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The Ecuadorian Amazon holds more biodiversity than most other places on Earth. Palms are a particularly dominant component of the vegetation; however, it remains unknown to what degree the pattern has persisted through time. Here, we investigate the persistence of palm dominance through time and the degree to which past human activities (e.g., fire, cultivation, and forest opening) have affected changes in palm abundances across five regions of the Ecuadorian Amazon. We analyzed soil cores (40-80 cm depth) from each region for charcoal (evidence of past fire) and phytoliths (evidence of past vegetation change). The timings of fires (based on 14C radiocarbon dates), the occurrence, recurrence, and number of fires (based on charcoal presence and abundance in samples), and the amount of change in palm abundances (based on phytoliths) varied within and between the studied regions. The charcoal and phytolith results indicate the presence of low levels of past human activity at all sites. Our results show that patterns of modern palm hyperdominance found in Amazonian forests have not been persistent through time, and that even low levels of past human activities can affect palm abundance.
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Global warming during the Last Glacial Termination was interrupted by millennial-scale cool intervals such as the Younger Dryas and the Antarctic Cold Reversal (ACR). Although these events are well characterized at high latitudes, their impacts at low latitudes are less well known. We present high-resolution temperature and hydroclimate records from the tropical Andes spanning the past ~16,800 y using organic geochemical proxies applied to a sediment core from Laguna Llaviucu, Ecuador. Our hydroclimate record aligns with records from the western Amazon and eastern and central Andes and indicates a dominant long-term influence of changing austral summer insolation on the intensity of the South American Summer Monsoon. Our temperature record indicates a ~4 °C warming during the glacial termination, stable temperatures in the early to mid-Holocene, and slight, gradual warming since ~6,000 y ago. Importantly, we observe a ~1.5 °C cold reversal coincident with the ACR. These data document a temperature change pattern during the deglaciation in the tropical Andes that resembles temperatures at high southern latitudes, which are thought to be controlled by radiative forcing from atmospheric greenhouse gases and changes in ocean heat transport by the Atlantic meridional overturning circulation.
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INTRODUCTION: Once-daily fixed-dose combinations (FDC) containing abacavir (ABC), dolutegravir (DTG), and lamivudine (3TC) have been approved in the US for adults and children with HIV weighing ≥ 6 kg. This analysis assessed the ability of previously developed ABC, DTG, and 3TC pediatric population pharmacokinetic (PopPK) models using multiple formulations to describe and predict PK data in young children using dispersible tablet (DT) and tablet formulations of ABC/DTG/3TC FDC in the IMPAACT 2019 study. METHODS: IMPAACT 2019 was a Phase I/II study assessing the PK, safety, tolerability, and efficacy of ABC/DTG/3TC FDC in children with HIV-1. Intensive and sparse PK samples were collected over 48 weeks. Existing drug-specific pediatric PopPK models for ABC (2-compartment), DTG (1-compartment), and 3TC (1-compartment) were applied to the IMPAACT 2019 drug concentration data without re-estimation (external validation) of PopPK parameters. Drug exposures were then simulated across World Health Organization weight bands for children weighing ≥ 6 to < 40 kg for each drug and compared with pre-defined exposure target ranges. RESULTS: Goodness-of-fit and visual predictive check plots demonstrated that the previously developed pediatric PopPK models sufficiently described and predicted the data. Thus, new PopPK models describing the IMPAACT 2019 data were unnecessary. Across weight bands, the predicted geometric mean (GM) for ABC AUC0-24 ranged from 14.89 to 18.50 µg*h/ml, DTG C24 ranged from 0.74 to 0.95 µg/ml, and 3TC AUC0-24 ranged from 10.50 to 13.20 µg*h/ml. These exposures were well within the pre-defined target ranges set for each drug. CONCLUSION: This model-based approach leveraged existing pediatric data and models to confirm dosing of ABC/DTG/3TC FDC formulations in children with HIV-1. This analysis supports ABC/DTG/3TC FDC dosing in children weighing ≥ 6 kg.
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The World Health Organization has recommended the use of dolutegravir (DTG) for both first and second-line antiretroviral treatment in both adults and children down to 4 weeks of age. We developed a population pharmacokinetic(PopPK) model following oral administration of DTG 50 mg QD and 50 mg BID in HIV-infected treatment-experienced adults (607) based on pooled data from four phase 2/3 trials. DTG population pharmacokinetics are described by a one-compartment model with first-order absorption, absorption lag-time, and first-order elimination. The PopPK parameter estimates were apparent oral clearance (CL/F) = 1.00 L/h, apparent volume of distribution (V/F) = 18.9 L, absorption rate constant (Ka) = 1.99 per hour, and absorption lag time = 0.333 h, respectively. The final model included inter-individual and inter-occasion variability on apparent clearance (CL/F). Weight, smoking status, use of metabolic inducers as part of background antiretroviral therapy (ART) classified by their level of induction, use of atazanavir or atazanavir-ritonavir as part of background ART, and albumin level were predictors of CL/F; weight and albumin level were predictors of V/F; and sex and concomitant use of metal cation-containing vitamin/mineral supplements were predictors of relative bioavailability (F). The current model-based analysis suggests that the DTG dose adjustment is not required based on the demographics, laboratory values, smoking status, concomitant use of mild metabolic inducers or inhibitors in the background therapy, or use of metal cation-containing vitamin/mineral supplements because these covariate effects are not predicted to have a clinically relevant impact on safety and efficacy.
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Dolutegravir (DTG) is a human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric subjects aged at least 4 weeks. The present work aimed to characterize the viral response based on a pooled analysis of exposure-response (E-R) from five studies in treatment-experienced and integrase-resistant (INI-r) patients infected with HIV-1. Importantly, model-based simulations of the E-R relationships with DTG provided insight into the clinical relevance of known intrinsic (e.g., sub-population with Q148-driven integrase mutation) and extrinsic (food, enzyme inducers, and metal cation-containing products) factors expected to influence the DTG E-R relationship. Model-based post hoc exposure metrics (Cmin and Cavg) were incorporated into a mechanistic population viral dynamic model describing the short-term effect of DTG on log10 HIV-1 RNA viral load over 8 or 10 days. In addition, the impact of DTG in combination with background ARTs on the 24-week HIV RNA response was also assessed using logistic regression. There was good concordance between model-based predictions and observed virologic response on day 10 and week 24. The E-R model-based simulations exploring the potential impact of a higher dose (100 mg b.i.d.) of DTG in subpopulations experiencing exposure changes due to covariates did not show clinically relevant changes in virological response compared with the approved 50 mg b.i.d. clinical dose. Overall, our study confirmed the current recommendation of dolutegravir 50 mg b.i.d. in the integrase inhibitor-resistant (INI-r) population.
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Underactive bladder (UAB) is essentially an inability of the bladder to properly empty. UAB symptoms, when they co-occur with posterior fornix syndrome (PFS) symptoms (urge, frequency, nocturia, chronic pelvic pain), can be cured/improved, surgically by uterosacral ligament (USL) repair, non-surgically, by devices which give mechanical support of the USLs or strengthening pelvic muscle and ligaments with squatting-based exercises. The pathogenic pathway from weak USLs to UAB (and PFS) is that, when the muscles which externally open the posterior wall of the urethra contract against lax USLs, their contractile force weakens, and they cannot open the urethra adequately. The detrusor then contracts against a relatively unopened urethra to cause obstructive symptoms (i.e., UAB) such as slow stream, intermittent stream (stopping and starting), hesitancy (difficulty starting), feeling of incomplete emptying, and post-micturition dribble. Co-occurrence of PFS symptoms indicates that UAB may be part of the PFS, with USL causation, which can be tested by a tampon or probe in the posterior fornix. If the emptying (and other) PFS symptoms improve, it is a sign that UAB, and Fowler's syndrome (FS) can potentially be cured or improved by USL repair. Following USL repair, many studies have recorded very significant improvement in emptying symptoms, and objective tests, for example, postvoid residual (PVR), decreased natural bladder volume, and decreased emptying time. FS and UAB are most likely a part of the PFS and, therefore, potentially curable by USL repair.
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The remit of this review is confined to experimental works and publications relevant to the integral theory of female urinary incontinence (IT). Since its first publication in 1990, the IT has challenged the general view that the pathogenesis of overactive bladder (OAB) (urge, frequency, nocturia) is unknown and there is no cure. According to the IT, normal function bladder control is binary, either closed or open. Control is cortical via a peripheral feedback component: oppositely acting reflex striated pelvic muscles contract against suspensory ligaments to close the urethra for continence, open it prior to evacuation, and stretch the vagina like a trampoline to prevent excess impulses from the urothelial stretch receptors which may cause unwanted urgency at low bladder volumes (OAB). The pathogenesis of female urinary incontinence is from outside the bladder, mainly weak ligaments or vagina, due to collagen deficiency. Damage in childbirth (collagen depolymerization) and age (collagen loss) make ligaments vulnerable to damage. With weak ligaments, muscles contracting against them weaken: the muscles cannot close the urethra (manifested as stress incontinence), open it (manifested as emptying problems or retention) or stretch the vagina to prevent the urothelial stretch receptors firing off prematurely (manifested as urge incontinence). Weak pubourethral ligaments can cause stress urinary incontinence (SUI), or SUI plus urge (mixed incontinence). Weak uterosacral ligaments (USLs) can cause urge, frequency, nocturia and emptying difficulties. Treatment consisting of surgical/non-surgical strengthening of ligaments can cure or improve SUI, OAB, and emptying dysfunctions. In summary, bladder control is from outside the bladder, binary, with cortical and peripheral components. A small change in definition, from "overactive" to "overactivated" is consistent with this concept, retains the acronym "OAB", and opens the door to probability of cure and a massive increase in research endeavours.
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It is critical to understand the impact of significant physiological changes during pregnancy on the extent of maternal and fetal drug exposure. Fostemsavir (FTR) is a prodrug of temsavir (TMR) and is approved in combination with other antiretrovirals for multi-drug-resistant human immunodeficiency virus (HIV) infections. This physiologically based pharmacokinetic model (PBPK) study was used to estimate TMR PK in pregnant populations during each trimester of pregnancy to inform FTR dosing. A PBPK model was developed and validated for TMR using PK data collected following intravenous TMR and oral FTR dosing (immediate-release and extended-release tablets) in healthy volunteers. Predicted TMR concentration-time profiles accurately predicted the reported clinical data and variability in healthy (dense data) and pregnant (sparse data) populations. Predicted versus observed TMR geometric mean (CV%) clearance following intravenous administration was 18.01 (29) versus 17 (21) (L/h). Predicted versus observed TMR AUC0-inf (ng.h/mL) in healthy volunteers following FTR administration of the extended-release tablet were 9542 (66) versus 7339 (33). The validated TMR PBPK model was then applied to predict TMR PK in a population of pregnant individuals during each trimester. Simulations showed TMR AUC in pregnant individuals receiving FTR 600 mg twice daily was decreased by 25% and 38% in the second and third trimesters, respectively. However, TMR exposure remained within the range observed in nonpregnant adults with no need for dose adjustment. The current PBPK model can also be applied for the prediction of local tissue concentrations and drug-drug interactions in pregnancy.
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Changes in land-use practices have been a central element of human adaptation to Holocene climate change. Many practices that result in the short-term stabilization of socio-natural systems, however, have longer-term, unanticipated consequences that present cascading challenges for human subsistence strategies and opportunities for subsequent adaptations. Investigating complex sequences of interaction between climate change and human land-use in the past-rather than short-term causes and effects-is therefore essential for understanding processes of adaptation and change, but this approach has been stymied by a lack of suitably-scaled paleoecological data. Through a high-resolution paleoecological analysis, we provide a 7000-year history of changing climate and land management around Lake Acopia in the Andes of southern Peru. We identify evidence of the onset of pastoralism, maize cultivation, and possibly cultivation of quinoa and potatoes to form a complex agrarian landscape by c. 4300 years ago. Cumulative interactive climate-cultivation effects resulting in erosion ended abruptly c. 2300 years ago. After this time, reduced sedimentation rates are attributed to the construction and use of agricultural terraces within the catchment of the lake. These results provide new insights into the role of humans in the manufacture of Andean landscapes and the incremental, adaptive processes through which land-use practices take shape.
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Phytoliths preserved in soils and sediments can be used to provide unique insights into past vegetation dynamics in response to human and climate change. Phytoliths can reconstruct local vegetation in terrestrial soils where pollen grains typically decay, providing a range of markers (or lack thereof) that document past human activities. The ca. 6 million km2 of Amazonian forests have relatively few baseline datasets documenting changes in phytolith representation across gradients of human disturbances. Here we show that phytolith assemblages vary on local scales across a gradient of (modern) human disturbance in tropical rainforests of Suriname. Detrended correspondence analysis showed that the phytolith assemblages found in managed landscapes (shifting cultivation and a garden), unmanaged forests, and abandoned reforesting sites were clearly distinguishable from intact forests and from each other. Our results highlight the sensitivity and potential of phytoliths to be used in reconstructing successional trajectories after site usage and abandonment. Percentages of specific phytolith morphotypes were also positively correlated with local palm abundances derived from UAV data, and with biomass estimated from MODIS satellite imagery. This baseline dataset provides an index of likely changes that can be observed at other sites that indicate past human activities and long-term forest recovery in Amazonia. Supplementary Information: The online version contains supplementary material available at 10.1007/s00334-023-00932-2.
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GSK3640254 (GSK'254) is a novel HIV-1 maturation inhibitor with pharmacokinetics supporting once-daily (QD) therapy for HIV-1 treatment. This thorough QT/corrected QT (QTc) study evaluated the effect of GSK'254 on cardiac repolarization. In this two-part, randomized study, healthy participants received GSK'254 or placebo QD for 7 days (part 1) to determine safety and pharmacokinetics of a 500-mg supratherapeutic dose. Four sequential treatment periods composed the main QTc study (part 2): GSK'254 100 mg, GSK'254 500 mg, placebo QD for 7 days, or placebo QD for 6 days with a 400-mg moxifloxacin dose on Day 7 (all with a moderate-fat meal). Concentration-QTc analyses modeled the relationship between GSK'254 plasma concentrations and placebo-adjusted change from baseline in QT interval corrected with Fridericia's formula (ΔΔQTcF). Of 50 participants enrolled, 48 completed the study (part 1, 8/8; part 2, 40/42). Least-squares (LS) mean change from baseline in QTcF for GSK'254 100 mg followed the placebo pattern across time points (maximum LS mean ΔΔQTcF, 1.7 ms); the upper bound of the 90% CI remained <10 ms. Maximum LS mean ΔΔQTcF for GSK'254 500 mg exceeded the 10-ms threshold: 10.6 ms (90% CI 7.75-13.38). Neither GSK'254 dose had clinically relevant effects on heart rate or cardiac conduction. By concentration-QTc analysis, no effect on ΔΔQTcF >10 ms is expected up to GSK'254 concentrations of ~3070 ng mL-1 . No clinically relevant effects on cardiac parameters were seen in healthy participants with GSK'254 at the 100-mg dose.
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VIH-1 , Humanos , Electrocardiografía , Fluoroquinolonas , Voluntarios Sanos , Método Doble CiegoRESUMEN
Tropical forests are changing in composition and productivity, probably in response to changes in climate and disturbances. The responses to these multiple environmental drivers, and the mechanisms underlying the changes, remain largely unknown. Here, we use a functional trait approach on timescales of 10,000 years to assess how climate and disturbances influence the community-mean adult height, leaf area, seed mass, and wood density for eight lowland and highland forest landscapes. To do so, we combine data of eight fossil pollen records with functional traits and proxies for climate (temperature, precipitation, and El Niño frequency) and disturbances (fire and general disturbances). We found that temperature and disturbances were the most important drivers of changes in functional composition. Increased water availability (high precipitation and low El Niño frequency) generally led to more acquisitive trait composition (large leaves and soft wood). In lowland forests, warmer climates decreased community-mean height probably because of increased water stress, whereas in highland forests warmer climates increased height probably because of upslope migration of taller species. Disturbance increased the abundance of acquisitive, disturbance-adapted taxa with small seeds for quick colonization of disturbed sites, large leaves for light capture, and soft wood to attain fast height growth. Fire had weak effects on lowland forests but led to more stress-adapted taxa that are tall with fast life cycles and small seeds that can quickly colonize burned sites. Site-specific analyses were largely in line with cross-site analyses, except for varying site-level effects of El Niño frequency and fire activity, possibly because regional patterns in El Niño are not a good predictor of local changes, and charcoal abundances do not reflect fire intensity or severity. With future global changes, tropical Amazonian and Andean forests may transition toward shorter, drought- and disturbance-adapted forests in the lowlands but taller forests in the highlands.
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Oceanic islands support unique biotas but often lack ecological redundancy, so that the removal of a species can have a large effect on the ecosystem. The larger islands of the Galápagos Archipelago once had one or two species of giant tortoise that were the dominant herbivore. Using paleoecological techniques, we investigate the ecological cascade on highland ecosystems that resulted from whalers removing many thousands of tortoises from the lowlands. We hypothesize that the seasonal migration of a now-extinct tortoise species to the highlands was curtailed by decreased intraspecific competition. We find the trajectory of plant community dynamics changed within a decade of the first whaling vessels visiting the islands. Novel communities established, with a previously uncommon shrub, Miconia, replacing other shrubs of the genera Alternanthera and Acalypha. It was, however, the introduction of cattle and horses that caused the local extirpation of plant species, with the most extreme impacts being evident after c. 1930. This modified ecology is considered the natural state of the islands and has shaped subsequent conservation policy and practice. Restoration of El Junco Crater should emphasize exclusion of livestock, rewilding with tortoises, and expanding the ongoing plantings of Miconia to also include Acalypha and Alternanthera.
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Ecosistema , Extinción Biológica , Tortugas , Animales , Evolución Biológica , Bovinos , Ecología , Ecuador , Herbivoria , Actividades Humanas , HumanosRESUMEN
Humans have been present in Amazonia throughout the Holocene, with the earliest archaeological sites dating to 12 000 years ago. The earliest inhabitants began managing landscapes through fire and plant domestication, but the total extent of vegetation modification remains relatively unknown. Here, we compile palaeoecological records from lake sediments containing charcoal and from pollen analyses to understand how human land-use affected vegetation during the early to mid-Holocene, and place our results in the context of previous archaeological work. We identified gradual, rather than abrupt changes in forest openness, disturbance and enrichment, with useful species at almost all sites. Early human occupations occurred in peripheral sites of Amazonia, where natural fires are part of the vegetation dynamics, so human-made fires did not exert a novel form of disturbance. Synchronicity between evidence of the onset of human occupation in lake records and archaeological sites was found for eastern Amazonia. For southwestern and western Amazonia and the Guiana Shield, the timing of the onset of human occupation differed by thousands of years between lake records and archaeological sites. Plant cultivation showed a different spatio-temporal pattern, appearing ca 2000 years earlier in western Amazonia than in other regions. Our findings highlight the spatial-temporal heterogeneity of Amazonia and indicate that the region cannot be treated as one entity when assessing ecological or cultural history. This article is part of the theme issue 'Tropical forests in the deep human past'.
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Incendios , Bosques , Arqueología , Actividades Humanas , Humanos , PlantasRESUMEN
Much has yet to be learned of the spatial patterning of pre-Columbian people across the Tropical Andes. Using compiled archaeological data and a suite of environmental variables, we generate an ensemble species distribution model (SDM) that incorporates general additive models, random forest models and Maxent models to reconstruct spatial patterns of pre-Columbian people that inhabited the Tropical Andes east of the continental divide, within the modern countries of Bolivia, Peru and Ecuador. Within this region, here referred to as the eastern Andean flank, elevation, mean annual cloud frequency, distance to rivers and precipitation of the driest quarter are the environmental variables most closely related to human occupancy. Our model indicates that 11.04% of our study area (65 368 km2) was likely occupied by pre-Columbian people. Our model shows that 30 of 351 forest inventory plots, which are used to generate ecological understanding of Andean ecosystems, were likely occupied in the pre-Columbian period. In previously occupied sites, successional trajectories may still be shaping forest dynamics, and those forests may still be recovering from the ecological legacy of pre-Columbian impacts. Our ensemble SDM links palaeo- and neo-ecology and can also be used to guide both future archaeological and ecological studies. This article is part of the theme issue 'Tropical forests in the deep human past'.
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Arqueología , Ecosistema , Bolivia , Humanos , PerúRESUMEN
Biodiversity contributes to the ecological and climatic stability of the Amazon Basin1,2, but is increasingly threatened by deforestation and fire3,4. Here we quantify these impacts over the past two decades using remote-sensing estimates of fire and deforestation and comprehensive range estimates of 11,514 plant species and 3,079 vertebrate species in the Amazon. Deforestation has led to large amounts of habitat loss, and fires further exacerbate this already substantial impact on Amazonian biodiversity. Since 2001, 103,079-189,755 km2 of Amazon rainforest has been impacted by fires, potentially impacting the ranges of 77.3-85.2% of species that are listed as threatened in this region5. The impacts of fire on the ranges of species in Amazonia could be as high as 64%, and greater impacts are typically associated with species that have restricted ranges. We find close associations between forest policy, fire-impacted forest area and their potential impacts on biodiversity. In Brazil, forest policies that were initiated in the mid-2000s corresponded to reduced rates of burning. However, relaxed enforcement of these policies in 2019 has seemingly begun to reverse this trend: approximately 4,253-10,343 km2 of forest has been impacted by fire, leading to some of the most severe potential impacts on biodiversity since 2009. These results highlight the critical role of policy enforcement in the preservation of biodiversity in the Amazon.
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Biodiversidad , Conservación de los Recursos Naturales/legislación & jurisprudencia , Sequías , Agricultura Forestal/legislación & jurisprudencia , Bosque Lluvioso , Incendios Forestales/estadística & datos numéricos , Animales , Brasil , Cambio Climático/estadística & datos numéricos , Bosques , Mapeo Geográfico , Plantas , Árboles/fisiología , VertebradosRESUMEN
The therapeutic indices (TIs) and efficacy of the non-steroidal mineralocorticoid receptor antagonist (MRA) KBP-5074 and steroidal MRA eplerenone were evaluated in a uninephrectomized Sprague Dawley rat model of aldosterone-mediated renal disease. In two parallel studies, rats were placed on a high-salt diet and received aldosterone by osmotic mini-pump infusion over the course of 27 days. The urinary albumin-to-creatinine ratio (UACR) was evaluated after 7, 14, and 26 days of treatment. Serum K+ was evaluated after 14 and 27 days of treatment. Urinary Na+, urinary K+, and urinary Na+/K+ ratio were evaluated after 7, 14, and 26 days of treatment. The TI was calculated for each drug as the ratio of the concentration of drug producing 50% of maximum effect (EC50) for increasing serum K+ to the EC50 for lowering UACR. The TIs were 24.5 for KBP-5074 and 0.620 for eplerenone, resulting in a 39-fold improved TI for KBP-5074 compared with eplerenone. Aldosterone treatment increased UACR, decreased serum K+, and decreased urinary Na+ relative to sham-operated controls that did not receive aldosterone infusion in both studies, validating the aldosterone/salt renal injury model. KBP-5074 prevented the increase in UACR at 0.5, 1.5, and 5 mg/kg BID while eplerenone did so only at the two highest doses of 50 and 450 mg/kg BID. Both KBP-5074 and eplerenone blunted the reduction in serum K+ seen in the aldosterone treatment group, with significant increases in serum K+ at the high doses only (5 mg/kg and 450 mg/kg BID, respectively). Additionally, the urinary Na+ and Na+/K+ ratio significantly increased at the middle and high doses of KBP-5074, but only at the highest dose of eplerenone. These results showed increased TI and efficacy for KBP-5074 compared with eplerenone over a wider therapeutic window.
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Intramuscular testosterone undecanoate is indicated as testosterone replacement in adult males with a deficiency in or absence of endogenous testosterone (hypogonadism). Intramuscular testosterone undecanoate 750 mg is approved to be administered at initiation and at 4 weeks, followed by a maintenance dose every 10 weeks. However, a more frequent maintenance regimen may improve symptom management of low testosterone at the end of each dosing interval. The current objective was to develop a population pharmacokinetic (PK) model for intramuscular testosterone undecanoate 750 mg and to perform PK simulations to assess the impact of an 8-week maintenance regimen on testosterone exposure. A 1-compartment model with first-order absorption and first-order elimination best described the PK of testosterone undecanoate. The model included time-dependent suppression and gradual recovery of endogenous testosterone production during testosterone undecanoate administration. Significant covariates included body weight and sex hormone-binding globulin level. With the final PK model, simulations were performed to evaluate the impact of an 8-week vs a 10-week maintenance regimen on testosterone exposure. The 8-week testosterone undecanoate regimen had a predicted 11% increase in average concentration and last observed concentration during a dosing interval before a subsequent dose and a 5% increase in maximum concentration. This translated into an ≈10% increase in the percentage of patients predicted to have a last observed concentration during a dosing interval before a subsequent dose >300 ng/dL, minimal change in the percentage of patients with average concentration in the normal range, and a low likelihood of maximum concentration >2500 ng/dL. These simulations suggest that more frequent administration of intramuscular testosterone undecanoate may be beneficial in some patients. Further clinical evaluation of an 8-week dose regimen is warranted.