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Background Cabotegravir plus rilpivirine (CAB + RPV) is a guideline-recommended long-acting (LA) injectable regimen for the maintenance of human immunodeficiency virus-1 (HIV-1) virologic suppression. This post hoc analysis summarizes CAB + RPV LA results by baseline body mass index (BMI) category among phase 3/3b trial participants. Methods Data from CAB + RPV-naive participants receiving every 4 or 8 week dosing in FLAIR, ATLAS, and ATLAS-2M were pooled through week 48. Data beyond week 48 were summarized by study (FLAIR through week 96 and ATLAS-2M through week 152). HIV-1 RNA <50 and ≥50 copies/mL, confirmed virologic failure (CVF; 2 consecutive HIV-1 RNA ≥200 copies/mL), safety and tolerability, and plasma CAB and RPV trough concentrations were evaluated by baseline BMI (<30 kg/m2, lower; ≥30 kg/m2, higher). Results Among 1245 CAB + RPV LA participants, 213 (17%) had a baseline BMI ≥30 kg/m2. At week 48, 92% versus 93% of participants with lower versus higher BMI had HIV-1 RNA <50 copies/mL, respectively. Including data beyond week 48, 18 participants had CVF; those in the higher BMI group (n = 8) all had at least 1 other baseline factor associated with CVF (archived RPV resistance-associated mutations or HIV-1 subtype A6/A1). Safety and pharmacokinetic profiles were comparable between BMI categories. Conclusions CAB + RPV LA was efficacious and well tolerated, regardless of baseline BMI category. Clinical Trials Registration NCT02938520, NCT02951052, and NCT03299049. [ABSTRACT FROM AUTHOR]

Background: Mouse double minute‐2 homolog (MDM2) plays a key role in downregulating p53 activity in hematologic malignancies, and its overexpression is associated with poor outcomes. Methods: This phase 1 study assessed the safety and efficacy of different dosing regimens of the MDM2 inhibitor milademetan as monotherapy and in combination with azacitidine (AZA) in patients with relapsed or refractory acute myeloid leukemia or high‐risk myelodysplastic syndromes. Results: Seventy‐four patients (monotherapy, n = 57; milademetan‐AZA combination, n = 17) were treated. The maximum tolerated dose of milademetan was 160 mg once daily given for the first 14–21 days of 28‐day cycles as monotherapy and on Days 5–14 in combination with AZA. Dose‐limiting toxicities were gastrointestinal, fatigue, or renal/electrolyte abnormalities. Treatment‐emergent adverse events related to milademetan occurred in 82.5% and 64.7% of participants in the monotherapy and AZA combination arms, respectively. Two participants (4.2%) in the monotherapy arm achieved complete remission (CR), and 1 (2.1%) achieved CR with incomplete blood count recovery (CRi). Two participants (13.3%) achieved CRi in the combination arm. New TP53 mutations, detected only during milademetan monotherapy, were found pre‐existing below standard detection frequency by droplet digital polymerase chain reaction. Interpretation: Milademetan was relatively well tolerated in this population; however, despite signals of activity, clinical efficacy was minimal. [ABSTRACT FROM AUTHOR]

Background Cabotegravir (CAB) + rilpivirine (RPV) dosed monthly or every 2 months is a complete long-acting (LA) regimen for the maintenance of human immunodeficiency virus type 1 virologic suppression. Across the phase 3/3b trials, the most frequently reported adverse events were injection site reactions (ISRs). Methods We present pooled ISR characteristics and outcomes for participants receiving CAB + RPV LA through week 96 of the FLAIR and ATLAS-2M studies, and survey results from healthcare providers (HCPs) giving injections (eg, injectors) in the ATLAS, FLAIR, and ATLAS-2M studies to determine optimal injection techniques. Surveys were anonymous, self-administered online questionnaires that queried provider demographics, injection experience, and techniques to minimize pre-/postinjection discomfort. Data were summarized using descriptive statistics. Results Overall, 8453 ISRs were reported by 801 participants receiving ≥1 injection of CAB LA/RPV LA. Most ISRs were mild to moderate in severity (grade 1–2, 99%), with a median duration of 3 days (interquartile range, 2–4 days), and rarely led to withdrawal (2%). Surveys were completed by 181 HCPs across 113 sites. Pushing the intramuscular injection at slow speed (66%), bringing the medication to room temperature (58%), and relaxing the gluteus muscle before injecting (53%) were ranked as effective preinjection/injection procedure practices for minimizing pain. Most injectors (60%) indicated that a prone position provided optimal patient comfort, and 41% had no preference on injection medication order. Conclusions Taken together, the data demonstrate favorable tolerability with CAB + RPV LA injections over the long term and simple techniques routinely used by injectors to help optimize the administration of CAB + RPV LA injections. [ABSTRACT FROM AUTHOR]

Objectives: Cabotegravir + rilpivirine (CAB + RPV) dosed monthly or every 2 months is the first complete long‐acting (LA) regimen recommended by treatment guidelines for the maintenance of HIV‐1 virological suppression. This post hoc analysis summarizes outcomes for Asian participants through week 96. Methods: Data from Asian participants naive to CAB + RPV randomized to receive dosing every 4 weeks (Q4W) or every 8 weeks (Q8W) in the FLAIR (NCT02938520) and ATLAS‐2M (NCT03299049) phase 3/3b studies were pooled. The proportion of participants with plasma HIV‐1 RNA ≥50 and <50 copies/mL (per FDA Snapshot algorithm), incidence of confirmed virological failure (CVF; two consecutive HIV‐1 RNA ≥200 copies/mL), pharmacokinetics, safety, and tolerability through week 96 were assessed. Results: Overall, 41 Asian participants received CAB + RPV (Q8W, n = 17; Q4W, n = 24). At week 96, 83% (n = 34/41) of participants maintained HIV‐1 RNA <50 copies/mL, none had HIV‐1 RNA ≥50 copies/mL, and 17% (n = 7/41) had no virological data. No Asian participant met the CVF criterion. Drug‐related adverse events occurred in 44% (n = 18/41) of participants; none were Grade ≥3. All injection site reactions were Grade 1 or 2; median duration was 2 days and most resolved within 7 days (90%, n = 390/435). CAB and RPV trough concentrations remained well above their respective protein‐adjusted 90% inhibitory concentrations (CAB, 0.166 μg/mL; RPV, 12 ng/mL) through week 96. Conclusions: CAB + RPV LA demonstrated high efficacy, with no participants having CVF, and an acceptable safety profile in Asian participants through week 96. These data support CAB + RPV LA as a complete regimen for the maintenance of HIV‐1 virological suppression in Asian individuals. [ABSTRACT FROM AUTHOR]

SAR's return signal sensitivity to dielectric constant and penetration through vegetation makes it ideal for large-scale soil moisture studies. High incidence angle SAR data is especially useful for understanding crop characteristics. However, interpreting the return signal requires considering both crop characteristics and underlying soil moisture. In this study, an attempt has been made to assess the potential of high incidence angle C-band SAR data for soil moisture retrieval by incorporating effects of crop on Radar signal using water cloud model. The simulated VV backscatter from water cloud model by considering Leaf Area Index (LAI) and plant water content as vegetation descriptors has shown Root Mean Square Error (RMSE) of 1.28 dB with actual VV backscatter. Later, a two-layer feedforward neural network comprising one hidden layer with sigmoid neurons has been considered to develop retrieval models. It is observed that the ANN with input of high incidence angle C-band VV backscatter over wheat crop has soil moisture retrieval performance with correlation coefficient (R) and RMSE of 0.55 and 9.18 m³ /m³ respectively. Another ANN model is developed to incorporate effects of crop on Radar signal by using VH backscatter, Radar Vegetation Index (RVI) and two-way attenuation factor derived from water cloud model along with VV backscatter. The overall performance of this model has been observed with R and RMSE of 0.77 and 5.81 m³ /m³ respectively. The study results indicate that the high incidence angle SAR data may be considered for soil moisture retrieval underneath crop cover by effectively incorporating the crop effects on Radar signal. This may further extend to develop a model to extract crop biophysical parameters as well as soil moisture from Sentinel-1 SAR data. [ABSTRACT FROM AUTHOR]

Background Previously reported post hoc multivariable analyses exploring predictors of confirmed virologic failure (CVF) with cabotegravir + rilpivirine long-acting (CAB + RPV LA) were expanded to include data beyond week 48, additional covariates, and additional participants. Methods Pooled data from 1651 participants were used to explore dosing regimen (every 4 or every 8 weeks), demographic, viral, and pharmacokinetic covariates as potential predictors of CVF. Prior dosing regimen experience was accounted for using 2 populations. Two models were conducted in each population—baseline factor analyses exploring factors known at baseline and multivariable analyses exploring baseline factors plus postbaseline model-predicted CAB/RPV trough concentrations (4 and 44 weeks postinjection). Retained factors were evaluated to understand their contribution to CVF (alone or in combination). Results Overall, 1.4% (n = 23/1651) of participants had CVF through 152 weeks. The presence of RPV resistance-associated mutations, human immunodeficiency virus-1 subtype A6/A1, and body mass index ≥30 kg/m2 were associated with an increased risk of CVF (P <.05 adjusted incidence rate ratio), with participants with ≥2 of these baseline factors having a higher risk of CVF. Lower model-predicted CAB/RPV troughs were additional factors retained for multivariable analyses. Conclusions The presence of ≥2 baseline factors (RPV resistance-associated mutations, A6/A1 subtype, and/or body mass index ≥30 kg/m2) was associated with increased CVF risk, consistent with prior analyses. Inclusion of initial model-predicted CAB/RPV trough concentrations (≤first quartile) did not improve the prediction of CVF beyond the presence of a combination of ≥2 baseline factors, reinforcing the clinical utility of the baseline factors in the appropriate use of CAB + RPV LA. [ABSTRACT FROM AUTHOR]

Background: Currently, the capacity to provide buprenorphine treatment (BT) is not sufficient to treat the growing number of people in the United States with opioid use disorder (OUD). We sought to examine participant retention in care rates of primary care delivered BT programs and to describe factors associated with retention/attrition for participants receiving BT in this setting. Objectives: A PRISMA-guided search of various databases was performed to identify the articles focusing on efficacy of BT treatment and OUD. Method: A systematic literature search identified 15 studies examining retention in care in the primary care setting between 2002 and 2020. Random effects meta-regression were used to identify retention rates across studies. Results: Retention rates decreased across time with a mean 0.52 rate at one year. Several factors were found to be related to retention, including: race, use of other drugs, receipt of counseling, and previous treatment with buprenorphine. Conclusions: While we only investigate BT through primary care, our findings indicate retention rates are equivalent to the rates reported in the specialty care literature. More work is needed to examine factors that may impact primary care delivered BT specifically and differentiate participants that may benefit from care delivered in specialty over primary care as well as the converse. [ABSTRACT FROM AUTHOR]

Background: Limited data exist on pregnant women living with HIV exposed to cabotegravir + rilpivirine (CAB + RPV). Outcomes in pregnant participants exposed to CAB + RPV, and pharmacokinetic washout data in those exposed to CAB + RPV long‐acting (LA) with live births, are presented. Methods: Women exposed to one or more doses of CAB + RPV (oral/LA) from ViiV Healthcare‐sponsored phase 2b/3/3b clinical trials and the compassionate use programme who became pregnant were included. Upon pregnancy in the trial programme, CAB + RPV was discontinued, an alternative antiretroviral regimen was initiated, and quarterly pharmacokinetic sampling for 52 weeks post‐last injection was obtained. CAB + RPV continuation or alternative antiretroviral regimen initiation was decided by pregnant compassionate use programme participants and their treating physicians. Results: As of 31 March 2021, 25 pregnancies following CAB + RPV exposure at conception were reported (five oral, 20 LA), including four who conceived during pharmacokinetic washout following treatment discontinuation. There were eight elective abortions, six miscarriages (five in first trimester), one ectopic pregnancy, and 10 live births (one oral, nine LA), including one infant born with congenital ptosis. Among participants exposed to CAB + RPV LA at conception with live births, plasma CAB and RPV washout concentrations during pregnancy were within the range of those observed in non‐pregnant women. Conclusion: In this first analysis of pregnancy outcomes following CAB + RPV exposure at conception, 10 live births, including one with congenital anomaly, were reported. Plasma CAB and RPV washout concentrations during pregnancy were within the range of those in non‐pregnant women. Pregnancy surveillance within ViiV Healthcare‐sponsored clinical trials is ongoing, with dedicated pregnancy studies planned. [ABSTRACT FROM AUTHOR]

Background: Increases in fatal synthetic opioid overdoses over the past 8 years have left states scrambling for effective means to curtail these deaths. Many states have implemented policies and increased service capacity to address this rise. To better understand the effectiveness of policy level interventions we estimated the impact of the presence of naloxone access laws (NALs) on synthetic opioid fatalities at the state level. Methods: A multivariable longitudinal linear mixed model with a random intercept was used to determine the relationship between the presence of NALs and synthetic opioid overdose death rates, while controlling for, Good Samaritan laws, opioid prescription rate, and capacity for medication for opioid use disorder (MOUD), utilizing a quadratic time trajectory. Data for the study was collected from the National Vital Statistics System using multiple cause-of-death mortality files linked to drug overdose deaths. Results: The presence of an NAL had a significant (univariate P -value =.013; multivariable p-value =.010) negative relationship to fentanyl overdose death rates. Other significant controlling variables were quadratic time (univariate and multivariable P -value <.001), MOUD (univariate P -value <.001; multivariable P -value =.009), and Good Samaritan Law (univariate P -value =.033; multivariable P -value =.018). Conclusion: Naloxone standing orders are strongly related to fatal synthetic opioid overdose reduction. The effect of NALs, MOUD treatment capacity, and Good Samaritan laws all significantly influenced the synthetic opioid overdose death rate. The use of naloxone should be a central part of any state strategy to reduce overdose death rate. [ABSTRACT FROM AUTHOR]

The launch of the Sentinel-1B satellite in April 2016 completed the two-satellite synthetic aperture radar (SAR) constellation of the European Copernicus Sentinel-1 mission. The European Space Agency executed the calibration of this sensor during the commissioning phase and an independent calibration by the German Aerospace Center (DLR) in 2016. The calibration parameters must be monitored to assess the stability of the instrument. This study reports the temporal stability assessment of radiometric calibration and image quality parameters of Sentinel-1B SAR data using the corner reflector (CR) array, Surat Basin, Australia. Impulse response functions generated from the CRs in the satellite images were used to derive the image quality parameters. The average radar cross-section difference between estimated and theoretical values (38.40 dB m2) was 0.53 dB m2 for 1.5 m CRs, which is accordant with the absolute radiometric accuracy specified for the Sentinel-1 SAR system. Derived image quality parameters viz. the mean peak-to-side lobe ratio, mean integrated side lobe ratio, and spatial resolutions in the range and azimuth directions were found to be accordant with the specified value for the Sentinel-1 SAR system. The results indicate the excellent quality of the Sentinel-1B data. [ABSTRACT FROM AUTHOR]

Aim: To characterize cabotegravir population pharmacokinetics using data from phase 1, 2 and 3 studies and evaluate the association of intrinsic and extrinsic factors with pharmacokinetic variability. Methods: Analyses were implemented in NONMEM and R. Concentrations below the quantitation limit were modelled with likelihood‐based approaches. Covariate relationships were evaluated using forward addition (P <.01) and backward elimination (P <.001) approaches. The impact of each covariate on trough and peak concentrations was evaluated through simulations. External validation was performed using prediction‐corrected visual predictive checks. Results: The model‐building dataset included 23 926 plasma concentrations from 1647 adult HIV‐1‐infected (72%) and uninfected (28%) subjects in 16 studies at seven dose levels (oral 10‐60 mg, long‐acting [LA] intramuscular injection 200‐800 mg). A two‐compartment model with first‐order oral and LA absorption and elimination adequately described the data. Clearances and volumes were scaled to body weight. Estimated relative bioavailability of oral to LA was 75.6%. Race and age were not significant covariates. LA absorption rate constant (KALA) was 50.9% lower in females and 47.8% higher if the LA dose was given as two split injections. KALA decreased with increasing BMI and decreasing needle length. Clearance was 17.4% higher in current smokers. The impact of any covariate was ≤32% on trough and peak concentrations following LA administration. The final model adequately predicted 5097 plasma concentrations from 647 subjects who were not included in the model‐building dataset. Conclusions: A cabotegravir population pharmacokinetic model was developed that can be used to inform dosing strategies and future study design. No dose adjustment based on subject covariates is recommended. [ABSTRACT FROM AUTHOR]

Background: Dengue fever and dengue haemorrhagic fever currently rank highly among the newly emerging infectious diseases and are the most important arboviral disease worldwide. Dengue virus can be distinguished by both serological and molecular methods. This study was aimed at analysing the prevalence and laboratory dynamics of the four dengue serotypes in tertiary care patients attending GMERS Medical College Gandhinagar. Material & methods: This study was an observational retrospective study. A total 105 samples were tested for Dengue serotyping by RT-PCR. Results: Among positive patients Dengue virus serotype-2 was the most common serotype 94 (89%) followed by DENV3 7(6%) and DENV4 2(2%). Co-infection with DENV 2/4 was 2(2%). A higher prevalence of dengue haemorrhagic fever was noted in serotype 2 compared to serotypes 3, 4, and coinfection. Thrombocytopenia was present in all serotypes of infection. There was a significant difference in the disturbance of liver function in DENV2, as compared to others serotype. Dengue serotype 2 was very common in rural areas, while dengue serotype 3 was seen in the urban Gandhinagar zone. Discussion: Dengue is the most extensively spread mosquito-borne disease. As per previous studies most common prevalent and severity of serotype wasDENV2, however in our study we were able to identify DENV3, DENV4 and confection with serotypes (DENV2 & DENV4). [ABSTRACT FROM AUTHOR]

Net surface radiation (Rn) at earth surface comprises of outgoing and incoming components of longwave and shortwave radiation fluxes at the surface. This influences energy and mass exchange over earth surface at sub-daily, seasonal and annual time scales. This is a critical component for land surface models which characterize climatic, ecological and biological processes. Measured net radiation datasets are rarely available and can be subjected to errors and high uncertainties due to equipment malfunctions and failure. In this study, a regional-scale model is developed and implemented to estimate the net surface radiation fluxes over Indian landmass under cloudless sky conditions using the data from an Indian Geostationary (GEO) Meteorological satellite (INSAT 3D) and polar-orbiting (LEO) MODIS-Aqua for daytime conditions. The estimates were evaluated over a 6-month period (Nov 2019–Apr 2020) during winter and summer months, at three in situ measurement sites, located in cropland and grassland. The results showed a correlation of 0.86 between satellite-based Rn estimates and in situ measurements with a root mean square error (RMSE) of 40.4 W m−2 (4.6% of measured mean) and a mean absolute error (MAE) of 5.6% of measured mean. The modelled estimates were compared with NCEP (National Center for Environmental Protection) reanalysis global surface radiation estimates diurnally. The NCEP model tends to under- or over-estimate during the study time period especially in the month of January. [ABSTRACT FROM AUTHOR]

Aims: Cabotegravir is an integrase strand transfer inhibitor in clinical development as long‐acting (LA) injectable HIV preexposure prophylaxis. Methods: This phase I study assessed pharmacokinetics of cabotegravir in plasma and anatomical sites associated with sexual HIV‐1 transmission after repeated oral and single intramuscular (IM) LA dosing in healthy adults. Following a 28‐day oral lead‐in period of cabotegravir 30 mg and a washout period of 14–42 days, participants were administered a single ultrasound‐guided gluteal IM cabotegravir LA 600‐mg injection. The study objective was to characterize cabotegravir concentrations in plasma, cervical, vaginal and rectal tissues, and cervicovaginal and rectal fluids and up to Week 12 after IM injection. Results: Nineteen participants enrolled and 16 completed the study through Week 52. Cabotegravir was detected in plasma and all tissues and fluids. Median plasma cabotegravir concentrations exceeded the in vitro protein‐adjusted 90% maximal inhibitory concentration through Week 12. Median tissue‐ and fluid‐to‐plasma cabotegravir concentration ratios across all visits were 0.32 for rectal fluid and 0.08–0.16 for other tissues and fluids. Adjusted R2 coefficients between cabotegravir concentrations in plasma and cervical, vaginal and rectal tissues were 0.78, 0.79 and 0.90, respectively. Injection‐site reactions were common (88% of participants) and were mostly grade 1 in intensity (82%). Two participants reported 11 non–drug‐related serious adverse events. Conclusion: Concentrations of cabotegravir in tissues and fluids were proportional to plasma over time, with strong correlations between tissue and plasma concentrations. Cabotegravir LA tissue‐to‐plasma ratios may be important for understanding its use as preexposure prophylaxis. [ABSTRACT FROM AUTHOR]

Aim: Cabotegravir long‐acting (LA) intramuscular (IM) injection is being investigated for HIV preexposure prophylaxis due to its potent antiretroviral activity and infrequent dosing requirement. A subset of healthy adult volunteers participating in a Phase I study assessing cabotegravir tissue pharmacokinetics underwent serial magnetic resonance imaging (MRI) to assess drug depot localization and kinetics following a single cabotegravir LA IM targeted injection. Methods: Eight participants (four men, four women) were administered cabotegravir LA 600 mg under ultrasonographic‐guided injection targeting the gluteal muscles. MRI was performed to determine injection‐site location in gluteal muscle (IM), subcutaneous (SC) adipose tissue and combined IM/SC compartments, and to quantify drug depot characteristics, including volume and surface area, on Days 1 (≤2 hours postinjection), 3 and 8. Linear regression analysis examined correlations between MRI‐derived parameters and plasma cabotegravir exposure metrics, including maximum observed concentration (Cmax) and partial area under the concentration–time curve (AUC) through Weeks 4 and 8. Results: Cabotegravir LA depot locations varied by participant and were identified in the IM compartment (n = 2), combined IM/SC compartments (n = 4), SC compartment (n = 1) and retroperitoneal cavity (n = 1). Although several MRI parameter and exposure metric correlations were determined, total depot surface area on Day 1 strongly correlated with plasma cabotegravir concentration at Days 3 and 8, Cmax and partial AUC through Weeks 4 and 8. Conclusion: MRI clearly delineated cabotegravir LA injection‐site location and depot kinetics in healthy adults. Although injection‐site variability was observed, drug depot surface area correlated with both plasma Cmax and partial AUC independently of anatomical distribution. [ABSTRACT FROM AUTHOR]

Spatio-temporal evolution of soil moisture is a complex process and controlled by several factors including hydro-meteorological forcings. This study borrows a recently developed concept of temporal networks to capture the time-varying association between hydro-meteorological forcings and spatio-temporal evolution of soil moisture. Climate change and dynamic terrestrial environment cause slow but continuous change in the characteristics of hydro-meteorological forcings leading to variation in spatio-temporal distribution of soil moisture. Keeping this in the focus of the study, temporal networks based time-varying modelling framework is adapted for one-month to one-season (three-months) in advance prediction of monthly soil moisture for entire Indian mainland. Results indicate that the association among the hydro-meteorological forcings varies with both space and time. With the increase in prediction lead-time, the strength of association with the variables, such as pressure, wind and temperature, decreases and that with the variables like leaf area index remains informative. Among different seasons, the model shows superior performance for the monsoon and post monsoon periods. Next, the soil moisture based extremes are assessed by utilizing two deficit indices and two wetness indices. The model performance is highly satisfactory but varies over space and seasons, with a marginally better performance for the wetness indices. Overall, given the vast spatial extent of the Indian mainland, the proposed model performs robustly for almost all the climatic regions and may be promising for other parts of the world as well. [ABSTRACT FROM AUTHOR]

Background: Cabotegravir is an HIV integrase inhibitor in clinical development with both oral and long-acting (LA) injectable formulations. Cabotegravir is primarily metabolized by uridine 5'-diphospho-glucuronosyltransferase (UGT) 1A1, a known polymorphic enzyme with functional variants that can affect drug metabolism and exposure.Objectives: To investigate the pharmacogenetic effects of the reduced-function alleles UGT1A1*6, UGT1A1*28 and/or UGT1A1*37 on steady-state pharmacokinetics (PK) and safety of oral cabotegravir (30 mg/day) and intramuscular cabotegravir LA (400 mg every 4 weeks or 600 mg every 8 weeks).Methods: Plasma cabotegravir PK was assessed in 346 UGT-genotyped participants with and without UGT1A1 functional variants across six studies (four Phase I and two Phase II) of oral cabotegravir, including 215 HIV-infected participants who received oral cabotegravir followed by cabotegravir LA. Changes from baseline in total bilirubin and ALT were assessed in one study (LATTE; NCT01641809).Results: Statistically significant (P < 0.05) associations were observed between UGT1A1 genotype and plasma cabotegravir PK parameters, with 28%-50% increases following oral cabotegravir [plasma cabotegravir concentration at the end of the dosing interval (Ctau), 1.50-fold; AUCtau, 1.41-fold; and Cmax, 1.28-fold] and 16%-24% increases following cabotegravir LA administration (48 week Ctau, 1.24-fold; AUCtau, 1.16-fold; and Cmax, 1.18-fold) among those with low-versus-normal genetically predicted UGT1A1 activity. A statistically significant (P < 10-5) association between predicted UGT1A1 activity and maximum change in total bilirubin was also observed (2.45-fold asymptomatic increase for low versus normal) without a corresponding change in ALT.Conclusions: This modest increase in oral and parenteral cabotegravir exposure associated with a reduced function of UGT1A1 is not considered clinically relevant based on accumulated safety data; no dose adjustment is required. [ABSTRACT FROM AUTHOR]

Leaf Area Index (LAI) is a key parameter to characterize the canopy–atmosphere interface, where most of the energy fluxes exchange. Space-borne satellite images have shown their relevance for various applications including LAI retrieval over large areas. Although optical data have been used for this purpose in previous studies, the constraints to acquire optical data during extreme weather conditions due to the presence of clouds, haze, smoke etc. hinders its use for uninterrupted monitoring. This study aims to analyze the relationships of C-band RISAT-1 hybrid polarized SAR data (σ˚RH and σ˚RV) with wheat LAI. The results have shown the correlation coefficient (|r|) of 0.57 and 0.73 for RH and RV backscatter, respectively, using non-linear regression approach. It is also observed that the accuracy of LAI retrieval has been significantly improved with |r| and RMSE of 0.81 and 0.54 (m2/m2), respectively, by considering both RH and RV backscatter as inputs for support vector machine-based model. [ABSTRACT FROM AUTHOR]

Background: Long-acting (LA) formulations of cabotegravir, an HIV integrase inhibitor, and rilpivirine, an NNRTI, are in development as monthly or 2 monthly intramuscular (IM) injections for maintenance of virological suppression.Objectives: To evaluate cabotegravir and rilpivirine CSF distribution and HIV-1 RNA suppression in plasma and CSF in HIV-infected adults participating in a substudy of the Phase 2b LATTE-2 study (NCT02120352).Methods: Eighteen participants receiving cabotegravir LA 400 mg + rilpivirine LA 600 mg IM [every 4 weeks (Q4W), n = 3] or cabotegravir LA 600 mg + rilpivirine LA 900 mg IM [every 8 weeks (Q8W), n = 15] with plasma HIV-1 RNA <50 copies/mL enrolled. Paired steady-state CSF and plasma concentrations were evaluable in 16 participants obtained 7 (±3) days after an injection visit. HIV-1 RNA in CSF and plasma were assessed contemporaneously using commercial assays.Results: Median total CSF concentrations in Q4W and Q8W groups, respectively, were 0.011 μg/mL and 0.013 μg/mL for cabotegravir (0.30% and 0.34% of the paired plasma concentrations) and 1.84 ng/mL and 1.67 ng/mL for rilpivirine (1.07% and 1.32% of paired plasma concentrations). Cabotegravir and rilpivirine total CSF concentrations exceeded their respective in vitro EC50 for WT HIV-1 (0.10 ng/mL and 0.27 ng/mL, respectively). All 16 participants had HIV-1 RNA <50 copies/mL in plasma and CSF, and 15 of 16 participants had HIV-1 RNA <2 copies/mL in CSF.Conclusions: A dual regimen of cabotegravir LA and rilpivirine LA achieved therapeutic concentrations in the CSF resulting in effective virological control in CSF. [ABSTRACT FROM AUTHOR]

Relebactam is a small‐molecule β‐lactamase inhibitor developed as a fixed‐dose combination with imipenem/cilastatin. The pharmacokinetics of relebactam and imipenem across 10 clinical studies were analyzed using data from adult healthy volunteers and patients with bacterial infections. Renal function estimated by creatinine clearance significantly affected the clearance of both compounds, whereas weight and health status were of less clinical significance. Simulations were used to calculate probability of joint target attainment (ratio of free drug area under the curve from 0 to 24 hours to minimum inhibitory concentration (MIC) for relebactam and percentage of time the free drug concentration exceeded the MIC for imipenem) for the proposed imipenem/relebactam dose of 500/250 mg, with adjustments for patients with renal impairment, administered as a 30‐minute intravenous infusion four times daily. These dosing regimens provide sufficient antibacterial coverage (MIC ≤ 4 μg/mL) for all renal groups. [ABSTRACT FROM AUTHOR]

The objective of this paper was to explore the potential of hybrid-polarized (RH and RV) RISAT-1 SAR data to retrieve the height of wheat crop—an important winter crop in South Asian countries including India. The images acquired over north-west India in 2015 covered critical growth stages of wheat. The field campaigns were carried out in synchronous with the SAR passes. Considering the dominant role of underlying soil cover in the total backscatter $({\boldsymbol{\sigma }_{\boldsymbol{total}}^0})$ response from a target, we propose that refining the $\boldsymbol{\sigma }_{\boldsymbol{total}}^0$ by reducing the effect of underlying soil can significantly improve the retrieval accuracy of crop height (CH). To achieve this, we modified the existing water cloud model (WCM) to estimate soil-corrected vegetation backscatter $({\boldsymbol{\sigma }_{\boldsymbol{veg}}^0})$. Leaf area index and interaction factor showed great potential as the vegetation descriptors in modeling $\boldsymbol{\sigma }_{\boldsymbol{total}}^0$ using WCM. A comparative analysis between the CH retrieved from $\boldsymbol{\sigma }_{\boldsymbol{total}}^0$ and $\boldsymbol{\sigma }_{\boldsymbol{veg}}^0$ using multilayer perceptron neural networks revealed the response of C-band backscatter to CH. CH was moderately correlated to $\boldsymbol{\sigma }_{\boldsymbol{total}}^0$ , but the results improved considerably with the substitution of $\boldsymbol{\sigma }_{\boldsymbol{total}}^0$ with $\boldsymbol{\sigma }_{\boldsymbol{veg}}^0$. This holds true particularly in the early growth stages of crop growth when the vegetation cover is scarce and there is a substantial effect of soil background on the remote sensing signal. Thus, the results suggest suitability of C-band hybrid-polarized data for the assessment of CH. [ABSTRACT FROM AUTHOR]

This study investigates the impact of severe renal impairment on the pharmacokinetics of cabotegravir, an investigational HIV‐1 integrase inhibitor. This was a phase I, open‐label, parallel‐group, multicenter study conducted in 8 participants with severe renal impairment (creatinine clearance <30 mL/min; no renal replacement therapy) and 8 healthy participants (creatinine clearance >90 mL/min; 2 women/group; 6 men/group) matched for sex, age (±10 years), and body mass index (±25%). Participants received a single 30‐mg oral cabotegravir tablet to determine total and unbound plasma cabotegravir concentrations. Arithmetic and geometric least squares means were calculated, and cabotegravir noncompartmental pharmacokinetic parameters were compared using geometric least squares mean ratios with 90% confidence intervals. Safety was assessed throughout the study. Geometric least squares mean ratios (90% confidence intervals) were 0.97 (0.84–1.14) for area under the plasma concentration‐time curve extrapolated to infinity, 1.01 (0.87–1.17) for maximum observed plasma concentration, 1.31 (0.84–2.03) for unbound cabotegravir 2 hours after dosing, and 1.51 (1.19–1.92) for unbound cabotegravir 24 hours after dosing. All adverse events were grade 1, except grade 3 lipase elevation in a participant with renal impairment. Severe renal impairment did not impact plasma cabotegravir exposure, and cabotegravir may be administered without dose adjustment in renal impairment among patients not receiving renal replacement. [ABSTRACT FROM AUTHOR]

Cabotegravir is an investigational integrase inhibitor in development for the treatment and pre‐exposure prophylaxis of HIV‐1 infection. Liver disease is a major cause of morbidity and mortality in HIV‐infected individuals and can impact the pharmacokinetics (PK) of HIV medications. This phase 1 study evaluated the PK of cabotegravir in individuals with moderate hepatic impairment (n = 8) versus healthy controls (n = 8). Participants received a single oral cabotegravir 30‐mg tablet and underwent PK sampling to determine total and unbound plasma cabotegravir concentrations. Calculated geometric least‐squares mean ratios (90% confidence intervals) for individuals with hepatic impairment versus healthy controls were 0.73 (0.50‐1.06) for AUC0‐∞, 0.69 (0.51‐0.93) for Cmax, 1.40 (0.80‐2.46) for unbound concentration (CU) 2 hours postdose, 1.55 (0.82‐2.94) for CU at 24 hours, 2.14 (1.57‐2.90) for unbound fraction (FU) at 2 hours, and 1.90 (1.14‐3.18) for FU at 24 hours. Adverse events (AEs) occurred in 2 individuals with hepatic impairment and 3 healthy controls and were grade 1/2 in severity. No participant discontinued because of AEs. Increased FU resulted in a modest decrease in total plasma exposure not considered clinically relevant. We conclude that cabotegravir may be administered without dose adjustment in patients with mild to moderate hepatic impairment. [ABSTRACT FROM AUTHOR]

Cabotegravir is an integrase inhibitor in clinical development for the treatment and prevention of HIV infection using oral tablets for short‐term, lead‐in use before subsequent administration of a long‐acting injectable formulation. This phase 1, single‐center, randomized, 2 × 2 crossover study evaluated the effect of a high‐fat meal on the pharmacokinetics (PK) of oral cabotegravir. Healthy adults received oral cabotegravir 30 mg as a single dose on 2 separate occasions, either after fasting or following a high‐fat meal (∼53% fat, ∼870 kcal). Safety evaluations and serial PK samples were collected, and a mixed‐effects model was used to determine within‐participant treatment comparison of noncompartmental PK parameters. Twenty‐four patients were enrolled and had a mean body mass index of 25.6 kg/m2; 67% were male. Compared with the fasting state, coadministration of cabotegravir with a high‐fat meal increased plasma cabotegravir area under the concentration‐time curve and maximal drug concentration, each by 14%. The slight 14% to 17% increase in exposure associated with a high‐fat, high‐calorie meal was not considered clinically significant. No grade 3/4 adverse events (AEs), drug‐related AEs, or AEs leading to discontinuation were reported. [ABSTRACT FROM AUTHOR]

Neuroendocrine tumors (NETs) have historically been subcategorized according to histologic features and the site of anatomic origin. Here, we characterize the genomic alterations in patients enrolled in three phase 3 clinical trials of NET of different anatomic origins and assess the potential correlation with clinical outcomes. Whole-exome and targeted panel sequencing was used to characterize 225 NET samples collected in the RADIANT series of clinical trials. Genomic profiling of NET was analyzed along with nongenomic biomarker data on the tumor grade and circulating chromogranin A (CgA) and neuron-specific enolase (NSE) levels from these patients enrolled in clinical trials. Our results highlight recurrent large-scale chromosomal alterations as a common theme among NET. Although the specific pattern of chromosomal alterations differed between tumor subtypes, the evidence for generalized chromosomal instability (CIN) was observed across all primary sites of NET. In pancreatic NET, although the P value was not significant, higher CIN suggests a trend toward longer survival (HR, 0.55, P = 0.077), whereas in the gastrointestinal NET, lower CIN was associated with longer survival (HR, 0.44, P = 0.0006). Our multivariate analyses demonstrated that when combined with other clinical data among patients with progressive advanced NETs, chromosomal level alteration adds important prognostic information. Large-scale CIN is a common feature of NET, and specific patterns of chromosomal gain and loss appeared to have independent prognostic value in NET subtypes. However, whether CIN in general has clin ical significance in NET requires validation in larger patient cohort and warrants further mechanistic studies. [ABSTRACT FROM AUTHOR]

Aims The aims of the study were to characterize the pharmacokinetics (PK) of selumetinib (AZD6244; ARRY-142886), a mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor in clinical development for various indications, and its N-desmethyl metabolite in healthy volunteers, and evaluate clinically important covariates. Methods A pooled-population PK analysis was performed using a nonlinear mixed-effects approach with plasma concentration data from 346 subjects who received single oral doses of selumetinib 20-75 mg across 10 phase I studies. Absolute bioavailability was determined using intravenous [14C] selumetinib. Results A two-compartment linear model with sequential zero-first order absorption and a lag time for the zero-order process was described for selumetinib PK. N-desmethyl metabolite disposition was described by a single compartment with linear elimination, without back transformation. The parent-only and joint models generally described pooled data adequately. For the median subject, not taking interacting drugs, estimates for clearance (CL) and central volume of distribution (V2) for selumetinib in the final joint model were 12.7 l h-1 and 35.6 l, respectively. Food effects, comedication with itraconazole [a cytochrome P450 (CYP) 3A4 inhibitor], fluconazole (a CYP2C19 inhibitor) and rifampicin (a CYP3A4 inducer) and formulation effects were incorporated into the base model a priori. Race and hepatic function were also influential in the PK model. Additional covariates affecting selumetinib disposition identified from covariate analysis were age on V2, bilirubin on CL, and weight on CL and V2. Conclusions Analysis confirmed previous clinical pharmacology study findings of drug-drug interactions and food effects, with additional covariates that influence selumetinib and N-desmethyl selumetinib PK identified. Dose modifications based on these additional covariates were not considered necessary. [ABSTRACT FROM AUTHOR]

배경 Cabotegravir (CAB) + rilpivirine (RPV) is the first guideline-recommended, complete long-acting (LA) injectable regimen for maintenance of HIV-1 virologic suppression. In a post-hoc, multivariable analysis, the presence of ≥2 of 3 baseline (BL) factors (archived RPV resistance-associated mutations [RAMs], HIV-1 subtype A6/A1, or BMI ≥30 kg/m2 ) modestly increased confirmed virologic failure (CVF) risk. Efficacy, safety, and pharmacokinetics of CAB+RPV by BL BMI category among Phase 3/3b trial participants through Week 48 (W48) were evaluated. 방법 Data were pooled from CAB+RPV-naive participants receiving every-4- or 8-week dosing (Q4W or Q8W) in the ATLAS, FLAIR, and ATLAS-2M studies. Baseline characteristics, HIV-1 RNA <50 and ≥50 copies/mL, CVF (2 consecutive HIV-1 RNA ≥200 copies/mL), injection site reaction adverse events (ISR AEs), and plasma CAB and RPV troughs were evaluated through W48 by lower or higher BMI category (<30 or ≥30 kg/m² ). 결과 Among 1245 CAB+RPV LA participants, 213 (17%) had a BL BMI ≥30 kg/m². At W48, 92% vs. 93% of participants with higher vs. lower BMI, respectively, had HIV-1 RNA <50 copies/mL. There were 8 vs. 5 CVFs in the higher vs. lower BMI group. All CVFs in the higher BMI group had at least one other BL risk factor (archived RPV RAMs [n=3], A6/A1 subtype [n=4], both [n=1]). No participant with higher BMI alone developed CVF at W48. Overall safety, including ISR AEs, was comparable between groups. CAB and RPV troughs remained above their respective PA-IC90 values regardless of BMI or dosing arm. 결론 CAB+RPV LA Q4W and Q8W maintained high virologic suppression rates through W48 in Phase 3/3b trials, regardless of BL BMI category. Injections were well-tolerated, with few ISR-related discontinuations. CAB+RPV offers a safe and effective long-acting treatment option in participants across a wide BMI range without need for daily oral dosing. [ABSTRACT FROM AUTHOR]

배경 Cabotegravir (CAB) + rilpivirine (RPV) is the first complete long-acting (LA) regimen approved and rec- ommended by treatment guidelines for the maintenance of virologic suppression in people living with HIV-1. To date, limited data are available for those who discontinued CAB+RPV LA and resumed daily oral antiretrovirals (ARVs). Here, we describe results for participants who discontinued CAB+RPV LA during the Phase III/IIIb program and entered 12-month (12M) long-term follow-up (LTFU). 방법 All participants exposed to CAB+RPV LA and discontinued from ATLAS, FLAIR, or ATLAS-2M were included. Demographics, reason(s) for discontinuing LA therapy, and efficacy/safety of subsequent ARV therapy are evaluated 결과 1723 unique participants were randomized across Phase III/IIIb studies, with 150 participants (n=138 from maintenance and extension and n=12 after switch in the extension phase) discontinuing CAB+RPV LA and entering LTFU. The median age in LTFU group was 38 years, 70% were white, and 30% female (Figure 1). Median duration of CAB+RPV LA treatment before discontinuing was 36.7 weeks (0.9-144 weeks). Reasons for entering LTFU included AEs, participant withdrawal, and lack of efficacy (Figure 2). Participants primarily switched to INSTI- (58%) or bPI- (21%) containing regimens; 82% of switches oc- curred within 4-8 weeks of CAB+RPV LA discontinuation. Of 150 entering LTFU, 92 completed M12, 4 withdrew, and 54 are ongoing. At M12, 97% (84/87) with viral load data maintained HIV-1 RNA <50 copies/ml. Thirteen (9%) participants reported drug-related AEs while on oral ARVs, with no AE-related discontinuations. 결론 Through up to 144 weeks, approximately 9% of study participants in Phase III/IIIb trials discontinued CAB+RPV LA and entered LTFU with the majority resuming an INSTI- or bPI-based oral regimen. High rates of suppression were maintained on subsequent ARV, with no efficacy or safety concerns in participants who switched to oral ARVs, regardless of reason for switch. [ABSTRACT FROM AUTHOR]

배경 Cabotegravir (CAB) and rilpivirine (RPV) is the first guideline-recommended complete long-acting (LA) regimen for the maintenance of HIV-1 virologic suppression. In Phase 3 studies, oral CAB+RPV given once daily was utilized as an oral lead-in (OLI) for ≥4 weeks prior to initiating LA dosing to assess in- dividual safety and tolerability. The FLAIR extension phase demonstrated that initiating CAB+RPV direct-to-injection (DTI) had comparable safety, tolerability, efficacy, and pharmacokinetics compared with initiating with an OLI, offering a practical treatment simplification strategy. This post hoc analysis com- pares the safety of CAB+RPV during the OLI to LA administration periods across the Phase 3 program. 방법 Week 48 data from participants naive to CAB+RPV in the FLAIR, ATLAS, and ATLAS-2M studies were pooled. Safety outcomes were summarized separately during OLI and LA periods for those randomized at baseline to CAB+RPV, and also for those switching from oral comparator to CAB+RPV (either via DTI or OLI) during the FLAIR extension phase (Week 100-Week 124). 결과 1245 participants were in cluded in the pooled population; 918 and 327 received CAB+RPV LA Q4W and Q8W following an OLI, respectively. Further, 232 FLAIR extension-switch participants received CAB+RPV LA Q4W, either DTI (n=111) or following an OLI (n=121). The OLI period was well tolerated, with few Grade 3/4 AEs (1%, n=15/1245), serious AEs (<1%, n=9/1245), or AEs leading to withdrawal (<1%, n=10/1245); after continuing to LA therapy, AE rates were comparable between participants electing to receive OLI or DTI (Figure). No drug hypersensitivity reactions or other serious AEs occurred during the 4-week OLI that prohibited transition to LA therapy. 결론 A 4-week OLI of CAB+RPV was well tolerated in >1200 participants across the Phase 3 program. The safety profile of CAB+RPV LA dosing was similar regardless of whether participants received OLI or proceeded DTI, supporting optional CAB+RPV DTI as a simplification strategy. Data included in this abstract have been previously presented in full at the 18th European AIDS Conference; October 27-30, 2021; Virtual & London, UK; Poster PE2/75. [ABSTRACT FROM AUTHOR]

Aims This study aimed to investigate whether cabotegravir (CAB), an integrase inhibitor in development for treatment and prevention of human immunodeficiency virus-1, influences the pharmacokinetics (PK) of a levonorgestrel (LNG) and ethinyl oestradiol (EO)-containing oral contraceptive (OC) in healthy women. Methods In this open-label, fixed-sequence crossover study, healthy female subjects received LNG 0.15 mg/EO 0.03 mg tablet once daily Days 1-10 alone and with oral CAB 30 mg once daily Days 11-21. At the end of each treatment period, subjects underwent predose sampling for concentrations of follicle-stimulating hormone, luteinizing hormone, and progesterone and serial PK sampling for plasma LNG, EO, and CAB concentrations. Results Twenty women were enrolled, and 19 completed the study. One subject was withdrawn due to an adverse event unrelated to study medications. Geometric least squares mean ratios (90% confidence interval) of LNG + CAB vs. LNG alone for LNG area under the plasma concentration-time curve over the dosing interval of duration τ and maximum observed plasma concentration were 1.12 (1.07-1.18) and 1.05 (0.96-1.15), respectively. Geometric least squares mean ratio (90% confidence interval) of EO + CAB vs. EO alone for EO area under the plasma concentration-time curve over the dosing interval of duration τ and maximum observed plasma concentration were 1.02 (0.97-1.08) and 0.92 (0.83-1.03), respectively. Steady-state CAB PK parameters were comparable to historical values. There was no apparent difference in mean luteinizing hormone, follicle-stimulating hormone, and progesterone concentrations between periods. No clinically significant trends in laboratory values, vital signs, or electrocardiography values were observed. Conclusions Repeat doses of oral CAB had no significant effect on LNG/EO PK or pharmacodynamics, which supports CAB coadministration with LNG/EO OCs in clinical practice. [ABSTRACT FROM AUTHOR]

Background: The current analysis was performed to evaluate the impact of PIK3CA hotspot mutations on everolimus efficacy in BOLERO-2 participants, using cell-free DNA (cfDNA) from plasma samples collected at the time of patient randomisation.Methods: PIK3CA H1047R, E545K, and E542K mutations in plasma-derived cfDNA were analysed by droplet digital PCR (ddPCR). Median PFS was estimated for patient subgroups defined by PIK3CA mutations in each treatment arm.Results: Among 550 patients included in cfDNA analysis, median PFS in everolimus vs placebo arms was similar in patients with tumours that had wild-type or mutant PIK3CA (hazard ratio (HR), 0.43 and 0.37, respectively). Everolimus also prolonged median PFS in patients with PIK3CA H1047R (HR, 0.37) and E545K/E542K mutations (HR=0.30) with a similar magnitude.Conclusions: Mutation analysis of plasma-derived cfDNA by ddPCR suggests that PFS benefit of everolimus was maintained irrespective of PIK3CA genotypes, consistent with the previous analysis of archival tumour DNA by next-generation sequencing. [ABSTRACT FROM AUTHOR]

This paper attempts to probabilistically estimate the surface soil moisture content (SMC) by using the synthetic aperture radar data provided by radar imaging satellite1. The novelty of this paper lies in: 1) developing a combined index to understand the role of all the backscattering coefficients with different polarization and soil texture information in influencing the SMC; 2) using normalized incidence angles, which enables the model to be applicable for different incidence angles; and 3) determination of uncertainty range of the estimated SMC. The dimensionality problem, which is frequently observed in the multivariate analysis, is reduced in the development of the combined index by the use of supervised principal component analysis (SPCA). The SPCA also ensures the maximum attainable association between the developed combined index and surface SMC above wilting point (WP). The association between the combined index and the surface SMC above WP is modeled through joint probability distribution by using the Frank copula. The model is developed and validated with the field soil moisture values over 334 monitoring points within the study area. The outcomes obtained by applying the proposed model indicate an encouraging potential of the model to be applied for bareland and vegetated land (<30 cm height). [ABSTRACT FROM PUBLISHER]

A randomized, partial-blind, repeat-dose, 3-period crossover study (NCT02027454) assessed the effect of cabotegravir on QT interval in healthy subjects. To achieve a supratherapeutic dose, each subject received cabotegravir 150 mg (30 mg × 5 tablets) every 12 hours for a total of 3 doses over 2 days, matching placebo (every 12 hours) over 2 days, or a single open-label 400-mg dose of the positive control moxifloxacin, with a 21-day washout between treatments. Blood samples for pharmacokinetic analyses were collected up to 24 hours after the third dose on day 2. QT interval data were obtained by continuous Holter monitoring for approximately 24 hours at baseline (day -1) and from 2 hours before to 24 hours after the third dose on day 2. Plasma cabotegravir exposure was approximately 3-fold above clinically relevant doses. After 3 doses of 150 mg of cabotegravir administered every 12 hours, all upper limits of 2-sided 90% confidence intervals for ΔΔQTcF (difference in time-matched change from baseline for QTcF between cabotegravir and placebo) were <10 milliseconds. There was no relationship between cabotegravir plasma concentrations and ΔΔQTcF. No subject receiving cabotegravir had a QTcF value > 450 milliseconds. There were no serious or grade 3 or 4 adverse events or clinically significant changes in laboratory values, vital signs, or electrocardiogram results. These data demonstrate that cabotegravir at a supratherapeutic dose had no effect on cardiac repolarization. [ABSTRACT FROM AUTHOR]

Background: Cabotegravir (CAB) and rilpivirine (RPV) is the first complete long-acting (LA) regimen recommended by treatment guidelines to maintain HIV-1 virologic suppression. Dosing every 4 weeks (Q4W) or every 8 weeks (Q8W) showed noninferior efficacy in Phase 3/3b trials. This post hoc analysis summarizes Asian participant (pt) outcomes through Week (W) 96. Methods: We pooled data from Asian pts naive to CAB+RPV (n=41) randomized to receive Q4W (n=24) or Q8W (n=17) dosing in Phase 3/3b FLAIR (NCT02938520) and ATLAS-2M (NCT03299049). The proportion of pts with HIV-1 RNA ≥50 and <50copies/mL (FDA Snapshot), incidence of confirmed virologic failure (CVF), adherence, and safety through W96 were assessed. Results: Median pt age was 39 years, 4 were female at birth, 1 had a body mass index ≥30 kg/m2; 0 were hepatitis B-reactive (non-reactive, n=12; negative, n=29). Pts enrolled at centers in Asia (59%, n=24), North America (27%, n=11), Europe (10%, n=4), Africa, and Australia (each 2%, n=1). At W96, 83% (n=34/41) of pts maintained HIV-1 RNA <50copies/mL, 0 had HIV-1 RNA ≥50copies/mL, and 17% (n=7/41) had no virologic data due to discontinuation. No pt met CVF criterion. 93% (n=38) of pts had non-injection site reaction [ISR] AEs; 95% (n=36/38) were Grade≤2, and 47% (n=18/38) were deemed drug-related. No pt had a Grade ≥3 drug-related AE. Serious AEs occurred in 12% (n=5/41) of pts. Most injection visits (97%, n=620/642) occurred within the ±7-day dosing window; one injection visit was missed and covered by oral CAB+RPV. The most common ISR was injection site pain (28% of injections, n=378/1360); all Grade≤2 with median 2-day duration. Pts withdrew due to drug-related non-ISR AEs (5%, n=2/41) and injection-related reasons (10%, n=4/41). Conclusion: CAB+RPV LA demonstrated high efficacy, with no pts having CVF, and acceptable safety in Asian pts through W96. These data support CAB+RPV LA as a complete regimen to maintain virologic suppression in Asian pts with HIV-1. [ABSTRACT FROM AUTHOR]

There is continued emphasis from the various worldwide regulatory agencies to ensure that the pharmaceutical industry fully understands the products they are developing. This emphasis is seen via development of quality-by-design (QbD) publications and guidelines generated by the International Committee on Harmonization. The challenge to meet these expectations is primarily associated with the generation of in vivo data (eg, pharmacokinetic data) that is resource intensive. A technique reducing the resources needed to generate this in vivo data permits a more extensive application of QbD principles. This paper presents the application of stable isotopes in pharmacokinetic studies. The data show that the use of stable isotopes can significantly reduce the number of subjects required for a study. This reduction in subjects thus translates into a significant reduction in resources and time needed to generate the required in vivo data to support QbD. [ABSTRACT FROM AUTHOR]