Background and Purpose: No drugs targeting the core social features of autism spectrum disorder (ASD) have been approved. Although clinical trials with oxytocin (OT) and vasopressin (AVP) have yielded mixed results, targeting their receptors remains the most promising pharmacological strategy for addressing social impairments in ASD. This study aims to identify which receptors and signalling pathways within this family can sustainably improve social impairments. Experimental Approach: We used dose-response and kinetic analyses, along with mathematical modelling, to evaluate OT, AVP, their homologs, and novel synthetic ligands on G protein coupling, β-arrestins recruitment, and internalisation of mouse oxytocin (OTR) and vasopressin (V1A, V1B, V2) receptors in Neuro-2a cells. We tested acute and subchronic administration of OTR agonists and the novel V1A receptor antagonist, alongside OT and AVP, for their effects on social interaction in Fmr1 KO mice, a model exhibiting ASD-like features. Key Results: While OT, AVP and most compounds were non-selective across the four receptors, the OTR agonists TGOT or RO6958375 and the V1A antagonist RO6893074 were selective. TGOT or RO6958375, favouring Gαq signalling, enhanced social interactions in Fmr1 KO mice while showing minimal effects in wild-type mice. In contrast, OT, AVP or RO6893074 exhibited limited efficacy in Fmr1 KO mice. Conclusion and Implications: Selective OTR agonists, unlike OT and AVP, effectively improved social impairments in Fmr1 KO mice after acute and subchronic treatment. These findings highlight the necessity for developing highly selective OTR Gαq-biased agonists to achieve clinical outcomes in ASD.

Aims. The exposure-response relationship of bevacizumab may be confounded by various factors, i.e. baseline characteristics, time-dependent target engagement and recursive relationships between exposure and response. This work aimed at investigating the exposure-response relationships of bevacizumab in mCRC patients while mitigating potential sources of bias. Methods. Bevacizumab pharmacokinetics was described using target-mediated drug disposition (TMDD) modeling. The relationships between target kinetics, and progression-free (PFS) and overall (OS) survivals were assessed using joint pharmacokinetic and parametric hazard function models. Both potential biases due to prognostic-driven and response-driven of the concentration-effect relationship were mitigated. These models were used to evaluate the effect of increased antigen target levels and clearance, as well as intensified dosing regimen, on survival. Results. Estimated target-mediated pharmacokinetic parameters in 130 assessed patients were: baseline target levels (R0=8.4 nM), steady-state dissociation constant (KSS=10 nM) and antibody-target complexes elimination constant (kint=0.52 day-1). Distribution of R0 was significantly associated with an increased baseline CEA and circulating VEGF levels, and the presence of extra-hepatic metastases. Unbound target levels (R) significantly influenced both progression and death hazard functions. Increased R0 or CL values led to decreased bevacizumab unbound concentrations, increased R levels, and shortened PFS and OS, whereas increasing bevacizumab dose led to decreased R and longer survival. Conclusion. This study is the first to show the relationship between bevacizumab concentrations, target involvement and clinical efficacy by mitigating potential sources of bias. Most of target amount may be tumoral in mCRC. A more in-depth description of this relationship should be made in future studies.