Aims: To investigate pharmacokinetics (PK) and exposure-response of the 400 mg once daily venetoclax dose regimen in combination with obinutuzumab in the phase 3 CLL14 study approved for the treatment of first-line (1L) chronic lymphocytic leukaemia (CLL). Methods: Parameter estimates and uncertainty estimated by a previously developed population PK (popPK) model were used as informative priors for this analysis. They were re-estimated, then used to evaluate additional covariate effects, describe venetoclax PK when administered with obinutuzumab, and provide empirical Bayes estimates of PK parameters and exposure. Exposure-progression-free survival (PFS) and exposure-safety relationships were assessed using CLL14 data, with steady-state exposure at the nominal target dose (C_{meanSS,nominal}) as the predictor variable. Exposure-safety analyses were conducted using logistic regression for selected treatment-emergent grade ≥3 adverse events (AEs) and serious AEs (SAEs). Dose intensities were summarized by tertiles of C_{meanSS,nominal}. Results: PK data from 274 patients (CLL14, n=194; phase 1b dose-finding study GP28331, n=80) were included. The final model provided good fit of observed data. Obinutuzumab co administration, history of prior treatments, and disease severity at baseline had no appreciable influence on venetoclax steady-state exposure. No significant correlations were observed between venetoclax exposure and PFS, or between venetoclax exposure and the probability of treatment-emergent grade ≥3 neutropenia, grade ≥3 thrombocytopenia, grade ≥3 infections and SAEs. Median dose intensities for venetoclax and obinutuzumab remained similar across venetoclax exposure tertiles. Conclusion: PopPK and exposure efficacy, -safety and -tolerability analyses support the 400 mg once-daily venetoclax dose plus obinutuzumab in patients with 1L CLL.