Population pharmacokinetics and exposure-response modeling analyses of guselkumab in patients with psoriatic arthritis.

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.

Translational PK/PD and model-informed development of JNJ-67842125, a F reversal agent for JNJ-64179375, a long-acting thrombin inhibitor.

Background And Purpose: Antigen-binding fragment (F ) reversal agents were developed to reverse, in bleeding emergency, the long-acting anticoagulant effect of JNJ-64179375 (JNJ-9375), a monoclonal antibody that binds exosite-1 on thrombin.

Experimental Approach: The pharmacokinetic and pharmacodynamic (PK/PD) activities of three reversal agents of varying in vitro binding affinities to JNJ-9375 were characterised in cynomolgus monkeys. The time course of JNJ-9375 anticoagulant activity and reversal effects of each agent were evaluated.

Open-label phase 3 study of intravenous golimumab in patients with polyarticular juvenile idiopathic arthritis.

Objectives: To assess efficacy, pharmacokinetics (PK) and safety of intravenous (i.v.) golimumab in patients with polyarticular-course JIA (pc-JIA).

Application of Trial Simulation in the Design of a Prospective Study for Concentration-QTc Analysis in Support of a Thorough QT Study Waiver.

The concentration-QTc (C-QTc) analysis is often applied in the first-in-human (FIH) study to demonstrate the absence of a QTc effect in support of a TQT waiver. However, a C-QTc analysis without properly designed sensitivity could fail to conclude the absence of a QTc effect at high concentrations, even though the compound is QTc negative. This is because the 90% confidence interval (CI) of the model-derived ∆∆QTc grows wider with increasing concentration, and the upper-bound could cross the 10-ms threshold, even though the slope is close to 0.

Trial Design and Statistical Considerations on the Assessment of Pharmacodynamic Similarity.

Pharmacodynamics (PD) similarity is an important component to support the claim of similarity between two drugs or devices. This article investigates the trial design and statistical considerations in the equivalence test of PD endpoints. Using bone resorption marker CTX as a case study, the relationship between the PD readouts and drug potency was explored to evaluate the sensitivity of the PD endpoint and guide equivalence margin selection.

Utilization of Adult Data in Designing Pediatric Pharmacokinetic Studies: How Much Are Historical Adult Data Worth?

In pediatric drug development, large amounts of adult data are often available before the start of a pediatric study. It is believed that borrowing this information will improve the efficiency. However, when adult information is not sufficiently similar to that of pediatrics, incorporating adult data will introduce bias and consequently result in efficiency loss.

Dynamic population pharmacokinetic-pharmacodynamic modelling and simulation supports similar efficacy in glycosylated haemoglobin response with once or twice-daily dosing of canagliflozin.

Aim: Canagliflozin is an SGLT2 inhibitor approved for the treatment of type-2 diabetes. A dynamic population pharmacokinetic-pharmacodynamic (PK/PD) model relating 24-h canagliflozin exposure profiles to effects on glycosylated haemoglobin was developed to compare the efficacy of once-daily and twice-daily dosing.

Methods: Data from two clinical studies, one with once-daily, and the other with twice-daily dosing of canagliflozin as add-on to metformin were used (n = 1347).

The method of averaging applied to pharmacokinetic/pharmacodynamic indirect response models.

The computational effort required to fit the pharmacodynamic (PD) part of a pharmacokinetic/pharmacodynamic (PK/PD) model can be considerable if the differential equations describing the model are solved numerically. This burden can be greatly reduced by applying the method of averaging (MAv) in the appropriate circumstances. The MAv gives an approximate solution, which is expected to be a good approximation when the PK profile is periodic (i.

Evaluating potential benefits of dose-exposure-response modeling for dose finding.

Dose-regimen selection for confirmatory trials and characterization of dose-response relationship are arguably among the most important and difficult tasks in clinical drug development. Inadequate dose-regimen selection is believed to be one of the key drivers of the high attrition rate in Phase III. Nowadays, drug concentrations are routinely measured in patients in clinical studies throughout the drug development process.

Innovative approaches for designing and analyzing adaptive dose-ranging trials.

Inadequate selection of the dose to bring forward in confirmatory trials has been identified as one of the key drivers of the decreasing success rates observed in drug development programs across the pharmaceutical industry. In recognition of this problem, the Pharmaceutical Research and Manufacturers of America (PhRMA), formed a working group to evaluate and develop alternative approaches to dose finding, including adaptive dose-ranging designs. This paper summarizes the work of the group, including the results and conclusions of a comprehensive simulation study, and puts forward recommendations on how to improve dose ranging in clinical development, including, but not limited to, the use of adaptive dose-ranging methods.

Phase I dose-finding study of weekly single-agent patupilone in patients with advanced solid tumors.

Purpose: To evaluate the safety and maximum-tolerated dose (MTD) of weekly patupilone, a natural epothilone B, in patients with advanced solid tumors.

Patients And Methods: Patients were treated with patupilone (0.3 to 3.

FTY720, a novel immunomodulator in de novo kidney transplant patients: pharmacokinetics and exposure-response relationship.

The pharmacokinetics, safety, and preliminary efficacy of FTY720, a novel immunomodulator, were examined in de novo renal transplant patients. Both noncompartmental and population methods were used to estimate pharmacokinetic estimates in the patients. The steady-state plasma concentrations of FTY720 increased in accordance with maintenance dose level, indicating linearity in clearance and volume of distribution over the 0.

Everolimus in de novo cardiac transplantation: pharmacokinetics, therapeutic range, and influence on cyclosporine exposure.

We evaluated exposure, safety, and efficacy data from an international Phase 3 trial of everolimus in de novo heart transplantation to characterize the longitudinal pharmacokinetics of everolimus and cyclosporine and to identify a therapeutic concentration range for everolimus. We randomized 634 patients to receive either 0.75 mg everolimus twice daily, 1.

Pharmacokinetics of an everolimus-cyclosporine immunosuppressive regimen over the first 6 months after kidney transplantation.

The pharmacokinetics of everolimus were characterized over the first 6 months post transplant in 731 patients receiving either 0.75 or 1.5 mg bid everolimus in addition to cyclosporine and corticosteroids.

The pharmacokinetics and pharmacodynamics of zoledronic acid in cancer patients with varying degrees of renal function.

An open-label pharmacokinetic and pharmacodynamic study of zoledronic acid (Zometa) was performed in 19 cancer patients with bone metastases and known, varying levels of renal function. Patients were stratified according to creatinine clearance (CLcr) into different groups of normal (CLcr > 80 mL/min), mildly (CLcr = 50-80 mL/min), or moderately/severely impaired (CLcr = 10-50 mL/min) renal function. Three intravenous infusions of 4 mg zoledronic acid were administered at 1-month intervals between doses.