Informatics: the fuel for pharmacometric analysis

The current informal practice of pharmacometrics as a combination art and science makes it hard to appreciate the role that informatics can and should play in the future of the discipline and to comprehend the gaps that exist because of its absence. The development of pharmacometric informatics has important implications for expediting decision making and for improving the reliability of decisions made in model-based development. We argue that well-defined informatics for pharmacometrics can lead to much needed improvements in the efficiency, effectiveness, and reliability of the pharmacometrics process. The purpose of this paper is to provide a description of the pervasive yet often poorly appreciated role of informatics in improving the process of data assembly, a critical task in the delivery of pharmacometric analysis results. First, we provide a brief description of the pharmacometric analysis process. Second, we describe the business processes required to create analysis-ready data sets for the pharmacometrician. Third, we describe selected informatic elements required to support the pharmacometrics and data assembly processes. Finally, we offer specific suggestions for performing a systematic analysis of existing challenges as an approach to defi ning the next generation of pharmacometric informatics

Efficacy, safety, tolerability and population pharmacokinetics of tedizolid, a novel antibiotic, in Latino patients with acute bacterial skin and skin structure infections

AbstractAcute bacterial skin and skin structure infections are caused mainly by Gram-positive bacteria which are often treated with intravenous vancomycin, daptomycin, or linezolid, with potential step down to oral linezolid for outpatients. Tedizolid phosphate 200mg once daily treatment for six days demonstrated non-inferior efficacy, with a favourable safety profile, compared with linezolid 600mg twice daily treatment for 10 days in the Phase 3 ESTABLISH-1 and -2 trials. The objective of the current post-hoc analysis of the integrated dataset of ESTABLISH-1 and -2 was to evaluate the efficacy and safety of tedizolid (N=182) vs linezolid (N=171) in patients of Latino origin enrolled into these trials. The baseline demographic characteristics of Latino patients were similar between the two treatment groups. Tedizolid demonstrated comparable efficacy to linezolid at 48–72h in the intent-to-treat population (tedizolid: 80.2% vs linezolid: 81.9%). Sustained clinical success rates were comparable between tedizolid- and linezolid-treated Latino patients at end-of-therapy (tedizolid: 86.8% vs linezolid: 88.9%). Tedizolid phosphate treatment was well tolerated by Latino patients in the safety population with lower abnormal platelet counts at end-of-therapy (tedizolid: 3.4% vs linezolid: 11.3%, p=0.0120) and lower incidence of gastrointestinal adverse events (tedizolid: 16.5% vs linezolid: 23.5%). Population pharmacokinetic analysis suggested that estimated tedizolid exposure measures in Latino patients vs non-Latino patients were similar. These findings demonstrate that tedizolid phosphate 200mg, once daily treatment for six days was efficacious and well tolerated by patients of Latino origin, without warranting dose adjustment

Nonclinical and pharmacokinetic assessments to evaluate the potential of tedizolid and linezolid to affect mitochondrial function

Prolonged treatment with the oxazolidinone linezolid is associated with myelosuppression, lactic acidosis, and neuropathies, toxicities likely caused by impairment of mitochondrial protein synthesis (MPS). To evaluate the potential of the novel oxazolidinone tedizolid to cause similar side effects, nonclinical and pharmacokinetic assessments were conducted. In isolated rat heart mitochondria, tedizolid inhibited MPS more potently than did linezolid (average [± standard error of the mean] 50% inhibitory concentration [IC50] for MPS of 0.31 ± 0.02 μM versus 6.4 ± 1.2 μM). However, a rigorous 9-month rat study comparing placebo and high-dose tedizolid (resulting in steady-state area under the plasma concentration-time curve values about 8-fold greater than those with the standard therapeutic dose in humans) showed no evidence of neuropathy. Additional studies explored why prolonged, high-dose tedizolid did not cause these mitochondriopathic side effects despite potent MPS inhibition by tedizolid. Murine macrophage (J774) cell fractionation studies found no evidence of a stable association of tedizolid with eukaryotic mitochondria. Monte Carlo simulations based on population pharmacokinetic models showed that over the course of a dosing interval using standard therapeutic doses, free plasma concentrations fell below the respective MPS IC50 in 84% of tedizolid-treated patients (for a median duration of 7.94 h) and 38% of linezolid-treated patients (for a median duration of 0 h). Therapeutic doses of tedizolid, but not linezolid, may therefore allow for mitochondrial recovery during antibacterial therapy. The overall results suggest that tedizolid has less potential to cause myelosuppression and neuropathy than that of linezolid during prolonged treatment courses. This, however, remains a hypothesis that must be confirmed in clinical studies

Introduction to population pharmacokinetic / pharmacodynamic analysis with nonlinear mixed effects models

xvi, 301 p. : ill. ; 24 c

Peginesatide parameter estimates and their associated precision for the final PK-PD Model, including bootstrap evaluation results.

<p>1. Based on 935/1000 successfully converged bootstrap runs;</p><p>SD: Standard deviation; NA: not applicable.</p

Visual predictive check for the PK-PD model of peginesatide using traditional visual predictive check.

<p>Visual predictive check for the PK-PD model of peginesatide using traditional visual predictive check.</p

Patient demographics and laboratory characteristics at baseline, by population group.

<p>1Total of 672 subjects contributed a total of 2665 samples.</p><p>2Total of 517 subjects contributed a total of 18857 samples.</p><p>ALP = alkaline phosphate; SGPT or ALT = alanine aminotransferase; SGOT or AST = aspartate aminotransferase; TBILI = total bilirubin; eGFR = estimated glomerular filtration rate; NR = not reported; Kt/V = dialyzer clearance of urea (K) • dialysis time over volume of distribution of urea, approximately equal to patient’s total body water.</p

Peginesatide parameter estimates and their associated precision for the final PK model, including bootstrap evaluation results.

<p>1.Based on 870/1000 successfully converged bootstrap runs.</p><p>2.PDIA = 1 for patients not on dialysis (covariate was considered only for those not on dialysis).</p

Prediction-corrected visual predictive checks for the final PK model of peginesatide following intravenous and subcutaneous dosing and the final PK-PD model of predicted hemoglobin levels.

<p>Upper left: visual predictive check for peginesatide PK model following intravenous administration; Upper right: visual predictive check for peginesatide PK model following subcutaneous administration; Lower panel: visual predictive check for hemoglobin based on final population PK-PD model for peginesatide.</p