Dose selection for aztreonam-avibactam, including adjustments for renal impairment, for Phase IIa and Phase III evaluation.

Purpose: A series of iterative population pharmacokinetic (PK) modeling and probability of target attainment (PTA) analyses based on emerging data supported dose selection for aztreonam-avibactam, an investigational combination antibiotic for serious Gram-negative bacterial infections.

Methods: Two iterations of PK models built from avibactam data in infected patients and aztreonam data in healthy subjects with "patient-like" assumptions were used in joint PTA analyses (primary target: aztreonam 60% fT > 8 mg/L, avibactam 50% fT > 2.5 mg/L) exploring patient variability, infusion durations, and adjustments for moderate (estimated creatinine clearance [CrCL] > 30 to ≤ 50 mL/min) and severe renal impairment (> 15 to ≤ 30 mL/min).

Population Pharmacokinetic Modeling for Ceftazidime-Avibactam Renal Dose Adjustments in Pediatric Patients 3 months and Older.

Ceftazidime-avibactam is a novel β-lactam/β-lactamase inhibitor combination developed to treat serious Gram-negative bacterial infections; approved indications include complicated urinary tract infection, complicated intra-abdominal infection, and hospital-acquired pneumonia including ventilator-associated pneumonia in patients ≥ 3 months old. Because of the predominantly renal clearance of ceftazidime and avibactam, dose adjustments (reductions) are required for patients with estimated creatinine clearance (CrCL) ≤ 50 mL/min. We describe the application of combined adult and pediatric population pharmacokinetic models in developing ceftazidime-avibactam dose recommendations for pediatric patients ≥ 2 to < 18 years old with body surface area-normalized CrCL ≤ 50 mL/min/1.

Maraviroc Population Pharmacokinetics Within the First 6 Weeks of Life.

Background: Treatment and prophylaxis options for neonatal HIV are limited. This study aimed to develop a population pharmacokinetic model to characterize the disposition of maraviroc in neonates to inform dosing regimens and expand available options.

Methods: Using maraviroc concentrations from neonates who received either a single dose or multiple doses of 8 mg/kg of maraviroc in the first 6 weeks of life, a population pharmacokinetic model was developed to determine the effects of age, sex, maternal efavirenz exposure and concomitant ARV therapy on maraviroc disposition.

Population Pharmacokinetic Modeling and Probability of Pharmacodynamic Target Attainment for Ceftazidime-Avibactam in Pediatric Patients Aged 3 Months and Older.

Increasing prevalence of infections caused by antimicrobial-resistant gram-negative bacteria represents a global health crisis, and while several novel therapies that target various aspects of antimicrobial resistance have been introduced in recent years, few are currently approved for children. Ceftazidime-avibactam is a novel β-lactam β-lactamase inhibitor combination approved for adults and children 3 months and older with complicated intra-abdominal infection, and complicated urinary tract infection or hospital-acquired ventilator-associated pneumonia (adults only in the United States) caused by susceptible gram-negative bacteria. Extensive population pharmacokinetic (PK) data sets for ceftazidime and avibactam obtained during the adult clinical development program were used to iteratively select, modify, and validate the approved adult dosage regimen (2,000-500 mg by 2-hour intravenous (IV) infusion every 8 hours (q8h), with adjustments for renal function).

The use of extrapolation based on modeling and simulation to support high-dose regimens of ceftaroline fosamil in pediatric patients with complicated skin and soft-tissue infections.

A model-informed drug development approach was used to select ceftaroline fosamil high-dose regimens for pediatric patients with complicated skin and soft-tissue infections caused by Staphylococcus aureus with a ceftaroline minimum inhibitory concentration (MIC) of 2 or 4 mg/L. Steady-state ceftaroline concentrations were simulated using a population pharmacokinetics (PK) model for ceftaroline fosamil and ceftaroline including data from 304 pediatric subjects and 944 adults. Probability of target attainment (PTA) for various simulated pediatric high-dose regimens and renal function categories were calculated based on patients achieving 35% fT>MIC (S.

Pregabalin Population Pharmacokinetic and Exposure-Response Analyses for Focal Onset Seizures in Children (4-16 years) and Adults, to Support Dose Recommendations in Children.

Pregabalin is approved in multiple countries as adjunctive therapy for adult patients with focal onset seizures (FOS; previously termed partial onset seizures). This study used population pharmacokinetic (PK) and exposure-response (E-R) analyses from pooled pregabalin concentration and efficacy data to compare pregabalin exposure and E-R relationships in pediatric and adult patients with FOS, to support pediatric dosage recommendations. A one-compartment disposition model was used, with first-order absorption and body surface area-normalized creatinine clearance on clearance.

Pharmacokinetics and safety of maraviroc in neonates.

Objective: The aim of this study was to evaluate safety and pharmacokinetics of maraviroc administered with standard antiretroviral prophylaxis to HIV-1 exposed infants and to determine the appropriate dose of maraviroc during the first 6 weeks of life.

Design: A phase I, multicentre, open-label study enrolling two sequential cohorts.

Methods: IMPAACT 2007 participants enrolled by day 3 of life and were stratified by exposure to maternal efavirenz.

Population Analysis of Anidulafungin in Infants to Older Adults With Confirmed or Suspected Invasive Candidiasis.

In a pooled population analysis, we investigated the pharmacokinetics of i.v. anidulafungin in four studies across a full range of adult and pediatric ages in patients with confirmed, suspected, or at high risk of invasive candidiasis (IC).

Incidence of CXCR4 tropism and CCR5-tropic resistance in treatment-experienced participants receiving maraviroc in the 48-week MOTIVATE 1 and 2 trials.

Unlabelled: Maraviroc blocks HIV-1 entry into CD4+ cells by interrupting the interaction between viral gp120 and cell-surface CCR5. Resistance to CCR5 antagonist–mediated inhibition can develop by unmasking pre-existing CXCR4-using virus or through selection of CCR5-tropic resistant virus, characterized by plateaus in maximum percent inhibition <95%. Here, we examine viral escape in maraviroc-treated participants during virologic failure through Week 48 in the MOTIVATE 1 and 2 trials.

A Retrospective Analysis of Probability of Target Attainment in Community-Acquired Pneumonia: Ceftaroline Fosamil Versus Comparators.

Introduction: This retrospective analysis compares the probability of target attainment (PTA) for ceftriaxone, levofloxacin and ceftaroline fosamil against Staphylococcus aureus, Streptococcus pneumoniae and Haemophilus influenzae in a representative patient population with moderate-to-severe community-acquired pneumonia (CAP).

Methods: Published pharmacokinetic (PK) models for levofloxacin and ceftriaxone, and an existing model for ceftaroline, were used with standard dosage regimens for simulating individual PK data with covariates representative of patients with CAP (5000 patients/drug regimen). PTA for clinically relevant pharmacokinetic/pharmacodynamic (PK/PD) targets was calculated from steady state PK profiles for a range of minimum inhibitory concentrations (MICs).

No Clinical Impact of CYP3A5 Gene Polymorphisms on the Pharmacokinetics and/or Efficacy of Maraviroc in Healthy Volunteers and HIV-1-Infected Subjects.

Maraviroc is a C-C chemokine receptor type-5 antagonist approved for the treatment of HIV-1. Previous studies show that cytochrome P450 3A5 (CYP3A5) plays a role in maraviroc metabolism. CYP3A5 is subject to a genetic polymorphism.

PharmTeX: a LaTeX-Based Open-Source Platform for Automated Reporting Workflow.

Every year, the pharmaceutical industry generates a large number of scientific reports related to drug research, development, and regulatory submissions. Many of these reports are created using text processing tools such as Microsoft Word. Given the large number of figures, tables, references, and other elements, this is often a tedious task involving hours of copying and pasting and substantial efforts in quality control (QC).

Population Pharmacokinetics of Fosdagrocorat (PF-04171327), a Dissociated Glucocorticoid Receptor Agonist, in Patients With Rheumatoid Arthritis.

Dissociated agonists of the glucocorticoid receptor (DAGRs) show similar antiinflammatory effects but improved tolerability compared with standard glucocorticoid receptor (GR) agonists. The prodrug fosdagrocorat (PF-04171327), with active DAGR metabolite PF-00251802 (Metabolite-1), is postulated to show superior efficacy over placebo and prednisone in patients with moderate to severe rheumatoid arthritis (RA). We investigated the population pharmacokinetics of active Metabolite-1 and its active metabolite PF-04015475 (Metabolite-2) in patients with moderate to severe RA enrolled in a 12-week, phase II, randomized, double-blind study (NCT01393639).

Pharmacokinetics, Safety and Efficacy of Maraviroc in Treatment-experienced Pediatric Patients Infected With CCR5-Tropic HIV-1.

Background: Maraviroc is a CC-chemokine receptor 5 antagonist approved to treat adults infected with CC-chemokine receptor 5-tropic (R5) HIV-1. Study A4001031 was conducted to evaluate the pharmacokinetics, safety and efficacy of maraviroc in combination with optimized background therapy in treatment-experienced pediatric patients infected with R5 HIV-1 and support registration of maraviroc for pediatric use.

Methods: This is an open-label, 2-stage, age-stratified, noncomparative multicenter study.

Once-daily maraviroc versus tenofovir/emtricitabine each combined with darunavir/ritonavir for initial HIV-1 treatment.

Objective: The aim of this study was to evaluate the efficacy of maraviroc along with darunavir/ritonavir, all once daily, for the treatment of antiretroviral-naive HIV-1 infected individuals.

Design: MODERN was a multicentre, double-blind, noninferiority, phase III study in HIV-1 infected, antiretroviral-naive adults with plasma HIV-1 RNA at least 1000 copies/ml and no evidence of reduced susceptibility to study drugs.

Methods: At screening, participants were randomized 1 : 1 to undergo either genotypic or phenotypic tropism testing.

Pharmacokinetics, safety, and tolerability of maraviroc in HIV-negative subjects with impaired renal function.

Purpose: This open-label, nonrandomized, parallel-group study was conducted to explore the pharmacokinetics, safety, and tolerability of maraviroc in renally impaired subjects.

Methods: Subjects with normal renal function; mild, moderate, or severe renal impairment; or end-stage renal disease (ESRD) (n = 6 per group) were enrolled. Subjects with normal function (period 1), severe impairment, and ESRD received a single 300 mg dose of maraviroc.

Maraviroc once-daily nucleoside analog-sparing regimen in treatment-naive patients: randomized, open-label pilot study.

Objective: This study was performed to evaluate a once-daily dual-therapy regimen, maraviroc (MVC) + atazanavir/ritonavir (ATV/r), in treatment-naive patients.

Design: A phase 2b, randomized, open-label pilot study.

Methods: In Study A4001078 (NCT00827112), treatment-naive patients with CCR5-tropic HIV-1 (HIV-1 RNA ≥1000 copies/mL; CD4 cell count ≥100 cells/mm) were randomized to receive either MVC 150 mg once daily (n = 60) or tenofovir/emtricitabine (TDF/FTC) 300/200 mg once daily (n = 61) + ATV/r 300/100 mg once daily.

Baseline CD4(+) T-cell counts and weighted background susceptibility scores strongly predict response to maraviroc regimens in treatment-experienced patients.

Background: Maraviroc-containing regimens are known to achieve virological suppression in many treatment-experienced patients. This study aimed to evaluate a more rigorous methodological approach to resistance-response analysis in large clinical studies and to better establish which subpopulations of patients were most likely to benefit from maraviroc by refining and extending previous subgroup analyses from the MOTIVATE studies.

Methods: Individual weighted optimized background therapy (OBT) susceptibility scores were calculated by combining genotypic or phenotypic resistance testing with prior drug use information.

The use of the SAEM algorithm in MONOLIX software for estimation of population pharmacokinetic-pharmacodynamic-viral dynamics parameters of maraviroc in asymptomatic HIV subjects.

Using simulated viral load data for a given maraviroc monotherapy study design, the feasibility of different algorithms to perform parameter estimation for a pharmacokinetic-pharmacodynamic-viral dynamics (PKPD-VD) model was assessed. The assessed algorithms are the first-order conditional estimation method with interaction (FOCEI) implemented in NONMEM VI and the SAEM algorithm implemented in MONOLIX version 2.4.

Translational pharmacokinetic-pharmacodynamic modelling; application to cardiovascular safety data for PF-00821385, a novel HIV agent.

Aim: To assess the translation of pharmacokinetic-pharmacodynamic (PK-PD) relationships for heart rate effects of PF-00821385 in dog and man.

Methods: Cardiovascular telemetric parameters and concentration data were available for animals receiving active doses (0.5-120 mg kg(-1), n= 4) or vehicle.

Basic PK/PD principles of drug effects in circular/proliferative systems for disease modelling.

Disease progression modelling can provide information about the time course and outcome of pharmacological intervention on the disease. The basic PK/PD principles of proliferative and circular systems within the context of modelling disease progression and the effect of treatment thereupon are illustrated with the goal to better understand/predict eventual clinical outcome. Circular/proliferative systems can be very complex.

Activity, pharmacokinetics and safety of lersivirine (UK-453,061), a next-generation nonnucleoside reverse transcriptase inhibitor, during 7-day monotherapy in HIV-1-infected patients.

Objective: To investigate the effects on viral load and assess dose-response relationships, pharmacokinetics, safety and tolerability of lersivirine (UK-453,061), a next-generation nonnucleoside reverse transcriptase inhibitor, in asymptomatic HIV-1-infected patients.

Design: Randomized, double-blind, placebo-controlled, parallel group, multicenter phase IIa clinical study.

Methods: Forty-eight HIV-1-infected patients were enrolled for the study of once-daily or twice-daily lersivirine at total daily doses ranging from 20 to 1000 mg.

Maraviroc modelling strategy: use of early phase 1 data to support a semi-mechanistic population pharmacokinetic model.

Aims: To model the basic pharmacokinetic (PK) characteristics of maraviroc to construct an integrated semi-mechanistic PK model for use in later population PK analyses.

Methods: Three analyses were performed utilizing intravenous, oral and radiolabel data. Firstly, a PK disposition model was developed from data from 20 healthy males who received 3, 10 or 30 mg of intravenous maraviroc.

The use of clinical irrelevance criteria in covariate model building with application to dofetilide pharmacokinetic data.

To characterise the pharmacokinetics of dofetilide in patients and to identify clinically relevant parameter-covariate relationships. To investigate three different modelling strategies in covariate model building using dofetilide as an example: (1) using statistical criteria only or in combination with clinical irrelevance criteria for covariate selection, (2) applying covariate effects on total clearance or separately on non-renal and renal clearances and (3) using separate data sets for covariate selection and parameter estimation. Pooled concentration-time data (1,445 patients, 10,133 observations) from phase III clinical trials was used.