Magnocellular neurons of the supraoptic nucleus receive glutamatergic excitatory inputs that regulate the firing activity and hormone release from these neurons. A strong, brief activation of these ...excitatory inputs induces a lingering barrage of tetrodotoxin-resistant miniature EPSCs (mEPSCs) that lasts for tens of minutes. This is known to accompany an immediate increase in large amplitude mEPSCs. However, it remains unknown how long this amplitude increase can last and whether it is simply a byproduct of greater release probability. Using in vitro patch clamp recording on acute rat brain slices, we found that a brief, high frequency stimulation (HFS) of afferents induced a potentiation of mEPSC amplitude lasting up to 20 min. This amplitude potentiation did not correlate with changes in mEPSC frequency, suggesting that it does not reflect changes in presynaptic release probability. Nonetheless, neither postsynaptic calcium chelator nor the NMDA receptor antagonist blocked the potentiation. Together with the known calcium dependency of HFS-induced potentiation of mEPSCs, our results imply that mEPSC amplitude increase requires presynaptic calcium. Further analysis showed multimodal distribution of mEPSC amplitude, suggesting that large mEPSCs were due to multivesicular glutamate release, even at late post-HFS when the frequency is no longer elevated. In conclusion, high frequency activation of excitatory synapses induces lasting multivesicular release in the SON, which is independent of changes in release probability. This represents a novel form of synaptic plasticity that may contribute to prolonged excitatory tone necessary for generation of burst firing of magnocellular neurons.
Aims
This study aimed to evaluate the impact of esomeprazole on the pharmacokinetics of sonidegib.
Methods
This Phase I study evaluated the impact of the proton pump inhibitor (PPI) esomeprazole on ...the oral absorption and pharmacokinetics (PKs) of a single dose of sonidegib under fasted conditions. A total of 42 healthy subjects were enrolled to receive either sonidegib alone (200 mg single dose) or sonidegib in combination with esomeprazole (40 mg pre‐treatment 5 days and combination were given on day 6). Primary PK parameters assessed in the study were area under the concentration‐time curve (AUC) from 0–14 days and 0–7 days and maximum observed plasma concentration (Cmax).
Results
The plasma exposure (AUC0‐14d, AUC0‐7d and Cmax) of a single 200 mg oral dose of sonidegib was decreased by 32–38% when sonidegib was co‐administered with esomeprazole compared with sonidegib alone, with no apparent change in elimination slope and tmax. Baseline gastric pH was similar between the two arms.
Conclusions
These results suggest a modest reduction in the extent of sonidegib absorption by esomeprazole. There was no obvious metabolic drug–drug interaction between the two agents. Both sonidegib and esomeprazole were well tolerated in the study population.
Asciminib is a first‐in‐class inhibitor of BCR::ABL1, specifically targeting the ABL myristoyl pocket. Asciminib is a substrate of CYP3A4 and P‐glycoprotein (P‐gp) and possesses pH‐dependent ...solubility in aqueous solution. This report summarizes the results of two phase I studies in healthy subjects aimed at assessing the impact of CYP3A and P‐gp inhibitors, CYP3A inducers and acid‐reducing agents (ARAs) on the pharmacokinetics (PK) of asciminib (single dose of 40 mg). Asciminib exposure (area under the curve AUC) unexpectedly decreased by ~40% when administered concomitantly with the strong CYP3A inhibitor itraconazole oral solution, whereas maximum plasma concentration (Cmax) decreased by ~50%. However, asciminib exposure was slightly increased in subjects receiving an itraconazole capsule (~3%) or clarithromycin (~35%), another strong CYP3A inhibitor. Macroflux studies showed that cyclodextrin (present in high quantities as excipient 40‐fold excess to itraconazole in the oral solution formulation of itraconazole) decreased asciminib flux through a lipid membrane by ~80%. The AUC of asciminib was marginally decreased by concomitant administration with the strong CYP3A inducer rifampicin (by ~13–15%) and the strong P‐gp inhibitor quinidine (by ~13–16%). Concomitant administration of the ARA rabeprazole had little or no effect on asciminib AUC, with a 9% decrease in Cmax. The treatments were generally well tolerated. Taking into account the large therapeutic window of asciminib, the observed changes in asciminib PK following multiple doses of P‐gp, CYP3A inhibitors, CYP3A inducers, or ARAs are not considered to be clinically meaningful. Care should be exercised when administering asciminib concomitantly with cyclodextrin‐containing drug formulations.
Introduction
Continuous glucose monitoring (CGM) devices capture longitudinal data on interstitial glucose levels and are increasingly used to show the dynamics of diabetes metabolism. Given the ...complexity of CGM data, it is crucial to extract important patterns hidden in these data through efficient visualization and statistical analysis techniques.
Methods
In this paper, we adopted the concept of glucodensity, and using a subset of data from an ongoing clinical trial in pediatric individuals and young adults with new-onset type 1 diabetes, we performed a cluster analysis of glucodensities. We assessed the differences among the identified clusters using analysis of variance (ANOVA) with respect to residual pancreatic beta-cell function and some standard CGM-derived parameters such as time in range, time above range, and time below range.
Results
Distinct CGM data patterns were identified using cluster analysis based on glucodensities. Statistically significant differences were shown among the clusters with respect to baseline levels of pancreatic beta-cell function surrogate (C-peptide) and with respect to time in range and time above range.
Discussion
Our findings provide supportive evidence for the value of glucodensity in the analysis of CGM data. Some challenges in the modeling of CGM data include unbalanced data structure, missing observations, and many known and unknown confounders, which speaks to the importance of--and provides opportunities for--taking an approach integrating clinical, statistical, and data science expertise in the analysis of these data.
Orexin neurons in the lateral hypothalamus (LH)/perifornical area (PFA) are known to promote food intake as well as provide excitatory influence on the dopaminergic reward pathway. Dopamine (DA), in ...turn, inhibits the reward pathway and food intake through its action in the LH/PFA. However, the cellular mechanism by which DA modulates orexin neurons remains largely unknown. Therefore, we examined the effect of DA on the excitatory neurotransmission to orexin neurons. Whole-cell patch-clamp recordings were performed using acute rat hypothalamic slices, and orexin neurons were identified by their electrophysiological and immunohistochemical characteristics. Pharmacologically isolated action potential-independent miniature EPSCs (mEPSCs) were monitored. Bath application of DA induced a bidirectional effect on the excitatory synaptic transmission dose dependently. A low dose of DA (1 microM) increased mEPSC frequency, which was blocked by the D1-like receptor antagonist SCH 23390, and mimicked by the D1-like receptor agonist SKF 81297. In contrast, higher doses of DA (10-100 microM) decreased mEPSC frequency, which could be blocked with the D2-like receptor antagonist, sulpiride. Quinpirole, the D2-like receptor agonist, also reduced mEPSC frequency. None of these compounds affected the mEPSCs amplitude, suggesting the locus of action was presynaptic. Furthermore, DA (1 microM) induced an increase in the action potential firing, whereas DA (100 microM) hyperpolarized and ceased the firing of orexin neurons, indicating the effect of DA on excitatory synaptic transmission may influence the activity of the postsynaptic cell. In conclusion, our results suggest that D1- and D2-like receptors have opposing effects on the excitatory presynaptic terminals impinging onto orexin neurons.
The glutamatergic synapses of the supraoptic nucleus display a unique activity-dependent plasticity characterized by a barrage
of tetrodotoxin-resistant miniature EPSCs (mEPSCs) persisting for 5â20 ...min, causing postsynaptic excitation. We investigated
how this short-term synaptic potentiation (STP) induced by a brief high-frequency stimulation (HFS) of afferents was initiated
and maintained without lingering presynaptic firing, using in vitro patch-clamp recording on rat brain slices. We found that following the immediate rise in mEPSC frequency, STP decayed with
two-exponential functions indicative of two discrete phases. STP depends entirely on extracellular Ca 2+ which enters the presynaptic terminals through voltage-gated Ca 2+ channels but also, to a much lesser degree, through a pathway independent of these channels or reverse mode of the plasma
membrane Na + âCa 2+ exchanger. Initiation of STP is largely mediated by any of the N-, P/Q- or L-type channels, and only a simultaneous application
of specific blockers for all these channels attenuates STP. Furthermore, the second phase of STP is curtailed by the inhibition
of mitochondrial Ca 2+ uptake or mitochondrial Na + âCa 2+ exchanger. mEPSCs amplitude is also potentiated by HFS which requires extracellular Ca 2+ . In conclusion, induction of mEPSC-STP is redundantly mediated by presynaptic N-, P/Q- and L-type Ca 2+ channels while the second phase depends on mitochondrial Ca 2+ sequestration and release. Since glutamate influences unique firing patterns that optimize hormone release by supraoptic
magnocellular neurons, a prolonged barrage of spontaneous excitatory transmission may aid in the induction of respective firing
activities.
Background and Objective
Renal impairment is common in patients with cancer and can alter the PK and thus the safety and efficacy of drugs. We assessed the impact of renal impairment during treatment ...with ribociclib, a cyclin-dependent kinase 4/6 inhibitor, and determined dose recommendations for patients with advanced breast cancer with renal impairment.
Methods
A comprehensive assessment integrating pharmacokinetic, safety, and efficacy data from a phase I dedicated renal impairment study in non-cancer subjects and six phase I–III trials in patients with cancer was performed.
Results
Ribociclib showed higher pharmacokinetic exposure in subjects with renal impairment than those with normal renal function following a single 400-mg dose in the dedicated renal impairment study. However, in patient trials, both single-dose and steady‑state ribociclib exposure was comparable between patients with cancer with mild/moderate renal impairment and those with normal renal function following the recommended starting dose of 600 mg. Model-predicted steady‑state exposure in patients with advanced breast cancer was also similar across the renal function groups. Progression-free survival was similar and safety profiles were generally consistent across the renal cohorts (normal/mild/moderate) in patients with advanced breast cancer, with low-grade and manageable adverse events, demonstrating a positive benefit-risk profile.
Conclusions
From the collective evidence and considering a real-world clinical setting, no dose adjustment is recommended for patients with mild/moderate renal impairment, whereas a reduced dose is recommended for patients with severe renal impairment. This report presented a holistic and innovative strategy to determine dose in patients with renal impairment and demonstrated the effectiveness of integrating the data of both a clinical pharmacology study and patient trials to justify doses in patients with renal impairment.
Clinical Trial Registration
Clinicaltrials.gov identifiers: NCT02431481, NCT01958021, NCT02422615, NCT02278120, NCT01237236, NCT01898845, NCT01872260.
Methods for estimating pharmaceutical shelf life based on tolerance intervals are proposed by Schwenke,
et al
. AAPS PharmSciTech. 2020;21:290, 1 where a critical quality attribute that follows a ...simple linear (straight line) response trend across storage time is presented as the traditional example. A random coefficient mixed linear regression model is used to characterize the between batch and within batch variation. These methods are further discussed for various stability study scenarios, number of stability batches, and levels of assumed risk in Schwenke,
et al
. AAPS PharmSciTech. 2021;22:273, 4 through a simulation study, again based on a critical quality attribute assuming a simple linear response. However, in practice, not all stability response profiles conveniently follow straight line or linear trends. The purpose of this paper is to extend the proposed tolerance interval and random coefficient mixed regression methods for estimating pharmaceutical shelf life to critical quality attributes that follow more complex stability response profiles. As an example, a nonlinear response is typically characterized by either an increasing or decreasing response, starting from an initial concentration, trending with storage time towards some limiting response or asymptote. Nonlinear responses cannot be statistically analyzed with linear model methods. Practical information supported by simulation results based on a pharmaceutical stability study are discussed to allow for appropriate statistical analyses and shelf life estimates through random coefficient mixed nonlinear regression and tolerance interval methods.
Instructions for administration with regard to food are a key aspect of how patients experience oral drugs. Through potential effects on pharmacokinetics, the food condition can influence safety and ...efficacy, and thereby is one of many dimensions of dose optimization. Regulatory guidance from major health authorities advocates for the early investigation of food effect (FE) in clinical development. In oncology, exploratory FE (eFE) evaluation is often incorporated into the first‐in‐human (FIH) studies in patients to inform food condition of later clinical studies. However, the design aspects of such exploratory assessments are generally under‐reported and barely described, and yet complex, due to uniqueness of FIH study design and drug development process in oncology. Herein, we review literature of eFE assessment study design in oncology in patients, and present the Novartis experience in the design, execution, and impact of eFE in FIH oncology studies from 2014 to 2021. Based on this, we propose a roadmap for eFE assessment in early clinical drug development for oncology drugs in patients, including a framework for common study design options with a focus on study‐ and patient‐level timing for typical scenarios. We also provide a broad spectrum of decision‐making factors which should be evaluated to drive the design and implementation of eFE assessment, spanning from clinical development strategy, FIH study design, to compound‐specific features.
This paper is a companion article to the research originally presented in “Estimating Shelf Life through Tolerance Intervals” (Schwenke et al., 21:290, 2020) published in
AAPS PharmSciTech
where ...tolerance intervals are introduced as an alternative methodology for estimating pharmaceutical shelf life. An industry stability shelf life example data set was used to demonstrate the proposed methods. Although using industry data does give relevance to examples demonstrating shelf life estimation, measures of how well the proposed methods accurately and effectively estimate shelf life cannot be obtained because the true shelf life values are not known for example data sets. In this current paper, the results of a computer simulation are reported where the tolerance interval estimates of shelf life are compared to theoretically known true shelf life values. Various factors that affect a tolerance interval estimate of pharmaceutical shelf life are investigated. A critical decision factor is the choice of the proportion of the stability distribution allowed out of specification at expiry to define the pharmaceutical risk. The number of stability batches available for shelf life estimation and the storage time at which the estimate is made are also considered in this simulation study. The industry example data are again used as the basis for the simulation study to give relevance to this research.
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