Population pharmacokinetics, efficacy, and safety of moxetumomab pasudotox in patients with relapsed or refractory hairy cell leukaemia.

AIMS: To characterize the pharmacokinetics (PK) of moxetumomab pasudotox, an anti-CD22 recombinant immunotoxin, in adults with relapsed or refractory hairy cell leukaemia, we examined data from a phase 1 study (Study 1001; n = 49) and from the pivotal clinical study (Study 1053; n = 74). METHODS: Data from both studies were pooled (n = 123) to develop a population PK model. Covariates included demographics, disease state, liver and kidney function, prior treatment, and antidrug antibodies (ADAs). Exposure-response and exposure-safety were analysed separately by study. A 1-compartment model with linear elimination from the central compartment and 2 clearance (CL) rates was developed. RESULTS: Moxetumomab pasudotox was cleared more rapidly after cycle 1, day 1 (CL1 = 24.7 L/h) than subsequently (CL2 = 3.76 L/h), with high interindividual variability (116 and 109%, respectively). In Study 1053, patients with ADA titres >10 240 showed ~4-fold increase in CL. Higher exposures (≥median) were related to higher response rates, capillary leak syndrome and increased creatinine (Study 1053 only), or grade ≥3 adverse events (Study 1001 only). Clinical benefits were still observed in patients with lower exposure or high ADA titres. CONCLUSION: Despite a high incidence of immunogenicity with increased clearance, moxetumomab pasudotox demonstrated efficacy in hairy cell leukaemia.

Population Pharmacokinetics and Pharmacodynamics of Pegozafermin in Patients with Nonalcoholic Steatohepatitis.

Pegozafermin is a long-acting glycoPEGylated analog of fibroblast growth factor 21 (FGF21) in development for the treatment of nonalcoholic steatohepatitis (NASH) and severe hypertriglyceridemia. In a phase Ib/IIa placebo-controlled, double-blind, multiple ascending dose study in patients with NASH (NCT04048135), administration of pegozafermin resulted in clinically meaningful reductions in hepatic fat fraction (HFF), with a favorable safety and tolerability profile. We aimed to characterize the relationship between pegozafermin dosing, exposure and effects on HFF reduction. We used pharmacokinetic (PK) and pharmacodynamic (PD) modeling of data from the phase Ib/IIa study to identify model parameters and covariates affecting the exposure-response relationship. Clinical simulations were performed to help support dose selection for larger studies. Pegozafermin exposure was adequately described by a one compartment PK model, with one additional transit absorption compartment. PK/PD modeling demonstrated that HFF reduction was significantly related to pegozafermin exposure. HFF outcomes were correlated with average pegozafermin concentrations regardless of weekly dosing (q.w.) or dosing every 2 weeks (q2w). The significant PK/PD model covariates included baseline body weight, alanine aminotransferase level, and liver volume. Simulations showed that the 30 mg q.w. dose approximated the full PD effect; almost all patients would benefit from a greater than or equal to 30% HFF reduction, suggesting fibrosis regression. Furthermore, 44 mg q2w dosing (~22 mg q.w.) appeared to be an effective regimen for HFF reduction. Our modeling supports the feasibility of q.w. and q2w dosing for achieving favorable treatment outcomes in patients with NASH, and provides the rationale for dose selection for the phase IIb ENLIVEN study (NCT04929483).

Elimination mechanisms of therapeutic monoclonal antibodies.

Targeted therapies using monoclonal antibodies have achieved important therapeutic applications in the treatment of various human diseases. Understanding the factors that impact the pharmacokinetics of monoclonal antibodies is of high importance for effective therapy. Many factors related to the target antigen, antibody and patients can affect antibody elimination. Evaluation of these factors will facilitate the understanding of the processes involved in antibody elimination.

Performance of Lymantria xylina (Lepidoptera: Lymantriidae) on artificial and host plant diets.

Lymantria xylina Swinhoe (Lepidoptera: Lymantriidae) is a serious defoliator of hardwood and fruit trees in Taiwan. The larvae of L. xylina feed on >63 species of host plants, belonging to 29 families. Because a large number of larvae are needed for the production of nucleopolyhedrosis virus (NPV) or other related studies, the development of a suitable artificial diet is very important for the mass rearing of this moth in the laboratory. In this study, eight artificial diets, modified from different formulas, and one host plant, Liquidambar formosana Hance, were used to feed L. xylina caterpillars. Through various bioassays (first instar survival trial and long- and short-term feeding trials), the most suitable diet for the L. xylina was selected by performance comparisons with L. formosana. After the first instar survival trial, two of the diets were discarded, because no larva survived on these diets. The results of the long-term feeding trial indicated that the larvae grew successfully on only three kinds of artificial diet. Finally, results of the short-term feeding trial revealed that a diet (diet A), modified from the gypsy moth, Lymantria dispar (L.), formula diet, was the most appropriate for the L. xylina. Larvae fed on diet A had better survival rate, pupal weight, adult size, efficiency of conversion, and relative growth rate than larvae fed on other diets; they did not grow as well as those fed on L. formosana, however, except for pupal and adult weight, and approximate digestibility. In summary, diet A was found to be the best of the artificial diets for the L. xylina and is suitable for mass rearing of this moth in the laboratory.