TY - JOUR
T1 - Impact of CYP3A4*22 on Pazopanib Pharmacokinetics in Cancer Patients
AU - Bins, Sander
AU - Huitema, Alwin D.R.
AU - Laven, Pim
AU - Bouazzaoui, Samira el
AU - Yu, Huixin
AU - van Erp, Nielka
AU - van Herpen, Carla
AU - Hamberg, Paul
AU - Gelderblom, Hans
AU - Steeghs, Neeltje
AU - Sleijfer, Stefan
AU - van Schaik, Ron H.N.
AU - Mathijssen, Ron H.J.
AU - Koolen, Stijn L.W.
N1 - Publisher Copyright:
© 2018, The Author(s).
PY - 2019/5/1
Y1 - 2019/5/1
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85055678404
U2 - 10.1007/s40262-018-0719-5
DO - 10.1007/s40262-018-0719-5
M3 - Article
C2 - 30367352
AN - SCOPUS:85055678404
SN - 0312-5963
VL - 58
SP - 651
EP - 658
JO - Clinical Pharmacokinetics
JF - Clinical Pharmacokinetics
IS - 5
ER -