Scientific and regulatory evaluation of empirical pharmacometric models: An application of the risk informed credibility assessment framework.

Empirical pharmacometric models are part of practically every regulatory submission for a new drug. The use of the models often exceeds descriptory roles and this change in their context of use increase the requirements on the evidence to support that they are credible. However, when it comes to assessing the trust in a model for a specific application, current tools are skewed to technical aspects and guidance documents often focused on model reporting or the iterative learning loops of model informed drug development (MIDD). There is an unmet need for a holistic tool that provide an end-to-end link from the initial question to the model-informed decision. We suggest the risk-informed credibility framework can be used for this purpose and offers strong support for the pharmacometrics models. We also introduce two tables for explicit description of key attributes of the model evaluation to facilitate and streamline the communication between stakeholders.

Dose Rationale for Amoxicillin in Neonatal Sepsis When Referral Is Not Possible.

BACKGROUND: Despite the widespread use of amoxicillin in young children, efforts to establish the feasibility of simplified dosing regimens in resource-limited settings have relied upon empirical evidence of efficacy. Given the antibacterial profile of beta-lactams, understanding of the determinants of pharmacokinetic variability may provide a more robust guidance for the selection of a suitable regimen. Here we propose a simplified dosing regimen based on pharmacokinetic-pharmacodynamic principles, taking into account the impact of growth, renal maturation and disease processes on the systemic exposure to amoxicillin. MATERIALS AND METHODS: A meta-analytical modeling approach was applied to allow the adaptation of an existing pharmacokinetic model for amoxicillin in critically ill adults. Model parameterization was based on allometric concepts, including a maturation function. Clinical trial simulations were then performed to characterize exposure, as defined by secondary pharmacokinetic parameters (AUC, Cmax, Cmin) and T>MIC. The maximization of the T>MIC was used as criterion for the purpose of this analysis and results compared to current WHO guidelines. RESULTS: A two-compartment model with first order absorption and elimination was found to best describe the pharmacokinetics of amoxicillin in the target population. In addition to the changes in clearance and volume distribution associated with demographic covariates, our results show that sepsis alters drug distribution, leading to lower amoxicillin levels and longer half-life as compared to non-systemic disease conditions. In contrast to the current WHO guidelines, our analysis reveals that amoxicillin can be used as a fixed dose regimen including two weight bands: 125 mg b.i.d. for patients with body weight < 4.0 kg and 250 mg b.i.d. for patients with body weight ≥ 4.0 kg. CONCLUSIONS: In addition to the effect of developmental growth and renal maturation, sepsis also alters drug disposition. The use of a model-based approach enabled the integration of these factors when defining the dose rationale for amoxicillin. A simplified weight-banded dosing regimen should be considered for neonates and young infants with sepsis when referral is not possible.

Commentary on the MID3 Good Practices Paper.

During the last 10 years the European Medicines Agency (EMA) organized a number of workshops on modeling and simulation, working towards greater integration of modeling and simulation (M&S) in the development and regulatory assessment of medicines. In the 2011 EMA - European Federation of Pharmaceutical Industries and Associations (EFPIA) Workshop on Modelling and Simulation, European regulators agreed to the necessity to build expertise to be able to review M&S data provided by companies in their dossier. This led to the establishment of the EMA Modelling and Simulation Working Group (MSWG). Also, there was agreement reached on the need for harmonization on good M&S practices and for continuing dialog across all parties. The MSWG acknowledges the initiative of the EFPIA Model-Informed Drug Discovery and Development (MID3) group in promoting greater consistency in practice, application, and documentation of M&S and considers the paper is an important contribution towards achieving this objective.

Modelled target attainment after meropenem infusion in patients with severe nosocomial pneumonia: the PROMESSE study.

OBJECTIVES: The objective of this study was to propose an optimal treatment regimen of meropenem in critically ill patients with severe nosocomial pneumonia. PATIENTS AND METHODS: Among 55 patients in intensive care treated with 1 g of meropenem every 8 h for severe nosocomial pneumonia, 30 were assigned to intermittent infusion (II; over 0.5 h) and 25 to extended infusion (EI; over 3 h) groups. Based on plasma and epithelial lining fluid (ELF) concentrations determined at steady-state, pharmacokinetic modelling and Monte Carlo simulations were undertaken to assess the probability of attaining drug concentrations above the MIC for 40%-100% of the time between doses (%T > 1-fold and 4-fold MIC), for 1 or 2 g administered by either method. RESULTS: Penetration ratio, measured by the ELF/plasma ratio of AUCs, was statistically higher in the EI group than in the II group (mean ± SEM: 0.29 ± 0.030 versus 0.20 ± 0.033, P = 0.047). Considering a maximum susceptibility breakpoint of 2 mg/L, all dosages and modes of infusions achieved 40%-100% T > 1-fold MIC in plasma, but none did so in ELF, and only the 2 g dose over EI achieved 40%-100% T > 4-fold MIC in plasma. CONCLUSIONS: The optimum regimen to treat severe nosocomial pneumonia was 2 g of meropenem infused over 3 h every 8 h. This regimen achieved the highest pharmacodynamic targets both in plasma and in ELF.

Population pharmacokinetic analysis of tacrolimus in the first year after pediatric liver transplantation.

PURPOSES: Tacrolimus (TAC) is the most widely used immunosuppressant for the prevention of acute rejection after solid organ transplantation. Its pharmacokinetics (PK) show considerable variability, making TAC a good candidate for therapeutic drug monitoring (TDM). The principal aim of the study was to describe the PK of TAC in pediatric patients during the first year after transplantation. METHODS: Routine TDM trough levels of TAC were obtained from 42 pediatric liver allograft recipients during the first year after transplantation. A population PK model was developed using nonlinear mixed-effects modeling to describe TAC PK during this period and to explain the observed variability by means of patients' demographics, biochemical test results and physiological characteristics. RESULTS: The PK of TAC were best described by a two-compartment model with first-order elimination. Apparent volumes of the central compartment, intercomparmental clearance and maximum blood clearance estimates were 253 L, 115 L/day and 314 L/day, respectively. The absorption first-order rate and volume of peripheral compartment were fixed to 4.5 h(-1) and 100 L, respectively. While hematocrit levels, time after transplantation and bodyweight influenced TAC clearance, bodyweight was the only covariate retained on volume of distribution. CONCLUSIONS: We developed a TAC population PK model in pediatrics covering the first year after liver transplantation that may serve as a tool for TAC dose individualization as part of TDM.

A simultaneous d-optimal designed study for population pharmacokinetic analyses of mycophenolic Acid and tacrolimus early after renal transplantation.

Mycophenolic acid (MPA) and tacrolimus (TAC) are immunosuppressive agents used in combination with corticosteroids for the prevention of acute rejection after solid organ transplantation. Their pharmacokinetics (PK) show considerable unexplained intraindividual and interindividual variability, particularly in the early period after transplantation. The main objective of the present work was to design a study based on D-optimality to describe the PK of the 2 drugs with good precision and accuracy and to explain their variability by means of patients' demographics, biochemical test results, and physiological characteristics. Pharmacokinetic profiles of MPA and TAC were obtained from 65 stable adult renal allograft recipients on a single occasion (ie, day 15 after transplantation). A sampling schedule was estimated based on the D-optimality criterion with the POPED software, using parameter values from previously published studies on MPA and TAC modeling early after transplantation. Subsequently, a population PK model describing MPA and TAC concentrations was developed using nonlinear mixed-effects modeling. Optimal blood-sampling times for determination of MPA and TAC concentrations were estimated to be at 0 (predose) and at 0.24, 0.64, 0.98, 1.37, 2.38, and 11 hours after oral intake of mycophenolate and TAC. The PK of MPA and TAC were best described by a 2-compartment model with first-order elimination. For MPA, the absorption was best described by a transit compartment model, whereas first-order absorption with a lag time best described TAC transfer from the gastrointestinal tract. Parameters were estimated with good precision and accuracy. While hematocrit levels and CYP3A5 genetic polymorphism significantly influenced TAC clearance, the pharmaceutical formulation and MRP2 genetic polymorphism were retained as significant covariates on MPA absorption and elimination, respectively. The prospective use of the simultaneous D-optimal design approach for MPA and TAC has allowed good estimation of MPA and TAC PK parameters in the early period after transplantation characterized by a very high unexplained variability. The influence of some relevant covariates could be shown.

Time of drug administration, CYP3A5 and ABCB1 genotypes, and analytical method influence tacrolimus pharmacokinetics: a population pharmacokinetic study.

Tacrolimus (TAC) pharmacokinetics are characterized by a very high variability that complicates its therapeutic use. The aims of this study were: 1) to identify and model the effect of demographic, clinical, and genetic factors and time of drug administration on TAC pharmacokinetic variability; and 2) to assess the influence of the analytical method by modeling the TAC blood concentrations measured simultaneously by microparticle enzyme immune assay (MEIA) and liquid chromatography-tandem mass spectroscopy. Data from 19 renal transplant candidates were analyzed. A total of 266 blood samples were analyzed for TAC by both techniques. Linear regression and Bland and Altman analyses were performed to compare TAC blood concentrations obtained with MEIA and liquid chromatography-tandem mass spectroscopy. A population pharmacokinetic analysis was performed. As expected, blood concentrations obtained by MEIA were higher than those obtained by liquid chromatography-tandem mass spectroscopy. A two-compartment model with first-order absorption and elimination best fit TAC blood concentrations. An exponential model was used to describe the interindividual and interoccasion variability and a mixed model was retained for the residual variability. A supplementary proportional term was necessary for the residual error in case of TAC blood concentrations determined by MEIA. The following covariates were retained in the final model: time of drug administration on the absorption rate constant and CYP3A5 and ABCB1 genotypes on the TAC apparent clearance. All parameter estimates had reliable values. The final model was found to be stable and generated parameters with good precision. The validation of the final model by bootstrapping (2000 bootstraps), case deletion diagnostics, crossvalidation, and visual predictive check (1000 simulated subjects) gave satisfactory results. This is the first population pharmacokinetic study confirming the chronopharmacokinetics of TAC and showing an effect of ABCB1 genotype and analytical method on TAC pharmacokinetics. These results may be helpful for TAC dose individualization.

A fast ultra-performance liquid chromatography method for simultaneous quantification of mycophenolic acid and its phenol- and acyl-glucuronides in human plasma.

Several studies have demonstrated a close relationship between mycophenolic acid (MPA) exposure and the risk for graft rejection or side effects. Measurements of MPA and its metabolites plasma levels are therefore recommended. A new chromatographic method has been developed using ultra-performance liquid chromatography (UPLC) to improve both analytical throughput and sensitivity. MPA and its phenol-glucuronide and acyl-glucuronide were extracted from plasma using Isolute C2 solid phase extraction (SPE) cartridges (100 mg, 3 mL). UPLC separations were performed with a Waters BEH C18 column (50 x 2.1 mm, 1.7 microm) maintained at 65 degrees C on a Waters Acquity instrument equipped with a photodiode array detector. The total UPLC run time was 3.5 minutes. The method was linear in the range of 0.1-40 microg/mL for MPA and acyl-glucuronide, and 1-400 microg/mL for phenol-glucuronide. Relative standard error and mean relative prediction error were <15% for all tested quality controls (in-house and external proficiency panels). UPLC performances are characterized by a dramatic reduction in retention times together with an improvement of the sensitivity without affecting peak resolution. Further validations have been obtained by analyzing routine and clinical trial patients' samples. Significant improvement of the analytical throughput (reduction of run time from >10 to 3.5 minutes) was obtained using UPLC for MPA analyses. This retention time reduction was accompanied by an improvement of other analytical performances such as sensitivity.