In the evolving discipline of quantitative systems pharmacology (QSP), QSP model (QSPM) applications are expanding. Recently, a QSPM was used by US Food and Drug Administration (FDA) clinical pharmacologists to evaluate the appropriateness of a proposed dosing regimen for a new biologic. This application expands the use-horizon for QSPMs into the regulatory domain. Here we retrace the evolution of the model and suggest a question-based approach to directing model scope, identifying applications, and understanding overall QSPM value.
A mathematical model component that extends an existing physiologically based multiscale systems pharmacology model (MSPM) of calcium and bone homeostasis was developed, enabling prediction of nonlinear changes in lumbar spine bone mineral density (LSBMD). Data for denosumab, a monoclonal antibody osteoporosis treatment, dosed at several levels and regimens, was used for fitting the BMD component. Bone marker and LSBMD data extracted from the literature described on/off-treatment effects of denosumab over 48 months [Miller, P.D. et al. Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: a randomized blinded phase 2 clinical trial. Bone 43, 222–229 (2008)]. An indirect model linking bone markers to LSBMD was embedded in the existing MSPM, reasonably predicting nonlinear increases in LSBMD during treatment (24 months); LSBMD declines following discontinuation and increases upon treatment reinstitution. This study demonstrates the utility of MSPM extension to describe a phenomena of interest not originally in a model, and the ability of this updated MSPM to predict nonlinear longitudinal changes in the clinically relevant endpoint, LSBMD, with denosumab treatment.
Reports of the rheumatic manifestations of Campylobacter jejuni and C. fetus infections in adults are reviewed in order to determine the most common presentations and which individuals are at risk for rheumatic disease. Relevant English-language articles were identified through a Medline search and from bibliographies of identified articles. 105 articles were reviewed in detail. 29 cases of reactive arthritis or Reiter's syndrome following Campylobacter jejuni enteritis were identified. The knee is the most commonly involved joint and an average of 3.2 joints were involved in affected persons. HL-A B27 positive patients are more frequently affected and have higher erythrocyte sedimentation rates than HL-A B27 negative patients. Eight cases of septic arthritis and 4 cases of osteomyelitis caused by C. fetus or C. jejuni were identified, and these cases generally occurred in compromised hosts or in diseased joints.
Campylobacter jejuni is a common enteric pathogen in healthy individuals and in patients with AIDS. It usually causes a self-limited diarrheal illness with fever and abdominal pain. We report what we believe is a unique case of C. jejuni osteomyelitis in a 60-year-old man who had hemophilia A, AIDS, and a hip prosthesis. He presented to the hospital with a 4-day history of fever and diarrhea and a 1-day history of hip pain. Findings on plain films and a bone scan were suggestive of osteomyelitis in the proximal femur. Cultures of blood and a hip aspirate yielded C. jejuni.
Fosdagrocorat (PF‐04171327), a dissociated agonist of the glucocorticoid receptor, has potent anti‐inflammatory activity in patients with rheumatoid arthritis with reduced adverse effects on bone health. To identify fosdagrocorat doses with bone formation marker changes similar to prednisone 5 mg, we characterized treatment‐related changes in amino‐terminal propeptide of type I collagen (P1NP) and osteocalcin (OC) with fosdagrocorat (1, 5, 10, or 15 mg) and prednisone (5 or 10 mg) in a phase II randomized trial (N = 323). The time course of markers utilized a mixed‐effects longitudinal kinetic‐pharmacodynamic model. Median predicted changes from baseline at week 8 with fosdagrocorat 5, 10, and 15 mg were −18, −22, and −22% (P1NP), and −7, −13, and −17% (OC), respectively. Changes with prednisone 5 and 10 mg were −15% and −18% (P1NP) and −10% and −17% (OC). The probability of fosdagrocorat doses up to 15 mg being noninferior to prednisone 5 mg for P1NP and OC changes was >90%.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.