Optimizing Moxifloxacin Dose in MDR-TB Participants with or without Efavirenz Coadministration Using Population Pharmacokinetic Modeling.

Moxifloxacin is included in some treatment regimens for drug-sensitive tuberculosis (TB) and multidrug-resistant TB (MDR-TB). Aiming to optimize dosing, we described moxifloxacin pharmacokinetic and MIC distribution in participants with MDR-TB. Participants enrolled at two TB hospitals in South Africa underwent intensive pharmacokinetic sampling approximately 1 to 6 weeks after treatment initiation. Plasma drug concentrations and clinical data were analyzed using nonlinear mixed-effects modeling with simulations to evaluate doses for different scenarios. We enrolled 131 participants (54 females), with median age of 35.7 (interquartile range, 28.5 to 43.5) years, median weight of 47 (42.0 to 54.0) kg, and median fat-free mass of 40.1 (32.3 to 44.7) kg; 79 were HIV positive, 29 of whom were on efavirenz-based antiretroviral therapy. Moxifloxacin pharmacokinetics were described with a 2-compartment model, transit absorption, and elimination via a liver compartment. We included allometry based on fat-free mass to estimate disposition parameters. We estimated an oral clearance for a typical patient to be 17.6 L/h. Participants treated with efavirenz had increased clearance, resulting in a 44% reduction in moxifloxacin exposure. Simulations predicted that, even at a median MIC of 0.25 (0.06 to 16) mg/L, the standard daily dose of 400 mg has a low probability of attaining the ratio of the area under the unbound concentration-time curve from 0 to 24 h to the MIC (fAUC0-24)/MIC target of >53, particularly in heavier participants. The high-dose WHO regimen (600 to 800 mg) yielded higher, more balanced exposures across the weight ranges, with better target attainment. When coadministered with efavirenz, moxifloxacin doses of up to 1,000 mg are needed to match these exposures. The safety of higher moxifloxacin doses in clinical settings should be confirmed.

Altered drug exposures of first-line TB drugs in a moxifloxacin-containing treatment regimen.

BACKGROUND: Pharmacokinetic variability arising from drug-drug interactions and pharmacogenetics may influence the effectiveness of treatment regimens for TB. The Improving Treatment Success Trial compared the WHO-recommended standard treatment in TB patients with an experimental regimen substituting ethambutol with moxifloxacin (MFX) in Durban, South Africa.METHODS: Non-linear mixed-effects modelling was used to investigate the population pharmacokinetics of rifampicin (RIF), isoniazid (INH) and pyrazinamide (PZA). A total of 25 single-nucleotide polymorphisms, including pregnane-X-receptor, were selected for analysis.RESULTS: TB drug concentrations were available in a subset of 101 patients: 58 in the MFX arm and 43 in the control arm. Baseline characteristics were well-balanced between study arms: median age and weight were respectively 36 years and 57.7 kg; 75.2% of the patients were living with HIV. Although weight-based drug dosing was the same in the two arms, we found that RIF exposure was increased by 19.3%, INH decreased by 19% and PZA decreased by 19.2% when administered as part of the MFX-containing regimen. Genetic variation in pregnane-X-receptor (rs2472677) was associated with a 25.3% reduction in RIF exposure.CONCLUSION: Optimised weight-based TB treatment dosing is essential when RIF, INH and PZA are co-administered with fluoroquinolones. The reduction in RIF exposure associated with pharmacogenetic variation is worrying.

Clinical standards for the dosing and management of TB drugs.

BACKGROUND: Optimal drug dosing is important to ensure adequate response to treatment, prevent development of drug resistance and reduce drug toxicity. The aim of these clinical standards is to provide guidance on 'best practice´ for dosing and management of TB drugs.METHODS: A panel of 57 global experts in the fields of microbiology, pharmacology and TB care were identified; 51 participated in a Delphi process. A 5-point Likert scale was used to score draft standards. The final document represents the broad consensus and was approved by all participants.RESULTS: Six clinical standards were defined: Standard 1, defining the most appropriate initial dose for TB treatment; Standard 2, identifying patients who may be at risk of sub-optimal drug exposure; Standard 3, identifying patients at risk of developing drug-related toxicity and how best to manage this risk; Standard 4, identifying patients who can benefit from therapeutic drug monitoring (TDM); Standard 5, highlighting education and counselling that should be provided to people initiating TB treatment; and Standard 6, providing essential education for healthcare professionals. In addition, consensus research priorities were identified.CONCLUSION: This is the first consensus-based Clinical Standards for the dosing and management of TB drugs to guide clinicians and programme managers in planning and implementation of locally appropriate measures for optimal person-centred treatment to improve patient care.

Pharmacokinetics of Sulfadoxine and Pyrimethamine for Intermittent Preventive Treatment of Malaria During Pregnancy and After Delivery.

Sulfadoxine/pyrimethamine is recommended for intermittent preventative treatment of malaria during pregnancy. Data from 98 women during pregnancy and 77 after delivery in four African countries were analyzed using nonlinear mixed-effects modeling to characterize the effects of pregnancy, postpartum duration, and other covariates such as body weight and hematocrit on sulfadoxine/pyrimethamine pharmacokinetic properties. During pregnancy, clearance increased 3-fold for sulfadoxine but decreased by 18% for pyrimethamine. Postpartum sulfadoxine clearance decreased gradually over 13 weeks. This finding, together with hematocrit-based scaling of plasma to whole-blood concentrations and allometric scaling of pharmacokinetics parameters with body weight, enabled site-specific differences in the pharmacokinetic profiles to be reduced significantly but not eliminated. Further research is necessary to explain residual site-specific differences and elucidate whether dose-optimization, to address the 3-fold increase in clearance of sulfadoxine in pregnant women, is necessary, viable, and safe with the current fixed dose combination of sulfadoxine/pyrimethamine.

Pharmacometrics: opportunity for reducing disease burden in the developing world: the case of Africa.

Pharmacometricians are virtually nonexistent in Africa and the developing world. The unrelenting burden of infectious diseases, which are often treated using medicines with narrow effectiveness and safety dose ranges, and the growing prevalence and recognition of non-communicable diseases represent significant threats for the patients, although affording an opportunity for advancing science. This article outlines the case for pharmacometricians to redirect their expertise to focus on the disease burden affecting the developing world.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e69; doi:10.1038/psp.2013.45; published online 28 August 2013.

The pharmacokinetics of nevirapine when given with isoniazid in South African HIV-infected individuals.

Isoniazid preventive therapy (IPT) is recommended in patients on antiretroviral treatment. Isoniazid (INH) inhibits CYP3A4, which metabolises nevirapine (NVP). Administration of INH may cause higher NVP concentrations and toxicity. We studied the effect of INH on NVP concentrations in 21 patients randomised to either placebo (n = 13) or INH (n = 8) in an ongoing trial of IPT in patients on ART. INH was associated with a 24% increase in median NVP area under the plasma concentration-time curve for the 12 h dosing interval, which was not statistically significant (P = 0.66).

Review of the MitraClip clinical evidence.

MitraClip system is the only catheter-based device for percutaneous mitral valve repair available for clinical use, after receipt of the CE Mark in 2008, while it is currently under review for FDA approval in the US. To date, over 3500 MitraClip implants have been performed worldwide, mainly in high risk surgical patients. The aim of this review is to review all the current evidences of the MitraClip therapy in an aim to define its clinical role in the treatment of mitral regurgitation (MR).

Patient selection for MitraClip therapy impaired left ventricular systolic function.

Mitral regurgitation (MR) is a disabling disease associated with poor prognosis and high incidence of clinical events if left untreated. To reduce the invasiveness of the surgical approach, different types of transcatheter procedures are becoming available. The MitraClip procedure (Abbott Vascular Inc. Menlo Park, CA, USA) is yet the only catheter-based procedure available in clinical practice at the moment. The device has been evaluated in a number of preclinical studies, registries and in FDA approved clinical trials. (EVEREST trial, ACCESS-EU trial). Indication and timing of intervention is a crucial step in the diagnostic-therapeutic pathway of patients with mitral regurgitation. The aim of this review is to clarify the potential of MitraClip in clinical practice, particularly focusing on patient selection for this novel therapy. Patient selection and overall decision making is strongly influenced by anatomical and clinical factors. Decision-making in degenerative MR (DMR) vs. functional (FMR) can be quite different. Generally, MitraClip is effective in treating either type II or IIIb dysfunction (at the moment FMR is the main indication for MitraClip in Europe, according to the ACCESS registry data). The relative role of MitraClip and surgery in the management of patients with MR is still unclear. From the global initial experience, MitraClip therapy could be complementary to surgery in those patients at high risk for surgery who have ideal anatomical characteristics for implantation. The procedure is quite predictable in patients with favorable anatomy. In patients with suboptimal anatomy, if the risk of surgery is too high, MitraClip could be still indicated sometimes. Our preliminary experience suggests that in patients with DMR, the EVEREST anatomical criteria are strong predictors of early and mid-term success. According to it, MitraClip therapy is appropriate in those DMR patients with high surgical risk and ideal anatomy for clip implantation according to the EVEREST criteria. In FMR refractory to medical therapy and resynchronization therapy, MitraClip could be considered as first option therapy, particularly in those patients with comorbidities, or advanced age, being the operative risk of surgery above 5% in this population. In the future, novel devices, improved knowledge, more efficient imaging and transcatheter mitral prosthetic valve implantation may expand the indications to those patients currently not treated by MitraClip for anatomical unsuitability, and may improve the results both in term of early efficacy and long term durability.

Radiation torque and force on optically trapped linear nanostructures.

We study the optical trapping of highly elongated linear nanostructures in the focal region of a high-numerical aperture lens (optical tweezers). The radiation torque and trapping force on these nanostructures that are modeled as chains of identical spherical scatterers are calculated by means of multipole field expansions in the framework of the transition matrix approach. We investigate both orientational and trapping stability and calculate force constants and trap parameters in order to clarify the role of the linear geometry in the optical trapping mechanism. Furthermore, we calculate optical trapping of nanowires of different materials and compare our theoretical findings with available experimental results.

A cardioplegia circuit with versatility: the 'ReVerse' system. How to do it.

Various methods of cardioplegia administration have been used in cardiac surgery: crystalloid, blood and mixed crystalloid/blood. Each of these types of cardioplegia administration typically needs a different circuit. This may correspond to an increase in cost and the time needed to change the circuit if required. When various modifications are performed on the circuit, this also increases the risk of contamination. In order to simplify the management of differing cardioplegia circuits, we devised one circuit for all solutions in all situations by adding one modification. The ReVerse cardioplegia circuit system is a description of a two-pump cardioplegia circuit which is adaptable to either blood or crystalloid cardioplegia. The change from one mode to another requires a manoeuvre of two clamps, allowing the blood solution to travel through shunt tubing into the apposite pumphead. In our experience the versatility of this circuit is a fast, safe method to administrate all types of cardioplegia solution, saving the space taken up by storing multiple circuits.

Identification of IVGTT minimal glucose model by nonlinear mixed-effects approaches.

Glucose minimal model parameters are commonly estimated by applying weighted nonlinear least squares to each individual subject's data. Sometimes, parameter precision is not satisfactory, especially in "data poor" conditions. In this work, the use of population analysis through nonlinear-mixed effects models is evaluated and its performance tested against the parameter estimates obtained by the standard individual approach through weighted nonlinear least squares. In particular, we compared the performance of two likelihood approximation methods to estimate nonlinear mixed-effects model parameters, i.e. the first-order conditional estimation (FOCE) and the Laplace approximation (Laplace) methods. The results show that nonlinear mixed-effects population modeling using the FOCE approximation can be successfully used in order to accurately estimate individual minimal model parameters.

Backscattered intensity from model atmospheric ice crystals in the millimeter-wave range.

The effectiveness of modeling atmospheric ice crystals of varying aspect ratios as clusters of spheres is investigated by calculation of the backscattered intensity in the millimeter-wave range by the transition matrix approach. Both single crystals and dispersions with a few choices of the orientational distribution are considered. Our calculations reproduce the features of the backscattered intensity that are due to the overall symmetry of the crystals and yield results in agreement with analogous calculations performed by other authors within the framework of the discrete dipole approximation.

Optical properties of a dispersion of randomly oriented identical aggregates of spheres deposited on a plane surface.

Our previous theory for calculating the scattering pattern from a single aggregate of spheres deposited on a dielectric substrate is extended to deal with a dispersion of identical aggregates onto the substrate with a random distribution of their orientations. To this end the definition of the transition matrix of an aggregate is generalized to take account of the presence of the substrate; then the transformation properties under rotation of the newly defined transition matrix are used to perform analytically the required orientational averages. When the patterns calculated with this theory are compared with the calculations for a single aggregate, it can easily be seen that the features that reveal the anisotropy of the scatterers are not canceled by the averaging procedure.

Resonance suppression in the extinction spectrum of single and aggregated hemispheres on a reflecting surface.

The extinction spectrum from single and aggregated hemispheres whose flat faces lie on a reflecting surface is calculated, and some of the expected resonances are found to disappear for specific choices of the direction and the polarization of the incident wave. This resonance-suppressing effect is fully explained for the case of single hemispheres, whereas for the case of aggregated hemispheres the guidelines for its explanation are given.

Effect of an electrostatic field on the optical properties of a cloud of dielectric particles.

The optical properties of a cloud of anisotropic dielectric particles when the orientational distribution is made nonrandom by interaction with an electrostatic field are studied. Since the interaction energy is determined by the polarizability of the particles, a general expression for the polarizability of nonspherical particles is worked out. In particular, we investigated the response to the electrostatic field of two different dispersions whose component particles are built as clusters of four identical spheres. Although in one cloud the clusters were shaped as linear chains, and in the other cloud the clusters were shaped as squares, the optical properties of both dispersions as a function of the static field are rather similar. There are, however, noticeable ranges of size within which the optical response of the two kinds of particles is substantially different.

Optical properties of spheres containing several spherical inclusions.

The formalism that was previously devised [J. Opt. Soc. Am. A 9, 1327 (1992)] to deal with the optical properties of homogeneous spheres containing an eccentric spherical inclusion is extended to the case of several inclusions. The extinction efficiency of dielectric spheres containing two identical metallic inclusions is calculated for a few significant geometries. Extinction by a low-density dispersion of the anisotropic scatterers mentioned above is also evaluated. Our results show that the subdivision of the included material has quite visible effects that strongly depend on both the polarization of the incident light and the geometric arrangement of the inclusions.

Histological evaluation of thyroid carcinomas: reproducibility of the "WHO" classification.

AIMS AND BACKGROUND: Thyroid carcinomas display several pathologic features, show different behavior and necessitate different treatment; thus correct classification is mandatory. METHODS: The kappa statistic was used as a measure of agreement in a panel of seven pathologists who reviewed 200 cases of thyroid tumors. RESULTS: Overall agreement was 83% (k = 68). Good agreement was found for anaplastic (k = 0.85) and papillary carcinomas (k = 0.81); agreement for medullary carcinoma was acceptable (k = 0.80), suboptimal for other (k = 0.67), and poor for follicular carcinoma (k = 0.54). CONCLUSIONS: Central pathology review of thyroid carcinomas is recommended when clinical and epidemiologic trials are planned.

Electromagnetic scattering by a cluster of spheres.

A method for studying the scattering properties of a cluster of dielectric spheres is proposed. The vector scattering problem is handled through Debye potentials and a mathematical technique that accounts for multiple scattering effects. The scattered field as well as the scattering and absorption cross sections can be computed without any restriction of principle on the angle of incidence of light and on the radia and refractive indexes of the spheres in the cluster. The resulting expressions take on the well known form when the cluster reduces to a single sphere.