Pharsight Consulting Services

Month 2 culture status and treatment duration as predictors of recurrence in pulmonary tuberculosis: model validation and update.

New regimens capable of shortening tuberculosis treatment without increasing the risk of recurrence are urgently needed. A 2013 meta-regression analysis, using data from trials published from 1973 to 1997 involving 7793 patients, identified 2-month sputum culture status and treatment duration as independent predictors of recurrence. The resulting model predicted that if a new 4-month regimen […]

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Safety and pharmacokinetics of single and multiple ascending doses of avibactam alone and in combination with ceftazidime in healthy male volunteers: results of two randomized, placebo-controlled studies.

Avibactam is a novel non-β-lactam β-lactamase inhibitor effective against Ambler class A, C and some class D β-lactamases that is currently in clinical development in combination with ceftazidime for the treatment of serious Gram-negative infections. It restores the in vitro activity of a range of β-lactams, including ceftazidime, against extended-spectrum β-lactamase-producing pathogens. Two phase I […]

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Effect of age and sex on the pharmacokinetics and safety of avibactam in healthy volunteers

Avibactam is a novel non-β-lactam β-lactamase inhibitor currently being assessed in combination with ceftazidime, ceftaroline fosamil, and aztreonam. The objectives of this study were to investigate the pharmacokinetics, safety, and tolerability of avibactam in healthy young (aged 18-45 years) and elderly (aged ≥65 years) volunteers of both sexes. This was a Phase I, open-label study […]

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Population pharmacokinetic analysis of axitinib in healthy volunteers.

Axitinib is a potent and selective second generation inhibitor of vascular endothelial growth factor receptors 1, 2 and 3 approved for second line treatment of advanced renal cell carcinoma. The objectives of this analysis were to assess plasma pharmacokinetics and identify covariates that may explain variability in axitinib disposition following single dose administration in healthy […]

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Axitinib in metastatic renal cell carcinoma: results of a pharmacokinetic and pharmacodynamic analysis.

Axitinib is a potent and selective inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, approved for second-line therapy for advanced renal cell carcinoma (RCC). Axitinib population pharmacokinetic and pharmacokinetic/pharmacodynamic relationships were evaluated. Using nonlinear mixed effects modeling with pooled data from 383 healthy volunteers, 181 patients with metastatic RCC, and 26 patients […]

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Onartuzumab with or without bevacizumab in combination with weekly paclitaxel does not prolong QTc or adversely affect other ECG parameters in patients with locally recurrent or metastatic triple-negative breast cancer.

The purpose of this study was to examine the potential effect of onartuzumab, when administered with or without bevacizumab in combination with weekly paclitaxel, on the corrected QT interval (QTc) and other electrocardiogram (ECG) parameters, was investigated in a randomized, phase 2 study OAM4861g of first- or second-line therapy in patients with locally recurrent or […]

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Population Pharmacokinetic and Pharmacodynamic Analyses from a 4-Month Intra–Dose Escalation and Its Subsequent 12-Month Dose Titration Studies for a Human Monoclonal Anti-FGF23 Antibody (KRN23) in Adults with X-Linked Hypophosphatemia

X-linked hypophosphatemia (XLH) is an inherited metabolic bone disease with abnormally elevated serum FGF23 resulting in low renal maximum threshold for phosphate reabsorption, low serum phosphate (Pi) and 1,25-dihydroxyvitamin D levels with subsequent development of short stature and skeletal deformities. KRN23 is a novel human anti-FGF23 antibody for the treatment of XLH. The pharmacokinetics (PK) […]

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A Modeling and Simulations Framework to Optimize Pediatric Studies and Facilitate Decision-Making

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Pharmacokinetic Analysis of Capsaicin After Topical Administration of a High-Concentration Capsaicin Patch to Patients With Peripheral Neuropathic Pain

Capsaicin, a pungent compound in chili peppers, is a highly selective agonist for the transient receptor potential vanilloid 1 receptor expressed in nociceptive sensory nerves. A high-concentration (640 μg/cm2) capsaicin patch, designated NGX-4010, is in clinical evaluation for the management of peripheral neuropathic pain. To determine systemic capsaicin exposure after single 60- or 90-minute NGX-4010 […]

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Activities of ceftazidime and avibactam against β-lactamase-producing enterobacteriaceae in a hollow-fiber pharmacodynamic model

Avibactam is a novel non-β-lactam β-lactamase inhibitor that is currently undergoing phase 3 clinical trials in combination with ceftazidime. Ceftazidime is hydrolyzed by a broad range of β-lactamases, but avibactam is able to inhibit the majority of these enzymes. The studies described here attempt to provide insight into the amount of avibactam required to suppress […]

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Population Pharmacokinetics of Vernakalant Hydrochloride Injection (RSD1235) in Patients With Atrial Fibrillation or Atrial Flutter

Vernakalant hydrochloride is a novel, predominantly atrial-selective antiarrhythmic drug that effectively and rapidly terminates atrial fibrillation (AF). Plasma vernakalant concentration data from 5 phase 2 and 3 clinical trials of vernakalant in patients with AF or atrial flutter and a phase 1 study in healthy volunteers were used to construct a population pharmacokinetic model

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Pharmacokinetic and Pharmacodynamic Modeling to Determine the Human Dose of ST-246(R) to Protect Against Smallpox.

Although smallpox has been eradicated, the United States government considers it a “material threat” and has funded the discovery and development of potential therapeutic compounds. As reported here, the human efficacious dose for one of these compounds, ST-246, was determined using efficacy studies in nonhuman primates (NHPs), together with pharmacokinetic and pharmacodynamic analysis that predicted […]

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Population Pharmacokinetics Analysis of Vigabatrin in Adults and Children with Epilepsy and Children with Infantile Spasms.

Vigabatrin is an inhibitor of γ-aminobutyric acid transaminase. The purpose of these analyses was to develop a population pharmacokinetics model to characterize the vigabatrin concentration–time profile for adults and children with refractory complex partial seizures (rCPS) and for children with infantile spasms (IS); to identify covariates that affect its disposition, and to enable predictions of […]

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On the Use of Change in Tumor Size to Predict Survival in Clinical Oncology Studies: Toward a New Paradigm to Design and Evaluate Phase II Studies

Drug-independent models that link biomarker response to clinical end points are critical to support early (end of phase II) clinical decisions. In oncology, change in tumor size (a biomarker of drug effect evaluated in phase II) is linked to survival (a phase III end point) in some solid tumors.

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Novel biocompatible disease modifying nanomedicine of VIP for rheumatoid arthritis.

Despite advances in rheumatoid arthritis (RA) treatment, efficacious and safe disease-modifying therapy still represents an unmet medical need. Here, we describe an innovative strategy to treat RA by targeting low doses of vasoactive intestinal peptide (VIP) self-associated with sterically stabilized micelles (SSMs). This spontaneous interaction of VIP with SSM protects the peptide from degradation or […]

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Armodafinil and Modafinil in Patients With Excessive Sleepiness Associated With Shift Work Disorder: A Pharmacokinetic and Pharmacodynamic Model for Predicting and Comparing Their Concentration-Effect Relationships

Armodafinil, the longer lasting R-isomer of racemic modafinil, improves wakefulness in patients with excessive sleepiness associated with shift work disorder (SWD). Pharmacokinetic studies suggest that armodafinil achieves higher plasma concentrations than modafinil late in a dose interval following equal oral doses.

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The ISoP Standards and Best Practices Committee

The mission of the International Society of Pharmacometrics (ISoP) Standards and Best Practices Committee is to provide best practices and recommendations for standard pharmacometric analyses—e.g., population pharmacokinetics/pharmacodynamics (PK/PD), exposure–response, disease models—with the goal of increasing consistency, productivity, quality, communication, and impact of pharmacometrics on decision making. We present the progress and plans of the committee […]

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Development of a Modeling Framework to Simulate Efficacy Endpoints for Motesanib in Thyroid Cancer Patients

To develop a modeling framework that simulates clinical endpoints (objective response rate and progression-free survival) to support development of motesanib. The framework was evaluated using results from a phase 2 study of motesanib in thyroid cancer. Models of probability and duration of dose modifications and overall survival were developed using data from 93 patients with […]

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Model-Based Drug Development in Oncology: What’s Next?

Model-based estimates of tumor growth inhibition (TGI) metrics have the potential to enhance learning in early (phase II) clinical studies. They can be used as end points and biomarkers to predict treatment effect on clinical outcome measures—e.g., overall survival (OS)—and support phase II study design, end-of-phase II decisions, and phase III planning and execution. Efforts […]

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Population dose-response analysis of daily seizure count following vigabatrin therapy in adult and pediatric patients with refractory complex partial seizures.

Vigabatrin is an irreversible inhibitor of γ-aminobutyric acid transaminase (GABA-T) and is used as an adjunctive therapy for adult patients with refractory complex partial seizures (rCPS). The purpose of this investigation was to describe the relationship between vigabatrin dosage and daily seizure rate for adults and children with rCPS and identify relevant covariates that might […]

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