Aripiprazole Lauroxil: Pharmacokinetic Profile of This Long-Acting Injectable Antipsychotic in Persons With Schizophrenia.

BACKGROUND: Aripiprazole lauroxil is an extended-release prodrug of aripiprazole for intramuscular injection, approved for schizophrenia treatment. We developed a population pharmacokinetic (PopPK) model to characterize aripiprazole lauroxil PK and evaluate dosing scenarios likely to be encountered in clinical practice. METHODS: Data from 616 patients with schizophrenia, collected from 5 clinical studies, were used to construct the PopPK model. The model was subsequently used to evaluate various dose levels and frequency and the impact of dosing delay on aripiprazole concentrations. FINDINGS: The results of the model indicate that aripiprazole is released into the systemic circulation after 5 to 6 days, and release continues for an additional 36 days. The slow increase in aripiprazole concentration after injection necessitates the coadministration of oral aripiprazole for 21 days with the first injection. Based on the PopPK model simulations, a dosing interval of 882 mg every 6 weeks results in aripiprazole concentrations that fall within the concentration range associated with the efficacious aripiprazole lauroxil dose range (441-882 mg dosed monthly). A 662-mg monthly dose also resulted in aripiprazole concentrations within the efficacious dose range. Aripiprazole lauroxil administration results in prolonged exposure, such that dose delays of 2 to 4 weeks, depending on the dose regimen, do not require oral aripiprazole supplementation upon resumption of dosing. CONCLUSIONS: This PopPK model and model-based simulations were effective means for evaluating aripiprazole lauroxil dosing regimens and management of missed doses. Such analyses play an important role in determining the use of this long-acting antipsychotic in clinical practice.

Model-Based Phase 3 Dose Selection for HIV-1 Attachment Inhibitor Prodrug BMS-663068 in HIV-1-Infected Patients: Population Pharmacokinetics/Pharmacodynamics of the Active Moiety, BMS-626529.

BMS-663068 is an oral prodrug of the HIV-1 attachment inhibitor BMS-626529, which prevents viral attachment to host CD4(+) T cells by binding to HIV-1 gp120. To guide dose selection for the phase 3 program, pharmacokinetic/pharmacodynamic modeling was performed using data from two phase 2 studies with HIV-1-infected subjects (n = 244). BMS-626529 population pharmacokinetics were described by a two-compartment model with first-order elimination from the central compartment, zero-order release of prodrug from the extended-release formulation into a hypothetical absorption compartment, and first-order absorption into the central compartment. The covariates of BMS-663068 formulation type, lean body mass, baseline CD8(+) T-cell percentage, and ritonavir coadministration were found to be significant contributors to intersubject variability. Exposure-response analyses showed a relationship between the loge-transformed concentration at the end of a dosing interval (Ctau) normalized for the protein binding-adjusted BMS-626529 half-maximal (50%) inhibitory concentration (PBAIC50) and the change in the HIV-1 RNA level from the baseline level after 7 days of BMS-663068 monotherapy. The probability of achieving a decline in HIV-1 RNA level of >0.5 or >1.0 log10 copies/ml as a function of the loge-transformed PBAIC50-adjusted Ctau after 7 days of monotherapy was 99 to 100% and 57 to 73%, respectively, for proposed BMS-663068 doses of 400 mg twice daily (BID), 600 mg BID (not studied in the phase 2b study), 800 mg BID, 600 mg once daily (QD), and 1,200 mg QD. On the basis of a slight advantage in efficacy of BID dosing over QD dosing, similar responses for the 600- and 800-mg BID doses, and prior clinical observations, BMS-663068 at 600 mg BID was predicted to have the optimal benefit-risk profile and selected for further clinical investigation. (The phase 2a proof-of-concept study AI438006 and the phase 2b study AI438011 are registered at ClinicalTrials.gov under numbers NCT01009814 and NCT01384734, respectively.).

Omnidirectional beacon-localization using a catadioptric system.

We present a catadioptric beacon localization system that can provide mobile network nodes with omnidirectional situational awareness of neighboring nodes. In this system, a receiver composed of a hyperboloidal mirror and camera is used to estimate the azimuth, elevation, and range of an LED beacon. We provide a general framework for understanding the propagation of error in the angle-of-arrival estimation and then present an experimental realization of such a system. The situational awareness provided by the proposed system can enable the alignment of communication nodes in an optical wireless network, which may be particularly useful in addressing RF-denied environments.

Dead time effects in non-line-of-sight ultraviolet communications.

By exploiting unique properties of the atmospheric propagation of radiation in the deep-ultraviolet band (200-300 nm), ultraviolet communications (UVC) offers the novel possibility of establishing non-line-of-sight (NLOS) optical links. UVC systems often employ photon-counting receivers, which may exhibit nonideal behavior owing to dead time, a period of time after the detection of a photon during which such a receiver is unable to detect subsequently impinging photons. In this paper, we extend a NLOS UVC channel model to account for dead time and then use this extended model to study the effects of dead time in representative system scenarios. Experimentally collected channel-sounding data is then used for model validation and real-world illustration of these effects. Finally, we investigate the effect of dead time on communication performance. The results demonstrate that dead time can have a significant impact in practical communication scenarios and suggest the usefulness of the proposed modeling framework in developing receiver designs that compensate for dead time effects.

Population pharmacokinetics of dolutegravir in HIV-infected treatment-naive patients.

AIM: Dolutegravir is the newest integrase inhibitor approved for HIV treatment and has demonstrated potent antiviral activity in patient populations with a broad range of treatment experience. This analysis aimed to characterize the population pharmacokinetics of dolutegravir in treatment-naive patients and to evaluate the influence of patient covariates. METHODS: A population pharmacokinetic model was developed using a non-linear mixed effect modelling approach based on data from 563 HIV-infected, treatment-naive adult patients in three phase 2/3 trials who received dolutegravir (ranging from 10-50 mg once daily) alone or in combination with abacavir/lamivudine or tenofovir/emtricitabine. RESULTS: The pharmacokinetics of dolutegravir were adequately described by a linear one compartment model with first order absorption, absorption lag time and first order elimination. Population estimates for apparent clearance, apparent volume of distribution, absorption rate constant and absorption lag time were 0.901 l h(-1) , 17.4 l, 2.24 h(-1) , and 0.263 h, respectively. Weight, smoking status, age and total bilirubin were predictors of clearance, weight was a predictor of volume of distribution and gender was a predictor of bioavailability. However, the magnitude of the effects of these covariates on steady-state dolutegravir plasma exposure was relatively small (<32%) and was not considered clinically significant. Race/ethnicity, HBV/HCV co-infection, CDC classification, albumin, creatinine clearance, alanine aminotransferase or aspartate aminotransferase did not influence the pharmacokinetics of dolutegravir in this analysis. CONCLUSIONS: A population model that adequately characterizes dolutegravir pharmacokinetics has been developed. No dolutegravir dose adjustment by patient covariates is necessary in HIV-infected treatment-naive patients.

Compressive spectral polarization imaging by a pixelized polarizer and colored patterned detector.

A compressive spectral and polarization imager based on a pixelized polarizer and colored patterned detector is presented. The proposed imager captures several dispersed compressive projections with spectral and polarization coding. Stokes parameter images at several wavelengths are reconstructed directly from 2D projections. Employing a pixelized polarizer and colored patterned detector enables compressive sensing over spatial, spectral, and polarization domains, reducing the total number of measurements. Compressive sensing codes are specially designed to enhance the peak signal-to-noise ratio in the reconstructed images. Experiments validate the architecture and reconstruction algorithms.

Design of dual-link (wide- and narrow-beam) LED communication systems.

We explore the design of an LED-based communication system comprising two free space optical links: one narrow-beam (primary) link for bulk data transmission and one wide-beam (beacon) link for alignment and support of the narrow-beam link. Such a system combines the high throughput of a highly directional link with the robust insensitivity to pointing errors of a wider-beam link. We develop a modeling framework for this dual-link configuration and then use this framework to explore system tradeoffs in power, range, and achievable rates. The proposed design presents a low-cost, compact, robust means of communication at short- to medium-ranges, and calculations show that data rates on the order of Mb/s are achievable at hundreds of meters with only a few LEDs.

Towards a Standard Mixed-Signal Parallel Processing Architecture for Miniature and Microrobotics.

The conventional analog-to-digital conversion (ADC) and digital signal processing (DSP) architecture has led to major advances in miniature and micro-systems technology over the past several decades. The outlook for these systems is significantly enhanced by advances in sensing, signal processing, communications and control, and the combination of these technologies enables autonomous robotics on the miniature to micro scales. In this article we look at trends in the combination of analog and digital (mixed-signal) processing, and consider a generalized sampling architecture. Employing a parallel analog basis expansion of the input signal, this scalable approach is adaptable and reconfigurable, and is suitable for a large variety of current and future applications in networking, perception, cognition, and control.

Ultraviolet scattering propagation modeling: analysis of path loss versus range.

Modeling of the complex atmospheric propagation of deep-ultraviolet (UV) radiation is important for applications such as non-line-of-sight (NLOS) UV communications. Building upon prior work in which it was observed that short-range, singly scattered NLOS path loss varies linearly with range, we formalize this relationship, generalizing it to consider any order of scattering and more-general system characteristics. In particular, we derive the approximate relationship PL[proportionality]r(2-n) between path loss PL and range r for nth-order scattered radiation, and investigate the region of validity of this approximation. Insight arising from the analysis can be invaluable in the development and study of UV systems, as demonstrated by numerical results that illustrate implications of the analysis.

An approximate closed-form link loss model for non-line-of-sight ultraviolet communication in noncoplanar geometry.

Non-line-of-sight UV communication link path loss models have been explored for both coplanar and noncoplanar geometries, and these typically require numerical evaluation. In this Letter, we propose a closed-form and easily applied model to describe link behavior, applicable to noncoplanar geometry. The model is compared with a recently reported analytical model and shows good agreement.

UV communications channel modeling incorporating multiple scattering interactions.

In large part because of advancements in the design and fabrication of UV LEDs, photodetectors, and filters, significant research interest has recently been focused on non-line-of-sight UV communication systems. This research in, for example, system design and performance prediction, can be greatly aided by accurate channel models that allow for the reproducibility of results, thus facilitating the fair and consistent comparison of different communication approaches. In this paper, we provide a comprehensive derivation of a multiple-scattering Monte Carlo UV channel model, addressing weaknesses in previous treatments. The resulting model can be used to study the contribution of different orders of scattering to the path loss and impulse response functions associated with general UV communication system geometries. Simulation results are provided that demonstrate the benefit of this approach.

Population Pharmacokinetics of Olanzapine and Samidorphan When Administered in Combination in Healthy Subjects and Patients With Schizophrenia.

A combination of olanzapine and samidorphan was recently approved by the US Food and Drug Administration for the treatment of patients with schizophrenia or bipolar I disorder. Population pharmacokinetic models for olanzapine and samidorphan were developed using data from 11 clinical studies in healthy subjects or patients with schizophrenia. A 2-compartment disposition model with first-order absorption and elimination and a lag time for absorption adequately described concentration-time profiles of both olanzapine and samidorphan. Age, sex, race, smoking status, and body weight were identified as covariates that impacted the pharmacokinetics of olanzapine. A moderate effect of body weight on samidorphan pharmacokinetics was identified by the model but was not considered clinically meaningful. The effects of food, hepatic or renal impairment, and coadministration with rifampin on the pharmacokinetics of olanzapine and samidorphan, as estimated by the population pharmacokinetic analysis, were consistent with findings from dedicated clinical studies designed to evaluate these specific covariates of interest. Food intake did not have a clinically relevant effect on the pharmacokinetics of olanzapine or samidorphan. Consistent with the known metabolic pathways for olanzapine (primarily via uridine 5'-diphospho-glucuronosyltransferase-mediated direct glucuronidation and cytochrome P450 [CYP]-mediated oxidation) and for samidorphan (predominantly mediated by CYP3A4), coadministration of olanzapine and samidorphan with rifampin, a strong inducer of CYP3A4 and an inducer of uridine 5'-diphospho-glucuronosyltransferase enzymes, significantly decreased the systemic exposure of both olanzapine and samidorphan. Severe renal impairment or moderate hepatic impairment resulted in a modest increase in olanzapine and samidorphan exposure.

Performance of short-range non-line-of-sight LED-based ultraviolet communication receivers.

Utilizing an empirical path loss model proposed in the first paper of a two-part series, the bit error rate performance of short-range non-line-of-sight ultraviolet communication receivers is analyzed. Typical photodetector models and modulation formats are considered. Our results provide semi-analytical prediction of the achievable communication performance as a function of system and channel parameters, and serve as a basis for system design.

Experimental demonstration of ultraviolet pulse broadening in short-range non-line-of-sight communication channels.

An experimental test-bed using a narrow-pulsed ultraviolet (UV) laser and high-bandwidth photomultiplier tube was set up to characterize pulse broadening effects in short-range non-line-of-sight (NLOS) scattering communication channels. Pulse broadening is reported as a function of the transmitter elevation angle, transmitter beam angle, receiver elevation angle, receiver field-of-view, and transmitter-receiver distance. The results provide insight into the channel bandwidth and achievable communication data rate.

Non-line-of-sight ultraviolet link loss in noncoplanar geometry.

Various path loss models have been developed for solar blind non-line-of-sight UV communication links under an assumption of coplanar source beam axis and receiver pointing direction. This work further extends an existing single-scattering coplanar analytical model to noncoplanar geometry. The model is derived as a function of geometric parameters and atmospheric characteristics. Its behavior is numerically studied in different noncoplanar geometric settings.

Experimental evaluation of LED-based solar blind NLOS communication links.

Experimental results are reported demonstrating non-line of sight short-range ultraviolet communication link losses, and performance of photon counting detectors, operating in the solar blind spectrum regime. We employ light emitting diodes with divergent beams, a solar blind filter, and a wide field-of-view detector. Signal and noise statistics are characterized, and receiver performance is demonstrated. The effects of transmitter and receiver elevation angles, separation distance, and path loss are included.

Oliceridine, a Novel G Protein-Biased Ligand at the µ-Opioid Receptor, Demonstrates a Predictable Relationship Between Plasma Concentrations and Pain Relief. II: Simulation of Potential Phase 3 Study Designs Using a Pharmacokinetic/Pharmacodynamic Model.

Oliceridine is a novel G protein-biased ligand at the µ-opioid receptor that differentially activates G protein coupling while mitigating ß-arrestin recruitment. Unlike morphine, oliceridine has no known active metabolites; therefore, analgesic efficacy is predictably linked to its concentration in the plasma. Oliceridine is primarily hepatically metabolized by CYP3A4 and CYP2D6. Using a pharmacokinetic/pharmacodynamic model relating oliceridine plasma concentrations to its effect on pain intensity as measured by numeric pain-rating scale (NPRS) scores, we have simulated potential dosing regimens using both fixed-dose regimens and as-needed (prn) dosing regimens in which various doses of oliceridine were administered if NPRS scores indicated moderate to severe pain (≥4 on a 0-10 scale). In addition, regimens in which oliceridine was self-administered via a patient-controlled analgesia device were also simulated. The simulated population included 10% CYP2D6 poor metabolizers (PM). The simulation results suggest that oliceridine doses of 1-3 mg prn should be effective in reducing NPRS scores relative to placebo. The simulations also revealed that a 1-mg "supplemental dose" given 0.25 hour after the loading dose would decrease NPRS scores further in almost one-third of patients. In addition, if oliceridine is administered prn, a longer interval between doses is observed in simulated PM patients, consistent with their reduced oliceridine clearance. Because this longer average dosing interval is predicted to decrease oliceridine exposure in PM patients, the need to know the patient's CYP2D6 genotype for dosing is effectively obviated.

Oliceridine (TRV130), a Novel G Protein-Biased Ligand at the µ-Opioid Receptor, Demonstrates a Predictable Relationship Between Plasma Concentrations and Pain Relief. I: Development of a Pharmacokinetic/Pharmacodynamic Model.

Conventional opioids bind to µ-opioid receptors and activate 2 downstream signaling pathways: G-protein coupling, linked to analgesia, and ß-arrestin recruitment, linked to opioid-related adverse effects and limiting efficacy. Oliceridine (TRV130) is a novel G protein-biased ligand at the µ-opioid receptor that differentially activates G-protein coupling while mitigating ß-arrestin recruitment. Using data derived from both phase 1 studies in healthy volunteers as well as data from a phase 2 study examining the efficacy of oliceridine for the treatment of postbunionectomy pain, we have developed a population pharmacokinetic/pharmacodynamic model linking the pharmacokinetics of oliceridine to its effect on pain, as measured by the Numeric Pain Rating Scale score. Phase 1 data consisted of 145 subjects (88% male, 12% female), who received single doses of oliceridine ranging between 0.15 and 7 mg, as well as multiple doses ranging from 0.4 to 4.5 mg every 4-6 hours. Sixteen of these subjects were CYP2D6 poor metabolizers, who have lower oliceridine clearance than extensive metabolizers. Approximately 265 subjects (10% male, 90% female) came from the phase 2 study, in which they received active doses ranging from 0.5 to 4 mg every 3-4 hours. The final model was a 3-compartment model that included covariates of body weight, sex, and CYP2D6 status. The PD model was an indirect response model linked to plasma oliceridine concentrations and included the placebo pain response over the 48-hour treatment period. The EC50 for oliceridine on pain relief was estimated as 10.1 ng/mL (95%CI, 8.4-12.1 ng/mL). Model qualification showed that the model robustly reproduced the original data.

Population Pharmacokinetic Analysis and Model-Based Simulations of Aripiprazole for a 1-Day Initiation Regimen for the Long-Acting Antipsychotic Aripiprazole Lauroxil.

BACKGROUND AND OBJECTIVES: Aripiprazole lauroxil (AL), a long-acting injectable antipsychotic for the treatment of schizophrenia, requires 21 days of oral aripiprazole supplementation upon initiation (21-day initiation regimen). An alternative 1-day initiation regimen utilizing a nano-crystalline milled dispersion of AL (ALNCD) plus a single 30 mg oral aripiprazole dose achieved aripiprazole concentrations associated with therapeutic doses of aripiprazole in the same time frame as the 21-day initiation regimen when starting AL (441 or 882 mg). A population pharmacokinetic (PopPK) model was developed to describe aripiprazole pharmacokinetics following administration of ALNCD, AL and oral aripiprazole, and evaluate dosing scenarios likely to be encountered in clinical practice. METHODS: In total, 12,768 plasma aripiprazole concentrations from 343 patients (from 4 clinical studies) were included in the PopPK analysis and used to construct the model. RESULTS: Concomitant administration of the 1-day initiation regimen with all approved AL dosing regimens (441, 662, or 882 mg monthly, 882 mg every 6 weeks, or 1064 mg every 2 months) is predicted to achieve aripiprazole concentrations associated with therapeutic doses of AL using the 21-day initiation regimen within 4 days, maintaining these concentrations until the next AL dose. Administration of the first AL injection 10 days after the 1-day initiation regimen resulted in median aripiprazole concentrations just before the second dose of AL ≥ 77% of that when coadministered on the same day. Coadministration of AL with a single ALNCD injection was predicted to be effective in rapidly re-establishing concentrations associated with therapeutic doses of AL following dose delay. CONCLUSIONS: Model-based simulations demonstrate that the 1-day initiation regimen is suitable for starting treatment with all AL doses, allowing a window of ≤ 10 days between initiation and AL administration. ALNCD may also be used to re-establish concentrations associated with therapeutic doses of AL in conjunction with a delayed AL dose.

Crowdsourced Asparagus Urinary Odor Population Kinetics.

The consumption of asparagus is associated with the production of malodorous urine with considerable interindividual variability (IIV). To characterize the urinary odor kinetics after consumption of asparagus spears, we conducted a study with consenting attendees from two American Society for Clinical Pharmacology and Therapeutics (ASCPT) meetings. Subjects were randomized to eat a specific number of asparagus spears, and then asked to report their urinary odor perception. Eighty-seven subjects were included in the final analysis. A mixed effect proportional odds model was developed that adequately characterized the dose-response relationship. We estimated the half-life of the asparagus effect on malodorous urine to be 4.7 hours (relative standard error (RSE) = 13.2%), and identified a dose-response slope term with good precision (24.3%). Age was found as the predictor of IIV in slope estimates. This study design and tools can be used as a demonstration "crowdsourcing" project for studying population kinetics in organizational and educational settings.