Background and Objective As pazopanib plasma trough concentrations are correlated with treatment outcome, we explored whether single nucleotide polymorphisms in the elimination pathway of pazopanib affect systemic pazopanib concentrations. Methods The decreased function alleles CYP3A4 15389 C  >  T (*22) , ABCB1 3435 C  > T , ABCG2 421 C  > A , and ABCG2 34G  > A were analyzed within a recently developed population-pharmacokinetic model. Results Incorporation of CYP3A4*22 in the model resulted in a 35% lower clearance for variant carriers (0.18 vs. 0.27 L/h; difference in objective function value: − 9.7; p  < 0.005). Simulated median trough concentrations of cancer patients with CYP3A4*22 with 600 mg once daily or 800 mg once daily were 31 and 35 mg/L, respectively. The simulated trough concentrations for the population excluding the CYP3A4*22 carriers after 600 mg once daily or 800 mg once daily were 18 and 20 mg/L, respectively. Conclusion This analysis shows that CYP3A4*22 heterozygotes have a substantial lower pazopanib clearance and that dose adjustments based on CYP3A4*22 status could be considered.