP models are well suited to the complexity of AD and have been used to predict treatment outcomes and support regulatory submissions. Therapies targeting the amyloid pathw…

The use of exposure-response (E-R) analysis to support drug development and treatment individualization requires estimating the causal effect of drug exposure on response. This may be challenging when the E-R relationship is confounded. This perspective examines the problem of confounding in E-R analyses in oncology through the lens of causal inference, demonstrating how a causal directed acyclic…

Danicopan is a first-in-class orally administered complement factor D inhibitor, approved as an add-on therapy to ravulizumab or eculizumab for the treatment of clinically significant extravascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria (PNH). Population pharmacokinetics (PK) and pharmacodynamics (PK-PD) modeling was used to characterize danicopan PK and to evaluate the re…

Telisotuzumab vedotin (Teliso-V) is a c-Met-directed antibody-drug conjugate that delivers a cytotoxic microtubule inhibitor monomethyl auristatin E (MMAE) payload to c-Met-expressing tumor cells. It received accelerated approval from the US FDA for the treatment of adults with locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) with high c-Met protein overexpression (≥…

Population pharmacokinetic-pharmacodynamic (PK-PD) modeling was used to explore covariate effects on zolpidem PKs and PDs in 30 healthy Korean volunteers (15 males, 15 females) who received a single 10 mg dose. The dataset included 325 PK observations and 388 observations each for the digit symbol substitution test (DSST), choice reaction time (CRT), and visual analog scale (VAS). A one-compartme…

In hematological malignancies, thrombocytopenia is a frequent feature of the disease. Anti-leukemic therapies are known to impact thrombocytopenia, which is commonly selected as a dose-limiting toxicity in early clinical trials. However, given the concurrent myelosuppressive effects of the drug and the underlying leukemia, it can be difficult to differentiate whether the dose of the investigation…

Model-informed drug development (MIDD) framework was employed to bridge sugemalimab dosing from an Asian population to European patients with non-small cell lung cancer. We evaluated whether a fixed dose of 1200 mg every 3 weeks (Q3W) provides adequate exposure for European patients and, if not, which weight threshold and alternative dose would restore pivotal-trial exposures and projected benefi…

Despite the fact that modeling and simulation are now recognized as promising innovative methodologies, their use in the context of development of drugs for sickle cell disease and Thalassemia has not yet been reviewed. Considering the challenges of conducting clinical trials for hemoglobinopathies, our work aims at exploring the current status of use of modeling and simulation by drug developers…

Hyperbilirubinemia, characterized by elevated total blood bilirubin levels including both unconjugated and conjugated forms, serves as a diagnostic marker for drug-induced liver toxicity associated with a wide range of medications. This study aimed to develop a mechanistic model for assessing hyperbilirubinemia risk using genetic markers. We developed an ordinary differential equation (ODE)-based…

Systemic sclerosis (SSc) is a complex autoimmune disorder characterized by extensive fibrosis, vascular abnormalities, and immune dysregulation, affecting clinical outcomes such as skin thickness and pulmonary function with high mortality rates. B cells play a pivotal role in the pathogenesis of SSc. This study aimed to develop a systems model for B cell differentiation and tissue distribution to…

Paracetamol (PCM) is extensively metabolized in the liver via glucuronidation, sulfation, and oxidation. Although oral and intravenous PCM are commonly used interchangeably, a comprehensive evaluation of PCM metabolism across both routes is lacking. This study aimed to characterize the full pharmacokinetic (PK) profiles of PCM and its metabolites following oral and intravenous administration, acc…