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African children are at risk of malaria and malnutrition. We quantified relationships between malaria and malnutrition among young Ugandan children in a high malaria transmission region. Data were used from a randomized controlled trial where Ugandan HIV-unexposed (n=393) and HIV-exposed (n=186) children were randomized to receive no malaria chemoprevention, monthly sulfadoxine-pyrimethamine, daily trimethoprim-sulfamethoxazole, or monthly dihydroartemisinin-piperaquine (DP) from age 6-24 months, and then were followed off chemoprevention until age 36 months. Monthly height and weight, and time of incident malaria episodes were obtained; 89 children who received DP contributed piperaquine (PQ) concentrations. Malaria hazard was modeled using parametric survival analysis adjusted for repeated events, and height and weight were modeled using a Brody growth model. Among 579 children, stunting (height-for-age z-score [ZHA]

Sickle cell disease (SCD) is characterized by the production of sickle hemoglobin (HbS), which when deoxygenated, polymerizes leading to red blood cell damage and hemolytic anemia, a defining feature of SCD. Voxelotor (Oxbryta) is a small molecule inhibitor of HbS polymerization that disrupts the polymerization mechanism by binding HbS to increase HbS oxygen affinity. Voxelotor is approved in the United States for the treatment of SCD in patients greater than or equal to 12 years of age at a 1500 mg once-daily (q.d.) dose. These exposure-response analyses aimed to evaluate the relationships between voxelotor whole blood concentration and change from baseline (CFB) in clinical measures of anemia and hemolysis and between voxelotor whole blood and plasma concentrations and the incidence of selected safety end points to confirm the voxelotor mechanism of action and to support the clinical dose recommendation. In patients treated with voxelotor up to 72 weeks, CFB hemoglobin (Hb) increased linearly (p0.001) with increasing voxelotor concentration and percent Hb occupancy and increases in CFB Hb corresponded to improvements in measures of hemolysis. The target 1 g/dl increase in CFB Hb was achieved with 1500 mg voxelotor q.d. Significant relationships were observed between voxelotor exposures and grade greater than or equal to 1 increased alanine aminotransferase and decreased white blood cell count; however, most events were grade 1. No clinically important covariate effects on voxelotor efficacy or safety were observed. Overall, these analyses support 1500 mg q.d. as the therapeutic dose for voxelotor in adults and adolescents.

Background Pharmacokinetic data for bedaquiline in children are limited. We described the pharmacokinetics and safety of bedaquiline in South African children and adolescents receiving treatment for multidrug/rifampicin-resistant tuberculosis (MDR/RR-TB) in routine care. Methods In this observational cohort study, children aged 6–17 years receiving bedaquiline at recommended doses as part of MDR/RR-TB treatment underwent semi-intensive pharmacokinetic sampling. Bedaquiline and the M2 metabolite plasma concentrations were quantified, and nonlinear mixed-effects modeling performed. Pediatric data were described using a pre-established model of bedaquiline pharmacokinetics in adults. The exposure reference was 187 µg ⋅ h/mL, the median weekly area under the curve (AUC) of adults at week 24 of treatment with bedaquiline. Safety was assessed through monthly clinical, blood and electrocardiogram monitoring, and treatment outcomes described. Results Fifteen children (3 human immunodeficiency virus [HIV]-positive) with median age 13.3 years (range 6.5–16.3) were included. A bedaquiline pharmacokinetic model was adapted to be allometrically scaled in clearance and volume, centered in the median child population weight. Bedaquiline bioavailability was 57% of that in adults. Overall bedaquiline exposures were below target, and AUC reference attainment was achieved in only 3 (20%) children. Ten children experienced 27 adverse events at least possibly related to bedaquiline; no adverse events led to bedaquiline withdrawal. Two adverse events (arthritis and arthralgia) were considered severe, and 2 children had mild QT interval corrected for heart rate using Fridericia’s formula (QT) prolongation. Conclusions The evaluated doses of bedaquiline in children ≥ 6 years of age were safe but achieved slightly lower plasma concentrations compared to adults receiving the recommended dose, possibly due to delayed food intake relative to bedaquiline administration.

The impact of solvent polarity on the kinetics, reducing capacity, antioxidant activity, and mineral composition of black locust (Robinia pseudoacacia) flowers extracts obtained by ultrasound-assis...

BackgroundSafer, better, and shorter treatments for multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) are an urgent global health need. The phase 3 clinical trial Nix-TB (NCT02333799) tested a 6-month treatment of MDR and XDR-TB consisting of high-dose linezolid, bedaquiline, and pretomanid (BPaL). In this study, we investigate the relationship between the pharmacokinetic characteristics of the drugs, patient characteristics and efficacy endpoints from Nix-TB.MethodsPharmacokinetic data were collected at weeks 2, 8, and 16. Efficacy endpoints including treatment outcomes, time to stable culture conversion, and longitudinal time to positivity in the mycobacterial growth indicator tube assay were each characterized using nonlinear mixed-effects modeling. Relationships between patient, treatment pharmacokinetics, and disease characteristics and efficacy endpoints were evaluated.ResultsData from 93 (85% of the total) participants were analyzed. Higher body mass index was associated with a lower incidence of unfavorable treatment outcomes. Median time to stable culture conversion was 3 months in patients with lower baseline burden compared with 4.5 months in patients with high baseline burden. Participants with minimal disease had steeper time to positivity trajectories compared with participants with high-risk phenotypes. No relationship between any drugs’ pharmacokinetics (drug concentration or exposure metrics) and any efficacy outcomes was observed.ConclusionsWe have successfully described efficacy endpoints of a BPaL regimen from the Nix-TB trial. Participants with high-risk phenotypes significantly delayed time to culture conversion and bacterial clearance. The lack of a relationship between pharmacokinetic exposures and pharmacodynamic biomarkers opens the possibility to use lower, safer doses, particularly for toxicity-prone linezolid.

Prothionamide, a second-line drug for multidrug-resistant tuberculosis (MDR-TB), has been in use for a few decades. However, its pharmacokinetic (PK) profile remains unclear. This study aimed to develop a population PK model for prothionamide and then apply the model to determine the optimal dosing regimen for MDR-TB patients. Multiple plasma samples were collected from 27 MDR-TB patients who had been treated with prothionamide at 2 different study hospitals. Prothionamide was administered according to the weight-band dose regimen (500 mg/day for weight 50 kg) recommended by the World Health Organization. The population PK model was developed using nonlinear mixed-effects modeling. The probability of target attainment, based on systemic exposure and MIC, was used as a response target. Fixed-dose regimens (500 or 750 mg/day) were simulated to compare the efficacies of various dosing regimens. PK profiles adequately described the two-compartment model with first-order elimination and the transit absorption compartment model with allometric scaling on clearance. All dosing regimens had effectiveness >90% for MIC values

Tuberculosis lung lesions are complex and harbor heterogeneous microenvironments that influence antibiotic effectiveness. Major strides have been made recently in understanding drug pharmacokinetics in pulmonary lesions, but the bacterial phenotypes that arise under these conditions and their contribution to drug tolerance is poorly understood. A pharmacodynamic marker called the RS ratio quantifies ongoing rRNA synthesis based on the abundance of newly-synthesized precursor rRNA relative to mature structural rRNA. Application of the RS ratio in the C3HeB/FeJ mouse model demonstrated thatMycobacterium tuberculosispopulations residing in different tissue microenvironments are phenotypically distinct and respond differently to drug treatment with rifampin, isoniazid or bedaquiline. This work provides a foundational basis required to address how anatomic and pathologic microenvironmental niches may contribute to the long treatment duration and drug tolerance during treatment of human tuberculosis.

BackgroundPhase 2a trials in tuberculosis typically use early bactericidal activity (EBA), the decline in sputum colony forming units (CFU) over 14 days, as the primary outcome for testing the efficacy of drugs as monotherapy. However, the cost of phase 2a trials can range from 7 to 19.6 million dollars on average, while more than 30% of drugs fail to progress to phase 3. Better utilizing preclinical data to predict and prioritize the most likely drugs to succeed will thus help accelerate drug development and reduce costs. We aim to predict clinical EBA using preclinical in vivo pharmacokinetic-pharmacodynamic (PKPD) data and a model-based translational pharmacology approach.Methods and FindingsFirst, mouse PK, PD and clinical PK models were compiled. Second, mouse PKPD models were built to derive an exposure response relationship. Third, translational prediction of clinical EBA studies was performed using mouse PKPD relationships and informed by clinical PK models and species-specific protein binding. Presence or absence of clinical efficacy was accurately predicted from the mouse model. Predicted daily decreases of CFU in the first 2 days of treatment and between day 2 and day 14 were consistent with clinical observations.ConclusionThis platform provides an innovative solution to inform or even replace phase 2a EBA trials, to bridge the gap between mouse efficacy studies and phase 2b and phase 3 trials, and to substantially accelerate drug development.

Background Current tuberculosis (TB) regimen development pathways are slow and in urgent need of innovation. We investigated novel phase IIc and seamless phase II/III trials utilizing multi-arm multi-stage and Bayesian response adaptive randomization trial designs to select promising combination regimens in a platform adaptive trial. Methods Clinical trial simulation tools were built using predictive and validated parametric survival models of time to culture conversion (intermediate endpoint) and time to TB-related unfavorable outcome (final endpoint). This integrative clinical trial simulation tool was used to explore and optimize design parameters for aforementioned trial designs. Results Both multi-arm multi-stage and Bayesian response adaptive randomization designs were able to reliably graduate desirable regimens in ≥ 95% of trial simulations and reliably stop suboptimal regimens in ≥ 90% of trial simulations. Overall, adaptive phase IIc designs reduced patient enrollment by 17% and 25% with multi-arm multi-stage and Bayesian response adaptive randomization designs respectively compared to the conventional sequential approach, while seamless designs reduced study duration by 2.6 and 3.5 years respectively (typically ≥ 8.5 years for standard sequential approach). Conclusions In this study, we demonstrate that adaptive trial designs are suitable for TB regimen development, and we provide plausible design parameters for a platform adaptive trial. Ultimately trial design and specification of design parameters will depend on clinical trial objectives. To support decision-making for clinical trial designs in contemporary TB regimen development, we provide a flexible clinical trial simulation tool that can be used to explore and optimize design features and parameters.

Background Isoniazid (INH) metabolism depends on the N-acetyl transferase 2 (NAT2) enzyme, whose maturation process remains unknown in low birth weight (LBW) and preterm infants. We aimed to assess INH exposure and safety in infants receiving oral tuberculosis prevention. Methods This population pharmacokinetics (PK) analysis used INH and N-acetyl-isoniazid (ACL) concentrations in infants (BW ≤ 4 kg), including preterm, with follow-up for 6 months. PK parameters were described using nonlinear mixed effects modeling. Simulations were performed to assess INH exposure and optimal dosing regimens, using 2 targets: Cmax at 3–6 mg/L and area under the curve (AUC) ≥ 10.52 mg h/L. Results We included 57 infants (79% preterm, 84% LBW) in the PK analysis, with a median (range) gestational age of 34 (28.7–39.4) weeks. At the time of sampling, postnatal age was 2.3 (0.2–7.3) months and weight (WT) was 3.7 (0.9–9.3) kg. NAT2 genotype was available in 43 (75.4%) patients (10 slow, 26 intermediate, and 7 fast metabolizers). Ninety percent of NAT2 maturation was attained by 4.4 post-natal months. WT, postmenstrual age, and NAT2 genotype significantly influenced INH exposure, with a 5-fold difference in AUC between slow and fast metabolizers for the same dose. INH appeared safe across the broad range of exposure for 61 infants included in the safety analysis. Conclusions In LBW/preterm infants, INH dosing needs frequent adjustment to account for growth and maturation. Pharmacogenetics-based dosing regimens is the most powerful approach to deliver safe and equalized exposures for all infants, because NAT2 genotype highly impacts INH pharmacokinetic variability.

This paper aimed to optimize the extraction of antioxidants from plum seeds (Prunus domestica L.) using ultrasound-assisted extraction. The Box–Behnken design was used for the optimization of the extraction process. The four extraction parameters, such as the extraction time (10–40 min), ethanol concentration (20–100%, v/v), liquid-to-solid ratio (10–30 cm3 g−1), and extraction temperature (30–70 °C) were varied to investigate their impact on the content of antioxidants. Using HPLC methods, the following phenolic compounds were identified and quantified per 100 g dry weight: rutin (6.39 mg), epigallocatechin (1.94 mg), gallic acid (0.64 mg), ferulic acid (14.30 mg), syringic acid (0.87 mg), epicatechin (0.95 mg), caffeic acid (0.30 mg), and coumaric acid (11.18 mg). The content of amygdalin was 1.5 mg g−1 of the dry extract obtained under optimal conditions. Antioxidant activity was determined using the DPPH assay and estimated based on the half-maximal inhibitory concentration (IC50). The IC50 value of the extract obtained under optimal conditions was 0.94 mg cm−3. The proposed green technique is an economical and alternative procedure for the extraction of antioxidants by application of non-toxic and eco-friendly solvents. From the ecological point of view, it is acceptable due to the reduction of waste either after plum cultivation or production of alcoholic beverages.

Conventional extraction techniques require high consumption of available resources and thus are ineffective and expensive, especially at an industrial scale. The aim of the study was to optimize the ultrasound-assisted extraction of polyphenols from fresh wheatgrass (Triticum aestivum L.). The effects of different extraction techniques and solvents were investigated on the yield of extractive substances and antioxidant activity. The ultrasound-assisted extraction technique and ethanol gave the highest yield of extractive substances so that they were used in the optimization studies. The central composite design was employed to find the optimal levels of ethanol concentration, extraction temperature, and extraction time. The total phenolic content was varied in the range of 10.50–15.50 grams of gallic acid equivalents per 100 g of dry weight of plant material (g GAE 100 g−1 dw). The optimal conditions for ultrasound-assisted extraction were: (1) 56% (v/v) ethanol, (2) temperature of 59 °C, and (3) extraction time of 28 min. The results of ANOVA indicated that the highest impact had the extraction temperature on the total phenolic content. The toxic solvents were not used in the developed extraction procedure. The consumption of energy and raw plant material is estimated to be lower by at least 10% compared to conventional techniques.

The recovery of bioactive compounds from waste and modification of their properties by encapsulation are the main challenges today. In this study, the ultrasound-assisted extraction of antioxidants from orange peels was optimized using a central composite design. Ethanol (50%, v/v) was the solvent of choice for their extraction. The obtained total antioxidant contents were fitted using the second-order polynomial equation. The optimal conditions were the extraction time of 30 min, temperature of 60 °C, and the liquid-to-solid ratio of 15 mL/g. After that, the optimal extract was encapsulated in alginate-chitosan beads to modify the release of antioxidants under gastrointestinal tract conditions. The average size of beads was 252 µm, while the encapsulation efficiency was 89.2%. The results of the FTIR analysis indicated that there are no interactions between compounds of the extract and alginate-chitosan. In vitro release studies showed an initial rapid and then slow release of antioxidants. This release followed the simple Fickian diffusion. The encapsulation of orange peel extract provided improvement in the delivery of antioxidants after gastrointestinal digestion. The obtained encapsulated beads can be applied as the natural active ingredient of food, cosmetics, and pharmaceutical products.

Background Pregnancy increases the risk of tuberculosis and its complications. A 3-month regimen of weekly isoniazid and rifapentine (3HP) is safe and effective for tuberculosis prevention in adults and children, including those with HIV, but 3HP has not been evaluated in pregnancy. Methods IMPAACT 2001 was a phase I/II trial evaluating the pharmacokinetics and safety of 3HP among pregnant women with indications for tuberculosis preventative therapy in Haiti, Kenya, Malawi, Thailand, and Zimbabwe (NCT02651259). Isoniazid and rifapentine were provided at standard doses (900 mg/week). Pharmacokinetic sampling was performed with the first (second/third trimester) and twelfth (third trimester/postpartum) doses. Nonlinear mixed-effects models were used to estimate drug population pharmacokinetics. Results Of 50 participants, 20 had HIV and were taking efavirenz-based antiretroviral therapy. Among women without HIV, clearance of rifapentine was 28% lower during pregnancy than postpartum (1.20 vs 1.53 L/hour, P Conclusions 3HP does not require dose adjustment in pregnancy. Rifapentine clearance is higher among women with HIV, but all women achieved exposures of rifapentine and isoniazid associated with successful tuberculosis prevention. The data support proceeding with larger safety-focused studies of 3HP in pregnancy. Clinical Trials Registration ClinicalTrials.gov, NCT02651259.

Background Moxifloxacin is a recommended drug for rifampin-resistant tuberculosis (RR-TB) treatment, but there is limited pediatric pharmacokinetic and safety data, especially in young children. We characterize moxifloxacin population pharmacokinetics and QT interval prolongation and evaluate optimal dosing in children with RR-TB. Methods Pharmacokinetic data were pooled from 2 observational studies in South African children with RR-TB routinely treated with oral moxifloxacin once daily. The population pharmacokinetics and Fridericia-corrected QT (QTcF)-interval prolongation were characterized in NONMEM. Pharmacokinetic simulations were performed to predict expected exposure and optimal weight-banded dosing. Results Eighty-five children contributed pharmacokinetic data (median [range] age of 4.6 [0.8–15] years); 16 (19%) were aged Conclusions Moxifloxacin doses above 10–15 mg/kg are likely required in young children to match adult exposures but require further safety assessment, especially when coadministered with other QT-prolonging agents.

The missense variant, breast cancer resistance protein (BCRP) p.Q141K, which encodes a reduced function BCRP, has been linked to poor response to allopurinol. Using a multifaceted approach, we aimed to characterize the relationship(s) between BCRP p.Q141K, the pharmacokinetics (PK) and pharmacodynamics (PD) of oxypurinol (the active metabolite of allopurinol), and serum uric acid (SUA) levels. A prospective clinical study (NCT02956278) was conducted in which healthy volunteers were given a single oral dose of 300mg allopurinol followed by intensive blood sampling. Data were analyzed using noncompartmental analysis and population PK/PD modeling. Additionally, electronic health records were analyzed to investigate whether clinical inhibitors of BCRP phenocopied the effects of the p.Q141K variant with respect to SUA. Subjects homozygous for p.Q141K had a longer half-life (34.2±12.2h vs. 19.1±1.42h) of oxypurinol. The PK/PD model showed that women had a 24.8% lower volume of distribution. Baseline SUA was affected by p.Q141K genotype and renal function; that is, it changed by 48.8% for every 1mg/dl difference in serum creatinine. Real-world data analyses showed that patients prescribed clinical inhibitors of BCRP have higher SUA levels than those that have not been prescribed inhibitors of BCRP, consistent with the idea that BCRP inhibitors phenocopy the effects of p.Q141K on uric acid levels. This study identified important covariates of oxypurinol PK/PD that could affect its efficacy for the treatment of gout as well as a potential side effect of BCRP inhibitors on increasing uric acid levels, which has not been described previously.

Adherence has been shown to be a major predictor of tuberculosis treatment failure and relapse. The current adherence metrics can be improved to provide higher resolution of adherence patterns and identify patients in need of alternative treatment interventions. We investigated how adherence patterns affect treatment outcomes, when adherence is likely to decrease during treatment and which patients are at risk of being nonadherent.Individual-level data were pooled from 3 clinical trials (n = 3724) for treatment of drug susceptible tuberculosis where monthly or weekly adherence patterns were collected and adherence patterns were quantified to assess the impact of clustered missed doses vs. randomly missed doses on tuberculosis treatment outcomes. Significance was determined through univariate and multivariate cox regression models.Patients who miss doses in clusters have an increased hazard risk for unfavourable outcomes and missing as little as 4 treatment days in 1 month resulted in 61% higher risk of unfavourable outcomes compared to patients who missed no treatment days (P .01). Patients older than 50 years, and patients who experienced an adverse event were associated with lower adherence.Our results show that the pattern in which patients miss their drugs is important to their overall outcomes and missing treatment days in clusters rather than randomly increases the risk of poor outcomes. In the future more intensive and longitudinal adherence measurements will be valuable for clinical trials and regimen design and interpretation.

The World Health Organization recommends pre-exposure prophylaxis (PrEP) for individuals at substantial risk of HIV infection. The aim of this analysis is to quantify the individual risk of HIV infection over time, using a large database of high-risk individuals (n = 5583). We used data from placebo recipients in five phase III PrEP trials: iPrEx, conducted in men who have sex with men and transgender women; VOICE, conducted in young women at high sexual risk; Partners PrEP, conducted in HIV serodiscordant heterosexual couples; TDF2, conducted in high-risk heterosexual men and women; and BTS, conducted in persons who inject drugs. The probability of HIV infection over time was estimated using NONMEM7.4. We identified predictors of HIV risk and found a substantial difference in the risk of infection among and within trial populations, with each study including a mix of low, moderate, and high-risk individuals (p < 0.05). Persons who were female at birth were at a higher risk of HIV infection than people who were male at birth. Final models were integrated in a tool that can assess person-specific risk and simulate cumulative HIV risk over time. These models can be used to optimize future PrEP clinical trials by identifying potential participants at highest risk.

This work aimed to isolate the essential oil from the nutmeg (Myristica fragrans Houtt.) seed, to determine the qualitative and quantitative chemical composition of the obtained essential oil, as w...

The extraction of bioactive compounds from the waste material in the food industry is an important approach because, in that way, the plant raw material can be utilized before its landfill disposal or combustion. The interest of scientists is great for the development of innovative procedures for the further application of these materials. Plum kernels obtained after plum processing can be used for the isolation of oil enriched with unsaturated fatty acids and cakes remaining after oil isolation from plant material. This study aimed to consider the possibilities of the further utilization of cakes obtained after oil isolation from plum seeds using organic solvents in the Soxhlet extractor. The physical–chemical and functional properties of the obtained cakes were determined. The results indicated that the plum seed cakes are rich in proteins (36.95–61.90%) and crude fiber (6.36–9.85%). The HPLC analysis showed that the highest content of phenolic compounds had coumaric acid in the concentration range of 11.31–12.98 mg/100 g of dry weight. The amygdalin content (0.005–0.139 mg/g of dry weight) was in the allowed concentration range so that the cakes can be considered safe for human use. The antioxidant potential of the cakes (IC50 0.40–0.65 mg/mL) indicated that antioxidants are also present in this waste material so that the cakes can be used as a raw material for the development of sustainable products in the food, pharmaceutical, and cosmetic industries.

Defining tissue and plasma‐specific prophylactic drug concentrations is central to pre‐exposure prophylaxis product development for sexual transmission of HIV‐1. Pharmacokinetic (PK) data from study RMP‐02/MTN‐006 comparing single dose oral tenofovir disoproxil fumarate with single and multiple dose rectal tenofovir (TFV) gel administration in HIV‐1 seronegative adults was used to construct a multicompartment plasma‐rectal tissue population PK model for TFV and tenofovir‐diphosphate (TFVdp) in plasma and rectal tissue. PK data were collected in five matrices: TFV (plasma, rectal tissue homogenate), TFVdp (peripheral blood mononuclear cells, rectal mononuclear cells (MMCs), rectal tissue homogenate). A viral growth compartment and a delayed effect compartment for p24 antigen expression measured from an ex vivo explant assay described HIV‐1 infection and replication. Using a linear PK/pharmacodynamic model, MMC TFVdp levels over 9,000 fmol/million cells in the explant assay provided apparent viral replication suppression down to 1%. Parameters were estimated using NONMEM version 7.4.

ZSM-5 zeolites are highly silicate materials that have significant application in catalytic processes in petrochemistry, especially due to their high selectivity. Most reactions in the petrochemical industry are acid-catalyzed. The acidic properties of zeolite depend on the number of acid centers, i.e. the presence of hydrogen ions, and therefore, in this paper the possibility of reducing the sodium content in the pores of high silicate zeolite ZSM-5 with the modulus (SiO2 / Al2O3 = 1000) will be investigated, by applying ion exchange with hydrochloric acid. Chemical analysis of samples before and after ion exchange, and application of instrumental methods of X-Ray diffraction, FT-IR spectroscopy, and SEM analysis monitored the influence of the quantity of hydrogen ions on the chemical composition and the structure of ZSM-5 zeolite at different acid concentrations and at different exchange times. It has been shown that the application of ion exchange with hydrochloric acid can reduce the sodium content in zeolite. Even with the application of 5% HCl for 6 hours, the content of sodium in the zeolite is reduced by over 98%. A similar effect is achieved by applying more concentrated hydrochloric acid solutions for a shorter ion exchange time. By prolonging the ion exchange time, there are no significant changes in terms of the final ion exchange. On the other hand, the application of HCl solutions of higher concentrations leads to a slight decrease in the aluminum content in the zeolite, which may partially affect the structural stability of the zeolite. The results obtained by FT-IR and SEM analysis and X-Ray diffraction confirm the possibility of ion exchange with hydrochloric acid, without significant changes in the crystal structure of the zeolite.

The aim of this study was to compare the stability and texture of three zinc oxide suspensions with different additives. Suspension 1 was made as official magistral formulation Suspensio album 7.5% from Formulae magistrales 2008. Suspension 2 was prepared when 1% carbomer gel was added to suspension 1 and suspension 3 was prepared when polysorbate 20 was added to suspension 2. After stability tests, texture analysis was performed on all suspensions. Following parameters were measured: hardness cycle 1, hardness cycle 2, cohesiveness, adhesiveness, resilience and springiness. The study showed that suspension 3 had the lowest value of hardness, and therefore the best spreadability. Also, suspension 3 was the least sticky of all three, since it was characterized with the lowest adhesiveness. Further, suspension 3 was the most cohesive and is predicted to withstand the stress during packing and use longer than others. On the other hand, the highest values of resilience and springiness were detected for suspension 1, while the lowest was related to suspension 2. Therefore, the best textural characteristics were assigned to suspension 3. This result is in accordance with the results of performed stability tests. The results of our study offer insight into potential improvements of the current magistral formulation Suspensio album 7.5%.

Background Current tuberculosis (TB) regimen development pathways are slow and in urgent need of innovation. We investigated novel phase IIc and seamless phase II/III trials utilizing multi-arm multi-stage and Bayesian response adaptive randomization trial designs to select promising combination regimens in a platform adaptive trial. Methods Clinical trial simulation tools were built using predictive and validated parametric survival models of time to culture conversion (intermediate endpoint) and time to TB-related unfavorable outcome (final endpoint). This integrative clinical trial simulation tool was used to explore and optimize design parameters for aforementioned trial designs. Results Both multi-arm multi-stage and Bayesian response adaptive randomization designs were able to reliably graduate desirable regimens in ≥95% of trial simulations and reliably stop suboptimal regimens in ≥90% of trial simulations. Overall, adaptive phase IIc designs reduced patient enrollment by 17% and 25% with multi-arm multi-stage and Bayesian response adaptive randomization designs respectively compared to the conventional sequential approach, while seamless designs reduced study duration by 2.6 and 3.5 years respectively (typically ≥8.5 years for standard sequential approach). Conclusions In this study, we demonstrate that adaptive trial designs are suitable for TB regimen development, and we provide plausible design parameters for a platform adaptive trial. Ultimately trial design and specification of design parameters will depend on clinical trial objectives. To support decision-making for clinical trial designs in contemporary TB regimen development, we provide a flexible clinical trial simulation tool that can be used to explore and optimize design features and parameters.

Background Daily dosing of tenofovir disoproxil fumarate, with or without emtricitabine, has high efficacy in preventing human immunodeficiency virus (HIV) infection when individuals are adherent. The target protective plasma concentration of tenofovir (TFV), however, is not fully understood. The aim of this study is to estimate the protective TFV plasma concentration. Methods Participant data from TFV-based daily oral and topical active arms of phase 3 trials (iPrEx, VOICE, and Partners PrEP) were pooled (n = 2950). Individual specific risk scores (low and high risk) of acquiring HIV, based on an earlier placebo analysis, were created. Longitudinal TFV pharmacokinetics (PK), HIV outcome, individual risk scores and the effect of sex at birth data were integrated and analyzed using non-linear mixed effects models. Results Around 50% of the individuals were estimated to be adherent, which differed from self-reported adherence (∼90%) and large variation between longitudinal adherence patterns were identified. Following oral administration, the estimated protective TFV trough concentration was substantially higher in high-risk females (45.8 ng/mL) compared with high-risk males (16.1 ng/mL) and to low-risk individuals (∼7.5 ng/mL). Dosing simulations indicated that high-risk women require full adherence to maintain protective levels. Conclusions Using the largest PK-HIV outcome database to date, we developed a population adherence-PK-risk-outcome model. Our results indicate that high-risk females need higher levels of plasma TFV to achieve HIV protection compared with males. HIV protection exceeds 90% in all populations if daily adherence is achieved.

Current tuberculosis (TB) regimen development pathways are slow and in urgent need of innovation. We investigated novel phase IIc and seamless phase II/III trials utilizing multi-arm multi-stage and Bayesian response adaptive randomization trial designs to select promising combination regimens in a platform adaptive trial.Clinical trial simulation tools were built using predictive and validated parametric survival models of time to culture conversion (intermediate endpoint) and time to TB-related unfavorable outcome (final endpoint). This integrative clinical trial simulation tool was used to explore and optimize design parameters for aforementioned trial designs.Both multi-arm multi-stage and Bayesian response adaptive randomization designs were able to reliably graduate desirable regimens in ≥ 95% of trial simulations and reliably stop suboptimal regimens in ≥ 90% of trial simulations. Overall, adaptive phase IIc designs reduced patient enrollment by 17% and 25% with multi-arm multi-stage and Bayesian response adaptive randomization designs respectively compared to the conventional sequential approach, while seamless designs reduced study duration by 2.6 and 3.5 years respectively (typically ≥ 8.5 years for standard sequential approach).In this study, we demonstrate that adaptive trial designs are suitable for TB regimen development, and we provide plausible design parameters for a platform adaptive trial. Ultimately trial design and specification of design parameters will depend on clinical trial objectives. To support decision-making for clinical trial designs in contemporary TB regimen development, we provide a flexible clinical trial simulation tool that can be used to explore and optimize design features and parameters.

BACKGROUND: Tuberculosis (TB) Trials Consortium Study 31/AIDS Clinical Trials Group A5349, an international randomized open-label phase 3 noninferiority trial showed that a 4-month daily regimen substituting rifapentine for rifampin and moxifloxacin for ethambutol had noninferior efficacy and was safe for the treatment of drug-susceptible pulmonary TB (DS-PTB) compared with the standard 6-month regimen. We explored results among the prespecified subgroup of people with human immunodeficiency virus (HIV) (PWH). METHODS: PWH and CD4+ counts ≥100 cells/μL were eligible if they were receiving or about to initiate efavirenz-based antiretroviral therapy (ART). Primary endpoints of TB disease-free survival 12 months after randomization (efficacy) and ≥ grade 3 adverse events (AEs) on treatment (safety) were compared, using a 6.6% noninferiority margin for efficacy. Randomization was stratified by site, pulmonary cavitation, and HIV status. PWH were enrolled in a staged fashion to support cautious evaluation of drug–drug interactions between rifapentine and efavirenz. RESULTS: A total of 2516 participants from 13 countries in sub-Saharan Africa, Asia, and the Americas were enrolled. Among 194 (8%) microbiologically eligible PWH, the median CD4+ count was 344 cells/μL (interquartile range: 223–455). The rifapentine-moxifloxacin regimen was noninferior to control (absolute difference in unfavorable outcomes −7.4%; 95% confidence interval [CI] −20.8% to 6.0%); the rifapentine regimen was not noninferior to control (+7.5% [95% CI, −7.3% to +22.4%]). Fewer AEs were reported in rifapentine-based regimens (15%) than the control regimen (21%). CONCLUSIONS: In people with HIV-associated DS-PTB with CD4+ counts ≥100 cells/μL on efavirenz-based ART, the 4-month daily rifapentine-moxifloxacin regimen was noninferior to the 6-month control regimen and was safe. CLINICAL TRIALS REGISTRATION: NCT02410772.

Background This study aimed to compare the P3 component between patients who have migraines with aura and healthy subjects, and to compare different subtypes of migraine with aura relative to the complexity of migraine aura. Methods Average Migraine Aura Complexity Score was calculated for each MwA patient. Visual oddball paradigm was used to elicit the P3 component. P3 amplitudes and latencies elicited from frequent and rare stimuli, as well as from difference wave, were compared with healthy subjects. Subsequently, subtypes of migraine with aura were compared and Average Migraine Aura Complexity Score was used to explore the connection between features of the P3 and complexity of migraine with aura. Results 37 patients who have migraine with aura (16 with simple aura and 21 with complex aura) patients and 28 healthy subjects were studied. Patients who have migraine with aura had significantly prolonged latencies compared to healthy subjects (411 ± 39 ms vs 372 ± 34 ms, p Conclusions Visual oddball paradigm, particularly rare stimuli, could serve as a potential new tool for deep profiling of different clinical complexities among patients who have migraine with aura. Also, the present pattern of P3 components provided new evidence for the cognitive dysfunctions in patients who have migraine with aura.

This study aimed to provide additional information on the influence of perinatal factors on fecal (f)-calprotectin values in preterm infants. Calprotectin was determined from the first spontaneous stool (analyzed on the Alegria device by using the enzyme-linked immunosorbent assay [ELISA] method) obtained from neonates at a mean age of 3.41 ± 2.44 days of life. We analyzed 114 subjects who had a body weight of 1847.67 ± 418.6 g and were born at a gestational age of 32.6 ± 2.43 weeks, without intestinal and other congenital anomalies or any diseases other than those related to premature birth. The values of f-calprotectin are in a positive correlation with female subjects, intrauterine growth restriction, significant ductus arteriosus, enteral feeding intolerance, postnatal prolonged use of broad-spectrum antibiotics, and values ​​of bicarbonates (analyzed in a sample of capillary arterial blood). Measurement of f-calprotectin in the first 7 days after birth can help to early detect the intestinal distress or early staging of necrotizing enterocolitis in premature infants.

Nontuberculous mycobacterial pulmonary disease (NTM-PD) is a potentially fatal infectious disease requiring long treatment duration with multiple antibiotics and against which there is no reliable cure. Among the factors that have hampered the development of adequate drug regimens is the lack of an animal model that reproduces the NTM lung pathology required for studying antibiotic penetration and efficacy. Given the documented similarities between tuberculosis and NTM immunopathology in patients, we first determined that the rabbit model of active tuberculosis reproduces key features of human NTM-PD and provides an acceptable surrogate model to study lesion penetration. We focused on clarithromycin, a macrolide and pillar of NTM-PD treatment, and explored the underlying causes of the disconnect between its favorable potency and pharmacokinetics and inconsistent clinical outcome. To quantify pharmacokinetic-pharmacodynamic target attainment at the site of disease, we developed a translational model describing clarithromycin distribution from plasma to lung lesions, including the spatial quantitation of clarithromycin and azithromycin in mycobacterial lesions of two patients on long-term macrolide therapy. Through clinical simulations, we visualized the coverage of clarithromycin in plasma and four disease compartments, revealing heterogeneous bacteriostatic and bactericidal target attainment depending on the compartment and the corresponding potency against nontuberculous mycobacteria in clinically relevant assays. Overall, clarithromycin's favorable tissue penetration and lack of bactericidal activity indicated that its clinical activity is limited by pharmacodynamic, rather than pharmacokinetic, factors. Our results pave the way toward the simulation of lesion pharmacokinetic-pharmacodynamic coverage by multidrug combinations to enable the prioritization of promising regimens for clinical trials.

Background Moxifloxacin (MOX) is used as a first-choice drug to treat multidrug-resistant tuberculosis (MDR-TB); however, evidence-based dosing optimization should be strengthened by integrative analysis. The primary goal of this study was to evaluate MOX efficacy and toxicity using integrative model-based approaches in MDR-TB patients. Methods In total, 113 MDR-TB patients from 5 different clinical trials were analyzed for the development of a population pharmacokinetics (PK) model. A final population PK model was merged with a previously developed lung-lesion distribution and QT prolongation model. Monte Carlo simulation was used to calculate the probability target attainment value based on concentration. An area under the concentration-time curve (AUC)-based target was identified as the minimum inhibitory concentration (MIC) of MOX isolated from MDR-TB patients. Results The presence of human immunodeficiency virus (HIV) increased clearance by 32.7% and decreased the AUC by 27.4%, compared with HIV-negative MDR-TB patients. A daily dose of 800 mg or a 400-mg, twice-daily dose of MOX is expected to be effective in MDR-TB patients with an MIC of ≤0.25 µg/mL, regardless of PK differences resulting from the presence of HIV. The effect of MOX in HIV-positive MDR-TB patients tended to be decreased dramatically from 0.5 µg/mL, in contrast to the findings in HIV-negative patients. A regimen of twice-daily doses of 400 mg should be considered safer than an 800-mg once-daily dosing regimen, because of the narrow fluctuation of concentrations. Conclusions Our results suggest that a 400-mg, twice-daily dose of MOX is an optimal dosing regimen for MDR-TB patients because it provides superior efficacy and safety.

This study presents a challenge in terms of the development of cleaner technologies and sustainable development. The main effort was invested in the improvement of oxidative stability of plum seed oil using an eco-friendly and easy-to-use procedure (maceration). The fixed oil of plum seeds is composed of unsaturated fatty acids that are very sensitive to oxidative processes, but the addition of antioxidants can solve this problem. Since the obtained oil was further applied for the preparation of topical formulation, the aim was to avoid the use of toxic solvents and the process of their evaporation during the extraction of antioxidants from plant material. The way to overcome this problem was to directly use oil for the extraction of non-polar antioxidants from black locust flowers. The reason of use this plant material was due to its pleasant odor and high content of antioxidants. The maceration was carried out at the different temperatures (25, 40, and 60 °C) and the liquid-to-solid ratio of 10 mL/g for 48 h. After the extraction, the reducing capacity of the fixed oils was determined using a standard spectrophotometric method with Folin-Ciocalteu reagent. The extraction process was described using two kinetic models, Ponomaryov and non-stationary diffusion models. The optimal extraction time and temperature were 16 h and 60 °C, respectively, for the extraction of antioxidants. Thus obtained oil with improved stability was incorporated in the moisturizing cream to develop an innovative topical formulation that can be used against the harmful effects of the environmental factors. During the oil stabilization, the addition of synthetic antioxidants was omitted so that the application of natural antioxidants was favored. This was acceptable from an ecological point of view because in this way the planting of black locust trees will be intensified and thus the carbon dioxide emissions will be reduced.

Chloroquine and hydroxychloroquine are quinoline derivatives used to treat malaria. To date, these medications are not approved for the treatment of viral infections and there are no well‐controlled, prospective, randomized clinical studies or evidence to support their use in patients with Coronavirus Infectious Disease‐2019 (COVID‐19). Nevertheless, chloroquine and hydroxychloroquine are being studied alone or in combination with other agents to assess their effectiveness in the treatment or prophylaxis for COVID‐19. The effective use of any medication involves an understanding of its pharmacokinetics (PK), safety and mechanism of action. This work provides basic clinical pharmacology information relevant for planning and initiating COVID‐19 clinical studies with chloroquine or hydroxychloroquine, summarizes safety data from healthy volunteer studies, and summarizes safety data from Phase 2 and Phase 2/3 clinical studies in patients with uncomplicated malaria, including a Phase 2/3 study in pediatric patients following administration of azithromycin and chloroquine in combination. In addition, this work presents data describing the proposed mechanisms of action against the severe acute respiratory distress syndrome (ARDS) coronavirus–2 (SARS‐CoV‐2) and summarizes clinical efficacy to date.

Item does not contain fulltext INTRODUCTION: Despite its longstanding role in tuberculosis (TB) treatment, there continues to be emerging rifampicin research that has important implications for pediatric TB treatment and outstanding questions about its pharmacokinetics and optimal dose in children. AREAS COVERED: This review aims to summarize and discuss emerging data on the use of rifampicin for: 1) routine treatment of drug-susceptible TB; 2) special subpopulations such as children with malnutrition, HIV, or TB meningitis; 3) treatment shortening. We also highlight the implications of these new data for child-friendly rifampicin formulations and identify future research priorities. EXPERT OPINION: New data consistently show low rifampicin exposures across all pediatric populations with 10-20 mg/kg dosing. Although clinical outcomes in children are generally good, rifampicin dose optimization is needed, especially given a continued push to shorten treatment durations and for specific high-risk populations of children who have worse outcomes. A pooled analysis of existing data using applied pharmacometrics would answer many of the important questions remaining about rifampicin pharmacokinetics needed to optimize doses, especially in special populations. Targeted clinical studies in children with TB meningitis and treatment shortening with high-dose rifampicin are also priorities.

Contains fulltext : 282960.pdf (Publisher’s version ) (Open Access) Tuberculosis (TB) remains one of the leading causes of death by a communicable agent, infecting up to one-quarter of the world's population, predominantly in disadvantaged communities. Pharmacometrics employ quantitative mathematical models to describe the relationships between pharmacokinetics and pharmacodynamics, and to predict drug doses, exposures and responses. Pharmacometric approaches have provided a scientific basis for improved dosing of anti-TB drugs and concomitantly administered antiretrovirals at the population level. The development of modelling frameworks including physiologically based pharmacokinetics, quantitative systems pharmacology and machine learning provides an opportunity to extend the role of pharmacometrics to in-silico quantification of drug-drug interactions, prediction of doses for special populations, dose optimization and individualization, and understanding the complex exposure-response relationships of multi-drug regimens in terms of both efficacy and safety, informing regimen design for future study. This short, clinically focused review explores what has been done, and what opportunities exist for pharmacometrics to impact TB pharmacotherapy.

Introduction: 8-hydroxyquinoline derivatives and their complexes with transition metals are the subject of many studies due to their anticancer, anti-inflammatory, anti-infective, and antidiabetic activities.Areas covered: Within this article, the authors review the synthesis and current applications of metal-8-hydroxyquinoline complexes in drug design with a critical overview of the latest advancements in the field.Expert opinion: Metal-8-hydroxyquinoline complexes are especially interesting because of their simple synthesis procedures and possible applications in modern medicine. The complexation between transition metal ions and 8-hydroxyquinoline or its derivatives is achieved via their O and N atoms. The main problem with their application is lipophilicity. This particular property has an impact on their solubility, biological activity, transport through the cell membrane, construction of the complex with a receptor, and development of drugs. Furthermore, in the treatment of neurodegenerative diseases and brain cancers, the passage of the complexes through the blood-brain barrier can only be ensured through novel drug design.

Murine tuberculosis drug efficacy studies have historically monitored bacterial burden based on colony forming units of M. tuberculosis in lung homogenate. In an alternative approach, a recently described molecular pharmacodynamic marker called the RS ratio quantifies drug effect on a fundamental cellular process: ongoing ribosomal RNA synthesis. Here we evaluated the ability of different pharmacodynamic markers to distinguish between treatments in three BALB/c mouse experiments at two institutions. We confirmed that different pharmacodynamic markers measure distinct biological responses. We found that a combination of pharmacodynamic markers distinguishes between treatments better than any single marker. The combination of the RS ratio with colony forming units showed the greatest ability to recapitulate the rank order of regimen treatment-shortening activity, providing proof of concept that simultaneous assessment of pharmacodynamic markers measuring different properties will enhance insight gained from animal models and accelerate development of new combination regimens. These results suggest potential for a new era in which antimicrobial therapies are evaluated not only on culture-based measures of bacterial burden but also on molecular assays that indicate how drugs impact the physiological state of the pathogen.

Background Intermittent preventive treatment with monthly dihydroartemisinin-piperaquine (DHA-PQ) is highly effective at preventing both malaria during pregnancy and placental malaria. Piperaquine prolongs the corrected QT interval (QTc), and it is possible that repeated monthly dosing could lead to progressive QTc prolongation. Intensive characterization of the relationship between piperaquine concentration and QTc interval throughout pregnancy can inform effective, safe prevention guidelines. Methods Data were collected from a randomized controlled trial, where pregnant Ugandan women received malaria chemoprevention with monthly DHA-PQ (120/960 mg DHA/PQ; n = 373) or sulfadoxine-pyrimethamine (SP; 1500/75 mg; n = 375) during the second and third trimesters of pregnancy. Monthly trough piperaquine samples were collected throughout pregnancy, and pre- and postdose electrocardiograms were recorded at 20, 28, and 36 weeks’ gestation in each woman. The pharmacokinetics–QTc relationship for piperaquine and QTc for SP were assessed using nonlinear mixed-effects modeling. Results A positive linear relationship between piperaquine concentration and Fridericia corrected QTc interval was identified. This relationship progressively decreased from a 4.42 to 3.28 to 2.13 millisecond increase per 100 ng/mL increase in piperaquine concentration at 20, 28, and 36 weeks’ gestation, respectively. Furthermore, 61% (n = 183) of women had a smaller change in QTc at week 36 than week 20. Nine women given DHA-PQ had grade 3–4 cardiac adverse events. SP was not associated with any change in QTc. Conclusions Repeated DHA-PQ dosing did not result in increased risk of QTc prolongation and the postdose QTc intervals progressively decreased. Monthly dosing of DHA-PQ in pregnant women carries minimal risk of QTc prolongation. Clinical Trials Registration NCT02793622.

Background Current TB treatment for children is not optimized to provide adequate drug levels in TB lesions. Dose optimization of first-line antituberculosis drugs to increase exposure at the site of disease could facilitate more optimal treatment and future treatment-shortening strategies across the disease spectrum in children with pulmonary TB. Objectives To determine the concentrations of first-line antituberculosis drugs at the site of disease in children with intrathoracic TB. Methods We quantified drug concentrations in tissue samples from 13 children, median age 8.6 months, with complicated forms of pulmonary TB requiring bronchoscopy or transthoracic surgical lymph node decompression in a tertiary hospital in Cape Town, South Africa. Pharmacokinetic models were used to describe drug penetration characteristics and to simulate concentration profiles for bronchoalveolar lavage, homogenized lymph nodes, and cellular and necrotic lymph node lesions. Results Isoniazid, rifampicin and pyrazinamide showed lower penetration in most lymph node areas compared with plasma, while ethambutol accumulated in tissue. None of the drugs studied was able to reach target concentration in necrotic lesions. Conclusions Despite similar penetration characteristics compared with adults, low plasma exposures in children led to low site of disease exposures for all drugs except for isoniazid.

Rifapentine has facilitated treatment shortening for latent tuberculosis infection (LTBI) in combination with isoniazid once weekly for 3 months (3HP) or daily for 1 month (1HP). Our objective was to determine the optimal rifapentine dose for a 6-week monotherapy regimen (6wP) and predict clinical efficacy. Rifapentine and isoniazid pharmacokinetics were simulated in mice and humans. Mouse lung CFU data were used to characterize exposure-response relationships of 1HP, 3HP, and 6wP and translated to predict clinical efficacy. A 600-mg daily dose for 6wP delivered greater cumulative rifapentine exposure than 1HP or 3HP. The maximum regimen effect (Emax) was 0.24 day21. The regimen potencies, measured as the concentration at 50% of Emax (EC50), were estimated to be 2.12 mg/liter for 3HP, 3.72 mg/liter for 1HP, and 4.71 mg/liter for 6wP, suggesting that isoniazid contributes little to 1HP efficacy. Clinical translation predicted that 6wP reduces bacterial loads at a higher rate than 3HP and to a greater extent than 3HP and 1HP. 6wP (600 mg daily) is predicted to result in equal or better efficacy than 1HP and 3HP for LTBI treatment without the potential added toxicity of isoniazid. Results from ongoing and future clinical studies will be required to support these findings.

Waste materials are receiving more attention as concerns about the future of our planet increase. Cellulose is the most common substance in agricultural waste. Agricultural wastes containing cellulose are misplaced resources that could be reused in various fields for both environmental and economic benefits. In this work, 32 different kinds of waste are investigated for chemical modification in order to obtain carboxymethyl cellulose for the production of a superabsorbent hydrogel that can be applied in agriculture. A brief literature review is provided to help researchers wishing to obtain carboxymethyl cellulose by carboxymethylation starting with waste materials. We also provide details about methods to obtain as well as verify carboxymethylation. Carboxymethyl cellulose (CMC), as a constituent of cellulosic water and superabsorbent hydrogels with applications in agriculture, is described. Superabsorbent hydrogels with CMC are able to absorb huge amounts of water and are biodegradable.

Rationale: No evidence-based tools exist to enhance precision in the selection of patient-specific optimal treatment durations to study in tuberculosis clinical trials. Objectives: To develop risk stratification tools that assign patients with tuberculosis into risk groups of unfavorable outcome and inform selection of optimal treatment duration for each patient strata to study in clinical trials. Methods: Publicly available data from four phase 3 trials, each evaluating treatment duration shortening from 6 to 4 months, were used to develop parametric time-to-event models that describe unfavorable outcomes. Regimen, baseline, and on-treatment characteristics were evaluated as predictors of outcomes. Exact regression coefficients of predictors were used to assign risk groups and predict optimal treatment durations. Measurements and Main Results: The parametric model had an area under the receiver operating characteristic curve of 0.72. A six-item risk score (HIV status, smear grade, sex, cavitary disease status, body mass index, and Month 2 culture status) successfully grouped participants into low (1,060/3,791; 28%), moderate (1,740/3,791; 46%), and high (991/3,791; 26%) risk, requiring treatment durations of 4, 6, and greater than 6 months, respectively, to reach a target cure rate of 93% when receiving standard-dose rifamycin-containing regimens. With current one-duration-fits-all approaches, high-risk groups have a 3.7-fold (95% confidence interval, 2.7-5.1) and 2.4-fold (1.9-2.9) higher hazard risk of unfavorable outcomes compared with low- and moderate-risk groups, respectively. Four-month regimens were noninferior to the standard 6-month regimen in the low-risk group. Conclusions: Our model discrimination was modest but consistent with current models of unfavorable outcomes. Our results showed that stratified medicine approaches are feasible and may achieve high cure rates in all patients with tuberculosis. An interactive risk stratification tool is provided to facilitate decision-making in the regimen development pathway.

Imperfect medication adherence remains the biggest predictor of treatment failure for patients with tuberculosis. Missed doses during treatment lead to relapse, tuberculosis resistance, and further spread of disease. Understanding individual patient phenotypes, population pharmacokinetics, resistance development, drug distribution to tuberculosis lesions, and pharmacodynamics at the site of infection is necessary to fully measure the impact of adherence on patient outcomes. To decrease the impact of expected variabilityin drug intake on tuberculosis outcomes, an improvement in patient adherence and new forgiving regimens that protect against missed doses are needed. In this review, we summarize emerging technologies to improve medication adherence in clinical practice and provide suggestions on how digital adherence technologies can be incorporated in clinical trials and practice and the drug development pipeline that will lead to more forgiving regimens and benefit patients suffering from tuberculosis.

Malaria is an infectious disease which disproportionately effects children and pregnant women. These vulnerable populations are often excluded from clinical trials resulting in one‐size‐fits‐all treatment regimens based on those established for a nonpregnant adult population. Pharmacokinetic/pharmacodynamic (PK/PD) models can be used to optimize dose selection as they define the drug exposure‐response relationship. Additionally, these models are able to identify patient characteristics that cause alterations in the expected PK/PD profiles and through simulations can recommend changes to dosing which compensate for the differences. In this review, we examine how PK/PD models have been applied to optimize antimalarial dosing recommendations for young children, including those who are malnourished, pregnant women, and individuals receiving concomitant therapies such as those for HIV treatment. The malaria field has had great success in utilizing PK/PD models as a foundation to update treatment guidelines and propose the next generation of dosing regimens to investigate in clinical trials. We propose how the malaria field can continue to use modeling to improve therapies by further integrating PK data into clinical studies and including data on drug resistance and host immunity in PK/PD models. Finally, we suggest that other disease areas can achieve similar success in applying pharmacometrics to improve outcomes by implementing three key principals.

The MIND-IHOP study was funded by the IHOP grant (NIH R01 HL090335), Lung MicroCHIP grant (NIH U01 HL098964), and K24 grant (NIH K24 HL087713). These sources provided the funding to support participant enrollment and specimen collection. Emmanuel Musisi was supported by a scholarship from the Pulmonary Complications of AIDS Research Training Program (NIH D43 TW009607). N.D.W., R.M.S., J.L.D., and P.N. acknowledge funding from the U.S. National Institutes of Health (1R01AI127300-01A1). N.D.W. and M.I.V. acknowledge funding from the U.S. National Institutes of Health (1R21AI135652-01). N.D.W. acknowledges funding from Veterans Affairs (1IK2CX000914-01A1 and 1I01BX004527-01A1) and from the Doris Duke Charitable Foundation Clinical Scientist Development Award. There is a critical need for improved pharmacodynamic markers for use in human tuberculosis (TB) drug trials. Pharmacodynamic monitoring in TB has conventionally used culture or molecular methods to enumerate the burden of Mycobacterium tuberculosis organisms in sputum. A recently proposed assay called the rRNA synthesis (RS) ratio measures a fundamentally novel property, how drugs impact ongoing bacterial rRNA synthesis. Here, we evaluated RS ratio as a potential pharmacodynamic monitoring tool by testing pretreatment sputa from 38 Ugandan adults with drug-susceptible pulmonary TB. We quantified the RS ratio in paired pretreatment sputa and evaluated the relationship between the RS ratio and microbiologic and molecular markers of M. tuberculosis burden. We found that the RS ratio was highly repeatable and reproducible in sputum samples. The RS ratio was independent of M. tuberculosis burden, confirming that it measures a distinct new property. In contrast, markers of M. tuberculosis burden were strongly associated with each other. These results indicate that the RS ratio is repeatable and reproducible and provides a distinct type of information from markers of M. tuberculosis burden. Importance This study takes a major next step toward practical application of a novel pharmacodynamic marker that we believe will have transformative implications for tuberculosis. This article follows our recent report in Nature Communications that an assay called the rRNA synthesis (RS) ratio indicates the treatment-shortening of drugs and regimens. Distinct from traditional measures of bacterial burden, the RS ratio measures a fundamentally novel property, how drugs impact ongoing bacterial rRNA synthesis. Publisher PDF