Journal of Pharmacokinetics and Pharmacodynamics

The paper extended the TMDD model to drugs with more than two (N > 2) identical binding sites (N-to-one TMDD). The quasi-steady-state (N-to-one QSS), quasi-equilibrium (N-to-one QE), irreversible binding (N-to-one IB), and Michaelis-Menten (N-to-one MM) approximations of the model were derived. To illustrate properties of new equations and approximations, N = 4 case was investigated numerically. Using simulations, the N-to-one QSS approximation was compared with the full N-to-one TMDD model...

Polymyxin B (PMB) is considered a last-line treatment for multidrug-resistant (MDR) gram-negative bacterial infections. Model-informed precision dosing with population pharmacokinetics (PopPK) models could help to individualize PMB dosing regimens and improve therapy. However, the external prediction ability of the established PopPK models has not been fully elaborated. This study aimed to systemically evaluate eleven PMB PopPK models from ten published literature based on a new independent population, which was divided into four different populations, patients with liver dysfunction, kidney dysfunction, liver and kidney dysfunction, and normal liver and kidney function...

The study aimed to provide quantitative information on the utilization of MRI transverse relaxation time constant (MRI-T2 ) of leg muscles in DMD clinical trials by developing multivariate disease progression models of Duchenne muscular dystrophy (DMD) using 6-min walk distance (6MWD) and MRI-T2 . Clinical data were collected from the prospective and longitudinal ImagingNMD study. Disease progression models were developed by a nonlinear mixed-effect modeling approach. Univariate models of 6MWD and MRI-T2 of five muscles were developed separately...

Covariate analysis in population pharmacokinetics is key for adjusting doses for patients. The main objective of this work was to compare the adequacy of various modeling approaches on covariate clinical relevance decision-making. The full model, stepwise covariate model (SCM) and SCM+ PsN algorithms were compared in a clinical trial simulation of a 383-patient population pharmacokinetic study mixing rich and sparse designs. A one-compartment model with first-order absorption was used. A base model including a body weight effect on CL/F and V/F and a covariate model including 4 additional covariates-parameters relationships were simulated...

The objective of this study was to compare the effectiveness of subcutaneous (SC) and sublingual (SL) formulations of apomorphine for the treatment of motor fluctuations in Parkinson's disease using a pharmacokinetics (PK)/pharmacodynamics (PD) modeling approach. The PK of SC and SL apomorphine are best described by a one-compartment model with first-order absorption and a two-compartment model with delayed absorption, respectively. The PK/PD model relating apomorphine plasma concentrations to the Unified Parkinson's Disease Rating Scale (UPDRS) motor scores was described by a sigmoidal Emax model assuming effective concentration = drug concentration in an effect compartment...

The new adjuvant chemotherapy of docetaxel, epirubicin, and cyclophosphamide has been recommended for treating breast cancer. It is necessary to investigate the potential drug-drug Interactions (DDIs) since they have a narrow therapeutic window in which slight differences in exposure might result in significant differences in treatment efficacy and tolerability. To guide clinical rational drug use, this study aimed to evaluate the DDI potentials of docetaxel, cyclophosphamide, and epirubicin in cancer patients using physiologically based pharmacokinetic (PBPK) models...

Belimumab was approved for active lupus nephritis (LN) in adults in the European Union and patients ≥ 5 years of age in the USA based on a Phase 3, double-blind, placebo-controlled, 104-week study. The study evaluated the efficacy of belimumab plus background standard therapy in adults with active LN using an intravenous (IV) dose of 10 mg/kg. A longitudinal analysis of Primary Efficacy Renal Response (PERR) and Complete Renal Response (CRR) was performed to assess whether patients with high proteinuria at the start of belimumab treatment would benefit from a higher dose...

Conventional pharmacokinetic (PK) models contain several useful inductive biases guiding model convergence to more realistic predictions of drug concentrations. Implementing similar biases in standard neural networks can be challenging, but might be fundamental for model robustness and predictive performance. In this study, we build on the deep compartment model (DCM) architecture by introducing constraints that guide the model to explore more physiologically realistic solutions. Using a simulation study, we show that constraints improve robustness in sparse data settings...

Dose personalization improves patient outcomes for many drugs with a narrow therapeutic index and high inter-individuality variability, including busulfan. Non-compartmental analysis (NCA) and model-based methods like maximum a posteriori Bayesian (MAP) approaches are two methods routinely used for dose optimization. These approaches vary in how they estimate patient-specific pharmacokinetic parameters to inform a dose and the impact of these differences is not well-understood. Using busulfan as an example application and area under the concentration-time curve (AUC) as a target exposure metric, these estimation methods were compared using retrospective patient data (N = 246) and simulated precision dosing treatment courses...

UNLABELLED: The development of optimized dosing regimens plays a crucial role in oncology drug development. This study focused on the population pharmacokinetic modelling and simulation of docetaxel, comparing the pharmacokinetic exposure of oral docetaxel plus encequidar (oDox + E) with the standard of care intravenous (IV) docetaxel regimen. The aim was to evaluate the feasibility of oDox + E as a potential alternative to IV docetaxel. The article demonstrates an approach which aligns with the FDA's Project Optimus which aims to improve oncology drug development through model informed drug development (MIDD)...

Non-Small Cell Lung Cancer (NSCLC) remains one of the main causes of cancer death worldwide. In the urge of finding an effective approach to treat cancer, enormous therapeutic targets and treatment combinations are explored in clinical studies, which are not only costly, suffer from a shortage of participants, but also unable to explore all prospective therapeutic solutions. Within the evolving therapeutic landscape, the combined use of radiotherapy (RT) and checkpoint inhibitors (ICIs) emerged as a promising avenue...

2023 marks the 10th anniversary of Natpara's submission to the US FDA, which led to the first recorded regulatory interaction where a decision was supported by Quantitative and Systems Pharmacology (QSP) simulations. It had taken about 5 years for the timid QSP discipline to emerge as an effective Model-Informed Drug Development (MIDD) tool with visible impact in the pharmaceutical industry. Since then, the presence of QSP in the regulatory environment has continued to increase, to the point that the Agency reported 60 QSP submissions in 2020 alone, representing ~ 4% of their annual IND submissions [1]...

Brepocitinib is an oral selective dual TYK2/JAK1 inhibitor and based on its cytokine inhibition profile is expected to provide therapeutic benefit in the treatment of plaque psoriasis. Efficacy data from a completed Phase 2a study in patients with moderate-to-severe plaque psoriasis were utilized to develop a population exposure-response model that can be employed to inform dose selection decisions for further clinical development. A modeling approach that employs the zero-inflated beta distribution was used to account for the bounded nature and distributional characteristics of the Psoriasis Area and Severity Index (PASI) score data...

No abstract text is available yet for this article.

Protein therapeutics have revolutionized the treatment of a wide range of diseases. While they have distinct physicochemical characteristics that influence their absorption, distribution, metabolism, and excretion (ADME) properties, the relationship between the physicochemical properties and PK is still largely unknown. In this work we present a minimal physiologically-based pharmacokinetic (mPBPK) model that incorporates a multivariate quantitative relation between a therapeutic's physicochemical parameters and its corresponding ADME properties...

Currently, model-informed precision dosing uses one population pharmacokinetic model that best fits the target population. We aimed to develop a subgroup identification-based model selection approach to improve the predictive performance of individualized dosing, using vancomycin in neonates/infants as a test case. Data from neonates/infants with at least one vancomycin concentration was randomly divided into training and test dataset. Population predictions from published vancomycin population pharmacokinetic models were calculated...

No abstract text is available yet for this article.

Aprocitentan is a novel, potent, dual endothelin receptor antagonist that recently demonstrated efficacy in the treatment of difficult-to-treat (resistant) hypertension. The aim of this study was to develop a population pharmacokinetic (PK) model describing aprocitentan plasma concentration over time, to investigate relationships between subject-specific factors (covariates) and model parameters, and to quantify the influence of the identified covariates on the exposure to aprocitentan via model-based simulations, enabling judgment about the clinical relevance of the covariates...

Balovaptan is a brain-penetrating vasopressin receptor 1a antagonist previously investigated for the core symptoms of autism spectrum disorder (ASD). A population pharmacokinetic (PK) model of balovaptan was developed, initially to assist clinical dosing for adult and pediatric ASD studies and subsequently for new clinical indications including malignant cerebral edema (MCE) and post-traumatic stress disorder. The final model incorporates one-compartment disposition and describes time- and dose-dependent non-linear PK through empirical drug binding and a gut extraction component with turnover...

Nifekalant hydrochloride is a class III antiarrhythmic agent which could increase the duration of the action potential and the effective refractory period of ventricular and atrial myocytes by blocking the K+ current. Nifekalant is used to prevent ventricular tachycardia/ventricular fibrillation. QT interval prolongation is the main measurable drug effect. However, due to the complicated dosing plan in clinic, the relationship among dosage, time, drug concentration and efficacy is not fully understood...