Pyrazinamide Safety, Efficacy, and Dosing for Treating Drug-Susceptible Pulmonary Tuberculosis: A Phase 3, Randomized, Controlled Clinical Trial.

RATIONALE: Optimizing pyrazinamide dosing is critical to improve treatment efficacy while minimizing toxicity during tuberculosis treatment. Study 31/ACTG A5349 represents the largest Phase 3 randomized controlled therapeutic trial to date for such investigation. OBJECTIVES: We sought to report pyrazinamide pharmacokinetic parameters, risk factors for lower pyrazinamide exposure, and relationships between pyrazinamide exposure with efficacy and safety outcomes. We aimed to determine pyrazinamide dosing strategies that optimize risks and benefits. METHODS: We analyzed pyrazinamide steady-state pharmacokinetic data using population nonlinear mixed-effects models. We evaluated the contribution of pyrazinamide exposure to long-term efficacy using parametric time-to-event models and safety outcomes using logistic regression. We evaluated optimal dosing with therapeutic windows targeting ≥95% durable cure and safety within the observed proportion of the primary safety outcome. MEASUREMENTS AND MAIN RESULTS: Among 2255 participants with 6978 plasma samples, pyrazinamide displayed 7-fold exposure variability (151-1053 mg·h/L). Body weight was not a clinically relevant predictor of drug clearance and thus did not justify the need for weight-banded dosing. Both clinical and safety outcomes were associated with pyrazinamide exposure, resulting in a therapeutic window of 231-355 mg·h/L for the control and 226-349 mg·h/L for the rifapentine-moxifloxacin regimen. Flat dosing of pyrazinamide at 1000 mg would have permitted an additional 13.1% (n=96) participants allocated to the control and 9.2% (n=70) to the rifapentine-moxifloxacin regimen dosed within the therapeutic window, compared to the current weight-banded dosing. CONCLUSIONS: Flat dosing of pyrazinamide at 1000 mg daily would be readily implementable and could optimize treatment outcomes in drug-susceptible tuberculosis. Clinical trial registration available at www. CLINICALTRIALS: gov, ID: NCT02410772.

Use of Model-Informed Drug Development to Streamline Development of Long-Acting Products: Can These Successes Be Translated to Long-Acting Hormonal Contraceptives?

Long-acting contraceptives are the most effective reversible contraceptive methods. Increasing patients' access to these contraceptives may translate into fewer unintended pregnancies and lead to substantial individual and public health benefits. However, development of long-acting products can be complex and challenging. This review provides (a) an overview of representative development programs for long-acting antipsychotics as cases for conceptual translation to long-acting contraceptives, (b) several case examples on how modeling and simulation have been used to streamline the development of long-acting products, and (c) examples of challenges andopportunities in developing long-acting contraceptives and information on how exposure-response relationships of commonly used progestins may enable regulators and developers to rely on prior findings of effectiveness and safety from an approved contraceptive to streamline the development of long-acting contraceptives. The US Food and Drug Administration is seeking assistance from stakeholders to provide data from studies in which pharmacokinetic and pharmacodynamic or clinical outcomes of hormonal contraceptives were evaluated and not previously submitted.

Model-informed drug development of envafolimab, a subcutaneously injectable PD-L1 antibody, in patients with advanced solid tumors.

BACKGROUND AND OBJECTIVES: Envafolimab is the first and only globally approved subcutaneously injectable PD-L1 antibody for the treatment of instability-high (MSI-H) or DNA mismatch repair deficient (dMMR) advanced solid tumors in adults, including those with advanced colorectal cancer that has progressed after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. The aim of this investigation was to examine the pharmacokinetic and exposure-response (E-R) profile of envafolimab in patients with solid tumors to support the approval of fixed and alternative dose regimens. METHODS: In this study, a population pharmacokinetic (PopPK) modeling approach will be employed to quantitatively evaluate intrinsic and extrinsic covariates. Additionally, PopPK-estimated exposure parameters were used to evaluate E-R relationship for safety and efficacy to provide a theoretical basis for recommending optimal treatment regimens. Simulations were performed on the dosing regimens of body weight-based regimen of 2.50 mg/kg QW, fixed dose 150 mg QW, and 300 mg Q2W for the selection of alternative dosing regimens. Data from 4 clinical studies (NCT02827968, NCT03101488, NCT03248843, and NCT03667170) were utilized. RESULTS: The PopPK dataset comprised 182 patients with 1810 evaluable envafolimab concentration records. Finally, a one-compartment model incorporating first-order absorption, first-order linear elimination, and time-dependent elimination according to an Emax function was found to accurately describe the concentration-time data of envafolimab in patients with advanced solid tumors. Creatinine clearance and country were identified as statistically significant factors affecting clearance, but had limited clinical significance. A relative flat exposure-response relationship was observed between early measures of safety and efficacy to verify that no dose adjustment is required. Simulation results indicated that 2.50 mg/kg QW, 150 mg QW, and 300 mg Q2W regimen yield similar steady-state exposure. CONCLUSIONS: No statistically significant difference was observed between weight-based and fixed dose regimens. Model-based simulation supports the adoption of a 150 mg weekly or 300 mg biweekly dosing regimen of envafolimab in the solid tumor population, as these schedules effectively balance survival benefits and safety risks.

Optimal exposure of mycophenolic acid for induction therapy of childhood lupus nephritis patients: an observational cohort study.

OBJECTIVES: Mycophenolic acid (MPA) is recommended for lupus nephritis (LN) treatment, but with large inter-individual variability in pharmacokinetics (PK). The aim of this study is to reveal the relationship between MPA exposure and disease response and adverse drug reactions in pediatric LN patients. METHOD: This was a population-based observational cohort study. A total of 86 pediatric LN patients treated with mycophenolate mofetil (MMF) for induction therapy were enrolled. The area-under the concentration-time curve (AUC) was calculated using MPA concentrations according to a limited sampling strategy. Receiver operating characteristic analysis was performed to assess the MPA-AUC threshold values. The cumulative incidence of renal remission and inactive SLE over time was evaluated by Kaplan-Meier's analysis. RESULTS: MPA-AUC was identified as an independent factor associated with renal remission and lupus activity at 6 and 12 months after MMF treatment, and the improved renal remission rates was correlated with higher MPA-AUC, with thresholds of 29.81 and 30.63 µg·h·mL - 1 at 6 and 12 months, respectively. Furthermore, the thresholds for maintaining the hypoactive state of LN were 30.96 and 31.19 µg·h·mL - 1at 6 months and 12 months, respectively. Patients reaching target thresholds for MPA-AUC achieved renal response or stable disease earlier. In addition, the MPA-AUC threshold for decreasing MMF-related adverse reactions was 50.80 µg·h·mL - 1. CONCLUSION: The initial and long-term treatments of pediatric LN patients with MMF should be individualized according to the MPA-AUC, and the recommended MPA exposure is 31.19-50.80 µg·h·mL - 1.

Ambient pollen exposure and pollen allergy symptom severity in the EPOCHAL study.

BACKGROUND: Ambient pollen exposure causes nasal, ocular, and pulmonary symptoms in allergic individuals, but the shape of the exposure-response association is not well characterized. We evaluated this association and determined (1) whether symptom severity differs between subpopulations; (2) how the association changes over the course of the pollen season; and (3) which pollen exposure time lags affect symptoms. METHODS: Adult study participants (n = 396) repeatedly scored severity of nasal, ocular, and pulmonary allergic symptoms, resulting in three composite symptom scores. We calculated hourly individually relevant pollen exposure to seven allergenic plants (alder, ash, birch, hazel, grasses, mugwort, and ragweed) considering personal sensitization and exposure time lags of up to 96 h. We fitted generalized additive mixed models, with a random personal intercept, adjusting for weather and air pollution as potential time-varying confounders. RESULTS: We identified a clear nonlinear positive association between pollen exposure and ocular and nasal symptom severity in the pollen allergy group: Symptom severity increased steeply with increasing exposure initially, but attenuated beyond approximately 80 pollen/m3. We found no evidence of an exposure threshold, below which no symptoms occur. While recent pollen exposure in the last approximately 5 h affected symptoms most, associations lingered for up to 60 h. Grass pollen exposure (compared to tree pollen) and younger age (18-30 years, as opposed to 30-65 years) were both associated with higher nasal and ocular symptom severity. CONCLUSIONS: The lack of a threshold and attenuated dose-response curve may have implications for pollen warning systems, which may be revised to include multiday pollen concentrations in the future.

Venetoclax in biomarker-selected multiple myeloma patients: Impact of exposure on clinical efficacy and safety.

Venetoclax, a potent BCL-2 inhibitor, is currently under development for treatment of t(11;14) Multiple myeloma (MM). The objective of this research was to investigate the exposure-response relationships of venetoclax for a phase 1/2 study evaluating venetoclax monotherapy or in combination with dexamethasone in relapsed or refractory MM. A total of 117 patients receiving venetoclax at 300, 600, 800, 900, or 1200 mg were included in the analysis. The impact of venetoclax exposures on efficacy (objective response rate [ORR], progression-free survival [PFS] and overall survival [OS]) as well as safety (treatment-emergent adverse effects (grade ≥3) of neutropenia, infection, and any grade of serious treatment-emergent adverse effects) was evaluated. In the t(11;14)-positive subpopulation, venetoclax exposure relationships to PFS and OS indicated a trend of longer PFS and OS with higher exposures. Moreover, logistic regression analyses for clinical response (ORR and ≥VGPR rate) demonstrated a statistically significant (p < 0.05) relationship with exposure. Evaluation of the exposure-safety relationships demonstrated a lack of a relationship between venetoclax exposures (AUCavg ) and grade ≥3 infections, grade ≥3 neutropenia, grade ≥3 treatment-emergent adverse events or any grade serious treatment-emergent adverse events. These findings support further study of venetoclax at 800 mg QD dose in combination with dexamethasone in the t(11;14)-positive patient population where increased efficacy was observed without an increase in safety events.Clinical Trial: NCT01794520 registered 20 February 2013.

Model-informed dose selection for an investigational human epidermal growth factor receptor 2 antibody-drug conjugate FS-1502 in patients with human epidermal growth factor receptor 2-expressing advanced malignant solid tumours.

AIMS: The dose-escalation phase (phase Ia study) of a novel human epidermal growth factor receptor 2 (HER2) antibody-drug conjugate (ADC) FS-1502 included a dose range from 0.1 to 3.5 mg/kg in HER2-expressing advanced malignant solid tumours. However, the defined maximum tolerated dose was not reached. This model-informed approach integrated population pharmacokinetic (PopPK) modelling and exposure-response (E-R) analysis to facilitate dose selection for phase II. METHODS: The PopPK model was constructed using PK data from 109 Chinese patients who received doses of 0.1-3.5 mg/kg FS-1502 every 3 (Q3W) or 4 weeks during a phase I dose-escalation and dose expansion trial. The structural model consisted of compartment models for FS-1502 and unconjugated monomethyl auristatin F. E-R was explored for the percentage change in tumour size, overall response rate and treatment-related adverse events. RESULTS: A semi-mechanistic 2-analyte PopPK model was developed. The FS-1502 PK data were best described by a 2-compartment PK model with parallel linear and nonlinear Michaelis-Menten eliminations. The PK of unconjugated monomethyl auristatin F was described by a 2-compartment model with first-order elimination. E-R analysis supported the clinically meaningful efficacy of FS-1502 at 2.3 mg/kg and above. However, 2.3 mg/kg Q3W was considered to have a better benefit-risk balance due to a lower incidence of safety events without a significant reduction in efficacy compared to 3.0 mg/kg Q3W. CONCLUSION: This PopPK and E-R analysis guided the recommended phase II dose selection of 2.3 mg/kg Q3W and supported body weight-based dosing for an investigational HER2 ADC FS-1502.

Confounding mitigation for the exposure-response relationship of bevacizumab in colorectal cancer patients.

AIMS: The exposure-response relationship of bevacizumab may be confounded by various factors, including baseline characteristics, time-dependent target engagement and recursive relationships between exposure and response, requiring effective mitigation. This study aimed to investigate the exposure-response relationships of bevacizumab in metastatic colorectal cancer (mCRC) patients while mitigating potential biases. METHODS: Bevacizumab pharmacokinetics was described using target-mediated drug disposition modelling. Relationships between target kinetics, progression-free (PFS) and overall (OS) survivals were assessed using joint pharmacokinetic and parametric hazard function models. Both prognostic-driven and response-driven potential biases were mitigated. These models evaluated the impact of increased antigen target levels, clearance and intensified dosing regimen on survival. RESULTS: Estimated target-mediated pharmacokinetic parameters in 130 assessed patients were baseline target levels (R0 = 8.4 nM), steady-state dissociation constant (KSS = 10 nM) and antibody-target complexes elimination constant (kint = 0.52 day-1). The distribution of R0 was significantly associated with increased baseline concentrations of carcinoembryonic antigen, circulating vascular endothelial growth factor and the presence of extrahepatic metastases. Unbound target levels (R) significantly influenced both progression and death hazard functions. Increasing baseline target levels and/or clearance values led to decreased bevacizumab unbound concentrations, increased R levels and shortened PFS and OS, while increasing bevacizumab dose led to decreased R and longer survival. CONCLUSION: This study is the first to demonstrate the relationship between bevacizumab concentrations, target involvement and clinical efficacy by effectively mitigating potential sources of bias. Most of the target amount may be tumoural in mCRC. Future studies should provide a more in-depth description of this relationship.

The association between humidex and tuberculosis: a two-stage modelling nationwide study in China.

BACKGROUND: Under a changing climate, the joint effects of temperature and relative humidity on tuberculosis (TB) are poorly understood. To address this research gap, we conducted a time-series study to explore the joint effects of temperature and relative humidity on TB incidence in China, considering potential modifiers. METHODS: Weekly data on TB cases and meteorological factors in 22 cities across mainland China between 2011 and 2020 were collected. The proxy indicator for the combined exposure levels of temperature and relative humidity, Humidex, was calculated. First, a quasi-Poisson regression with the distributed lag non-linear model (DLNM) was constructed to examine the city-specific associations between humidex and TB incidence. Second, a multivariate meta-regression model was used to pool the city-specific effect estimates, and to explore the potential effect modifiers. RESULTS: A total of 849,676 TB cases occurred in the 22 cities between 2011 and 2020. Overall, a conspicuous J-shaped relationship between humidex and TB incidence was discerned. Specifically, a decrease in humidex was positively correlated with an increased risk of TB incidence, with a maximum relative risk (RR) of 1.40 (95% CI: 1.11-1.76). The elevated RR of TB incidence associated with low humidex (5th humidex) appeared on week 3 and could persist until week 13, with a peak at approximately week 5 (RR: 1.03, 95% CI: 1.01-1.05). The effects of low humidex on TB incidence vary by Natural Growth Rate (NGR) levels. CONCLUSION: A J-shaped exposure-response association existed between humidex and TB incidence in China. Humidex may act as a better predictor to forecast TB incidence compared to temperature and relative humidity alone, especially in regions with higher NGRs.

Individual and joint associations of air pollutants exposure with semen quality: A retrospective longitudinal study in Wenzhou, China.

PURPOSE: The impact of air pollution on semen quality has been confirmed, yet the joint effect remains unclear. We evaluate the individual and joint associations of particulate (PM2.5 and PM10) and gaseous pollutants (NO2, SO2, O3 and CO) with semen quality. METHODS: We included 5,114 men in this study from 2014 to 2022. The individual and joint associations were measured by multiple linear regression models. RESULTS: Sperm motility and semen volume were inversely associated with pollutant concentrations during every stage of sperm development, especially at lag days 0-9 and 10-14 (all P < 0.05). Stratified analyses showed that the study pollutants (except CO) had a positive effect on semen concentration during the stage of sperm development, especially in spring and autumn, while a decreased total sperm number was associated with CO (all P < 0.05). However, joint associations of particulate and gaseous pollutants with semen quality parameters were not statistically significant (all P > 0.05). CONCLUSIONS: During all stages of sperm development, particulate and gaseous pollutants had individual negative impacts on sperm motility and semen volume, and these impacts were less pronounced in spring and autumn. Our findings highlight the importance and necessity of reducing the exposure to pollutants especially in the critical stage of sperm development to improve semen quality.

Employing zero-inflated beta distribution in an exposure-response analysis of TYK2/JAK1 inhibitor brepocitinib in patients with plaque psoriasis.

Brepocitinib is an oral selective dual TYK2/JAK1 inhibitor and based on its cytokine inhibition profile is expected to provide therapeutic benefit in the treatment of plaque psoriasis. Efficacy data from a completed Phase 2a study in patients with moderate-to-severe plaque psoriasis were utilized to develop a population exposure-response model that can be employed to inform dose selection decisions for further clinical development. A modeling approach that employs the zero-inflated beta distribution was used to account for the bounded nature and distributional characteristics of the Psoriasis Area and Severity Index (PASI) score data. The developed exposure-response model provided an adequate description of the observed PASI scores across all the treatment arms tested and across both the induction and maintenance dosing periods of the study. In addition, the developed model exhibited a good predictive capacity with regard to the derived responder metrics (e.g., 75%/90%/100% improvement in PASI score [PASI75/90/100]). Clinical trial simulations indicated that the induction/maintenance dosing paradigm explored in this study does not offer any advantages from an efficacy perspective and that doses of 10, 30, and 60 mg once-daily may be suitable candidates for clinical evaluation in subsequent Phase 2b studies.

Longitudinal modeling of efficacy response in patients with lupus nephritis receiving belimumab.

Belimumab was approved for active lupus nephritis (LN) in adults in the European Union and patients ≥ 5 years of age in the USA based on a Phase 3, double-blind, placebo-controlled, 104-week study. The study evaluated the efficacy of belimumab plus background standard therapy in adults with active LN using an intravenous (IV) dose of 10 mg/kg. A longitudinal analysis of Primary Efficacy Renal Response (PERR) and Complete Renal Response (CRR) was performed to assess whether patients with high proteinuria at the start of belimumab treatment would benefit from a higher dose. Responder probability was modeled as a logistic regression with probability a function of time and treatment (belimumab or placebo). Dropout risk at each visit was incorporated into a joint model of efficacy response; only efficacy data prior to dropout events (belimumab discontinuation, treatment failure, or withdrawal) were included. Average belimumab concentration over the first 4 and 12 weeks and baseline proteinuria were considered as continuous covariates. In general, renal response (PERR and CRR) over time was higher in patients receiving belimumab than in those receiving placebo. Baseline proteinuria was considered the most relevant predictor of renal response, with reduced efficacy in patients with increased proteinuria for both belimumab or placebo treatment. For belimumab-treated patients, belimumab exposure was not found to be an important predictor of renal response. In conclusion, the 10 mg/kg IV dose was considered appropriate in all patients and there was no evidence to suggest a higher response would be achieved by increasing the dose.

Air pollution and the risk of incident chronic kidney disease in patients with diabetes: An exposure-response analysis.

Impact of air pollution on incident chronic kidney disease (CKD) in diabetic patients is insufficiently studied. We aimed to examine exposure-response associations of PM2.5, PM10, PM2.5-10, NO2, and NOX with incident CKD in diabetic patients in the UK. We also widened exposure level of PM2.5 and examined PM2.5-CKD association in diabetic patients across the entire range of global concentration. Based on data from UK biobank cohort, we applied Cox proportional hazards models and the shape constrained health impact function to investigate the associations between air pollutants and incident CKD in diabetic patients. Global exposure mortality model was applied to combine the PM2.5-CKD association in diabetic patients in the UK with all other published associations. Multiple air pollutants were positively associated with incident CKD in diabetic patients in the UK, with hazard ratios (HRs) of 1.034 (95 %CI: 1.015-1.053) and 1.021 (95 %CI: 1.007-1.036) for every 1 µg/m3 increase in PM2.5 and PM10 concentration, and 1.113 (95 %CI: 1.053-1.177) and 1.058 (95 %CI: 1.027-1.091) for every 10 µg/m3 increase in NO2 and NOX concentration, respectively. For PM2.5-10, associations with CKD in diabetic patients did not reach the statistical significance. Exposure-response associations with CKD in diabetic patients showed a near-linear trend for PM2.5, PM10, NO2, and NOX in the UK, whereas PM2.5-DKD associations in the globe exhibited a non-linear increasing trend. This study supports that air pollution could significantly increase the risk of CKD onset in diabetic patients.

Ligelizumab in adolescents with chronic spontaneous urticaria: Results of a dedicated phase 2b randomized clinical trial supported with pharmacometric analysis.

BACKGROUND: Chronic spontaneous urticaria (CSU), a long-lasting disease in children, impacts their quality of life. We report the results of a phase 2b dose-finding trial of ligelizumab (NCT03437278) and a high-affinity humanized monoclonal anti-IgE antibody, in adolescents with CSU, supported by modeling and simulation analyses, mitigating challenges in pediatric drug development. METHODS: This multicenter, double-blind, placebo-controlled trial, randomized H1-antihistamine-refractory adolescent CSU patients (12-18 years) 2:1:1 to ligelizumab 24 mg, 120 mg, or placebo every 4 weeks for 24 weeks. Patients on placebo transitioned to ligelizumab 120 mg at week 12. Integrating data from the previous adult and present adolescent trial of ligelizumab, a nonlinear mixed-effects modeling described the longitudinal changes in ligelizumab pharmacokinetics, and its effect on weekly Urticaria Activity Score (UAS7). RESULTS: Baseline UAS7 (mean ± SD) was 30.5 ± 7.3 (n = 24), 29.3 ± 7.7 (n = 13), and 32.5 ± 9.0 (n = 12) for patients (median age, 15 years) on ligelizumab 24 mg, 120 mg, and placebo, respectively. Change from baseline in UAS7 at week 12 with ligelizumab 24 mg, 120 mg, and placebo was -15.7 ± 10.9, -18.4 ± 12.3, and -13.0 ± 13.0, respectively. Ligelizumab was well-tolerated. The modeling analysis showed that body weight, but not age, affected ligelizumab's apparent clearance. No significant differences between adolescents and adults were detected on the model-estimated maximum effect and potency. CONCLUSIONS: Ligelizumab exhibited efficacy and safety in adolescent CSU patients, consistent with that in adults. The PK and potency of ligelizumab were not impacted by age, and the same dose of ligelizumab can be used for treating adolescents and adults with CSU. Our study shows how modeling and simulation can complement pediatric drug development.

Detecting the spatial clustering of exposure-response relationships with estimation error: a novel spatial scan statistic.

Detecting the spatial clustering of the exposure-response relationship (ERR) between environmental risk factors and health-related outcomes plays important roles in disease control and prevention, such as identifying highly sensitive regions, exploring the causes of heterogeneous ERRs, and designing region-specific health intervention measures. However, few studies have focused on this issue. A possible reason is that the commonly used cluster-detecting tool, spatial scan statistics, cannot be used for multivariate spatial datasets with estimation error, such as the ERR, which is often defined by a vector with its covariance estimated by a regression model. Such spatial datasets have been produced in abundance in the last decade, which suggests the importance of developing a novel cluster-detecting tool applicable for multivariate datasets with estimation error. In this work, by extending the classic scan statistic, we developed a novel spatial scan statistic called the estimation-error-based scan statistic (EESS), which is applicable for both univariate and multivariate datasets with estimation error. Then, a two-stage analytic process was proposed to detect the spatial clustering of ERRs in practical studies. A published motivating example and a simulation study were used to validate the performance of EESS. The results show that the clusters detected by EESS can efficiently reflect the clustering heterogeneity and yield more accurate ERR estimates by adjusting for such heterogeneity.

Randomized, open-label, phase 2a study to evaluate the contribution of artefenomel to the clinical and parasiticidal activity of artefenomel plus ferroquine in African patients with uncomplicated Plasmodium falciparum malaria.

BACKGROUND: The contribution of artefenomel to the clinical and parasiticidal activity of ferroquine and artefenomel in combination in uncomplicated Plasmodium falciparum malaria was investigated. METHODS: This Phase 2a, randomized, open-label, parallel-group study was conducted from 11th September 2018 to 6th November 2019 across seven centres in Benin, Burkina Faso, Gabon, Kenya, and Uganda. Patients aged ≥ 14-69 years with microscopically confirmed infection (≥ 3000 to ≤ 50,000 parasites/µL blood) were randomized 1:1:1:1 to 400 mg ferroquine, or 400 mg ferroquine plus artefenomel 300, 600, or 1000 mg, administered as a single oral dose. The primary efficacy analysis was a logistic regression evaluating the contribution of artefenomel exposure to Day 28 PCR-adjusted adequate clinical and parasitological response (ACPR). Safety was also evaluated. RESULTS: The randomized population included 140 patients. For the primary analysis in the pharmacokinetic/pharmacodynamic efficacy population (N = 121), the contribution of artefenomel AUC0-∞ to Day 28 PCR-adjusted ACPR was not demonstrated when accounting for ferroquine AUC0-d28, baseline parasitaemia, and other model covariates: odds ratio 1.1 (95% CI 0.98, 1.2; P = 0.245). In the per-protocol population, Day 28 PCR-adjusted ACPR was 80.8% (21/26; 95% CI 60.6, 93.4) with ferroquine alone and 90.3% (28/31; 95% CI 74.2, 98.0), 90.9% (30/33; 95% CI 75.7, 98.1) and 87.1% (27/31; 95% CI 70.2, 96.4) with 300, 600, and 1000 mg artefenomel, respectively. Median time to parasite clearance (Kaplan-Meier) was 56.1 h with ferroquine, more rapid with artefenomel, but similar for all doses (30.0 h). There were no deaths. Adverse events (AEs) of any cause occurred in 51.4% (18/35) of patients with ferroquine 400 mg alone, and 58.3% (21/36), 66.7% (24/36), and 72.7% (24/33) with 300, 600, and 1000 mg artefenomel, respectively. All AEs were of mild-to-moderate severity, and consistent with the known profiles of the compounds. Vomiting was the most reported AE. There were no cases of QTcF prolongation ≥ 500 ms or > 60 ms from baseline. CONCLUSION: The contribution of artefenomel exposure to the clinical and parasitological activity of ferroquine/artefenomel could not be demonstrated in this study. Parasite clearance was faster with ferroquine/artefenomel versus ferroquine alone. All treatments were well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03660839 (7 September, 2018).

A population pharmacokinetic-pharmacodynamic model evaluating efficacy of nalbuphine extended-release in patients with prurigo nodularis.

AIMS: Population pharmacokinetic (PK) and pharmacokinetic-pharmacodynamic (PK-PD) models were used to describe the exposure-response (E-R) relationship between nalbuphine exposure and two widely used rating scales for itch: the Numerical Rating Scale for the subject's 'average'; itch experience (NRS-AV) and the Worst Itch (WI-NRS), with 24-h recall. Simulations based on the model E-R relationship were used to support dose selection for Phase 3 clinical trials and were evaluated with a target of reducing the 7-day average of the 24-h WI-NRS by at least 30% from baseline in most of the analysis population. METHODS: Data from two clinical trials (NCT02373215: 9 healthy subjects; NCT02174419: 62 subjects with PN), in patients with prurigo nodularis (PN) with moderate to severe itch who received treatment with either of two doses of nalbuphine extended release (ER) or placebo, were used for the analysis. A two-compartment PK model with serial zero and first-order oral absorption was used to describe drug exposure. A maximum effect ( E max ) model with a placebo effect was used to model the itch response endpoints (NRS-AV, WI-NRS). RESULTS: The PK-PD model predicted the exposure-related reduction in both NRS-AV and WI-NRS over time with approximately 63% and 27% of E max , respectively. Exposures associated with 80% of E max were achieved in about 78% of the patients at 162 mg, twice daily (BID), compared to 35% at 81 mg BID. CONCLUSION: Simulated dose response indicated that 108 and 162 mg BID doses result in the highest proportion of patients achieving at least a 30% reduction in NRS-AV and WI-NRS, respectively.

Population pharmacokinetic and exposure-response modelling to inform upadacitinib dose selection in adolescent and adult patients with atopic dermatitis.

AIMS: First, population pharmacokinetic analyses were used to characterize upadacitinib pharmacokinetics in adolescent and adult participants with atopic dermatitis (AD) and to identify patient covariates that may impact upadacitinib pharmacokinetics. Second, the exposure-response relationship for upadacitinib with efficacy and safety endpoints, and the effect of age and concomitant use of topical corticosteroids (TCS) on the exposure-response relationship and dose selection for patients with AD were evaluated. METHODS: A two-compartment model with combined first- and zero-order absorption adequately characterized the upadacitinib concentration-time profiles in 911 healthy volunteer adolescent and adult participants with AD who received upadacitinib 15 or 30 mg orally once daily (QD) as monotherapy or in combination with TCS for 16 weeks. Logistic regression models were developed to characterize the exposure-efficacy and safety relationships, and simulations were performed based on final exposure-response models to predict efficacy responses in participants with AD who received placebo or upadacitinib as monotherapy or in combination with TCS. RESULTS: Upadacitinib exposures were comparable between adolescents and adults. Mild or moderate renal impairment was predicted to increase the upadacitinib area under the plasma concentration-time curve from time zero to 24 h after dosing (AUC24 ) approximately 12% and 25%, respectively, compared to participants with normal renal function. Female participants were predicted to have 20% higher AUC24 compared to male participants. Participants with AD were predicted to have 18% higher AUC24 compared to healthy participants. Simulated clinical efficacy responses showed added clinical efficacy benefit for all endpoints evaluated (8-14%) with the upadacitinib 30 mg once-daily regimen compared to 15 mg once-daily in both age groups. In participants receiving upadacitinib in combination with TCS, significant exposure-dependent increases in upadacitinib efficacy endpoints were observed. No significant effects of age or weight were identified in any of the exposure-response models. CONCLUSION: The results of these analyses support the dose justification for upadacitinib in adult and adolescent patients with moderate to severe AD.

Population pharmacokinetics and exposure-response analyses of daratumumab plus pomalidomide/dexamethasone in relapsed or refractory multiple myeloma.

AIM: A population pharmacokinetic (PPK) model was developed to characterize pharmacokinetics (PK) of subcutaneous or intravenous daratumumab administration in a new indication (i.e., combination with pomalidomide and dexamethasone [D-Pd] in patients with relapsed or refractory multiple myeloma [RRMM]). Analyses were conducted to explore exposure-response (E-R) relationships for efficacy and select treatment-emergent adverse events (TEAEs). METHODS: The PPK analysis included pooled data from the D-Pd cohorts of the phase 3 APOLLO and phase 1b EQUULEUS studies. Covariates were evaluated in the PPK model. Model-predicted exposures to daratumumab were compared between covariate subgroups of interest and used to investigate relationships between daratumumab exposure and efficacy and safety in APOLLO. RESULTS: The PPK analysis included 1146 daratumumab PK samples from 239 patients (APOLLO, n = 140; EQUULEUS, n = 99). Observed concentration-time data of daratumumab were well described by a two-compartment PPK model with first-order absorption and parallel linear and nonlinear elimination pathways. Treatment with D-Pd provided similar daratumumab PK characteristics versus historical daratumumab monotherapy. The E-R dataset contained data from 290 APOLLO patients (D-Pd, n = 140; Pd, n = 150). The PK-efficacy relationship of daratumumab supported improved progression-free survival for patients in the D-Pd group vs. the Pd group. Additionally, TEAEs did not increase with increasing PK exposure in the D-Pd group. CONCLUSIONS: The PPK and E-R analyses support the daratumumab subcutaneous 1800 mg dosing regimen in combination with Pd for treatment of patients with RRMM. No dose adjustment is recommended in this indication for any of the investigated factors, none of which had clinically relevant effects on daratumumab PK.

Population pharmacokinetics and exposure-response of trilaciclib in extensive-stage small cell lung cancer and triple-negative breast cancer.

AIMS: Trilaciclib is a first-in-class, intravenous cyclin-dependent kinase 4/6 inhibitor that provides multilineage protection from chemotherapy-induced myelosuppression. This analysis aimed to characterize the population pharmacokinetics (PK) of trilaciclib, identify potential covariates influencing trilaciclib PK, and evaluate exposure-response relationships in extensive-stage small cell lung cancer (ES-SCLC) and triple-negative breast cancer (TNBC) trials. METHODS: Population PK analysis was performed using data from healthy volunteers (n = 72), patients with ES-SCLC (n = 111) and patients with TNBC (n = 14). Exposure-response analyses were conducted to investigate the impact of trilaciclib exposure (AUC) on myeloprotective efficacy, antitumour efficacy and safety. Logistic regression and Cox regression models were used for binary and time-to-event endpoints, respectively. RESULTS: Trilaciclib PK was described by a three-compartment model. Sex, body surface area, baseline albumin concentration and age were identified as significant covariates on trilaciclib PK but did not have clinically relevant impact on exposure. Based on exposure-response analyses, lower and higher exposures of trilaciclib at clinical doses (200-280 mg/m2 ) were associated with similar myeloprotective effects. Trilaciclib exposure did not impact the antitumour effects of chemotherapy. Higher exposure to trilaciclib was associated with higher probabilities of headache, phlebitis/thrombophlebitis and injection site reactions. CONCLUSION: No dose adjustments are required based on the covariates tested. Trilaciclib resulted in optimal myeloprotective effects with no impact on antitumour effects of chemotherapy. However, higher exposure increased the probabilities of adverse events. The data further support selection of the recommended phase 2 dose (trilaciclib 240 mg/m2 ).