NOVEL STUDY DESIGNS TO ADVANCE POPULATION PHARMACOKINETIC MODELING AND SIMULATION IN VULNERABLE POPULATIONS

Despite advances in drug development, more than half of recent clinical trials in children and pregnant mothers failed to achieve new drug approvals. Common reasons for trial failure in these vulnerable populations include inadequate study design and poor dose selection by not accounting for the physiologic changes altering drug disposition. The physiologic changes are particularly relevant for drugs such as hydroxychloroquine (HCQ) and indomethacin, where clearance may be higher in children and during pregnancy. Moreover, ethical concerns in children and pregnant mothers limit traditional clinical trial designs, including intense blood sampling. As a result of the challenges to clinical trials, there is very limited pharmacokinetic/pharmacodynamic (PK/PD) data to guide appropriate dosing in vulnerable populations. Accordingly, new and innovative study designs that collect data using minimal risk techniques such as opportunistic drug dosing and blood sampling are imperative to develop the models necessary for dosage optimization in these populations. This dissertation demonstrates 3 case examples that leverage innovative, minimal risk study designs to support population PK modeling and simulation for vulnerable populations. Central to this innovation is developing the models using real-world data collected from novel, minimal risk study designs (e.g., disease registries, opportunistic trials, and direct-to-family studies) that increase the feasibility of drug studies in vulnerable populations. In Chapter 2, hydroxychloroquine (HCQ) PK and exposure-response were characterized during pregnancy using real-world registry data. In Chapter 3, indomethacin PK and exposure-response were characterized during pregnancy using data from an opportunistic clinical trial. In Chapter 4, HCQ PK and exposure-response were characterized in children with systemic lupus using data from a novel, direct-to-family trial. In each chapter, the models were used to provide clinical guidance on the optimal dose of each drug in children and/or pregnancy.Doctor of Philosoph

Prescribing for Children With Rheumatic Disease: Perceived Treatment Approaches Between Pediatric and Adult Rheumatologists

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141687/1/acr23273.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141687/2/acr23273_am.pd

Abatacept Pharmacokinetics and Exposure Response in Patients Hospitalized With COVID-19: A Secondary Analysis of the ACTIV-1 IM Randomized Clinical Trial

IMPORTANCE: The pharmacokinetics of abatacept and the association between abatacept exposure and outcomes in patients with severe COVID-19 are unknown. OBJECTIVE: To characterize abatacept pharmacokinetics, relate drug exposure with clinical outcomes, and evaluate the need for dosage adjustments. DESIGN, SETTING, AND PARTICIPANTS: This study is a secondary analysis of data from the ACTIV-1 (Accelerating COVID-19 Therapeutic Interventions and Vaccines) Immune Modulator (IM) randomized clinical trial conducted between October 16, 2020, and December 31, 2021. The trial included hospitalized adults who received abatacept in addition to standard of care for treatment of COVID-19 pneumonia. Data analysis was performed between September 2022 and February 2024. EXPOSURE: Single intravenous infusion of abatacept (10 mg/kg with a maximum dose of 1000 mg). MAIN OUTCOMES AND MEASURES: Mortality at day 28 was the primary outcome of interest, and time to recovery at day 28 was the secondary outcome. Drug exposure was assessed using the projected area under the serum concentration time curve over 28 days (AUC0-28). Logistic regression modeling was used to analyze the association between drug exposure and 28-day mortality, adjusted for age, sex, and disease severity. The association between time to recovery and abatacept exposure was examined using Fine-Gray modeling with death as a competing risk, and was adjusted for age, sex, and disease severity. RESULTS: Of the 509 patients who received abatacept, 395 patients with 848 serum samples were included in the population pharmacokinetic analysis. Their median age was 55 (range, 19-89) years and most (250 [63.3%]) were men. Abatacept clearance increased with body weight and more severe disease activity at baseline. Drug exposure was higher in patients who survived vs those who died, with a median AUC0-28 of 21 428 (range, 8462-43 378) mg × h/L vs 18 262 (range, 9628-27 507) mg × h/L (P \u3c .001). Controlling for age, sex, and disease severity, an increase of 5000 units in AUC0-28 was associated with lower odds of mortality at day 28 (OR, 0.52 [95% CI, 0.35-0.79]; P = .002). For an AUC0-28 of 19 400 mg × h/L or less, there was a higher probability of recovery at day 28 (hazard ratio, 2.63 [95% CI, 1.70-4.08] for every 5000-unit increase; P \u3c .001). Controlling for age, sex, and disease severity, every 5000-unit increase in AUC0-28 was also associated with lower odds of a composite safety event at 28 days (OR, 0.46 [95% CI, 0.33-0.63]; P \u3c .001). Using the dosing regimen studied in the ACTIV-1 IM trial, 121 of the 395 patients (30.6%) would not achieve an abatacept exposure of at least 19 400 mg × h/L, particularly at the extremes of body weight. Using a modified, higher-dose regimen, only 12 patients (3.0%) would not achieve the hypothesized target abatacept exposure. CONCLUSIONS AND RELEVANCE: In this study, patients who were hospitalized with severe COVID-19 and achieved higher projected abatacept exposure had reduced mortality and a higher probability of recovery with fewer safety events. However, abatacept clearance was high in this population, and the current abatacept dosing (10 mg/kg intravenously with a maximum of 1000 mg) may not achieve optimal exposure in all patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04593940

Azathioprine metabolite levels and outcomes during pregnancies with rheumatic disease

Objective Despite widespread use of azathioprine (AZA) during pregnancy, no studies evaluated the impact of pregnancy on AZA metabolites 6-thioguanine nucleotide (6-TGN) and 6-methylmercaptopurine nucleotide (6-MMPN) disposition in rheumatic diseases. This study characterises changes in AZA metabolite concentrations throughout pregnancy in women with rheumatic disease and explores relationships between metabolite concentrations, maternal disease activity, and neonatal outcomes.Methods Patients with rheumatic disease from a single centre prescribed AZA prior to pregnancy and ≥1 blood sample during pregnancy (5/2016 to 4/2022) were included. Commercial laboratories quantified AZA metabolite concentrations. The upper safety limit for 6-MMPN was >5700 pmol/8×108 RBC. The therapeutic target for 6-TGN was ≥159 pmol/8×108 RBC. Repeated correlation measures were used to evaluate the relationship between metabolite concentrations and pregnancy duration, and the relationship between 6-TGN concentration and SLE Physician Global Assessment (PGA). The relationship between pregnancy average 6-TGN and neonatal gestational age at birth was analysed using linear regression.Results Thirty-seven pregnancies in 35 women with 108 serum samples were included. There was no significant difference in dose-adjusted 6-TGN concentrations across pregnancy and peripartum, whereas 6-MMPN concentrations appeared higher during pregnancy. No elevated transaminases or cholestasis were observed concurrently with 6-MMPN above 5700 pmol/8×108 RBC. Metabolite concentrations were related to total AZA dosage, weight-based dosage and TPMT phenotype. In pregnant women with SLE achieving average 6-TGN in the therapeutic range, we observed a non-significant reduction in PGA and increase in neonatal gestational age at birth.Conclusions In this exploratory study, we did not observe systematic changes in 6-TGN concentrations throughout pregnancy and peripartum, whereas 6-MMPN concentrations were higher during pregnancy. Monitoring AZA metabolite concentrations in pregnancy is a potential tool to identify medication non-adherence as well as patients with high 6-MMPN in whom dosage adjustment or close laboratory monitoring may optimise safety

Comparative effectiveness of a second TNF inhibitor versus a non-TNF biologic in the treatment of polyarticular course juvenile idiopathic arthritis

Objective: The objective of this study was to compare the effectiveness of a second tumor necrosis factor inhibitor (TNFi) versus a non-TNFi biologic following discontinuation of a TNFi for patients with polyarticular-course juvenile idiopathic arthritis (pJIA). Methods: Using the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry, patients with pJIA who started a second biologic following a first TNFi were identified. Patients were required to have no active uveitis on index date and a visit 6 months after the index date. Outcome measures included clinical juvenile arthritis disease activity score 10 (cJADAS10), cJADAS10 inactive disease (ID<2.5) and cJADAS10 minimal disease activity (MiDA<5). Multiple imputation was used to account for missing data. Adjusted odds ratios (aOR) were calculated using propensity score quintiles to compare outcomes at 6 months following second biologic initiation. Results: There were 216 patients included, 84% initially received etanercept and most patients stopped it for ineffectiveness (74%). 183 (85%) started a second TNFi and 33 (15%) started a non-TNFi. Adalimumab was the most common second biologic (71% overall, 84% of second TNFi) and tocilizumab was the most common non-TNFi second biologic (9% overall, 58% of non-TNFi). There was no difference between TNFi and non-TNFi in cJADAS ID (29% versus 25%; aOR 1.23 [0.47-3.20]) or at least MiDA (43% versus 39%; aOR 1.11 [0.47-2.62]) at 6 months. 21514658, ja, Downloaded from https://acrjournals.onlinelibrary.wiley.com/doi/10.1002/acr.25339 by The University Of Manchester, Wiley Online Library on [09/04/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License JIA outcomes after second biologicConclusion: Most patients with polyarticular course JIA started TNFi rather than non- TNFi as their second biologic, and there were no differences in disease activity at 6 months. Significance and Innovations• Etanercept is the most commonly used first biologic (84%) in JIA, and after discontinuation of a first TNFi, most will start a second TNFi (85%), usually adalimumab, rather than change to a different class of biologic.• In a large North American Registry, among patients with polyarticular course JIA who started a second biologic, there was no difference in achievement of inactive disease or minimal disease activity at 6-months between a second TNFi and a non-TNFi.• Similar results were seen in an updated analysis of the UK JIA Biologics Register

Interpreting hydroxychloroquine blood levels for medication non-adherence: a pharmacokinetic study

Objective Characterise the relationship between hydroxychloroquine (HCQ) blood levels and the number of missed doses, accounting for dosage, dose timing and the large variability in pharmacokinetics (PK) between patients.Methods We externally validated a published PK model and then conducted dosing simulations. We developed a virtual population of 1000 patients for each dosage across a range of body weights and PK variability. Using the model, 10 Monte Carlo simulations for each patient were conducted to derive predicted whole blood concentrations every hour over 24 hours (240 000 HCQ levels at steady state). To determine the impact of missed doses on levels, we randomly deleted a fixed proportion of doses.Results For patients receiving HCQ 400 mg daily, simulated random blood levels <200 ng/mL were exceedingly uncommon in fully adherent patients (<0.1%). In comparison, with 80% of doses missed, approximately 60% of concentrations were <200 ng/mL. However, this cut-off was highly insensitive and would miss many instances of severe non-adherence. Average levels quickly dropped to <200 ng/mL after 2–4 days of missed doses. Additionally, mean levels decreased by 29.9% between peak and trough measurements.Conclusions We propose an algorithm to optimally interpret HCQ blood levels and approximate the number of missed doses, incorporating the impact of dosage, dose timing and pharmacokinetic variability. No single cut-off has adequate combinations of both sensitivity and specificity, and cut-offs are dependent on the degree of targeted non-adherence. Future studies should measure trough concentrations to better identify target HCQ levels for non-adherence and efficacy

Adverse Reactions in a Phase 1 Trial of the Anti-Malarial DM1157: An Example of Pharmacokinetic Modeling and Simulation Guiding Clinical Trial Decisions

Introduction: There is an urgent need to develop new drugs to treat malaria due to increasing resistance to first-line therapeutics targeting the causative organism, Plasmodium falciparum (P. falciparum). One drug candidate is DM1157, a small molecule that inhibits the formation of hemozoin, which protects P. falciparum from heme toxicity. We describe a first-in-human, phase 1 trial of DM1157 in healthy adult volunteers that was halted early because of significant toxicity. Methods: Adverse events were summarized using descriptive statistics. We used pharmacokinetic modeling to quantitatively assess whether the DM1157 exposure needed for P. falciparum inhibition was achievable at safe doses. Results: We found that there was no dose where both the safety and efficacy target were simultaneously achieved; conversely, the model predicted that 27 mg was the highest dosage at which patients would consistently maintain safe exposure with multiple dosing. By pre-defining dose escalation stopping rules and conducting an interim pharmacokinetic/pharmacodynamic analysis, we determined that the study would be unable to safely achieve a dosage needed to observe an anti-malarial effect, thereby providing strong rationale to halt the study. Conclusion: This study provides an important example of the risks and challenges of conducting early phase research as well as the role of modeling and simulation to optimize participant safety (ClinicalTrials.gov, NCT03490162)

Increasing contraception use among women receiving teratogenic medications in a rheumatology clinic

Teratogenic medications are often prescribed to women of childbearing age with autoimmune diseases. Literature suggests that appropriate use of contraception among these women is low, potentially resulting in high-risk unintended pregnancies. Preliminary review in our clinic showed suboptimal documentation of women’s contraceptive use. We therefore designed a quality improvement initiative to target three process measures: documentation of contraception usage and type, contraception counselling and provider action after counselling. We reviewed charts of rheumatology clinic female patients aged 18–45 over the course of 10 months; for those who were on teratogenic medications (methotrexate, leflunomide, mycophenolate and cyclophosphamide), we looked for evidence of documentation of contraception use. We executed multiple plan-do-study-act (PDSA) cycles to develop and evaluate interventions, which centred on interprofessional provider education, modification of electronic medical record (EMR) templates, periodic provider reminders, patient screening questionnaires and frequent feedback to providers on performance. Among eligible patients (n=181), the baseline rate of documentation of contraception type was 46%, the rate of counselling was 30% and interventions after counselling occurred in 33% of cases. Averaged intervention data demonstrated increased provider performance in all three domains: documentation of contraception type increased to 64%, counselling to 45% and provider action to 46%. Of the patients with documented contraceptives, 50% used highly effective, 27% used effective and 23% used ineffective contraception methods. During this project, one unintentional pregnancy occurred in a patient on methotrexate not on contraception. Our interventions improved three measures related to contraception counselling and documentation, but there remains a need for ongoing quality improvement efforts in our clinic. This high-risk population requires increased provider engagement to improve contraception compliance, coupled with system-wide EMR changes to increase sustainability