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Aims Examine relationships between the systemic exposure of acalabrutinib, a highly selective, next-generation Bruton tyrosine kinase inhibitor, and its active metabolite (ACP-5862) vs. efficacy and safety responses in patients with B-cell malignancies who received acalabrutinib as monotherapy or in combination with obinutuzumab. Methods For exposure-efficacy analyses, patients with untreated chronic lymphocytic leukaemia were assessed for best overall response, progression-free survival and tumour regression. For exposure-safety analyses, incidences of grade ≥2 adverse events (AEs), grade ≥3 AEs and grade ≥2 events of clinical interest were assessed in patients with B-cell malignancies. Acalabrutinib and ACP-5862 pharmacokinetic (PK) parameter estimates were obtained from population PK modelling. Exposure calculations were based on study dosing regimens. Total active moieties were calculated to account for contributions of ACP-5862 to overall efficacy/safety. Results A total of 573 patients were included (exposure-efficacy analyses, n = 274; exposure-safety analyses, n = 573). Most patients (93%) received acalabrutinib 100 mg twice daily. Median total active area under the concentration-time curve (AUC24h,ss ) and total active maximal concentration at steady-state (Cmax,ss ) were similar for patients who received acalabrutinib as monotherapy or in combination with obinutuzumab, and for responders and nonresponders. No relationship was observed between AUC24h,ss /Cmax,ss and progression-free survival or tumour regression. Acalabrutinib AUC24h,ss and Cmax,ss were generally comparable across groups regardless of AE incidence. Conclusion No clinically meaningful correlations between acalabrutinib PK exposure and efficacy and safety outcomes were observed. These data support the fixed acalabrutinib dose of 100 mg twice daily in the treatment of patients with B-cell malignancies.

This paper shares experiences and learning from introducing patient-centric sampling (PCS) into AstraZeneca trials. Through two case studies we show how modeling approaches can assist pharmacokinetic (PK) bridging studies accounting for blood partitioning and hematocrit and how reduced PK sampling schedules, profiles constructed from composite data (plasma & dry blood) and combined assays (PK & pharmacodynamic) can all reduce patient sampling burden without impacting study outcomes. Following sharing some clinical operational challenges, we finally highlight some key requirements for implementing a patient-centric sampling strategy such as collaborative working across organizational silos, continuous patient engagement throughout the study life cycle and accepting that if the aim is to give patient choice, then one solution (device, procedure and design) will not fit all.

BACKGROUND: The relationship between concentrations of antituberculosis drugs, sputum culture conversion, and treatment outcome remains unclear. We sought to determine the association between antituberculosis drug concentrations and sputum conversion among patients coinfected with tuberculosis and human immunodeficiency virus (HIV) and receiving first-line antituberculosis drugs. METHODS: We enrolled HIV-infected Ugandans with pulmonary tuberculosis. Estimation of first-line antituberculosis drug concentrations was performed 1, 2, and 4 hours after drug intake at 2, 8, and 24 weeks of tuberculosis treatment. Serial sputum cultures were performed at each visit. Time-to-event analysis was used to determine factors associated with sputum culture conversion. RESULTS: We enrolled 268 HIV-infected patients. Patients with low isoniazid and rifampicin concentrations were less likely to have sputum culture conversion before the end of tuberculosis treatment (hazard ratio, 0.54; 95% confidence interval, .37–.77; P = .001) or by the end of follow-up (0.61; .44–.85; P = .003). Patients in the highest quartile for area under the rifampicin and isoniazid concentration-time curves for were twice as likely to experience sputum conversion than those in the lowest quartile. Rifampicin and isoniazid concentrations below the thresholds and weight

Background: Acalabrutinib is a selective BTK inhibitor approved for the treatment of Mantle Cell Lymphoma. Relationship between plasma exposures to acalabrutinib and ACP-5862 versus clinical efficacy and safety were evaluated in subjects with B-cell malignancies, following administration of acalabrutinib monotherapy or in combination with obinutuzumab. Methods: Acalabrutinib and ACP-5862 exposures (AUC24h,ss) were generated using population pharmacokinetic (PK) analysis. To account for the contribution of ACP-5862 to overall activity, an exposure metric (total active AUC24h,ss) accounting for relative BTK potency and protein binding was estimated. Efficacy data from the pivotal Phase 3 study in previously untreated (PU) CLL subjects (n=274), who received acalabrutinib 100 mg twice daily (BID) as monotherapy or in combination, were included. Safety data pooled across 8 studies in PU or relapsed/refractory (R/R) subjects with B-cell malignancies (n=567), who received acalabrutinib 100, 175, 200, and 250 once daily or 100 mg and 200 mg BID as monotherapy or in combination, were included. Efficacy endpoints including best overall response rate (BOR), progression -free survival (PFS) and sum of products of the greatest perpendicular diameters (SPD) of index lesions were evaluated. Safety endpoints including all AEs Grade ≥2 in severity, and Grade ≥2 events of clinical interest such as, anemia, cardiac events, diarrhea, headache, hemorrhage, hepatic events, hypertension, infections, neutropenia, and thrombocytopenia were evaluated. Kaplan-Meier survival and logistic regression analyses were conducted for key efficacy and safety endpoints. Results: Median acalabrutinib/ACP-5862/total active AUC24h,ss were similar between responders versus non-responders, and across the 4 response categories (i.e. complete response, partial response, stable disease or progressive disease). No correlation between AUC24h,ss and PFS or SPD were noted. With the exception of Grade ≥2 anemia, no significant relationship between AUC24h,ss and safety outcomes was observed. Model-based analyses revealed baseline hemoglobin levels and line of therapy as highly significant predictors of Grade ≥2 anemia (p Conclusions: No clinically meaningful correlation between PK exposures and selected efficacy and safety outcomes was observed. In pivotal studies, the 100 mg BID acalabrutinib regimen demonstrated an acceptable safety profile and robust efficacy (consistent with ≥95% BTK occupancy over a dosing interval) in PU and R/R CLL. Overall, these data support a fixed 100 mg BID acalabrutinib dose for the treatment of subjects with CLL. Citation Format: Helena Edlund, Karthick Vishwanathan, Ming Yin, Rakesh Raman, Miné de Kock, Zhongqing He, Huan Liu, Marshall Baek, Nidal Al-Huniti, Joseph Ware, Shringi Sharma. Exposure versus efficacy/safety of acalabrutinib and its pharmacologically active metabolite, ACP-5862, for the treatment of chronic lymphocytic leukemia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3023.

We thank Dr Salman and Professor Davis1 for their comments on our publication on the pharmacokinetics of sulfadoxinepyrimethamine in African women during pregnancy and postpartum. 2 We reported that, compared to during pregnancy, pyrimethamine clearance was 18% higher postpartum, with large variability in the data across the four study sites, which sampled the patients at different times postpartum. In the Letter to the Editor by Salman and Davis,1 they suggest that lactation status could explain the increased clearance postpartum and our result would, therefore, not contradict findings in other studies using nonpregnant women as a control group.