Key Points• Rituximab exposure decreased as metabolic tumor volume increased, and correlated with metabolic response and survival.• Rituximab dose could be individualized according to metabolic tumor volume to achieve optimal exposure and therefore optimal response.High variability in patient outcome after rituximab-based treatment is partly explained by rituximab concentrations, and pharmacokinetic (PK) variability could be influenced by tumor burden. We aimed at quantifying the influence of baseline total metabolic tumor volume (TMTV 0 ) on rituximab PK and of TMTV 0 and rituximab exposure on outcome in patients with diffuse large B-cell lymphoma (DLBCL). TMTV 0 was measured by 18 F-fluorodeoxyglucosepositron emission tomography-computed tomography in 108 previously untreated DLBCL patients who received four 375 mg/m 2 rituximab infusions every 2 weeks in combination with chemotherapy in 2 prospective trials. A 2-compartment population model allowed describing rituximab PK and calculating rituximab exposure (area under the concentration-time curve; AUC). The association of TMTV 0 and AUC with metabolic response after 4 cycles, as well as progression-free survival (PFS) and overall survival (OS), was assessed using logistic regression and Cox models, respectively. Cutoff values for patient outcome were determined using receiver operating characteristic curve analysis. Exposure to rituximab decreased as TMTV 0 increased (R 2 5 0.41, P < .0001). A high AUC in cycle 1 ( ‡9400 mg 3 h per liter) was associated with better response (odds ratio, 5.56; P 5 .0006) and longer PFS (hazard ratio [HR], 0.38; P 5 .011) and OS (HR, 0.17; P 5 .001).A nomogram for rituximab dose needed to obtain optimal AUC according to TMTV 0 was constructed, and the 375 mg/m 2 classical dose would be suitable for patients with TMTV 0 <281 cm 3 . In summary, rituximab exposure is influenced by TMTV 0 and correlates with response and outcome of DLBCL patients. Dose individualization according to TMTV 0 should be evaluated in prospective studies. These studies were registered at www.clinicaltrials.gov as #NCT00498043 and

NCT01370772.

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