Safety, Tolerability, and Pharmacokinetics of Zagotenemab in Participants with Symptomatic Alzheimer's Disease: A Phase I Clinical Trial.

Background: Zagotenemab (LY3303560), a monoclonal antibody, preferentially binds to extracellular, misfolded, aggregated tau that has been implicated in Alzheimer's disease (AD). Objective: The goal of this study was to assess the safety and pharmacokinetics of multiple doses of zagotenemab in participants with AD. Methods: This was a Phase Ib, multi-site, participant- and investigator-blind, placebo-controlled, parallel-group study in participants with mild cognitive impairment due to AD or mild to moderate AD. After screening, participants were randomized to zagotenemab 70 mg, 210 mg, or placebo every 4 weeks for up to 49 weeks and were followed up for 16 weeks. Results: A total of 13 males and 9 females, aged 59 to 84 years, were dosed. No deaths occurred during this study. A total of 4 serious adverse events occurred in 2 participants who then discontinued the study. The most commonly reported (3 or more participants) treatment-emergent adverse events were sinus bradycardia, headache, fall, and bronchitis. The pharmacokinetics profile showed generally linear exposures across the dose range studied with a clearance of ~8 mL/h. The half-life of zagotenemab in serum was ~20 days. A dose-dependent increase in plasma tau was observed. No other significant pharmacodynamic differences were observed due to low dose levels and limited treatment duration. Conclusions: No dose-limiting adverse events were observed with zagotenemab treatment. Pharmacokinetics of zagotenemab were typical for a monoclonal antibody. Meaningful pharmacodynamic differences were not observed.Clinicaltrials.gov: NCT03019536.

Pharmacokinetics and Pharmacodynamics of Human Regular U-500 Insulin Administered via Continuous Subcutaneous Insulin Infusion Versus Subcutaneous Injection in Adults With Type 2 Diabetes and High-Dose Insulin Requirements.

INTRODUCTION: Human regular U-500 insulin (U-500R) is approved for subcutaneous (SC) injection in patients with diabetes requiring >200 units/day of insulin. Here, pharmacokinetic and pharmacodynamic (PK/PD) profiles following U-500R administered by continuous subcutaneous insulin infusion (CSII) and SC injection in adults with type 2 diabetes (T2D) on high-dose insulin were studied. METHODS: In this randomized, crossover, euglycemic clamp study, patients received a 100-unit bolus of U-500R via SC injection or CSII with basal infusion using a U-500R specific pump. PK parameters were estimated using non-compartmental methods. PD estimates were derived from the glucose infusion rate during the euglycemic clamp procedure. RESULTS: When corrected for the basal infusion, the PK profiles for the 100-unit bolus of U-500R were similar for CSII and SC injection. Without correction for basal infusion, PK and PD profiles showed a greater insulin concentration and effect when U-500R was administered via CSII compared to SC injection, primarily due to basal insulin infusion for CSII. The ratio of geometric least squares AUC0-tlast means SC:CSII (90% CI) is 0.857 (0.729, 1.01) with correction (mean AUC0-tlast: 5230 pmol*L/h [SC injection] and 6070 pmol*L/h [CSII, with correction]) and 0.424 (0.361, 0.499) without correction (mean AUC0-tlast: 12300 pmol*L/h [CSII, without correction]). Median time-to-peak insulin concentration was six hours (range 0.5-8 hours) via SC injection and five hours (0.5-12 hours) via CSII. CONCLUSIONS: In adults with T2D on high-dose insulin, U-500R PK/PD parameters were similar for a 100-unit bolus when given by SC injection or CSII via a U-500R pump.

Incorporating dried blood spot LC-MS/MS analysis for clinical development of a novel oncolytic agent.

AIM: Design and execution of a dried blood spot (DBS-LC-MS/MS) assay for pharmacokinetic analyses in oncology patients. RESULTS & DISCUSSION: The methodology was validated to collect and store DBS samples from multiple clinical sites, and analyze blood with diverse hematocrit ranges (25-55) to match the potential patient population. Bridging data comparing DBS and plasma showed high degree of concordance with DBS:plasma ratios of 0.81, demonstrating no preferential uptake or association with cellular components of the blood. Pharmacokinetic analysis supporting clinical development was performed using 20 µl of blood collected as DBS. Incurred sample reanalysis showed high correlation. CONCLUSION: Successful validation of a DBS method and implementation in the clinic enabled pharmacokinetic analysis during the clinical development of a novel oncolytic agent in oncology patients.

Population Pharmacokinetic and Exposure-Response Analyses of Prasugrel in Pediatric Patients with Sickle Cell Anemia.

BACKGROUND AND OBJECTIVE: Prasugrel, a P2Y12 adenosine diphosphate (ADP) receptor antagonist, inhibits ADP-mediated platelet activation and aggregation in patients with sickle cell anemia (SCA). We developed a population pharmacokinetic (popPK) model in pediatric patients from 2 to <18 years of age with SCA, and performed exposure-response evaluations to characterize the effects of prasugrel in a subset of these patients who weighed 19 kg or more and experienced at least two episodes of vaso-occlusive crises (VOC) in the past year. METHODS: A three-compartment popPK model adapted from that used in adults with acute coronary syndrome was used to describe the relationship between plasma concentrations of prasugrel's active metabolite (Pras-AM) and time using data from phase II and III clinical studies in children. A VOC event rate model was developed from the phase III study to explore the exposure-response relationship between Pras-AM exposure and VOC, and included evaluation of covariates. RESULTS: The final popPK model for children with SCA provided a reasonable fit to Pras-AM plasma concentrations over time, with estimates of apparent clearance (CL/F) (172 L/h) and apparent volume of distribution (Vd/F) (51.7 L) that were comparable to previous studies in adults. The final model included weight as a covariate on both CL/F and Vd/F, and age as a covariate on CL/F. Analyses of safety (bleeding events requiring medical intervention) and efficacy (VOC event rate) variables showed no apparent relationship to model-predicted Pras-AM exposure quartiles, and no statistically significant effects of intrinsic or extrinsic factors on the VOC event rate were identified in the VOC event rate model. The effect of post hoc exposures on the VOC event rate did not reach statistical significance. CONCLUSIONS: A popPK model was developed that provided reasonable parameter estimates, goodness-of-fit diagnostics, and visual predictive checks when applied to Pras-AM plasma concentrations in pediatric patients with SCA. Post hoc exposures obtained from this model did not correlate with measures of VOC or bleeding events in this population.