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A formal assessment of the drug-drug interaction potential of any investigational drug product often requires multiple metabolic and pharmacokinetic evaluations. In contrast to a small-molecule drug, investigating the drug-drug interaction [...]

Currently, 14 intact, unconjugated, monoclonal antibodies (Mabs) are approved for therapeutic use in the United States, and more than 100 Mabs are presently undergoing clinical development or regulatory review. Mabs [...]

Golimumab is a fully human antitumor necrosis factor alpha (TNF-α) monoclonal antibody that is being developed for intravenous and subcutaneous administration. To assess the pharmacokinetics and safety of the intravenous [...]

Population-based assessments of drug-drug interactions have become more common since the introduction and acceptance of the population pharmacokinetic approach. Unlike traditional methods, population-based studies provide clinically relevant results that can [...]

Etanercept, a fully humanized soluble recombinant tumor necrosis factor receptor fusion protein, is an approved treatment for rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and psoriasis. Etanercept is [...]

This study was performed to estimate the population pharmacokinetic (PK) parameters of etanercept in pediatric juvenile rheumatoid arthritis (JRA) patients and to compare the steady-state time-concentration profiles between etanercept 0.8-mg/kg [...]

The purpose of this study is to characterize the population pharmacokinetics (popPK) of subcutaneous (SC) daratumumab in combination with bortezomib, cyclophosphamide, and dexamethasone and explore the relationship between daratumumab systemic exposure and selected efficacy and safety end points in patients with newly diagnosed systemic amyloid light‐chain amyloidosis. The popPK analysis included pharmacokinetic and immunogenicity data from patients receiving daratumumab SC in combination with bortezomib, cyclophosphamide, and dexamethasone in the ANDROMEDA study (AMY3001; safety run‐in, n = 28; randomized phase, n = 183). Nonlinear mixed‐effects modeling was used to characterize the popPK and quantify the impact of potential covariates. The exposure‐response (E‐R) analysis included data from all patients in the randomized phase of ANDROMEDA (n = 388). Logistic regression and survival analysis were used to evaluate the relationships between daratumumab systemic exposure and efficacy end points. The E‐R analysis on safety was conducted using quartile comparison and logistic regression analysis. The observed concentration‐time data of daratumumab SC were well described by a 1‐compartment popPK model with first‐order absorption and parallel linear and nonlinear Michaelis‐Menten elimination pathways. None of the investigated covariates were determined to be clinically meaningful. Daratumumab systemic exposure was generally similar across subgroups that achieved different levels of hematologic response, and there was no apparent relationship between daratumumab systemic exposure and the investigated safety end points. In conclusion, the popPK and E‐R analyses supported the selected 1800‐mg flat dose of daratumumab SC in combination with the bortezomib, cyclophosphamide, and dexamethasone regimen for the treatment of light‐chain amyloidosis. No dose adjustment was recommended for investigated covariates. [ABSTRACT FROM AUTHOR]

Guselkumab is an anti‐interleukin‐23 human monoclonal antibody effective in treating psoriatic arthritis (PsA). To characterize the pharmacokinetics (PKs) and exposure‐response relationship of guselkumab in PsA, population PKs, and exposure‐response modeling, analyses were conducted using data from pivotal phase III studies of subcutaneous guselkumab in patients with PsA. The observed serum concentration‐time data of guselkumab were adequately described by a one‐compartment linear PK model with first‐order absorption and elimination. Covariates identified as contributing to the observed guselkumab PK variability were body weight and diabetes comorbidity; however, the magnitude of the effects of these covariates was not considered clinically relevant, and dose adjustment was not warranted for the patient population investigated. Positive exposure‐response relationships were demonstrated with landmark and longitudinal exposure‐response analyses between guselkumab exposure and clinical efficacy end points (American College of Rheumatology [ACR] 20%, 50%, and 70% improvement criteria and Investigator's Global Assessment [IGA] of psoriasis) at weeks 20 and/or 24, with no clinically relevant differences observed in improvement of PsA signs and symptoms between the two guselkumab treatment regimens evaluated (100 mg every 4 weeks or 100 mg at weeks 0 and 4, then every 8 weeks). Baseline Disease Activity Score in 28 joints (DAS28), Psoriasis Area and Severity Index (PASI) score, and/or C‐reactive protein level were identified as influencing covariates on guselkumab exposure‐response model parameters. These results provide a comprehensive evaluation of subcutaneous guselkumab PKs and exposure‐response relationship that supports the dose regimen of 100 mg at weeks 0 and 4, then every 8 weeks in patients with PsA. [ABSTRACT FROM AUTHOR]

It is known that interleukin‐6 (IL‐6) can significantly modulate some key drug‐metabolizing enzymes, such as phase I cytochrome P450s (CYPs). In this study, a physiologically‐based pharmacokinetic (PBPK) model was developed to assess CYPs mediated therapeutic protein drug interactions (TP‐DIs) in patients with immune‐mediated inflammatory diseases (IMIDs) with elevated systemic IL‐6 levels when treated by anti‐IL‐6 therapies. Literature data of IL‐6 levels in various diseases were incorporated in SimCYP to construct respective virtual patient populations. The modulation effects of systemic IL‐6 level and local IL‐6 level in the gastrointestinal tract (GI) on CYPs activities were assessed. Upon blockade of the IL‐6 signaling pathway by an anti‐IL‐6 treatment, the area under plasma concentration versus time curves (AUCs) of S‐warfarin, omeprazole, and midazolam were predicted to decrease by up to 40%, 42%, and 46%, respectively. In patients with Crohn's disease and ulcerative colitis treated with an anti‐IL‐6 therapy, the lowering of the elevated IL‐6 levels in the local GI tissue were predicted to result in further decreases in AUCs of those CYP substrates. The propensity of TP‐DIs under comorbidity conditions, such as in patients with cancer with IMID, were also explored. With further validation with relevant clinical data, this PBPK model may provide an in silico way to quantify the magnitude of potential TP‐DI in patients with elevated IL‐6 levels when an anti‐IL‐6 therapeutic is used with concomitant small‐molecule drugs. This model may be further adapted to evaluate the CYP modulation effect by other therapeutic modalities, which would significantly alter levels of proinflammatory cytokines during the treatment period. [ABSTRACT FROM AUTHOR]