Population Pharmacokinetics of Meropenem in Preterm Infants

Background. Meropenem, a broad spectrum carbapenem antibiotic, is often used for newborns despite of limited data available on neonatal pharmacokinetics. Due to pharmacokinetic and pharmacodynamic differences as well as to significant changes in the human body related to growth and maturation of organs and systems, direct scaling and dosing extrapolation from adults or older children with adjustment on patients weight can result in increased risk of toxicity or treatment failures. Aims to evaluate the pharmacokinetics of meropenem in premature neonates based on therapeutic drug monitoring data in real clinical settings. Materials. Of 53 pre-term neonates included in the pharmacokinetic/pharmacodynamic analysis, in 39 (73.6%) patients, gestational age ranged from 23 to 30 weeks. Population and individual pharmacokinetic parameter values were estimated by the NPAG program from the Pmetrics package based on peak-trough therapeutic drug monitoring. Samples were assayed by high-performance liquid chromatography. One-compartment pharmacokinetic model with zero-order input and first-order elimination was used to fit concentration data and to predict pharmacokinetic parameter (%T MIC of free drug) for virtual patients with simulated fast, moderate and slow meropenem elimination received different dosage by minimum inhibitory concentration (MIC) level. Univariate and multivariate regression analysis was used to evaluate the influence of patients covariates (gestational age, postnatal age, postconceptual age, body weight, creatinine clearance calculated by Schwartz formula, etc) on estimated meropenem pharmacokinetic parameters. Results. The identified population pharmacokinetic parameters of meropenem in pre-term newborns (elimination half-lives T1/2 = 1.93 0.341 h; clearance CL = 0.26 0.085 L/h/ kg; volume of distribution V = 0.71 0.22 L/h) were in good agreement with those published in the literature for adults, neonates and older children. Pharmacokinetic/pharmacodynamic modeling demonstrated that a meropenem dosage regimen of 90 mg/kg/day administered using prolonged 3-hour infusion every 8 hours should be considered as potentially effective therapy if nosocomial infections with resistant organisms (MIC 8 mg/L) are treated. Conclusions. Neonates and especially pre-term neonates have a great pharmacokinetic variability. Meropenem dosing in premature newborns derived from population pharmacokinetic/pharmacodynamic model can partly overcome the variability, but not all pharmacokinetic variability can be explained by covariates in a model. Further personalizing based on Bayesian forecasting approach and a patients therapeutic drug monitoring data can help to achieve desired pharmacodynamic target.

Micronutrient Deficiency in Pulmonary Tuberculosis – Perspective on hepatic drug metabolism and pharmacokinetic variability of first-line anti-tuberculosis drugs: Special reference to fat-soluble vitamins A, D, & E and nutri-epigenetics

: The liver plays a crucial role in endogenous metabolic activity and homeostasis of macro and micronutrients. Further, it acts as a metabolic hub in mammals, where the ingested food-derived nutrients and xenobiotics or drugs are metabolized for utilization and/or excretion through its enzymatic and non-enzymatic machinery. Nutritional deficiency, one of the major public health problems, is associated with global disease burden, including pulmonary tuberculosis (PTB) caused by Mycobacterium tuberculosis (Mtb) infection. Though it is a curable and preventable infectious disease, millions of people succumb to death, and people in numbers larger than this are still suffering. This scenario is further complicated by the addition of new cases, disease recurrence, and the emergence of drug-resistant, all of which contribute to the spread of this epidemic. Though the manifestation of TB disease has multiple aetiologies, poor nutritional status and sub-optimal therapeutic concentrations of first-line anti-TB drugs are considered as potential contributors to its widespread prevalence. Among various factors, the pharmacokinetic variability of anti-TB drugs is one of the main causes for sub-optimal therapeutic drug concentration in TB patients, which is influenced by the host’s genetic make-up and nutritional status, besides several others. However, the role of epigenetic changes in hepatic drug metabolic pathways and their transcript levels is largely unexplored. Therefore, in this review, an attempt has been made to understand the role of micronutrient deficiencies with special reference to fat-soluble vitamins, namely vitamin A, D, & E in pulmonary TB, their possible impact on epigenetic changes on the drug-metabolizing pathway genes, thus their expression levels and plausible influence on pharmacokinetic variability of anti-TB drugs, besides discussing the limitations and emerging potential opportunities. Eventually, this would help in developing the host-directed/personalized therapeutic strategies for the elimination of pulmonary tuberculosis (PTB).

The pharmacogenetics of treatment with olanzapine

Genetic polymorphism in olanzapine-metabolizing enzymes, transporters and drug targets is associated with alterations in safety and efficacy. The aim of this systematic review is to describe all clinically relevant pharmacogenetic information on olanzapine and to propose clinically actionable variants. Two hundred and eighty-four studies were screened; 76 complied with the inclusion criteria and presented significant associations. DRD2 Taq1A (rs1800497) *A1, LEP -2548 (rs7799039) G and CYP1A2*1F alleles were related to olanzapine effectiveness and safety variability in several studies, with a high level of evidence. DRD2 –141 (rs1799732) Ins, A-241G (rs1799978) G, DRD3 Ser9Gly (rs6280) Gly, HTR2A rs7997012 A, ABCB1 C3435T (rs1045642) T and G2677T/A (rs2032582) T and UGT1A4*3 alleles were related to safety, effectiveness and/or pharmacokinetic variability with moderated level of evidence.

Case Report: Low Hematocrit Leading to Tacrolimus Toxicity

Tacrolimus is a calcineurin inhibitor characterized by a narrow therapeutic index and high intra- and inter-individual pharmacokinetic variability. Therapeutic drug monitoring in whole-blood is the standard monitoring procedure. However, tacrolimus extensively binds to erythrocytes, and tacrolimus whole-blood distribution and whole-blood trough concentrations are strongly affected by hematocrit. High whole-blood tacrolimus concentrations at low hematocrit may result in high unbound plasma concentrations and increased toxicity. We present the case of a 16-year-old girl with kidney and liver transplant in whom low concentrations of tacrolimus in the context of low hematocrit led to significant increase in the dosage of tacrolimus and participate, along with a genetic polymorphism of ABCB1, in nephrotoxicity.

Gut Microbiota and Host Cyp450s Co-contribute to Pharmacokinetic Variability in Mice With Non-Alcoholic Steatohepatitis: Vary From Drug to Drug

Background: Pharmacokinetic variability in disease state is common in clinical practice, but the underlying mechanism remains unclear. We aim to investigate the effects of gut microbiota and host Cyp450s on pharmacokinetic variability in mice with non-alcoholic steatohepatitis (NASH).Methods: The pharmacokinetic variability of mice with NASH was explored under intragastric and intravenous administration of a cocktail mixture of omeprazole, phenacetin, midazolam, tolbutamide, chlorzoxazone, and metoprolol compared with the control group. The pharmacokinetic variability of the drugs and its relation with changes of gut microbiota and host Cyp450s were compared and analyzed.Results: The exposure of all drugs, except metoprolol, significantly increased in the NASH group under intragastric administration. However, no significant increase in the exposure of all drugs, except tolbutamide, was observed in the NASH group under intravenous administration. The pharmacokinetic variabilities of phenacetin, midazolam, omeprazole, and chlorzoxazone were mainly associated with decreased elimination activity of the gut microbiota. By contrast, the pharmacokinetic variability of tolbutamide was mainly related to the change in host Cyp2c65. However, gut microbiota and host Cyp450s exerted minimal effect on the pharmacokinetic variability of metoprolol.Conclusions: Gut microbiota and host Cyp450s co-contribute the pharmacokinetic variability in mice with NASH, and the degree of contribution varies from drug to drug.