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Open Access Publications from the University of California

Scholarly Works (9 results)

  • Thesis
  • Peer Reviewed
UC San Francisco Electronic Theses and Dissertations (2020)

Tuberculosis (TB) infects 10 million people each year and kills more than any other infectious disease. All current approaches to TB treatment are based on a one-size-fits-all approach, which leads to undertreatment of patients with severe forms of disease and entails unnecessarily long treatment with potential toxicities for many patients in whom the disease is less severe. Shorter, efficacious, and better-tolerated oral regimens for TB are needed. Unfortunately, all recent Phase 3 clinical trials aimed to shorten treatment duration from 6 months to 4 months for drug susceptible TB failed. The aims of this dissertation were to quantitively characterize treatment response in TB patients and develop model-based tools that provide informed recommendations on optimal treatment regimens and strategies that: i.) maximize durable cure in all patients, ii.) maximize success of late stage regimen development, and iii.) minimize safety concerns associated with a highly potent, but toxic, high-dose linezolid-containing regimen.

In a patient-level pooled analysis of all recent Phase 3 clinical trials evaluating shorter treatments for drug susceptible TB , survival analysis identified risk factors of treatment outcomes. Based on these risk factors, a risk stratification algorithm and clinical simulation tool were developed to provide more individualized predictions of optimal treatment regimens to achieve high cure rates in TB patients.

TB regimen development is plagued with many challenges, the most serious being the inability to identify optimal regimens early and efficiently. To facilitate decisions on novel TB regimens that move forward through the development process, an integrated model was developed to describe the translational link between Phase 2 intermediate biomarkers, treatment characteristics, and patient risk factors to Phase 3 clinical outcomes. We provide clinical trial simulation tools to design innovative clinical trial designs that permit evidence-based decisions on moving the best regimens forward in late stage clinical development .

The TB regimen development process is also challenged by the lack of reliable, quantitative, non-culture-based biomarkers that inform individual level and trial level treatment response. We showed that leveraging longitudinal sputum culture results and drug exposure and applying advanced nonlinear mixed effect modeling with machine learning approaches offer insights into the response dynamics following anti-TB treatment. We identified candidate proteomic signatures that can potentially predict treatment response.

Lastly, using modeling and simulation approaches, we quantified the pharmacokinetic-toxicodynamic relationship of a high-dose linezolid-containing regimen for extensively drug resistant TB. We provide practical data-driven recommendations about linezolid dosing adjustments to optimize therapeutic effects and minimize adverse events.

The quantitative, model-based tools developed in this dissertation contributes to providing evidence-based recommendations on optimal treatment strategies for current and novel TB regimens.

    Cover page: Model-based tools to improve treatment of tuberculosis patients
    • Article
    • Peer Reviewed
    UC San Francisco Previously Published Works (2023)
    Answering challenging questions in drug development sometimes requires pharmacokinetic (PK) data analysis across different studies, for example, to characterize PKs across diverse regions or populations, or to increase statistical power for subpopulations by combining smaller size trials. Given the growing interest in data sharing and advanced computational methods, knowledge integration based on multiple data sources is increasingly applied in the context of model-informed drug discovery and development. A powerful analysis method is the individual patient data meta-analysis (IPDMA), leveraging systematic review of databases and literature, with the most detailed data type of the individual patient, and quantitative modeling of the PK processes, including capturing heterogeneity of variance between studies. The methodology that should be used in IPDMA in the context of population PK analysis is summarized in this tutorial, highlighting areas of special attention compared to standard PK modeling, including hierarchical nested variability terms for interstudy variability, and handling between-assay differences in limits of quantification within a single analysis. This tutorial is intended for any pharmacological modeler who is interested in performing an integrated analysis of PK data across different studies in a systematic and thorough manner, to answer questions that transcend individual primary studies.
      Cover page: Pharmacokinetic analysis across studies to drive knowledge-integration: A tutorial on individual patient data meta-analysis (IPDMA).
      • Article
      • Peer Reviewed
      UC San Francisco Previously Published Works (2021)
      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.
        Cover page: Precision-Enhancing Risk Stratification Tools for Selecting Optimal Treatment Durations in Tuberculosis Clinical Trials
        • Article
        • Peer Reviewed
        UC San Francisco Previously Published Works (2022)

        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, <1% for both daily doses). Generally, neuropathy occurred after 3 to 6 months of treatment and, with protocol-specified management, reversed within 15 months after onset. Simulations indicated that a >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.
          Cover page: Proposed linezolid dosing strategies to minimize adverse events for treatment of extensively drug-resistant tuberculosis
          • Article
          • Peer Reviewed
          UC San Francisco Previously Published Works (2018)
          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 <2+, 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 by <2+ sputum smear grade or non-cavitary disease. A hard-to-treat phenotype, defined by high smear grades and cavitation, may require durations >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.
            Cover page: A patient-level pooled analysis of treatment-shortening regimens for drug-susceptible pulmonary tuberculosis
            • Article
            • Peer Reviewed
            UC San Francisco Previously Published Works (2019)
            The version of this article originally published was not open access. This article should have been open access. The error has been fixed, and the article is now open access.
              Cover page: Publisher Correction: A patient-level pooled analysis of treatment-shortening regimens for drug-susceptible pulmonary tuberculosis
              • Article
              • Peer Reviewed
              UC San Francisco Previously Published Works (2024)
              TBI-223, a novel oxazolidinone for tuberculosis, is designed to provide improved efficacy and safety compared to linezolid in combination with bedaquiline and pretomanid (BPaL). We aim to optimize the dosing of TBI-223 within the BPaL regimen for enhanced therapeutic outcomes. TBI-223 is investigated in preclinical monotherapy, multidrug therapy, and lesion penetration experiments to describe its efficacy and safety versus linezolid. A translational platform incorporating linezolid and BPaL data from preclinical experiments and 4 clinical trials (NCT00396084, NCT02333799, NCT03086486, NCT00816426) is developed, enabling validation of the framework. TBI-223 preclinical and Phase 1 data (NCT03758612) are applied to the translational framework to predict clinical outcomes and optimize TBI-223 dosing in combination with bedaquiline and pretomanid. Results indicate that daily doses of 1200-2400 mg TBI-223 may achieve efficacy comparable to the BPaL regimen, with >90% of patients predicted to reach culture conversion by two months.
                Cover page: Dose optimization of TBI-223 for enhanced therapeutic benefit compared to linezolid in antituberculosis regimen.
                • Article
                • Peer Reviewed
                UC San Francisco Previously Published Works (2020)
                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.).
                  Cover page: Piperaquine Exposure Is Altered by Pregnancy, HIV, and Nutritional Status in Ugandan Women
                  • Article
                  • Peer Reviewed
                  UC San Francisco Previously Published Works (2024)
                  The Phase 3 randomized controlled trial, TBTC Study 31/ACTG A5349 (NCT02410772) demonstrated that a 4-month rifapentine-moxifloxacin regimen for drug-susceptible pulmonary tuberculosis was safe and effective. The primary efficacy outcome was 12-month tuberculosis disease free survival, while the primary safety outcome was the proportion of grade 3 or higher adverse events during the treatment period. We conducted an analysis of demographic, clinical, microbiologic, radiographic, and pharmacokinetic data and identified risk factors for unfavorable outcomes and adverse events. Among participants receiving the rifapentine-moxifloxacin regimen, low rifapentine exposure is the strongest driver of tuberculosis-related unfavorable outcomes (HR 0.65 for every 100 µg∙h/mL increase, 95%CI 0.54-0.77). The only other risk factors identified are markers of higher baseline disease severity, namely Xpert MTB/RIF cycle threshold and extent of disease on baseline chest radiography (Xpert: HR 1.43 for every 3-cycle-threshold decrease, 95%CI 1.07-1.91; extensive disease: HR 2.02, 95%CI 1.07-3.82). From these risk factors, we developed a simple risk stratification to classify disease phenotypes as easier-, moderately-harder, or harder-to-treat TB. Notably, high rifapentine exposures are not associated with any predefined adverse safety outcomes. Our results suggest that the easier-to-treat subgroup may be eligible for further treatment shortening while the harder-to-treat subgroup may need higher doses or longer treatment.
                    Cover page: Risk-stratified treatment for drug-susceptible pulmonary tuberculosis
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