Target engagement and cellular fate of otelixizumab: a repeat dose escalation study of an anti-CD3ε mAb in new-onset type 1 diabetes mellitus patients.

AIMS: This paper describes the pharmacological findings from a study where otelixizumab, an anti-CD3ɛ mAb, was dosed in new onset Type 1 diabetes mellitus (NOT1DM) patients. This is the first time that the full dose-response of an anti-CD3ɛ mAb has been investigated in the clinic. The data have been validated using a previously developed pharmacokinetic/pharmacodynamic (PK/PD) model of otelixizumab to simulate the interplay between drug administration, CD3ɛ target engagement and downmodulation. METHODS: Patients were randomized to control or active treatment with otelixizumab (1:4), administered via infusion over 6 days, in a dose-ascending study consisted of three cohorts (n = 10 per cohort) at doses of 9, 18 or 27 mg respectively. The study allowed quantification of otelixizumab PK, CD3ɛ target engagement and its pharmacodynamic effect (CD3ε/TCR modulation on circulating T lymphocytes). RESULTS: Otelixizumab concentrations increased and averaged to 364.09 (54.3), 1625.55 (72.5) and 2781.35 (28.0) ng ml-1 (Geom.mean, %CV) at the 9, 18 and 27 mg dose respectively. CD3ɛ target engagement was found to be rapid (within the first 30 min), leading to a receptor occupancy of ~60% within 6 h of dosing in all three doses. A dose-response relationship was observed with the two highest doses achieving a ~90% target engagement and consequential CD3ɛ/TCR downmodulation by Day 6. CONCLUSIONS: Data from this study revealed maximum target engagement and CD3ɛ/TCR modulation is achieved at doses of 18, 27 mg of otelixizumab. These findings can be useful in guiding dose selection in clinical trials with anti-CD3ɛ mAbs.

Erdafitinib's effect on serum phosphate justifies its pharmacodynamically guided dosing in patients with cancer.

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 [<5.5 mg/dl] and tolerability at 14-21 days of treatment). The serum phosphate concentrations increased after the first dose and reached near maximal level after 14 days of continuous treatment. Serum phosphate increased with erdafitinib free drug concentrations: doubling the free concentration resulted in a 1.8-fold increase in drug-related phosphate changes. Dose adjustment after at least 14 days of dosing was supported by achievement of >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.

Effect of Ponesimod Exposure on Total Lymphocyte Dynamics in Patients with Multiple Sclerosis.

OBJECTIVE: The aim of this study was to characterize the relationship between ponesimod plasma concentrations and the temporal evolution of lymphocyte counts in multiple sclerosis (MS) patients. METHODS: Population pharmacokinetic (PK) and PK/pharmacodynamic (PD) models were developed using data from phase I, II, and III trials, and the impact of clinically relevant covariates on PK and PD parameters was assessed. Simulations were conducted to evaluate the maximal lymphocyte count reduction after ponesimod treatment, and the time required for total lymphocyte counts to return to normal values after treatment interruption. RESULTS: In MS patients, ponesimod PK were characterized by a low mean apparent plasma clearance (5.52 L/h) and a moderate mean apparent volume of distribution at steady state (239 L). The model developed indicated that none of the evaluated covariates (age, sex, formulation, food, body weight, clinical condition, and renal impairment) had a clinically relevant impact on the PK/PD parameters. In MS patients, total lymphocyte counts were characterized by a maximum reduction of 88.0% and a half maximal inhibitory concentration (IC50) of 54.9 ng/mL. Simulations indicated that in patients with normal hepatic function treated with ponesimod 20 mg daily, total lymphocyte counts were reduced to 41% of baseline at trough. After stopping treatment, lymphocyte counts were restored to normal levels within one week. CONCLUSIONS: The population PK/PD model well-characterized the PK of ponesimod and the time course of total lymphocyte counts in MS patients. Additionally, none of the evaluated covariates had a clinically relevant impact. This should be taken into consideration when assessing the risk of infection, administration of live-attenuated vaccines, and concomitant use of immunosuppressants.