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Abstract Mechanistic model‐based simulations can be deployed to project the persistence of humoral immune response following vaccination. We used this approach to project the antibody persistence through 24 months from the data pooled across five clinical trials in severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2)‐seronegative participants following vaccination with Ad26.COV2.S (5 × 1010 viral particles), given either as a single‐dose or a homologous booster regimen at an interval of 2, 3, or 6 months. Antibody persistence was quantified as the percentage of participants with detectable anti‐spike binding and wild‐type virus neutralizing antibodies. The projected overall 24‐month persistence after single‐dose Ad26.COV2.S was 70.5% for binding antibodies and 55.2% for neutralizing antibodies, and increased after any homologous booster regimen to greater than or equal to 89.9% for binding and greater than or equal to 80.0% for neutralizing antibodies. The estimated model parameters quantifying the rates of antibody production attributed to short‐lived and long‐lived plasma cells decreased with increasing age, whereas the rate of antibody production mediated by long‐lived plasma cells was higher in women relative to men. Accordingly, a more pronounced waning of antibody responses was predicted in men aged greater than or equal to 60 years and was markedly attenuated following any homologous boosting regimen. The findings suggest that homologous boosting might be a viable strategy for maintaining protective effects of Ad26.COV2.S for up to 24 months following prime vaccination. The estimation of mechanistic modeling parameters identified the long‐lived plasma cell pathway as a key contributor mediating antibody persistence following single‐dose and homologous booster vaccination with Ad26.COV2.S in different subgroups of recipients stratified by age and sex.

Abstract A population pharmacokinetic (PK)–pharmacodynamic (PD) model was developed using data from 345 patients with cancer. The population PK‐PD model evaluated the effect of erdafitinib total and free plasma concentrations on serum phosphate concentrations after once‐daily oral continuous (0.5–12 mg) and intermittent (10–12 mg for 7 days on/7 days off) dosing, and investigated the potential covariates affecting erdafitinib‐related changes in serum phosphate levels. Phosphate is used as a biomarker for erdafitinib's efficacy and safety: increases in serum phosphate were observed after dosing with erdafitinib, which were associated with fibroblast growth factor receptor target engagement via inhibition of renal fibroblast growth factor 23–mediated signaling. PK‐PD model‐based simulations were performed to assess the approved PD‐guided dosing algorithm of erdafitinib (8 mg once‐daily continuous dosing, with up‐titration to 9 mg based on phosphate levels [95% maximal serum phosphate concentration. The peak‐to‐trough fluctuation within a dosing interval was limited for serum phosphate concentrations (5.68–5.65 mg/dl on Day 14), supporting phosphate monitoring at any time relative to dosing. Baseline phosphate was higher in women, otherwise, none of the investigated covariate–parameter relationships were considered clinically relevant. Simulations suggest that the starting dose of 8‐mg with up‐titration to 9‐mg on Days 14–21 maximized the number of patients within the target serum phosphate concentrations (5.5–7 mg/dl) while limiting the number of treatment interruptions. The findings from the PK‐PD model provided a detailed understanding of the erdafitinib concentration‐related phosphate changes over time, which supports erdafitinib's dosing algorithm.

Abstract The COVID‐19 pandemic has forced clinical studies to accommodate imposed limitations. In this study, the bioequivalence part could not be conducted as planned. Thus, the aim was to demonstrate bioequivalence, using an adaptive study design, of tadalafil in fixed‐dose combination (FDC) tablets of macitentan/tadalafil with single macitentan and tadalafil (Canadian‐sourced) tablets and assess the effect of food on FDC tablets in healthy subjects. This Phase 1, single‐center, open‐label, single‐dose, two‐part, two‐period, randomized, crossover study enrolled 62 subjects. Tadalafil bioequivalence as part of FDC of macitentan/tadalafil (10/40 mg) with single‐component tablets of macitentan (10 mg) and tadalafil (40 mg) was determined by pharmacokinetic (PK) assessment under fasted conditions. The effect of food on FDC was evaluated under fed and fasted conditions. Fasted 90% confidence intervals (CIs) for geometric mean ratios (GMRs) were within bioequivalence limits for tadalafil and macitentan. Fed and fasted 90% CIs for area under the curve (AUC) GMR were within bioequivalence limits. However, 90% CIs for maximum plasma concentration (Cmax) GMR for macitentan and tadalafil were outside bioequivalence limits. One FDC‐treated subject experienced a serious adverse event of transient ischemic attack (bioequivalence part). To address pandemic‐imposed limitations, an adaptive study design was implemented to demonstrate that the FDC tablet was bioequivalent to the free combination of macitentan and tadalafil (Canadian‐sourced). No clinically significant differences in PK were determined between fed and fasted conditions; the FDC formulation could be taken irrespective of meals. The FDC formulation under fasted and fed conditions was well tolerated with no clinically relevant differences in safety profiles between the treatment groups. NCT Number: NCT04235270.