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Pharmacokinetics and Safety of Intravenous Ceftolozane/Tazobactam in Healthy Adult Subjects Following Single and Multiple Ascending Doses

The pharmacokinetics and safety of ceftolozane, a novel cephalosporin, and tazobactam, a β-lactamase inhibitor, alone and in combination as a 2:1 ratio in single doses of up to 2,000 and 1,000 mg of ceftolozane and tazobactam, respectively, and multiple doses of up to 3,000 and 1,500 mg of ceftolozane and tazobactam, respectively, per day were […]

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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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Population PK & Dosing Implications for Cobimetinib in Cancer Patients

A population pharmacokinetic model was developed for cobimetinib in cancer patients. Covariates had minimal impact on steady-state exposure, suggesting no need for dose adjustments and supporting the recommended dose for all patients.

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Modeling & Simulation Relating Survival to Tumor Growth Inhibition in Patients

The published OS model and resultant simulations can be leveraged to support Phase II design and predict expected OS and HR (based on early observed TGI data obtained in Phase II or Phase III studies), thereby informing important mRCC development decisions, e.g., Go/No Go and dose regimen selection.

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Using PopPK Modeling to Optimize Dosing in Patients with Organ Impairment

The FDA-approved drug label is the official description of a drug product and includes what the drug is used for, who should take it, side effects, instructions for use, and safety information for clinicians and patients. For drug companies, the label is the culmination of years of work and millions, if not billions of dollars. […]

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Population Pharmacokinetic Analysis of Thrombomodulin Alfa to Support Dosing Rationale in Patients with Renal Impairment

Thrombomodulin alfa is a soluble recombinant human thrombomodulin that was reported to enhance the reversal of disseminated intravascular coagulation (DIC) in subjects with sepsis or hematologic malignancy and reduce mortality in subjects with sepsis and DIC. Population pharmacokinetic (PK) analysis of thrombomodulin alfa was performed based on rich samples collected in 24 healthy subjects (0.02 […]

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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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Modeling and Simulation to Support Pediatric Drug Development

Conducting clinical drug trials in children poses numerous practical and ethical challenges. The benefits of using modeling and simulation for pediatrics include an increased likelihood of success, a reduced trial duration, and minimizing blood draws. In this presentation, Dr. JF Marier discussed how to use modeling and simulation to address the challenges of pediatric drug […]

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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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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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Population Pharmacokinetics of Ceftolozane/Tazobactam in Healthy Volunteers, Subjects with Varying Degrees of Renal Function and Patients with Bacterial Infections

Ceftolozane/tazobactam is a novel antipseudomonal cephalosporin and a β-lactamase inhibitor in clinical development for treatment of complicated urinary tract (cUTI) and intra-abdominal (cIAI) infections and nosocomial pneumonia. The population pharmacokinetics of ceftolozane/tazobactam were characterized in healthy volunteers, subjects with varying degrees of renal function, and patients with cIAI or cUTI. Serum concentration data from 376 […]

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The Effect of Plasmapheresis on Blood Pressure in Voluntary Plasma Donors

Donor plasmapheresis involves the removal of a weight-adjusted volume of plasma and the return of cellular components to the donor. Although plasma volume generally returns to normal, some residual effect on vital signs may be possible. This analysis was performed to determine the possible effects of plasmapheresis on blood pressure. A 16-week study was conducted […]

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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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Pharmacokinetics of Injectable, Long-acting Nevirapine for HIV Prophylaxis in Breastfeeding Infants

Mother-to-child transmission (MTCT) of HIV-1 remains a global health problem. The World Health Organization (WHO recommendations advise the administration of a once-daily, oral, prophylactic regimen of the nonnucleoside reverse transcriptase inhibitor nevirapine (NVP) from birth until four to six weeks of age for infants born to HIV-infected mothers in regions without access to safe and […]

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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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Meropenem in Children Receiving Continuous Renal Replacement Therapy: Clinical Trial Simulations Using Realistic Covariates

Meropenem is frequently prescribed in children receiving continuous renal replacement therapy (CRRT). Fluid overload is often present in critically ill children and affects drug disposition. The purpose of this study was to develop a pharmacokinetic model to 1) evaluate target attainment of meropenem dosing regimens against P. aeruginosa in children receiving CRRT and 2) estimate […]

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Vigabatrin Pediatric Dosing Information for Refractory Complex Partial Seizures: Results from a Population Dose-response Analysis

We predicted vigabatrin dosages for adjunctive therapy for pediatric patients with refractory complex partial seizures (rCPS) that would produce efficacy comparable to that observed for approved adult dosages.

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Modeling and Simulation for Medical Product Development and Evaluation: Highlights from the FDA-C-Path-ISOP 2013 Workshop

Medical-product development has become increasingly challenging and resource-intensive. In 2004, the Food and Drug Administration (FDA) described critical challenges facing medical-product development by establishing the critical path initiative. Priorities identified included the need for improved modeling and simulation tools, further emphasized in FDA’s 2011 Strategic Plan for Regulatory Science. In an effort to support and […]

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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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Cardiac Safety Research Consortium: Can the Thorough QT/QTc Study Be Replaced by Early QT Assessment in Routine Clinical Pharmacology Studies? Scientific Update and a Research Proposal for a Path Forward

The International Conference on Harmonization E14 guidance for the clinical evaluation of QT/QTc interval prolongation requires almost all new drugs to undergo a dedicated clinical study, primarily in healthy volunteers, the so-called TQT study. Since 2005, when the E14 guidance was implemented in United States and Europe, close to 400 TQT studies have been conducted. […]

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