Population Pharmacokinetic Analyses for Tebipenem after Oral Administration of Pro-Drug Tebipenem Pivoxil Hydrobromide.

Tebipenem pivoxil hydrobromide (TBP-PI-HBr) is an oral (PO) carbapenem pro-drug that is converted to the active moiety tebipenem in the enterocytes. Tebipenem has activity against multidrug-resistant Gram-negative pathogens, including extended-spectrum beta lactamase-producing Enterobacterales, and is being developed for the treatment of patients with complicated urinary tract infections (cUTI) and acute pyelonephritis (AP). The objectives of these analyses were to develop a population pharmacokinetic (PK) model for tebipenem using data from three phase 1 studies and one phase 3 study and to identify covariates that described the variability in tebipenem PK. Following construction of the base model, a covariate analysis was conducted. The model was then qualified by performing a prediction-corrected visual predictive check and evaluated by using a sampling-importance-resampling procedure. The final population PK data set was composed of data from 746 subjects who provided 3,448 plasma concentrations, including 650 patients (1,985 concentrations) with cUTI/AP. The final population PK model that best described tebipenem PK was found to be a two-compartment model with linear, first-order elimination and two transit compartments to describe the rate of drug absorption after PO administration of TBP-PI-HBr. The relationship between renal clearance (CLR) and creatinine clearance (CLcr), the most clinically significant covariate, was described using a sigmoidal Hill-type function. No dose adjustments are warranted on the basis of age, body size, or sex as none of these covariates were associated with substantial differences in tebipenem exposure in patients with cUTI/AP. The resultant population PK model is expected to be appropriate for model-based simulations and assessment of pharmacokinetic-pharmacodynamic relationships for tebipenem.

Evaluation of the Impact of Comorbidities on Omadacycline Pharmacokinetics.

Omadacycline is approved in the United States for the treatment of patients with community-acquired bacterial pneumonia or acute bacterial skin and skin structure infections. Analyses were undertaken to evaluate pharmacokinetic differences among subjects or patients stratified by comorbidities. Differences in clearance by smoking status, history of diabetes mellitus, chronic lung disease, hypertension, heart failure, or coronary artery disease were evaluated using a Welch two-sample t test. Smoking was the only significant comorbidity after correction for sex, with a clinically insignificant difference of 13%. Omadacycline dose adjustments based on these comorbidities do not appear to be warranted.

Pharmacokinetic-Pharmacodynamic Target Attainment Analyses as Support for Meropenem-Vaborbactam Dosing Regimens and Susceptibility Breakpoints.

Meropenem-vaborbactam is a fixed-dose beta-lactam/beta-lactamase inhibitor with potent in vitro and in vivo activity against Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacterales. Pharmacokinetic-pharmacodynamic (PK-PD) target attainment analyses were undertaken using population pharmacokinetic models, nonclinical PK-PD targets for efficacy, in vitro surveillance data, and simulation to provide support for 2 g meropenem-2 g vaborbactam every 8 h (q8h) administered as a 3-h intravenous (i.v.) infusion, and dosing regimens adjusted for patients with renal impairment. Simulated patients varying by renal function measure (estimated glomerular filtration rate [eGFR], mL/min/1.73 m2 and absolute eGFR, mL/min) and resembling the clinical trial population (complicated urinary tract infection, including acute pyelonephritis) were generated. The PK-PD targets for meropenem, the percentage of time on day 1 that free-drug plasma concentrations were above the MIC (%T>MIC), and vaborbactam, the ratio of free-drug plasma area under the concentration-time curve (AUC) on day 1 to the MIC (AUC:MIC ratio), were calculated. Percent probabilities of achieving meropenem free-drug plasma %T>MIC and vaborbactam free-drug plasma AUC:MIC ratio targets were assessed. MIC distributions for Enterobacterales, KPC-producing Enterobacterales, and Pseudomonas aeruginosa were considered as part of an algorithm to assess PK-PD target attainment. For assessments of free-drug plasma PK-PD targets associated with a 1-log10 CFU reduction from baseline, percent probabilities of PK-PD target attainment ranged from 81.3 to 100% at meropenem-vaborbactam MIC values of 4 or 8 µg/mL among simulated patients. The results of these PK-PD target attainment analyses provide support for a dosing regimen of 2 g meropenem-2 g vaborbactam q8h administered as a 3-h i.v. infusion, with dosing regimens adjusted for patients with renal impairment and a meropenem-vaborbactam susceptibility breakpoint of ≤8 µg/mL (tested with a fixed vaborbactam concentration of 8 µg/mL) for Enterobacterales and P. aeruginosa based on these dosing regimens.

Population Pharmacokinetics of Meropenem and Vaborbactam Based on Data from Noninfected Subjects and Infected Patients.

Meropenem-vaborbactam is a broad-spectrum carbapenem-beta-lactamase inhibitor combination approved in the United States and Europe to treat patients with complicated urinary tract infections and in Europe for other serious bacterial infections, including hospital-acquired and ventilator-associated pneumonia. Population pharmacokinetic (PK) models were developed to characterize the time course of meropenem and vaborbactam using pooled data from two phase 1 and two phase 3 studies. Multicompartment disposition model structures with linear elimination processes were fit to the data using NONMEM 7.2. Since both drugs are cleared primarily by the kidneys, estimated glomerular filtration rate (eGFR) was evaluated as part of the base structural models. For both agents, a two-compartment model with zero-order input and first-order elimination best described the pharmacokinetic PK data, and a sigmoidal Hill-type equation best described the relationship between renal clearance and eGFR. For meropenem, the following significant covariate relationships were identified: clearance (CL) decreased with increasing age, CL was systematically different in subjects with end-stage renal disease, and all PK parameters increased with increasing weight. For vaborbactam, the following significant covariate relationships were identified: CL increased with increasing height, volume of the central compartment (Vc) increased with increasing body surface area, and CL, Vc, and volume of the peripheral compartment were systematically different between phase 1 noninfected subjects and phase 3 infected patients. Visual predictive checks demonstrated minimal bias, supporting the robustness of the final models. These models were useful for generating individual PK exposures for pharmacokinetic-pharmacodynamic (PK-PD) analyses for efficacy and Monte Carlo simulations to evaluate PK-PD target attainment.

Impact on testicular function of a single ablative activity of 3.7 GBq radioactive iodine for differentiated thyroid carcinoma.

STUDY QUESTION: What are the consequences of radioactive iodine (RAI) therapy for testicular function? SUMMARY ANSWER: A single activity of 3.7 GBq RAI for differentiated thyroid carcinoma (DTC) treatment in young men transiently altered Sertoli cell function and induced sperm chromosomal abnormalities. WHAT IS KNOWN ALREADY: Few studies, mainly retrospective, have reported the potential impacts of RAI on endocrine and exocrine testicular function. STUDY DESIGN, SIZE, DURATION: A longitudinal prospective multi-center study on testicular function performed in DTC patients before a single 131I ablative activity of 3.7 GBq (V0) and at 3 months (V3) and 13 months (V13) after treatment. PARTICIPANTS/MATERIALS, SETTING, METHODS: Forty male patients, aged 18-55 years, with DTC participated. Hormonal analysis included FSH, LH, testosterone and inhibin B serum levels at V0, V3 and V13. Furthermore, sperm parameters, DNA fragmentation and sperm chromosomal abnormalities were evaluated at each time points. The differences in all parameters, between V0-V3, V0-V13 and V3-V13, were analyzed, using a Wilcoxon test. MAIN RESULTS AND THE ROLE OF CHANCE: Prior to RAI administration, all patients had normal gonadal function. At V3, a statistically significant increase in FSH levels and a decrease in inhibin B levels were observed and sperm concentration, as well as the percentage of morphologically normal spermatozoa, were significantly decreased (P < 0.0001). These modifications were transient as both sperm concentration and normal morphology rate returned to baseline values at V13. However, at this later time point, FSH and inhibin B levels were still impacted by RAI administration but remained in the normal range. Although no DNA fragmentation was observed at V3 nor V13, our study revealed a statistically significant increase in the number of sperm chromosomal abnormalities both at V3 (P < 0.001) and V13 (P = 0.01). LIMITATIONS, REASONS FOR CAUTION: Among the 40 patients included in the study, only 24 had all the parameters available at all visits. WIDER IMPLICATIONS OF THE FINDINGS: Prospective studies with longer term follow up would be helpful to determine whether the chromosome abnormalities persist. These studies would be required before sperm banking should be suggested for all patients. However, sperm preservation for DTC patients who require cumulative radioiodine activities higher than 3.7 GBq should be proposed. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Programme Hospitalier de Recherche Clinique, AP-HP (No. P040419). The authors report no conflict of interest in this work. TRIAL REGISTRATION NUMBER: NCT01150318.

Are dietary reports in a case-control study on thyroid cancer biased by risk perception of Chernobyl fallout?

BACKGROUND: In retrospective case-control studies performed following nuclear tests or nuclear accidents, individual thyroid radiation dose reconstructions are based on fallout and meteorological data from the residential area, demographic characteristics, and lifestyle as well as dietary information. Collecting the latter is a controversial step, as dietary declarations may be affected by the subjects' beliefs about their risk behavior. This report analyses the potential for such bias in a case-control study performed in eastern France. METHODS: The study included 765 cases of differentiated thyroid carcinoma matched with 831 controls. Risk perceptions and beliefs of cases and controls were compared using Chi2 tests and differences in dietary reports were analyzed using a two-way ANOVA. RESULTS: In general, atmospheric pollution and living near a nuclear power plant were the two major risks that may influence thyroid cancer occurrence cited by cases and controls. When focusing in particular on the consequences of the Chernobyl accident, cases were more likely to think that the consequences were responsible for thyroid cancer occurrence than controls. Vegetable consumption during the two months after the Chernobyl accident was correlated with the status of subjects, but not to their beliefs. Conversely, consumption of fresh dairy products was not correlated with the status or beliefs of subjects. CONCLUSION: We found no evidence of systematic bias in dietary reports according to the status or beliefs held by subjects about the link between thyroid cancer occurrence and Chernobyl fallout. As such, these dietary reports may be used in further studies involving individual dosimetric reconstructions.

VRAM-pedicled island flap for the coverage of an exposed prosthetic vascular graft in the suprapubic area.

The exposure of prosthetic vascular graft is a dangerous complication in revascularization procedures. In this case report, we describe a successful coverage of an exposed prosthetic femorofemoral vascular graft in the suprapubic area, with a vertical rectus abdominis myocutaneous (VRAM) island flap.

Population pharmacokinetic analysis for a single 1,200-milligram dose of oritavancin using data from two pivotal phase 3 clinical trials.

Oritavancin is a lipoglycopeptide antibiotic with activity against Gram-positive bacteria. Here we describe oritavancin population pharmacokinetics and the impact of patient-specific covariates on drug exposure variability. Concentration-time data were analyzed from two phase 3 clinical trials, SOLO I and SOLO II, in which oritavancin was administered as a single 1,200-mg dose to patients with acute bacterial skin and skin structure infections. A total of 1,337 drug concentrations from 297 patients (90% of whom had 4 or 5 pharmacokinetic samples) were available for analysis. A previously derived population model based on data from 12 phase 1, 2, and 3 oritavancin studies was applied to the SOLO data set. Alterations to the structural model were made, as necessary, based on model fit. Analyses utilized Monte Carlo parametric expectation maximization (S-ADAPT 1.5.6). The previous population pharmacokinetic model fit the data well (r(2) = 0.972), and population pharmacokinetic parameters were estimated with acceptable precision and lack of bias. Covariate evaluations revealed statistically significant relationships between central compartment volume and age and between clearance and height; however, these relationships did not indicate a clinically relevant impact on oritavancin exposure over the range of age and height observed in the SOLO studies. The mean (coefficient of variation [CV]) area under the plasma concentration-time curve from time zero to 72 h (AUC0-72) and maximum plasma concentration (Cmax) were 1,530 (36.9%) µg · h/ml and 138 (23%) µg/ml, respectively. The mean (CV) half-life at alpha phase (t1/2α), t1/2ß, and t1/2γ were 2.29 (49.8%), 13.4 (10.5%), and 245 (14.9%) hours, respectively. These analyses are the first to describe oritavancin pharmacokinetics following a single 1,200-mg dose. Covariate analyses suggested that no dose adjustments are required for renal impairment (creatinine clearance, >29 ml/min), mild or moderate hepatic impairment, age, weight, gender, or diabetes status.

Population pharmacokinetic analyses for BC-3781 using phase 2 data from patients with acute bacterial skin and skin structure infections.

BC-3781, a pleuromutilin antimicrobial agent, is being developed for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia. Data from a phase 2 study of patients with ABSSSI were used to refine a previous population pharmacokinetic (PK) model and explore potential predictors of PK variability. The previously derived population PK model based on data from three phase 1 studies was applied to sparse sampling data from a phase 2 ABSSSI study and modified as necessary. Covariate analyses were conducted to identify descriptors (e.g., body size, renal function, age) associated with interindividual variability in PK. All population PK analyses were conducted by using Monte Carlo parametric expectation maximization implemented in S-ADAPT 1.5.6. The population PK data set contained 1,167 concentrations from 129 patients; 95% of the patients had 5 or more PK samples (median, 11). The previous population PK model (three-compartment model with first-order elimination and nonlinear protein binding) provided an acceptable and unbiased fit to the data from the 129 patients. Population PK parameters were estimated with acceptable precision; individual clearance values were particularly well estimated (median individual precision of 9.15%). Graphical covariate evaluations showed no relationships between PK and age or renal function but modest relationships between body size and clearance and volume of distribution, which were not statistically significant when included in the population PK model. This population PK model will be useful for subsequent PK-pharmacodynamic analyses and simulations conducted to support phase 3 dose selection. (This study has been registered at ClinicalTrials.gov under registration no. NCT01119105.).

The localization of the distal perforators of posterior tibial artery: a cadaveric study for the correct planning of medial adipofascial flaps.

PURPOSE: The adipofascial flap, introduced by Lin in 1994, has many advantages compared to fasciocutaneous or free flaps. Its dissection is relatively easy and fast with low donor-site morbidity, and it does not alter the shape of the leg. The aim of this dissection study is to evaluate the anatomic localization of the most distal perforator of the posterior tibial vessels to provide an anatomical rationale for the safe harvesting of distally based medial adipofascial flaps of the leg. MATERIALS AND METHODS: 30 Lower limbs from 15 cadavers were used for this study. The most distal perforator from posterior tibial perforator artery, accompanied by at least one vein, was identified and its distance from the medial malleolus was noted. RESULTS: A distal perforator was found in all specimens; the mean caliber was 0.77 mm. In all cases, the perforator artery passed in the septum between flexor hallucis longus m. and flexor digitorum longus m. and was accompanied by two veins. In our series, the distance between the lowest perforator and the medial malleolus ranged from 3.5 to 8.2 cm. The median was 6.75 cm, the 5th percentile 4 cm and the 95th percentile 8.1 cm. The mean distance of the perforator from the medial tibial border was 1.23 cm. The mean ratio between the distance of perforator from the medial malleolus and the total leg length was 21%. CONCLUSION: Compared to all previous researches, our study has found more distal perforators from posterior tibial perforator artery. This fact may have important clinical consequences, because the anteromedial adipofascial flap would cover more distal soft tissue defects. Moreover, our data suggest some safety parameters to make the rising of a medial adipofascial leg flap safer in surgical practice.

A simple and cheap system to speed up and to control the tumescent technique procedure: the Tedde's system.

We have devised a low cost system to quickly infiltrate tumescent solution: we call it the "Tedde's system". This low-cost system offers an improvement in quality and quantity of the infiltration because all the procedure depends on the operators, reducing also the time of the infiltration and consequently of the whole surgical procedure. Moreover, this system can be applied to other surgical procedure that requires large infiltration volumes.

A new contrast agent for radiological and dissection studies of the arterial network of anatomic specimens.

PURPOSE: The aim of the present study is to propose a new contrast agent that can be easily applied both to CT and dissection studies to replace lead oxide based formulas for comparative anatomical analyses of the vascularisation of cadaveric specimens. METHODS: The infusion material was an epoxy resin, especially modified by the addition of barium sulphate to enhance its radiopacity. The final copolymer was toxicologically safe. To test the properties of the new material, several cadaveric limb injections were performed. The injected specimens were both CT scanned to perform 3D vascular reconstructions and dissected by anatomical planes. RESULTS: There was a perfect correspondence between the image studies and the dissections: even the smallest arteries on CT scan can be identified on the specimen and vice versa. The properties of the epoxy allowed an easy dissection of the vessels. CONCLUSIONS: The new imaging techniques available today, such as CT scan, can evaluate the vascular anatomy in high detail and 3D. This new contrast agent may help realising detailed vascular studies comparing CT scan results with anatomical dissections. Moreover, it may be useful for teaching surgical skills in the field of plastic surgery.

Pharmacometric Analyses to Support Early Development Decisions for LY2878735: A Novel Serotonin Norepinephrine Reuptake Inhibitor.

LY2878735 is a novel dual serotonin (5-hydroxytryptamine (5-HT)) and norepinephrine (NE) reuptake inhibitor (SNRI) in development for chronic pain indications. In vitro profile suggests a more balanced profile as compared with other SNRI's, which is expected to confer superior clinical efficacy. LY2878735 is metabolized partly by the genetically polymorphic cytochrome P450 (CYP) 2D6 pathway, raising pharmacokinetic (PK) variability concerns. Phase 1 PK and biomarker data were analyzed by pharmacometric methods to characterize the balance between dual-target engagement and adverse effects on heart rate (HR) and blood pressure (BP). A narrow range of plasma LY2878735 levels was associated with an acceptable balance. As compared with poor metabolizers (PM), CYP2D6 extensive metabolizers (EM) have 21- and threefold higher clearance and distribution volume, respectively. Even with a CYP2D6-based dosing paradigm, a superior therapeutic index comparable to duloxetine, a widely used SNRI, was not achievable and LY2878735 development was thus terminated. Model-based approach effectively synthesizes PK-pharmacodynamic (PD) relationships, enabling efficient early development decisions.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e66; doi:10.1038/psp.2013.43; published online 21 August 2013.

Bilobed perforator free flaps for combined hemitongue and floor-of-the-mouth defects.

INTRODUCTION: Combined hemiglossectomy and floor-of-the-mouth defects need accurate reconstructive planning to restore swallowing and speech function. The aim of this prospective study was to evaluate outcomes of the bilobed design applied to perforator free flaps for combined hemitongue and floor-of-the-mouth defects. PATIENTS AND METHODS: Twelve patients with a mean age of 71 years (range, 60-84) addressed to combined hemiglossectomy and floor-of-the-mouth resection and bilobed-shaped perforator free-flap reconstruction were prospectively enrolled. Defects were classified as follows: type 1, including only the anterior mobile portion of the tongue (n = 3); type 2, involving both mobile tongue and tongue base (n = 6); and type 3, including segmental mandibulectomy combined with a type 1 or type 2 defect (n = 3). The Kruskal-Wallis and Bonferroni post hoc tests were used to compare outcomes. RESULTS: Type 1 defects were reconstructed by three anterolateral thigh (ALT) perforator flaps; type 2 defects were reconstructed by four ALT flaps and two vertical deep inferior epigastric perforator flaps; and type 3 defects were restored by three osteocutaneous fibula flaps. Eleven flaps (91.6%) healed uneventfully, while one (8.4%) suffered a small area of skin necrosis whose revision did not compromise functional results. Six patients achieved normal intelligible speech, five had acceptable intelligible speech and one had unintelligible speech (p = 0.356). Swallowing function was considered normal in eight patients and with mild impairment in four (p = 0.178). Cosmesis resulted excellent in seven patients and good in five (p = 0.855). CONCLUSION: The bilobed-shaped perforator free flaps were shown to be a safe and predictable solution for combined hemitongue and floor-of-the-mouth defects providing optimal aesthetic and functional outcomes.

A case series study on complications after breast augmentation with Macrolane™.

BACKGROUND: The use of Macrolane™ seems to have several advantages compared to the other standard methods for breast augmentation: it is faster, less invasive, and requires only local anesthesia. Nevertheless, various complications associated with the use of Macrolane™ have been described, e.g., encapsulated lumps in breast tissue, infection, and parenchymal fibrosis. We report the results of our case series study on the clinical and imaging evaluations of patients who came to our attention after breast augmentation with Macrolane™ injection and evaluate the effect of this treatment on breast cancer screening procedures. METHODS: Between September 2009 and July 2010, seven patients, treated elsewhere with intramammary Macrolane™ injection for cosmetic purposes, presented to our institution complaining of breast pain. In all patients, Macrolane™ had been injected under local anesthesia in the retromammary space through a surgical cannula. RESULTS: On mammography, nodules appeared as gross lobulated radiopacities with polycyclic contours. On breast ultrasound, the nodules showed hypo-anaechogenic cystlike features. In all cases, image analysis by the radiologist was hindered by the presence of the implanted substance, which did not allow the complete inspection of the whole breast tissue. CONCLUSIONS: From our experience, although safe in other areas, injection of Macrolane™ into breast tissue cannot be recommended at this time. Our study, along with other reports, supports the need to start a clinical trial on the use of injectable fillers in the breast to validate their safety and effectiveness. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Thyroid volume measurement in external beam radiotherapy patients using CT imaging: correlation with clinical and anthropometric characteristics.

The aim of this study is to define criteria for accurate representation of the thyroid in human models used to represent external beam radiotherapy (EBRT) patients and evaluate the relationship between the volume of this organ and clinical and anthropometric characteristics. From CT images, we segmented the thyroid gland and calculated its volume for a population of 188 EBRT patients of both sexes, with ages ranging from 1 to 89 years. To evaluate uncertainties linked to measured volumes, experimental studies on the Livermore anthropomorphic phantom were performed. For our population of EBRT patients, we observed that in children, thyroid volume increased rapidly with age, from about 3 cm(3) at 2 years to about 16 cm(3) at 20. In adults, the mean thyroid gland volume was 23.5 ± 9 cm(3) for males and 17.5 ± 8 cm(3) for females. According to anthropometric parameters, the best fit for children was obtained by modeling the log of thyroid volume as a linear function of body surface area (BSA) (p < 0.0001) and age (p = 0.04) and for adults, as a linear function of BSA (p < 0.0001) and gender (p = 0.01). This work enabled us to demonstrate that BSA was the best indicator of thyroid volume for both males and females. These results should be taken into account when modeling the volume of the thyroid in human models used to represent EBRT patients for dosimetry in retrospective studies of the relationship between the estimated dose to the thyroid and long-term follow-up data on EBRT patients.