Positron emission tomography (PET) imaging of programmed cell death-ligand 1 (PD-L1) may help to noninvasively predict and monitor responses to anti-PD-1/anti-PD-L1 immunotherapies. In this study, we compared the imaging characteristics of three radioligands derived from the anti-PD-L1 IgG1 C4. In addition to the IgG C4, we produced a fragment antigen-binding (Fab) C4, and a double mutant IgG C4 (H310A/H435Q) with minimal affinity for the murine neonatal Fc receptor (FcRn). Methods: The pharmacokinetics (PK), biodistribution and dosimetry of the three 89 Zr-labeled C4 ligands were compared by longitudinal PET/CT imaging in nude mice bearing subcutaneous human non-small cell lung cancer (NSCLC) xenografts with positive (H1975 model) or negative (A549 model) endogenous PD-L1 expression. Results: The C4 radioligands substantially accumulated in PD-L1 + tumors, but not in PD-L1tumors or in blocked PD-L1 + tumors, confirming their PD-L1-specific tumor targeting. 89 Zr-Fab C4 and 89 Zr-IgG C4 (H310A/H435Q) were rapidly eliminated compared to 89 Zr-IgG C4. Consequently, maximal tumor-to-muscle ratios (TMRs) were obtained earlier, at 4 h post-injection (p.i.) for 89 Zr-Fab C4 (TMR of ~6) and 24 h p.i. for 89 Zr-IgG C4 (H310A/H435Q) (TMR of ~9), versus 48 h p.i. for 89 Zr-IgG C4 (TMR of ~8). Background activity in non-tumor tissues was low, except for high kidney retention of 89 Zr-Fab C4 and persistent liver accumulation of 89 Zr-IgG C4 (H310A/H435Q) compared to 89 Zr-IgG C4. Dosimetry estimates suggested that the C4 radioligands would yield organ absorbed doses tolerable for repeated clinical PET imaging studies. Conclusion: This study highlights the potential of designing radioligands with shorter PK for PD-L1 immunoPET imaging in a preclinical model, and encourages further clinical translation of such radioligands.

Baclofen has been proposed for few years to help treating alcohol dependence at higher doses than those used in neurology. Baclofen pharmacokinetics has been previously well described at low oral or intravenous doses but remains poorly investigated with such high oral doses. We here describe dose regimens of baclofen in 143 alcohol-dependent patients treated with steady-state oral doses of baclofen. Plasma baclofen levels were measured in blood samples using liquid chromatography coupled with tandem mass spectrometry. One hundred and forty-nine baclofen concentrations were sampled 30 min to 15 h after the last dose, and baclofen pharmacokinetics was determined using population pharmacokinetics approach. Our population, whose average age and BMI were 51.5 years and 25.5 kg/m , respectively, was composed of two-thirds of men. Daily baclofen doses ranged from 15 to 250 mg and 26% were higher than 120 mg. A one-compartment model with first-order absorption and elimination allowed to determine mean values for clearance (CL/F), volume of distribution (V/F) and absorption rate constant at 8.0 L/h, 44.5 L and 2.23 h , respectively. Inter-individual variability on CL/F and V/F was 27.4 and 86% for the parameters. None of the demographic and biological covariates significantly decreased inter-individual variability. A proportional relationship between oral dose and plasma baclofen exposure indicated a linear pharmacokinetics of baclofen even at doses over 120 mg/day. Our large population study evidenced a linear pharmacokinetics of oral baclofen even at high daily doses with an inter-individual variability of baclofen exposure that could not be explained by demographic and biological data.