Ceftazidime-Avibactam Population Pharmacokinetic Modeling and Pharmacodynamic Target Attainment Across Adult Indications and Patient Subgroups.

Ceftazidime-avibactam is a novel ß-lactam/ß-lactamase inhibitor combination for the treatment of serious infections caused by resistant gram-negative pathogens. Population pharmacokinetic (PopPK) models were built to incorporate pharmacokinetic (PK) data from five phase III trials in patients with complicated intra-abdominal infection (cIAI), complicated urinary tract infection (cUTI), or nosocomial (including ventilator-associated) pneumonia. Ceftazidime and avibactam pharmacokinetics were well-described by two-compartment disposition models, with creatinine clearance (CrCL) the key covariate determining clearance variability. Steady-state ceftazidime and avibactam exposure for most patient subgroups differed by ≤ 20% vs. healthy volunteers. Probability of PK/pharmacodynamic (PD) target attainment (free plasma ceftazidime > 8 mg/L and avibactam > 1 mg/L for ≥ 50% of dosing interval) was ≥ 94.9% in simulations for all patient subgroups, including indication and renal function categories. No exposure-microbiological response relationship was identified because target exposures were achieved in almost all patients. These modeling results support the approved ceftazidime-avibactam dosage regimens (2000-500 mg every 8 hours, adjusted for CrCL ≤ 50 mL/min).

Ipsilateral input modifies the primary somatosensory cortex response to contralateral skin flutter.

We recorded the optical intrinsic signal response of squirrel monkey primary somatosensory cortex (SI) to 25 Hz vibrotactile ("flutter") stimulation applied independently to the thenar eminence on each hand and also to bilateral (simultaneous) stimulation of both thenars. The following observations were obtained in every subject (n = 5). (1) Ipsilateral stimulation was accompanied by an increase in absorbance within the SI hand region substantially smaller than the absorbance increase evoked by contralateral stimulation. (2) The absorbance increase evoked by simultaneous bilateral stimulation was smaller (by approximately 30%) than that evoked by contralateral stimulation. (3) The spatiointensive pattern of the SI response to bilateral flutter was distinctly different than the pattern that accompanied contralateral flutter stimulation: with contralateral flutter, the center of the responding region of SI underwent a large increase in absorbance, whereas absorbance decreased in the surrounding region; in contrast, during bilateral flutter, absorbance decreased (relative to that evoked by contralateral flutter) in the central region of SI but increased in the surround. The results raise the possibility that somatosensory perceptual experiences specific to bimanual tactile object exploration derive, at least in part, from the unique spatiointensive activity pattern evoked in SI when the stimulus makes contact with both hands. It is suggested that modulatory influences evoked by ipsilateral thenar flutter stimulation reach SI via a two-stage pathway involving interhemispheric (callosal) connections between information processing levels higher than SI and subsequently via intrahemispheric (corticocortical) projections to the SI hand region.

Activation of cat SII cortex by flutter stimulation of contralateral vs. ipsilateral forepaws.

A distinguishing feature of SII cortex is that it receives substantial input from skin mechanoreceptors located on both sides of the body. It remains uncertain, however, if integration of bilateral inputs occurs mainly in those regions of SII that represent near-midline body regions or also occurs to a significant extent in those regions of SII that represent the distal extremities. This issue was addressed using extracellular microelectrode recordings in cat SII in combination with the method of optical intrinsic signal (OIS) imaging. Stimulation of the central pad of either the contra- or ipsilateral forepaw with a 25-Hz sinusoidal vertical skin displacement ("skin flutter") stimulus evoked a prominent OIS response ("activation") in an extensive anteroposterior sector of SII. In the anteriorly located SII region that yielded the maximal OIS response to stimulation of the contralateral central pad, neurons consistently possessed receptive fields that included the stimulated skin site. This "forepaw" SII region also exhibited significant although 75% weaker OIS activation in response to stimulation of the ipsilateral central pad. Stimulation of the central pads of either contra- or ipsilateral forepaws also evoked OIS activation in the posteriorly located 'hindlimb' region of SII--defined as the SII region comprised of neurons with receptive fields on the contralateral hindlimb. The OIS response to ipsilateral central pad stimulation was strongest in the posterior SII region that borders the suprasylvian fringe--a region in which neurons have very large, and frequently bilateral, cutaneous receptive fields. The results indicate that widespread regions within cat SII receive cutaneous inputs from the ipsilateral distal forelimb. It is suggested that the functional role of these ipsilateral inputs may be different in different SII regions.

Population pharmacokinetics and exposure-response of trametinib, a MEK inhibitor, in patients with BRAF V600 mutation-positive melanoma.

PURPOSE: To characterize the pharmacokinetics of oral trametinib, a first in class MEK inhibitor, identify covariates, and describe the relationship between exposure and clinical effects in patients with BRAF V600 metastatic melanoma. EXPERIMENTAL DESIGN: Trametinib concentrations obtained in three clinical studies were included in the population pharmacokinetic analysis. Trametinib 2 mg once daily was administered in the Phase 2 and 3 studies. The impact of exposure [trough (C min) or average concentration] on response rates and progression-free survival (PFS) was examined. RESULTS: Plasma concentrations (n = 3120) obtained in 493 patients were described using a two-compartment model. Trametinib oral clearance was lower in women relative to men (1.26-fold) and increased with body weight. There was no significant effect of age, mild or moderate renal impairment, or mild hepatic impairment on oral clearance. Between-subject variability was low (24 %). The number of responders was consistent across median exposure range, although tended to be lower at trough concentration <10 ng/mL. Disease stage was found to be a significant predictor of response with a lower response rate in patients with disease stage of M1c. Lactate dehydrogenase was significant in the analysis of PFS. Patients with observed C min above the median had longer PFS than those below median based on Phase 2 study (median 10.6 ng/mL), while the effect of exposure was not statistically significant in the Phase 3 study (median 13.6 ng/mL). CONCLUSIONS: No dosage adjustments are required with any of the covariates tested. Clinical efficacy was associated with trametinib trough concentrations greater than 10 ng/mL.

Stimulus-dependent spatial patterns of response in SI cortex.

BACKGROUND: Recently we reported that vibrotactile flutter stimulation of a skin locus at different amplitudes evokes an optical response confined to the same local region of the primary somatosensory cortex (SI), where its overall magnitude varies proportionally to the flutter amplitude. In this report, we characterize the impact of the flutter amplitude on the spatial patterns of activity evoked within the responding SI region. RESULTS: In order to characterize the spatial pattern of activity within the responding SI region, images of the flutter-evoked SI optical response were segmented and analyzed with spatial frequency analysis. The analysis revealed that: (1) dominant spatial frequencies in the optical intrinsic signal emerge within the responding SI region within 3-5 sec of stimulus onset; (2) the stimulus-evoked activity is spatially organized in a form of several roughly parallel, anterior-posteriorly extended waves, spaced 0.4-0.5 mm apart; (3) the waves themselves exhibit spatial periodicities along their long axis; and (4) depending on the flutter stimulus amplitude, these periodicities can range from fine 0.15 mm "ripples" at 50 microm amplitude to well-developed 0.5 mm fluctuations at the amplitude of 400 microm. CONCLUSION: The observed spatiointensive fractionation on a sub-macrocolumnar scale of the SI response to skin stimulation might be the product of local competitive interactions within the stimulus-activated SI region and may be a feature that could yield novel insights into the functional interactions that take place in SI cortex.

Response of SII cortex to ipsilateral, contralateral and bilateral flutter stimulation in the cat.

BACKGROUND: A distinctive property of SII is that it is the first cortical stage of the somatosensory projection pathway that integrates information arising from both sides of the body. However, there is very little known about how inputs across the body mid-line are processed within SII. RESULTS: Optical intrinsic signal imaging was used to evaluate the response of primary somatosensory cortex (SI and SII in the same hemisphere) to 25 Hz sinusoidal vertical skin displacement stimulation ("skin flutter") applied contralaterally, ipsilaterally, and bilaterally to the central pads of the forepaws. A localized increase in absorbance in both SI and SII was evoked by both contralateral and bilateral flutter stimulation. Ipsilateral flutter stimulation evoked a localized increase in absorbance in SII, but not in SI. The SII region that responded with an increase in absorbance to ipsilateral stimulation was posterior to the region in which absorbance increased maximally in response to stimulation of the contralateral central pad. Additionally, in the posterior SII region that responded maximally to ipsilateral stimulation of the central pad, bilateral central pad stimulation approximated a linear summation of the SII responses to independent stimulation of the contralateral and ipsilateral central pads. Conversely, in anterior SII (the region that responded maximally to contralateral stimulation), bilateral stimulation was consistently less than the response evoked from the contralateral central pad. CONCLUSIONS: The results indicate that two regions located at neighboring, but distinctly different A-P levels of the anterior ectosylvian gyrus process input from opposite sides of the body midline in very different ways. The results suggest that the SII cortex, in the cat, can be subdivided into at least two functionally distinct regions and that these functionally distinct regions demonstrate a laterality preference within SII.

Amplitude-dependency of response of SI cortex to flutter stimulation.

BACKGROUND: It is established that increasing the amplitude of a flutter stimulus increases its perceived intensity. Although many studies have examined this phenomenon with regard to the responding afferent population, the way in which the intensity of a stimulus is coded in primary somatosensory cortex (SI) remains unclear. RESULTS: Optical intrinsic signal (OIS) imaging was used to study the evoked responses in SI of anesthetized squirrel monkeys by 25 Hz sinusoidal vertical skin displacement stimulation. Stimuli were 10 sec duration with a 50 sec inter-stimulus interval. Stimulus amplitude ranged from 50 to 400 microns and different amplitudes were interleaved. Control levels of activity were measured in the absence of stimulation, and used to compare with activation levels evoked by the different stimulus amplitudes. Stimulation of a discrete skin site on the forelimb evoked a prominent increase in absorbance within the forelimb representational region in cytoarchitectonic areas 3b and 1 of the contralateral hemisphere. An increase in stimulus amplitude led to a proportional increase in the magnitude of the absorbance increase in this region of areas 3b and 1 while surrounding cortex underwent a decrease in absorbance. Correlation maps revealed that as stimulus amplitude is increased, the spatial extent of the activated region in SI remains relatively constant, and the activity within this region increases progressively. Additionally, as stimulus amplitude is increased to suprathreshold levels, activity in the surround of the activated SI territory decreases, suggesting an increase in inhibition of neuronal activity within these regions. CONCLUSION: Increasing the amplitude of a flutter stimulus leads to a proportional increase in absorbance within the forelimb representational region of SI. This most likely reflects an increase in the firing rate of neurons in this region of SI. The relatively constant spatial extent of this stimulus-evoked increase in absorbance suggests that an increase in the amplitude of a 25 Hz skin stimulus does not evoke a larger area of SI neuronal activation due to an amplitude-dependent lateral inhibitory effect that spatially funnels the responding SI neuronal population.

Response of SI cortex to ipsilateral, contralateral and bilateral flutter stimulation in the cat.

BACKGROUND: While SII cortex is considered to be the first cortical stage of the pathway that integrates tactile information arising from both sides of the body, SI cortex is generally not considered as a region in which neuronal response is modulated by simultaneous stimulation of bilateral (and mirror-image) skin sites. RESULTS: Optical intrinsic signal imaging was used to evaluate the response of SI and SII in the same hemisphere to 25 Hz sinusoidal vertical skin displacement stimulation ("skin flutter") applied contralaterally, ipsilaterally, and bilaterally (simultaneously) to the central pads of the forepaws. A localized increase in absorbance in both SI and SII occurred in response to both contralateral and bilateral flutter stimulation. Ipsilateral flutter stimulation evoked a localized increase in absorbance in SII, but little or no change in SI absorbance. In the forepaw representational region of SI, however, bilateral stimulation of the central pads evoked a response substantially smaller (approximately 30-35% smaller) than the response to flutter stimulation of the contralateral central pad. CONCLUSION: The finding that the response of SI cortex to bilateral central pad flutter stimulation is substantially smaller than the response evoked by a contralateral flutter stimulus, together with the recently published observation that a region located posteriorly in SII responds with a substantially larger response to a bilateral flutter stimulus than the response evoked from the contralateral central pad, lead us to propose that the SI activity evoked by contralateral skin stimulation is suppressed/inhibited (via corticocortical connections between SII and SI in the same hemisphere) by the activity a simultaneous ipsilateral skin stimulus evokes in posterior SII.