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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.

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.

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.

Background Safe, more efficacious treatments are needed to address the considerable morbidity and mortality associated with pulmonary tuberculosis (TB). However, the current practice in TB therapeutics trials is to use composite binary outcomes, which in the absence of standardization may inflate false positive and negative errors in evaluating regimens. The lack of standardization of outcomes is a barrier to the identification of highly efficacious regimens and the introduction of innovative methodologies Methods We conducted a systematic review of trials designed to advance new pulmonary TB drugs or regimens for regulatory approval and inform practice guidelines. Trials were primarily identified from the WHO International Clinical Trial Registry Platform (ICTRP). Only trials that collected post-treatment follow-up data and enrolled at least 100 patients were included. Protocols and Statistical Analysis Plans (SAP) for eligible trials from 1995 to the present were obtained from trial investigators. Details of outcome data, both explicit and implied, were abstracted and organized into three broad categories: favorable, unfavorable, and not assessable. Within these categories, individual trial definitions were recorded and collated, and areas of broad consensus and disagreement were identified and described. Results From 2205 trials in any way related to TB, 51 were selected for protocol and SAP review, from which 31 were both eligible and had accessible documentation. Within the three designated categories, we found broad consensus in the definitions of favorable and unfavorable outcomes, although specific details were not always provided, and when explicitly addressed, were heterogeneous. Favorable outcomes were handled the most consistently but were widely variable with respect to specification. In some cases, the same events were defined differently by different protocols, particularly in distinguishing unfavorable from not assessable events. Death was often interpreted as conditional on cause. Patients who did not complete the study because of withdrawal or loss to follow-up presented a particular challenge to consistent interpretation and analytic treatment of outcomes. Conclusions In a review of 31 clinical trials, we found that outcome definitions were heterogeneous, highlighting the need to establish clearer specification and a move towards universal standardization of outcomes across pulmonary TB trials. The ICH E9 (R1) addendum provides guidelines for undertaking and achieving this goal. PROSPERO registration PROSPERO CRD42020197993. Registration 11 August 2020.

The identification of sensitive, specific, and reliable biomarkers that can be quantified in the early phases of tuberculosis treatment and predictive of long-term outcome is key for the development of an effective short-course treatment regimen. Time to positivity (TTP), a biomarker of treatment outcome against Mycobacterium tuberculosis, measures longitudinal bacterial growth in mycobacterial growth indicator tube broth culture and may be predictive of standard time to stable culture conversion (TSCC). In two randomized phase 2b trials investigating dose-ranging rifapentine (Studies 29 and 29X), 662 participants had sputum collected over 6 months where TTP, TSCC, and time to culture conversion were quantified. The goals of this post hoc study were to characterize longitudinal TTP profiles and to identify individual patient characteristics associated with delayed time to culture conversion. In order to do so, a nonlinear mixed-effects model describing longitudinal TTP was built. Independent variables associated with increased bacterial clearance (increased TTP), assessed by subject-specific and population-level trajectories, were higher rifapentine exposure, lower baseline grade of sputum acid-fast bacillus smear, absence of productive cough, and lower extent of lung infiltrates on radiographs. Importantly, sensitivity analysis revealed that major learning milestones in phase 2b trials, such as significant exposure-response and covariate relationships, could be detected using truncated TTP data as early as 6 weeks from start of treatment, suggesting alternative phase 2b study designs. The TTP model built depicts a novel phase 2b surrogate endpoint that can inform early assessment of experimental treatment efficacy and treatment failure or relapse in patients treated with shorter and novel TB treatment regimens, improving efficiency of phase 2 clinical trials. (The studies discussed in this paper have been registered at ClinicalTrials.gov under identifiers NCT00694629 and NCT01043575.).

BackgroundRifapentine-based regimens have potent antimycobacterial activity that may allow for a shorter course in patients with drug-susceptible pulmonary tuberculosis.MethodsIn an open-label, phase 3, randomized, controlled trial involving persons with newly diagnosed pulmonary tuberculosis from 13 countries, we compared two 4-month rifapentine-based regimens with a standard 6-month regimen consisting of rifampin, isoniazid, pyrazinamide, and ethambutol (control) using a noninferiority margin of 6.6 percentage points. In one 4-month regimen, rifampin was replaced with rifapentine; in the other, rifampin was replaced with rifapentine and ethambutol with moxifloxacin. The primary efficacy outcome was survival free of tuberculosis at 12 months.ResultsAmong 2516 participants who had undergone randomization, 2343 had a culture positive for Mycobacterium tuberculosis that was not resistant to isoniazid, rifampin, or fluoroquinolones (microbiologically eligible population; 768 in the control group, 791 in the rifapentine-moxifloxacin group, and 784 in the rifapentine group), of whom 194 were coinfected with human immunodeficiency virus and 1703 had cavitation on chest radiography. A total of 2234 participants could be assessed for the primary outcome (assessable population; 726 in the control group, 756 in the rifapentine-moxifloxacin group, and 752 in the rifapentine group). Rifapentine with moxifloxacin was noninferior to the control in the microbiologically eligible population (15.5% vs. 14.6% had an unfavorable outcome; difference, 1.0 percentage point; 95% confidence interval [CI], -2.6 to 4.5) and in the assessable population (11.6% vs. 9.6%; difference, 2.0 percentage points; 95% CI, -1.1 to 5.1). Noninferiority was shown in the secondary and sensitivity analyses. Rifapentine without moxifloxacin was not shown to be noninferior to the control in either population (17.7% vs. 14.6% with an unfavorable outcome in the microbiologically eligible population; difference, 3.0 percentage points [95% CI, -0.6 to 6.6]; and 14.2% vs. 9.6% in the assessable population; difference, 4.4 percentage points [95% CI, 1.2 to 7.7]). Adverse events of grade 3 or higher occurred during the on-treatment period in 19.3% of participants in the control group, 18.8% in the rifapentine-moxifloxacin group, and 14.3% in the rifapentine group.ConclusionsThe efficacy of a 4-month rifapentine-based regimen containing moxifloxacin was noninferior to the standard 6-month regimen in the treatment of tuberculosis. (Funded by the Centers for Disease Control and Prevention and others; Study 31/A5349 ClinicalTrials.gov number, NCT02410772.).

Background. Safe, more efficacious treatments are needed to address the considerable morbidity and mortality associated with tuberculosis (TB). However, the current practice in TB therapeutics trials is to use composite binary outcomes, which in the absence of standardization may inflate false positive and negative errors in evaluating regimens. The lack of standardization of outcomes is a barrier to the identification of highly efficacious regimens and the introduction of innovative methodologiesMethods. We conducted a systematic review of trials designed to advance new TB drugs or regimens for regulatory approval and inform practice guidelines. Trials were primarily identified from the WHO International Clinical Trial Registry Platform (ICTRP). Only trials that collected post-treatment follow-up data and enrolled at least 100 patients were included. Protocols and Statistical Analysis Plans (SAP) for eligible trials from 1995 to the present were obtained from trial investigators. Details of outcome data, both explicit and implied, were abstracted and organized into three broad categories: Favorable, Unfavorable, and Not Assessable. Within these categories, individual trial definitions were recorded and collated, and areas of broad consensus and disagreement were identified and described. Results. From 2205 TB-related trials, 51 were selected for protocol and SAP review, from which 31 were both eligible and had accessible documentation. Within the three designated categories, we found broad consensus in the definitions of Favorable and Unfavorable outcomes, although specific details were not always provided, and when explicitly addressed, were heterogeneous. Favorable outcomes were handled the most consistently but were widely variable with respect to specification. In some cases, the same events were defined differently by different protocols, particularly in distinguishing Unfavorable from Not Assessable events. Death was often interpreted conditional on cause. Patients who did not complete the study because of withdrawal or loss to follow-up presented a particular challenge to consistent interpretation and analytic treatment of outcomes.Conclusions. In a review of 31 clinical trials, we found that outcome definitions were heterogeneous, highlighting the need to establish clearer specification and a move towards universal standardization of outcomes across TB trials. The ICH E9 (R1) addendum provides guidelines for undertaking and achieving this goal.Registration PROSPERO 2020 CRD42020197993

Background We evaluated Nix-TB trial data (NCT02333799, N = 109) to provide dosing recommendations to potentially minimize linezolid toxicity in patients with extensively drug-resistant tuberculosis. . Methods A pharmacokinetic model and toxicodynamic models for peripheral neuropathy, hemoglobin, and platelets were developed. Simulations compared safety outcomes for daily linezolid of 1200 and 600 mg, with and without dose adjustments for toxicity. Severe neuropathy was based on symptom scores from the Brief Peripheral Neuropathy Screen. Severe anemia and thrombocytopenia were defined as ≥ grade 3 adverse events according to the NIAID Division of Microbiology and Infectious Disease Adult Toxicity table. Results Predicted concentration-time profiles were a major predictor in all toxicodynamic models. Simulations showed higher percentages of patients with severe neuropathy (median, 19%; 90% confidence interval [CI], 17%–22% vs 5%, 4%–7%) and severe anemia (15%, 12%–17% vs 1%, 0%–2%) between 1200 and 600 mg daily linezolid. No differences in severe thrombocytopenia were observed (median, 10% decrease in hemoglobin level after 4 weeks of treatment would have maximum sensitivity (82%) and specificity (84%) for predicting severe anemia. Reducing the dose from 1200 to 600 mg triggered by this marker may prevent 60% (90% CI, 45%–72%) of severe anemia. Conclusions Simple neuropathy symptom and hemoglobin monitoring may guide linezolid dosing to avoid toxicities, but prospective testing is needed to confirm the benefit-to-risk ratio.

Intermittent preventive treatment (IPT) with dihydroartemisinin-piperaquine (DP) is highly protective against malaria in children, but is not standard in malaria-endemic countries. Optimal DP dosing regimens will maximize efficacy and reduce toxicity and resistance selection. We analyze piperaquine (PPQ) concentrations (n = 4573), malaria incidence data (n = 326), and P. falciparum drug resistance markers from a trial of children randomized to IPT with DP every 12 weeks (n = 184) or every 4 weeks (n = 96) from 2 to 24 months of age (NCT02163447). We use nonlinear mixed effects modeling to establish malaria protective PPQ levels and risk factors for suboptimal protection. Compared to DP every 12 weeks, DP every 4 weeks is associated with 95% protective efficacy (95% CI: 84–99%). A PPQ level of 15.4 ng/mL reduces the malaria hazard by 95%. Malnutrition reduces PPQ exposure. In simulations, we show that DP every 4 weeks is optimal across a range of transmission intensities, and age-based dosing improves malaria protection in young or malnourished children., Intermittent preventive treatment with dihydroartemisinin-piperaquine (DP) is protective in children against malaria. Here, the authors analyze plasma drug concentration, malaria incidence, and drug resistance markers from a clinical trial in Uganda and determine the optimal DP dosing regimen.

Clinical trials of pharmacologic treatments of coronavirus disease 2019 (COVID-19) are being rapidly designed and implemented in adults. Children are often not considered during development of novel treatments for infectious diseases until very late. Although children appear to have a lower risk compared with adults of severe COVID-19 disease, a substantial number of children globally will benefit from pharmacologic treatments. It will be reasonable to extrapolate efficacy of most treatments from adult trials to children. Pediatric trials should focus on characterizing a treatment’s pharmacokinetics, optimal dose, and safety across the age spectrum. These trials should use an adaptive design to efficiently add or remove arms in what will be a rapidly evolving treatment landscape, and should involve a large number of sites across the globe in a collaborative effort to facilitate efficient implementation. All stakeholders must commit to equitable access to any effective, safe treatment for children everywhere.

RationaleStandardized weight-based dose of anti-tubercular drugs contributes to a substantial incidence of toxicities, inadequate treatment response, and relapse, in part due to variable drug levels achieved. Single nucleotide polymorphisms (SNPs) in the N-acetyltransferase-2 (NAT2) gene explain the majority of interindividual pharmacokinetic variability of isoniazid (INH). However, an obstacle to implementing pharmacogenomic-guided dosing is the lack of a point-of-care assay.ObjectivesTo develop and test a NAT2 classification algorithm, validate its performance in predicting isoniazid clearance, and develop a prototype pharmacogenomic assay.MethodsWe trained random forest models to predict NAT2 acetylation genotype from unphased SNP data using a global collection of 8,561 phased genomes. We enrolled 48 pulmonary TB patients, performed sparse pharmacokinetic sampling, and tested the acetylator prediction algorithm accuracy against estimated INH clearance. We then developed a cartridge-based multiplex qPCR assay on the GeneXpert platform and assessed its analytical sensitivity on whole blood samples from healthy individuals.Measurements and Main ResultsWith a 5-SNP model trained on two-thirds of the data (n=5,738), out-of-sample acetylation genotype prediction accuracy on the remaining third (n=2,823) was 100%. Among the 48 TB patients, predicted acetylator types were: 27 (56.2%) slow, 16 (33.3%) intermediate and 5 (10.4%) rapid. INH clearance rates were lowest in predicted slow acetylators (median 19.3 L/hr), moderate in intermediate acetylators (median 41.0 L/hr) and highest in fast acetylators (median 46.7 L/hr). The cartridge-based assay accurately detected all allele patterns directly from 25ul of whole blood.ConclusionsAn automated pharmacogenomic assay on a platform widely used globally for tuberculosis diagnosis could enable personalized dosing of isoniazid.SummaryThis manuscript describes the development and validation of point-of-care multiplex pharmacogenomic assay to guide personalized dosing of isoniazid for treatment or prevention of tuberculosis.

Dihydroartemisinin-piperaquine (DHA-PQ) provides highly effective therapy and chemoprevention for malaria in pregnant African women. PQ concentrations of >10.3 ng/ml have been associated with reduced maternal parasitemia, placental malaria, and improved birth outcomes. We characterized the population pharmacokinetics (PK) of PQ in a post hoc analysis of human immunodeficiency virus (HIV)-infected and -uninfected pregnant women receiving DHA-PQ as chemoprevention every 4 or 8 weeks. The effects of covariates such as pregnancy, nutritional status (body mass index [BMI]), and efavirenz (EFV)-based antiretroviral therapy were investigated. PQ concentrations from two chemoprevention trials were pooled to create a population PK database from 274 women and 2,218 PK observations. A three-compartment model with an absorption lag best fit the data. Consistent with our prior intensive PK evaluation, pregnancy and EFV use resulted in a 72% and 61% increased PQ clearance, compared to postpartum and HIV-uninfected pregnant women, respectively. Low BMI at 28 weeks of gestation was associated with increased clearance (2% increase per unit decrease in BMI). Low-BMI women given DHA-PQ every 8 weeks had a higher prevalence of parasitemia, malaria infection, and placental malaria compared to women with higher BMIs. The reduced piperaquine exposure in women with low BMI as well as during EFV coadministration, compared to pregnant women with higher BMIs and not taking EFV, suggests that these populations could benefit from weekly instead of monthly dosing for prevention of malaria parasitemia. Simulations indicated that because of the BMI-clearance relationship, weight-based regimens would not improve protection compared to a 2,880 mg fixed-dose regimen when provided monthly. (The clinical trials described in this paper have been registered at ClinicalTrials.gov under identifiers NCT02163447 and NCT02282293.).

Standard treatment for active tuberculosis (TB) requires drug treatment with at least four drugs over six months. Shorter-duration therapy would mean less need for strict adherence, and reduced risk of bacterial resistance. A system pharmacology model of TB infection, and drug therapy was developed and used to simulate the outcome of different drug therapy scenarios. The model incorporated human immune response, granuloma lesions, multi-drug antimicrobial chemotherapy, and bacterial resistance. A dynamic population pharmacokinetic/pharmacodynamic (PK/PD) simulation model including rifampin, isoniazid, pyrazinamide, and ethambutol was developed and parameters aligned with previous experimental data. Population therapy outcomes for simulations were found to be generally consistent with summary results from previous clinical trials, for a range of drug dose and duration scenarios. An online tool developed from this model is released as open source software. The TB simulation tool could support analysis of new therapy options, novel drug types, and combinations, incorporating factors such as patient adherence behavior., Author summary A comprehensive in-silico model of pulmonary tuberculosis successfully predicted previous clinical trials and could simulate future therapeutics.

Hydroxychloroquine (HCQ) is a promising candidate for Coronavirus disease of 2019 (COVID-19) treatment. The optimal dosing of HCQ is unknown. Our goal was to integrate historic and emerging pharmacological and toxicity data to understand safe and efficacious HCQ dosing strategies for COVID-19 treatment. The data sources included were (i) longitudinal clinical, pharmacokinetic (PK), and virologic data from patients with severe acute respiratory syndrome-2 (SARS-CoV-2) infection who received HCQ with or without azithromycin (n=116), (ii) in vitro viral replication data and SARS-CoV-2 viral load inhibition by HCQ, (iii) a population PK model of HCQ, and (iv) a model relating chloroquine PKs to corrected QT (QTc) prolongation. A mechanistic PK/virologic/QTc model for HCQ was developed and externally validated to predict SARS-CoV-2 rate of viral decline and QTc prolongation. SARS-CoV-2 viral decline was associated with HCQ PKs (P400mg b.i.d. for ≥5days were predicted to rapidly decrease viral loads, reduce the proportion of patients with detectable SARS-CoV-2 infection, and shorten treatment courses, compared with lower dose (≤400mg daily) regimens. However, HCQ doses >600mg b.i.d. were also predicted to prolong QTc intervals. This prolongation may have clinical implications warranting further safety assessment. Due to COVID-19's variable natural history, lower dose HCQ regimens may be indistinguishable from controls. Evaluation of higher HCQ doses is needed to ensure adequate safety and efficacy.

This study was conducted in treatment-naive adults with drug-susceptible pulmonary tuberculosis in Port-au-Prince, Haiti, to assess the safety, bactericidal activity, and pharmacokinetics of nitazoxanide (NTZ). This was a prospective phase II clinical trial in 30 adults with pulmonary tuberculosis. Twenty participants received 1 g of NTZ orally twice daily for 14 days. A control group of 10 participants received standard therapy over 14 days. The primary outcome was the change in time to culture positivity (TTP) in an automated liquid culture system. The most common adverse events seen in the NTZ group were gastrointestinal complaints and headache. The mean change in TTP in sputum over 14 days in the NTZ group was 3.2 h ± 22.6 h and was not statistically significant (P = 0.56). The mean change in TTP in the standard therapy group was significantly increased, at 134 h ± 45.2 h (P

Tuberculosis kills more people than any other infectious disease. Three pivotal trials testing 4-month regimens failed to meet non-inferiority margins; however, approximately four-fifths of participants were cured. Through a pooled analysis of patient-level data with external validation, we identify populations eligible for 4-month treatment, define phenotypes that are hard to treat and evaluate the impact of adherence and dosing strategy on outcomes. In 3,405 participants included in analyses, baseline smear grade of 3+ relative to 6 months to cure all. Regimen duration can be selected in order to improve outcomes, providing a stratified medicine approach as an alternative to the 'one-size-fits-all' treatment currently used worldwide.

SUMMARY POINTS: (*) Adherence to prescribed treatment remains a critical component of clinical trials in tuberculosis (TB) treatment. Recent evidence indicates that adherence strongly influences the outcome of therapy; attention to its quantification and measures to assure its implementation should increase. (*) In the context of a World Health Organization (WHO) Technical Consultation on “Advances in Clinical Trial Design for Development of New TB Treatments,” we reviewed the challenges related to adherence confronting the trials community. (*) We discuss the importance of adherence to therapy in TB clinical trials, consider several definitions and measures of adherence, comment on the standard provided by directly observed therapy (DOT), and briefly review evolving electronic methods for the assessment of adherence. (*) Adherence affects both the outcome of therapy and the risk of acquired drug resistance. Assessment of adherence should consider not only overall adherence but also the timing and intensity of nonadherence. (*) Appropriate methods for pooling and analyzing electronic data on adherence are needed. (*) Better methods are needed for linking information on adherence to individual pharmacokinetics and pharmacodynamics and to individual patient outcomes.

Disappointing results of recent tuberculosis chemotherapy trials suggest that knowledge gained from preclinical investigations was not utilized to maximal effect. A mouse-to-human translational pharmacokinetics (PKs) - pharmacodynamics (PDs) model built on a rich mouse database may improve clinical trial outcome predictions. The model included Mycobacterium tuberculosis growth function in mice, adaptive immune response effect on bacterial growth, relationships among moxifloxacin, rifapentine, and rifampin concentrations accelerating bacterial death, clinical PK data, species-specific protein binding, drug-drug interactions, and patient-specific pathology. Simulations of recent trials testing 4-month regimens predicted 65% (95% confidence interval [CI], 55-74) relapse-free patients vs. 80% observed in the REMox-TB trial, and 79% (95% CI, 72-87) vs. 82% observed in the Rifaquin trial. Simulation of 6-month regimens predicted 97% (95% CI, 93-99) vs. 92% and 95% observed in 2RHZE/4RH control arms, and 100% predicted and observed in the 35 mg/kg rifampin arm of PanACEA MAMS. These results suggest that the model can inform regimen optimization and predict outcomes of ongoing trials.

In preclinical studies, selenite had single agent activity and radiosensitized tumors in vivo. Here we report results from a Phase 1 trial in 15 patients with metastatic cancer treated with selenite (5.5 to 49.5 mg) orally as a single dose 2 hours before each radiation therapy (RT) treatment. Patients received RT regimens that were standard of care. The primary objective of the study was to assess the safety of this combination therapy. Secondary objectives included measurement of pharmacokinetics (PK) and evaluation of efficacy. Endpoints included assessment of PK, toxicity, tumor response, and pain before and after treatment. The half-life of selenite was 18.5 hours. There were no adverse events attributable to selenite until the 33 mg dose level, at which the primary toxicities were grade 1 GI side effects. One patient treated with 49.5 mg had grade 2 GI toxicity. Although this was not a DLT, it was felt that the highest acceptable dose in this patient population was 33 mg. Most patients had stabilization of disease within the RT fields, with some demonstrating objective evidence of tumor regression. Most patients had a marked improvement in pain and seven out of nine patients with prostate cancer had a decrease in PSA ranging from 11-78%. Doses up to 33 mg selenite were well tolerated in combination with RT. A randomized, well controlled study is needed at the 33 mg dose level to determine if selenite results in clinically meaningful improvements in the response to palliative RT.

Summary Background Malnourished and young children are particularly susceptible to severe forms of tuberculosis and poor treatment response. WHO dosing guidelines for drugs for tuberculosis treatment are based only on weight, which might lead to systematic underdosing and poor outcomes in these children. We aimed to assess and quantify the population effect of WHO guidelines for drug-susceptible tuberculosis in children in the 20 countries with the highest disease burden. Methods We used an integrated model that linked country-specific demographic data at the individual level from the 20 countries with the highest disease burden to pharmacokinetic, outcome, and epidemiological models. We estimated tuberculosis treatment outcomes in children younger than 5 years following WHO guidelines (children are dosed by weight bands corresponding to the number of fixed-dose combination tablets [75 mg rifampicin, 50 mg isoniazid, 150 mg pyrazinamide]) and two alternative dosing strategies: one based on a proposed algorithm that uses age, weight, and available formulations, in which underweight children would receive the same drug doses as would normal weight children of the same age; and another based on an individualised algorithm without dose limitations, in which derived doses results in target exposure attainment for the typical child. Findings We estimated that 57 234 (43%) of 133 302 children younger than 5 years who were treated for tuberculosis in 2017 were underdosed with WHO dosing and only 47% of children would reach the rifampicin exposure target. Underdosing and subtherapeutic exposures were more common among malnourished children than among age-matched healthy children. The proposed dosing approach improved estimated rifampicin target exposure attainment to 62% and equalised outcomes by nutritional status. An estimated third of unfavourable treatment outcomes might be resolved with this dosing strategy, saving the lives of a minimum of 2423 children in these countries annually. With individualised dosing approaches, almost all children could achieve adequate exposure for cure. Interpretation This work shows that a simple change in dosing procedure to include age and nutritional status, requiring no additional measurements or new drug formulations, is one approach to improve tuberculosis treatment outcomes in children, especially malnourished children who are at high risk of mortality. Funding Eunice Kennedy Shriver National Institute of Child Health and Human Development and UK Medical Research Council.

Background Linezolid is increasingly important for multidrug-resistant tuberculosis (MDR-TB) treatment. However, among children with MDR-TB, there are no linezolid pharmacokinetic data, and its adverse effects have not yet been prospectively described. We characterised the pharmacokinetics, safety, and optimal dose of linezolid in children treated for MDR-TB. Methods and findings Children routinely treated for MDR-TB in 2 observational studies (2011–2015, 2016–2018) conducted at a single site in Cape Town, South Africa, underwent intensive pharmacokinetic sampling after either a single dose or multiple doses of linezolid (at steady state). Linezolid pharmacokinetic parameters, and their relationships with covariates of interest, were described using nonlinear mixed-effects modelling. Children receiving long-term linezolid as a component of their routine treatment had regular clinical and laboratory monitoring. Adverse events were assessed for severity and attribution to linezolid. The final population pharmacokinetic model was used to derive optimal weight-banded doses resulting in exposures in children approximating those in adults receiving once-daily linezolid 600 mg. Forty-eight children were included (mean age 5.9 years; range 0.6 to 15.3); 31 received a single dose of linezolid, and 17 received multiple doses. The final pharmacokinetic model consisted of a one-compartment model characterised by clearance (CL) and volume (V) parameters that included allometric scaling to account for weight; no other evaluated covariates contributed to the model. Linezolid exposures in this population were higher compared to exposures in adults who had received a 600 mg once-daily dose. Consequently simulated, weight-banded once-daily optimal doses for children were lower than those currently used for most weight bands. Ten of 17 children who were followed long term had a linezolid-related adverse event, including 5 with a grade 3 or 4 event, all anaemia. Adverse events resulted in linezolid dose reductions in 4, temporary interruptions in 5, and permanent discontinuation in 4 children. Limitations of the study include the lack of very young children (none below 6 months of age), the limited number who were HIV infected, and the modest number of children contributing to long-term safety data. Conclusions Linezolid-related adverse effects were frequent and occasionally severe. Careful linezolid safety monitoring is required. Compared to doses currently used in children in many settings for MDR-TB treatment, lower doses may approximate current adult target exposures, might result in fewer adverse events, and should therefore be evaluated., Using data from two cohorts, Anthony Garcia-Prats and colleagues model the appropriate dosing necessary to achieve target concentrations for linezolid to treat children with multidrug-resistant tuberculosis., Author summary Why was this study done? Linezolid is an antibiotic that has recently been repurposed for the treatment of multidrug-resistant tuberculosis (MDR-TB). Based on emerging data from clinical trials, it is now recommended for inclusion as a priority in treatment regimens for adults and children. There is a lack of evidence-based dosing guidelines for linezolid in children for MDR-TB. Linezolid has frequent adverse effects that are associated with higher doses and longer durations of treatment, but this has not been well described in children treated for MDR-TB. What did the researchers do and find? We assessed linezolid pharmacokinetics (concentrations) and safety among children routinely treated for MDR-TB from 2 observational studies. We modelled this pharmacokinetic data and simulated the doses in children that would be needed to achieve current targets. Doses supported by our data for some weight bands were lower than currently in use, which may reduce the risk of adverse effects. Linezolid-related adverse effects were frequent—with low haemoglobin being the most common—and occasionally severe (grade 3 or 4). What do these findings mean? Revised linezolid doses supported by this study now provide an evidence base for international dosing recommendations. All linezolid-treated children with MDR-TB should have careful safety monitoring to include at least regular haemoglobin monitoring. Larger studies, evaluating the revised dosing, are needed to better characterise linezolid safety and to assess the risk of more rare linezolid-related events, especially given the small number of children in this study.

Dihydroartemisinin-piperaquine (DHA-PQ) is under study for intermittent preventive treatment during pregnancy (IPTp), but it may accelerate selection for drug resistance. Understanding the relationships between piperaquine concentration, prevention of parasitemia, and selection for decreased drug sensitivity can inform control policies and optimization of DHA-PQ dosing. Piperaquine concentrations, measures of parasitemia, and Plasmodium falciparum genotypes associated with decreased aminoquinoline sensitivity in Africa (pfmdr1 86Y, pfcrt 76T) were obtained from pregnant Ugandan women randomized to IPTp with sulfadoxine-pyrimethamine (SP) or DHA-PQ. Joint pharmacokinetic/pharmacodynamic models described relationships between piperaquine concentration and the probability of genotypes of interest using nonlinear mixed effects modeling. An increase in the piperaquine plasma concentration was associated with a log-linear decrease in risk of parasitemia. Our models predicted that higher median piperaquine concentrations would be required to provide 99% protection against mutant infections than against wild-type infections (pfmdr1: N86, 9.6 ng/ml; 86Y, 19.6 ng/ml; pfcrt: K76, 6.5 ng/ml; 76T, 19.6 ng/ml). Comparing monthly, weekly, and daily dosing, daily low-dose DHA-PQ was predicted to result in the fewest infections and the fewest mutant infections per 1,000 pregnancies (predicted mutant infections for pfmdr1 86Y: SP monthly, 607; DHA-PQ monthly, 198; DHA-PQ daily, 1; for pfcrt 76T: SP monthly, 1,564; DHA-PQ monthly, 283; DHA-PQ daily, 1). Our models predict that higher piperaquine concentrations are needed to prevent infections with the pfmdr1/pfcrt mutant compared to those with wild-type parasites and that, despite selection for mutants by DHA-PQ, the overall burden of mutant infections is lower for IPTp with DHA-PQ than for IPTp with SP. (This study has been registered at ClinicalTrials.gov under identifier {"type":"clinical-trial","attrs":{"text":"NCT02282293","term_id":"NCT02282293"}}NCT02282293.)

Background: Malnourished and young children are particularly vulnerable to severe forms of tuberculosis and poor treatment response. Current World Health Organization (WHO) dosing guidelines are only based on weight, which may lead to systematic underdosing and worse outcomes in these vulnerable children. We evaluate and quantify the population impact of current WHO guidelines for drug-susceptible tuberculosis in children in the 20 countries with highest disease burden. Methods: Using an integrated model which links country-specific individual-level demographic data to pharmacokinetic, outcome, and epidemiological models, we assessed tuberculosis treatment outcomes in children under five years of age following the current WHO guidelines and two alternative dosing strategies: a simple algorithm that utilizes age, weight, and available formulations, and an individualized algorithm without dose limitations. Findings: We estimated that 11-55% of all children and >70% of underweight children were underdosed with WHO dosing. Rifampicin exposure target attainment was only 48% following WHO dosing. Subtherapeutic exposures were more common in malnourished children. The proposed simple dosing approach improved exposure attainment to 62% and equalized outcomes by nutritional status. At least one-third of unfavorable treatment outcomes might be resolved with this simple dosing strategy, saving a minimum of 2436 children in these countries annually. With individualized dosing approaches, almost all children could be cured. Interpretation: A simple change in dosing procedure to include age and nutritional status would require no additional measurements or new drug formulations and could improve tuberculosis treatment outcomes in children, especially malnourished children who are at high risk of mortality. Funding Statement: Research reported in this publication was supported by The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) of the National Institutes of Health under award number R01HD083047 (AGP, RMS). This work was also supported by a fellowship from the UK Medical Research Council (MRC) (MR/P022081/1; PJD). Declaration of Interests: The authors declare no competing interests.

Tuberculosis kills more people than any other infectious disease. Three pivotal trials testing 4-month regimens failed to meet non-inferiority margins; however, approximately four-fifths of participants were cured. Through a pooled analysis of patient-level data with external validation, we identify populations eligible for 4-month treatment, define phenotypes that are hard to treat and evaluate the impact of adherence and dosing strategy on outcomes. In 3,405 participants included in analyses, baseline smear grade of 3+ relative to2+, HIV seropositivity and adherence of ≤90% were significant risk factors for unfavorable outcome. Four-month regimens were non-inferior in participants with minimal disease defined by2+ sputum smear grade or non-cavitary disease. A hard-to-treat phenotype, defined by high smear grades and cavitation, may require durations6 months to cure all. Regimen duration can be selected in order to improve outcomes, providing a stratified medicine approach as an alternative to the 'one-size-fits-all' treatment currently used worldwide.

In vitro, disulfiram activated HIV transcription in a primary T-cell model of HIV latency and in a pilot clinical study increased plasma HIV RNA in individuals with adequate drug exposure. We assessed the effect of disulfiram on HIV transcription in a dose-escalation study.In this prospective dose-escalation study, to optimise disulfiram exposure we included adults with HIV on suppressive antiretroviral therapy, with plasma HIV RNA of less than 50 copies per mL and a CD4 cell count greater than 350 cells per μL. Participants were allocated sequentially to one of three dosing groups (500 mg, 1000 mg, and 2000 mg) and received disulfiram daily for 3 days. Only the staff who did laboratory assays were masked to group assignment. The primary endpoint was change in cell-associated unspliced HIV RNA in CD4 cells. The primary analysis method was a negative binomial regression, with the number of copies as the outcome variable and the input total RNA or plasma volume as an exposure variable, which is equivalent to modelling copies or input. We used these models to estimate changes from before disulfiram to timepoints during and after disulfiram administration. This study is registered with ClinicalTrials.gov, number NCT01944371.Of 34 participants screened for eligibility at The Alfred Hospital (Melbourne, VIC, Australia), and San Francisco General Hospital (San Francisco, CA, USA), 30 people were enrolled between Sept 24, 2013, and March 31, 2014. The estimated fold increases in cell-associated unspliced HIV RNA from baseline were 1·7 (95% CI 1·3-2·2; p0·0001) to the timepoint during disulfiram treatment and 2·1 (1·5-2·9; p0·0001) to the timepoint after disulfiram in the 500 mg group; 1·9 (1·6-2·4; p0·0001) and 2·5 (1·9-3·3; p0·0001) in the 1000 mg group; and 1·6 (1·2-2·1; p=0·0026) and 2·1 (1·5-3·1; p=0·0001) in the 2000 mg group. No deaths occurred, and no serious adverse events were noted. Disulfiram was well tolerated at all doses.Short-term administration of disulfiram resulted in increases in cell-associated unspliced HIV RNA at all doses, consistent with activating HIV latency. Disulfiram may be suited for future studies of combination and prolonged therapy to activate latent HIV.The Foundation for AIDS Research (amfAR); National Institute of Allergy and Infectious Diseases, National Institutes of Health; Australian National Health and Medical Research Council.

The End TB Strategy, proposed by the World Health Organization (WHO) in 2014, calls for a 90% reduction in tuberculosis (TB)-related deaths and an 80% reduction in the TB incidence by 2030 [1]. TB remains a leading cause of death in children under five years of age [2], and interventions to eliminate preventable child deaths from TB are urgently needed. Additional and effective TB prevention measures are crucial for the End TB Strategy goals to be met [3]. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Dr. Radtke has nothing to disclose. Conflict of interest: Dr. Hibma reports I am an employee of Pfizer Inc. Conflict of interest: Dr. Hesseling has nothing to disclose. Conflict of interest: Dr. Savic has nothing to disclose.

This work aimed to evaluate the once-daily antituberculosis treatment as recommended by the new Indian pediatric guidelines. Isoniazid, rifampin, and pyrazinamide concentration-time profiles and treatment outcome were obtained from 161 Indian children with drug-sensitive tuberculosis undergoing thrice-weekly dosing as per previous Indian pediatric guidelines. The exposure-response relationships were established using a population pharmacokinetic-pharmacodynamic approach. Rifampin exposure was identified as the unique predictor of treatment outcome. Consequently, children with low body weight (4-7 kg) and/or HIV infection, who displayed the lowest rifampin exposure, were associated with the highest probability of unfavorable treatment (therapy failure, death) outcome (Punfavorable ). Model-based simulation of optimized (Punfavorable ≤ 5%) rifampin once-daily doses were suggested per treatment weight band and HIV coinfection status (33% and 190% dose increase, respectively, from the new Indian guidelines). The established dose-exposure-response relationship could be pivotal in the development of future pediatric tuberculosis treatment guidelines.

In clinical trials of two rifamycin antibiotics (rifampin and rifapentine) for treating tuberculosis (TB), patients with cavitary lung lesions did not appear to derive benefit from rifapentine. Rifapentine was found not to outperform rifampin, despite a lower minimum inhibitory concentration against Mycobacterium tuberculosis in mouse models of TB. To understand these findings, we have developed a rabbit model of TB that reliably develops lung cavities with features similar to those of patients with pulmonary cavitary TB. After single or multiple doses of rifampin or rifapentine that produced human-equivalent plasma exposures, rabbits were sacrificed at different time points after dosing. We measured site-of-disease drug pharmacokinetics and tissue drug distribution. We used pharmacokinetic-pharmacodynamic (PK/PD) modeling to estimate drug penetration into different types of tubercular lesions. Both drugs penetrated rabbit lung cellular lesions, as well as the fibrotic cavity wall of cavitary lesions (penetration coefficients ≥1 compared to plasma). For the necrotic liquefied material inside cavitary lesions known as caseum (which contains high numbers of bacteria), the penetration coefficient was 1.0 for rifampin but only 0.25 for rifapentine. When estimates of site-of-disease drug PK were substituted into clinical PK/PD models, the relationship between site-of-action exposure and sputum culture conversion was significant (P < 10-7). We propose that poor penetration of rifapentine into lung cavitary lesions explains, in part, why rifapentine doses required to improve treatment outcomes in two phase 2 clinical trials were four times higher in TB patients with large cavities compared to TB patients without cavitary lung disease.

BACKGROUND: A monthly treatment course of dihydroartemisinin-piperaquine (DHA-PQ) effectively prevents malaria during pregnancy. However, a drug–drug interaction pharmacokinetic (PK) study found that pregnant human immunodeficiency virus (HIV)–infected women receiving efavirenz-based antiretroviral therapy (ART) had markedly reduced piperaquine (PQ) exposure. This suggests the need for alternative DHA-PQ chemoprevention regimens in this population. METHODS: Eighty-three HIV-infected pregnant women who received monthly DHA-PQ and efavirenz contributed longitudinal PK and corrected QT interval (QTc) (n = 25) data. Population PK and PK-QTc models for PQ were developed to consider the benefits (protective PQ coverage) and risks (QTc prolongation) of alternative DHA-PQ chemoprevention regimens. Protective PQ coverage was defined as maintaining a concentration >10 ng/mL for >95% of the chemoprevention period. RESULTS: PQ clearance was 4540 L/day. With monthly DHA-PQ (2880 mg PQ), 96% of women, respectively. All regimens were safe, with ≤2% of women predicted to have ≥30 msec QTc increase. CONCLUSIONS: For HIV-infected pregnant women receiving efavirenz, low daily DHA-PQ dosing was predicted to improve protection against parasitemia and reduce risk of toxicity compared to monthly dosing. CLINICAL TRIALS REGISTRATION: NCT02282293.

Rifapentine has potent activity in mouse models of tuberculosis chemotherapy but its optimal dose and exposure in humans are unknown.We conducted a randomized, partially blinded dose-ranging study to determine tolerability, safety, and antimicrobial activity of daily rifapentine for pulmonary tuberculosis treatment.Adults with sputum smear-positive pulmonary tuberculosis were assigned rifapentine 10, 15, or 20 mg/kg or rifampin 10 mg/kg daily for 8 weeks (intensive phase), with isoniazid, pyrazinamide, and ethambutol. The primary tolerability end point was treatment discontinuation. The primary efficacy end point was negative sputum cultures at completion of intensive phase.A total of 334 participants were enrolled. At completion of intensive phase, cultures on solid media were negative in 81.3% of participants in the rifampin group versus 92.5% (P = 0.097), 89.4% (P = 0.29), and 94.7% (P = 0.049) in the rifapentine 10, 15, and 20 mg/kg groups. Liquid cultures were negative in 56.3% (rifampin group) versus 74.6% (P = 0.042), 69.7% (P = 0.16), and 82.5% (P = 0.004), respectively. Compared with the rifampin group, the proportion negative at the end of intensive phase was higher among rifapentine recipients who had high rifapentine areas under the concentration-time curve. Percentages of participants discontinuing assigned treatment for reasons other than microbiologic ineligibility were similar across groups (rifampin, 8.2%; rifapentine 10, 15, or 20 mg/kg, 3.4, 2.5, and 7.4%, respectively).Daily rifapentine was well-tolerated and safe. High rifapentine exposures were associated with high levels of sputum sterilization at completion of intensive phase. Further studies are warranted to determine if regimens that deliver high rifapentine exposures can shorten treatment duration to less than 6 months. Clinical trial registered with www.clinicaltrials.gov (NCT 00694629).

Clinical pharmacology studies that describe the pharmacokinetics and pharmacodynamics of drugs in pregnant women are critical for informing on the safe and effective use of drugs during pregnancy. That being said, multiple factors have hindered the ability to study drugs in pregnant patients. These include concerns for maternal and fetal safety, ethical considerations, the difficulty in designing appropriate trials to assess the study objectives, and funding limitations. This document summarizes the recommendations of a panel of experts convened by the Division of Microbiology and Infectious Diseases at the National Institute of Allergy and Infectious Diseases, National Institutes of Health. These experts were charged with reviewing the issues related to the development of preclinical and clinical drug studies in pregnant women and to develop strategies for addressing these issues. These findings may also be utilized in the development of future drug studies involving pregnant women and their fetus/neonate.

Levofloxacin is increasingly used in the treatment of multidrug-resistant tuberculosis (MDR-TB). There are limited pediatric pharmacokinetic data to inform dose selection for children. Children routinely receiving levofloxacin (250-mg adult tablets) for MDR-TB prophylaxis or disease in Cape Town, South Africa, underwent pharmacokinetic sampling following receipt of a dose of 15 or 20 mg/kg of body weight given as a whole or crushed tablet(s) orally or via a nasogastric tube. Pharmacokinetic parameters were estimated using nonlinear mixed-effects modeling. Model-based simulations were performed to estimate the doses across weight bands that would achieve adult exposures with 750-mg once-daily dosing. One hundred nine children were included. The median age was 2.1 years (range, 0.3 to 8.7 years), and the median weight was 12 kg (range, 6 to 22 kg). Levofloxacin followed 2-compartment kinetics with first-order elimination and absorption with a lag time. After inclusion of allometric scaling, the model characterized the age-driven maturation of clearance (CL), with the effect reaching 50% of that at maturity at about 2 months after birth and 100% of that at maturity by 2 years of age. CL in a typical child (weight, 12 kg; age, 2 years) was 4.7 liters/h. HIV infection reduced CL by 16%. By use of the adult 250-mg formulation, levofloxacin exposures were substantially lower than those reported in adults receiving a similar dose on a milligram-per-kilogram basis. To achieve adult-equivalent exposures at a 750-mg daily dose, higher levofloxacin pediatric doses of from 18 mg/kg/day for younger children with weights of 3 to 4 kg (due to immature clearance) to 40 mg/kg/day for older children may be required. The doses of levofloxacin currently recommended for the treatment of MDR-TB in children result in exposures considerably lower than those in adults. The effects of different formulations and formulation manipulation require further investigation. We recommend age- and weight-banded doses of 250-mg tablets of the adult formulation most likely to achieve target concentrations for prospective evaluation.

One-third of type 2 diabetes patients do not respond to metformin. Genetic variants in metformin transporters have been extensively studied as a likely contributor to this high failure rate. Here, we investigate, for the first time, the effect of genetic variants in transcription factors on metformin pharmacokinetics (PK) and response. Overall, 546 patients and healthy volunteers contributed their genome-wide, pharmacokinetic (235 subjects), and HbA1c data (440 patients) for this analysis. Five variants in specificity protein 1 (SP1), a transcription factor that modulates the expression of metformin transporters, were associated with changes in treatment HbA1c (P < 0.01) and metformin secretory clearance (P < 0.05). Population pharmacokinetic modeling further confirmed a 24% reduction in apparent clearance in homozygous carriers of one such variant, rs784888. Genetic variants in other transcription factors, peroxisome proliferator-activated receptor-α and hepatocyte nuclear factor 4-α, were significantly associated with HbA1c change only. Overall, our study highlights the importance of genetic variants in transcription factors as modulators of metformin PK and response.

Background In a phase 3, randomized clinical trial (PREVENT TB) of 8053 people with latent tuberculosis infection, 12 once-weekly doses of rifapentine and isoniazid had good efficacy and tolerability. Children received higher rifapentine milligram per kilogram doses than adults. In the present pharmacokinetic study (a component of the PREVENT TB trial), rifapentine exposure was compared between children and adults. Methods Rifapentine doses in children ranged from 300 to 900 mg, and adults received 900 mg. Children who could not swallow tablets received crushed tablets. Sparse pharmacokinetic sampling was performed with 1 rifapentine concentration at 24 hours after drug administration (C24). Rifapentine area under concentration-time curve (AUC) was estimated from a nonlinear, mixed effects regression model (NLME). Results There were 80 children (age: median, 4.5 years; range, 2-11 years) and 77 adults (age: median, 40 years; all ≥18 years) in the study. The geometric mean rifapentine milligram per kilogram dose was greater in children than in adults (children, 23 mg/kg; adults, 11 mg/kg). Rifapentine geometric mean AUC and C24 were 1.3-fold greater in children (all children combined) than in adults. Children who swallowed whole tablets had 1.3-fold higher geometric mean AUC than children who received crushed tablets, and children who swallowed whole tablets had a 1.6-fold higher geometric mean AUC than adults. The higher rifapentine doses in children were well tolerated. To obtain rifapentine exposures comparable in children to adults, dosing algorithms modeled by NLME were developed. Conclusions A 2-fold greater rifapentine dose for all children resulted in a 1.3-fold higher AUC compared to adults administered a standard dose. Use of higher weight-adjusted rifapentine doses for young children are warranted to achieve systemic exposures that are associated with successful treatment of latent tuberculosis infection in adults.

The current treatment used for tuberculosis (TB) is lengthy and needs to be shortened and improved. Pyrazinamide (PZA) has potent sterilizing activity and has the potential to shorten the TB treatment duration, if treatment is optimized. The goals of this study were (i) to develop a population pharmacokinetic (PK) model for PZA among patients enrolled in PK substudies of Tuberculosis Trial Consortium (TBTC) trials 27 and 28 and (ii) to determine covariates that affect PZA PK. (iii) We also performed simulations and target attainment analysis using the proposed targets of a maximum plasma concentration ( C max ) of >35 μg/ml or an area under the concentration-versus-time curve (AUC) of >363 μg · h/ml to see if higher weight-based dosing could improve PZA efficacy. Seventy-two patients participated in the substudies. The mean (standard deviation [SD]) C max was 30.8 (7.4) μg/ml, and the mean (SD) AUC from time zero to 24 h (AUC 0–24 ) was 307 (83) μg · h/ml. A one-compartment open model best described PZA PK. Only body weight was a significant covariate for PZA clearance. Women had a lower volume of distribution ( V / F ) than men, and both clearance (CL/ F ) and V / F increased with body weight. Our simulations show that higher doses of PZA (>50 mg/kg of body weight) are needed to achieve the therapeutic target of an AUC/MIC of >11.3 in >80% of patients, while doses of >80 mg/kg are needed for target attainment in 90% of patients, given specific assumptions about MIC determinations. For the therapeutic targets of a C max of >35 μg/ml and/or an AUC of >363 μg · h/ml, doses in the range of 30 to 40 mg/kg are needed to achieve the therapeutic target in >90% of the patients. Further clinical trials are needed to evaluate the safety and efficacy of higher doses of PZA.

Little information is currently available regarding the pharmacokinetics (PK) of busulfan in infants and small children to help guide decisions for safe and efficacious drug therapy. The objective of this study was to develop an algorithm for individualized dosing of i.v. busulfan in infants and children weighing ≤12 kg, that would achieve targeted exposure with the first dose of busulfan. Population PK modeling was conducted using intensive time-concentration data collected through the routine therapeutic drug monitoring of busulfan in 149 patients from 8 centers. Busulfan PK was well described by a 1-compartment base model with linear elimination. The important clinical covariates affecting busulfan PK were actual body weight and age. Based on our model, the predicted clearance of busulfan increases approximately 1.7-fold between 6 weeks to 2 years of life. For infants age

Pregnancy and food insecurity may impact antiretroviral (ART) pharmacokinetics (PK) adherence and response. We sought to quantify and characterize the PK of lopinavir/ritonavir (LPV/r) and efavirenz (EFV) by pregnancy and nutritional status among HIV-infected women in Tororo Uganda. In 2011 62/225 ante-partum/post-partum single dried blood spot samples DBS and 43 post-partum hair samples for LPV/r were derived from 116 women 51/194 ante-/post-partum DBS and 53 post-partum hair samples for EFV from 105 women. Eighty percent of Ugandan participants were severely food insecure 26% lost weight ante-partum and median BMI post-partum was only 20.2 kg/m(2) . Rich PK-data of normally nourished (pregnant) women and healthy Ugandans established prior information. Overall drug exposure was reduced (LPV -33% EFV -15% ritonavir -17%) compared to well-nourished controls (P < 0.001) attributable to decreased bioavailability. Pregnancy increased LPV/r clearance 68% (P < 0.001) whereas EFV clearance remained unchanged. Hair concentrations correlated with plasma-exposure (P < 0.001) explaining 29% PK-variability. In conclusion pregnancy and food insecurity were associated with lower ART exposures in this cohort of predominantly underweight women compared to well-nourished women. Much variability in plasma-exposure was quantified using hair concentrations. Addressing malnutrition as well as ART-PK in this setting should be a priority. (c) 2013 The American College of Clinical Pharmacology.

Rationale: Current first-line treatments for stress related disorders such as major depressive disorder (MDD) act on monoaminergic systems and take weeks to achieve a therapeutic effect with poor response and low remission rates. Recent research has implicated the GABAergic system in the pathophysiology of depression, including deficits in interneurons targeting the dendritic compartment of cortical pyramidal cells. Objectives: The present study evaluates whether SH-053-2'F-R-CH3 (denoted "alpha 5-PAM"), a positive allosteric modulator selective for (alpha 5-subunit containing GABA(A) receptors found predominantly on cortical pyramidal cell dendrites, has anti stress effects. Methods: Female and male C57BL6/J mice were exposed to unpredictable chronic mild stress (UCMS) and treated with alpha 5-PAM acutely (30 min prior to assessing behavior) or chronically before being assessed behaviorally. Results: Acute and chronic alpha 5-PAM treatments produce a pattern of decreased stress induced behaviors (denoted as "behavioral emotionality") across various tests in female, but not in male mice. Behavioral Z-scores calculated across a panel of tests designed to best model the range and heterogeneity of human symptomatology confirmed that acute and chronic alpha 5-PAM treatments consistently produce significant decreases in behavioral emotionality in several independent cohorts of females. The behavioral responses to alpha 5-PAM could not be completely accounted for by differences in drug brain disposition between female and male mice. In mice exposed to UCMS, expression of the Gabra5 gene was increased in the frontal cortex after acute treatment and in the hippocampus after chronic treatment with alpha 5-PAM in females only, and these expression changes correlated with behavioral emotionality. Conclusion: We showed that acute and chronic positive modulation of alpha 5 subunit containing GABA(A) receptors elicit anti-stress effects in a sex-dependent manner, suggesting novel therapeutic modalities.

Tuberculosis is a major cause of morbidity and mortality in women of childbearing age (15-44 years). Despite increased tuberculosis risk during pregnancy, optimal clinical treatment remains unclear: safety, tolerability, and pharmacokinetic data for many tuberculosis drugs are lacking, and trials of promising new tuberculosis drugs exclude pregnant women. To advance inclusion of pregnant and postpartum women in tuberculosis drug trials, the US National Institutes of Health convened an international expert panel. Discussions generated consensus statements (>75% agreement among panelists) identifying high-priority research areas during pregnancy, including: (1) preventing progression of latent tuberculosis infection, especially in women coinfected with human immunodeficiency virus; (2) evaluating new agents/regimens for treatment of multidrug-resistant tuberculosis; and (3) evaluating safety, tolerability and pharmacokinetics of tuberculosis drugs already in use during pregnancy and postpartum. Incorporating pregnant women into clinical trials would extend evidence-based tuberculosis prevention and treatment standards to this special population.

BACKGROUND:The combination of rifapentine and moxifloxacin administered daily with other anti-tuberculosis drugs is highly active in mouse models of tuberculosis chemotherapy. The objective of this phase 2 clinical trial was to determine the bactericidal activity, safety, and tolerability of a regimen comprised of rifapentine, moxifloxacin, isoniazid, and pyrazinamide administered daily during the first 8 weeks of pulmonary tuberculosis treatment. METHODS:Adults with sputum smear-positive pulmonary tuberculosis were randomized to receive either rifapentine (approximately 7.5 mg/kg) plus moxifloxacin (investigational arm), or rifampin (approximately 10 mg/kg) plus ethambutol (control) daily for 8 weeks, along with isoniazid and pyrazinamide. The primary endpoint was sputum culture status at completion of 8 weeks of treatment. RESULTS:121 participants (56% of accrual target) were enrolled. At completion of 8 weeks of treatment, negative cultures using Löwenstein-Jensen (LJ) medium occurred in 47/60 (78%) participants in the investigational arm vs. 43/51 (84%, p = 0.47) in the control arm; negative cultures using liquid medium occurred in 37/47 (79%) in the investigational arm vs. 27/41 (66%, p = 0.23) in the control arm. Time to stable culture conversion was shorter for the investigational arm vs. the control arm using liquid culture medium (p = 0.03), but there was no difference using LJ medium. Median rifapentine area under the concentration-time curve (AUC0-24) was 313 mcg*h/mL, similar to recent studies of rifapentine dosed at 450-600 mg daily. Median moxifloxacin AUC0-24 was 28.0 mcg*h/mL, much lower than in trials where rifapentine was given only intermittently with moxifloxacin. The proportion of participants discontinuing assigned treatment for reasons other than microbiological ineligibility was higher in the investigational arm vs. the control arm (11/62 [18%] vs. 3/59 [5%], p = 0.04) although the proportions of grade 3 or higher adverse events were similar (5/62 [8%] in the investigational arm vs. 6/59 [10%, p = 0.76] in the control arm). CONCLUSION:For intensive phase daily tuberculosis treatment in combination with isoniazid and pyrazinamide, a regimen containing moxifloxacin plus low dose rifapentine was at least as bactericidal as the control regimen containing ethambutol plus standard dose rifampin. TRIAL REGISTRATION:www.ClinicalTrials.gov NCT00728507.

Pediatric tuberculous meningitis (TBM) is a highly morbid, often fatal disease. Standard treatment includes isoniazid, rifampin, pyrazinamide, and ethambutol. Current rifampin dosing achieves low cerebrospinal fluid (CSF) concentrations, and CSF penetration of ethambutol is poor. In adult trials, higher-dose rifampin and/or a fluoroquinolone reduced mortality and disability. To estimate optimal dosing of rifampin and levofloxacin for children, we compiled plasma and CSF pharmacokinetic (PK) and outcomes data from adult TBM trials plus plasma PK data from children. A population PK/pharmacodynamic (PD) model using adult data defined rifampin target exposures (plasma area under the curve (AUC)0-24 = 92 mg*h/L). Levofloxacin targets and rifampin pediatric drug disposition information were literature-derived. To attain target rifampin exposures, children require daily doses of at least 30 mg/kg orally or 15 mg/kg intravenously (i.v.). From our pediatric population PK model, oral levofloxacin doses needed to attain exposure targets were 19-33 mg/kg. Our results provide data-driven guidance to maximize pediatric TBM treatment while we await definitive trial results.

The efficiency of denatured muscle grafting in nerve repair has been confirmed in experimental models and animals. The first clinical trials to repair digital nerves and mixed sensory-motor nerves were encouraging regarding sensory recovery but motor recovery was poor, probably because of delayed repair. We present the functional outcome of repair of motor nerves using denatured muscle graft and compare the results with those using standard nerve graft techniques.This prospective study included 9 radial nerve defects repaired with denatured muscle grafts and 23 radial nerve defects repaired using nerve grafts. Missile induced nerve injury, mid-arm level of lesion, a nerve gap smaller than 6 cm, and a preoperative interval of less than 5 months were characteristics shared by all patients. None of the patients had concomitant vascular injury, severe scarring, or significant soft tissue damage in the region of nerve repair. Motor recovery was estimated with 0-5 points, at least 4.7 years after surgery, according to the BMRC scale.A successful outcome (or=M3) was achieved in 7 out of the 9 patients treated using a muscle graft and in 21 out of the 23 patients treated using nerve grafts (P0.05). Excellent recovery and the clinically significant re-establishment of thumb extension (M5 grade) were never achieved in the patients treated using muscle grafts. The average motor score was significantly better in patients treated with nerve grafts than in those who received muscle grafts (3.8 +/- 0.9 and 3.2 +/- 0.8; P = 0.035). With the patients who received muscle grafts, an inverse correlation existed between motor recovery and the length of the nerve gap (P = 0.017).Denatured muscle grafts can be useful for bridging short radial nerve defects, but the quality of recovery is significantly worse than after nerve graft repair. Even if relatively short nerve defects are bridged with denatured muscle grafts, the outcomes correlate inversely with the length of the gap.

The objective of the study was to determine the differences in systemic stress response in patients undergoing transurethral resection of the prostate (TURP) versus endoscopic laser ablation of the prostate (ELAP) for benign prostatic hyperplasia (BPH). The study included 48 patients with BPH (24 treated by TURP and 24 by ELAP). Blood samples were taken from each patient before and immediately after the procedure and on postoperative days 1, 6, and 20, respectively. TURP caused more intense acute-phase response during 24 h after the procedure considering the serum c-reactive protein (CRP) level (p

Objectives: Alternatively to the modified Stoppa approach, the Pararectus approach is used clinically for treatment of acetabular fractures. This study assessed the surgical exposure and the options for instrumentation using both of these approaches. Methods: Dissections were conducted on five human[for full text, please go to the a.m. URL], Deutscher Kongress für Orthopädie und Unfallchirurgie (DKOU 2016)

Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved. Background: Population pharmacokinetic (PK) studies of busulfan in children have shown that individualized model-based algorithms provide improved targeted busulfan therapy when compared with conventional dose guidelines. The adoption of population PK models into routine clinical practice has been hampered by the tendency of pharmacologists to develop complex models too impractical for clinicians to use. The authors aimed to develop a population PK model for busulfan in children that can reliably achieve therapeutic exposure (concentration at steady state) and implement a simple model-based tool for the initial dosing of busulfan in children undergoing hematopoietic cell transplantation. Patients and Methods: Model development was conducted using retrospective data available in 90 pediatric and young adult patients who had undergone hematopoietic cell transplantation with busulfan conditioning. Busulfan drug levels and potential covariates influencing drug exposure were analyzed using the nonlinear mixed effects modeling software, NONMEM. The final population PK model was implemented into a clinician-friendly Microsoft Excel-based tool and used to recommend initial doses of busulfan in a group of 21 pediatric patients prospectively dosed based on the population PK model. Results: Modeling of busulfan time-concentration data indicates that busulfan clearance displays nonlinearity in children, decreasing up to approximately 20% between the concentrations of 250-2000 ng/mL. Important patient-specific covariates found to significantly impact busulfan clearance were actual body weight and age. The percentage of individuals achieving a therapeutic concentration at steady state was significantly higher in subjects receiving initial doses based on the population PK model (81%) than in historical controls dosed on conventional guidelines (52%) (P = 0.02). Conclusions: When compared with the conventional dosing guidelines, the model-based algorithm demonstrates significant improvement for providing targeted busulfan therapy in children and young adults.