Litaty C Mbatchi1,2,3, Matthieu Gassiot1,2, Philippe Pourquier2, Alejando Goberna4, Hakim Mahammedi5, Loic Mourey6, Florence Joly7, Serge Lumbroso1, Alexandre Evrard8,9,10, Nadine Houede2,11. 1. Laboratoire de Biochimie et Biologie Moléculaire, CHU Nîmes, Hôpital Carémeau, Place du Professeur Robert Debré, 30029, Nîmes, Cedex 9, France. 2. IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, 34298, Montpellier, France. 3. Laboratoire de Pharmacocinétique, Faculté de Pharmacie, Université de Montpellier, Montpellier, France. 4. Département de Recherche Clinique et d'Epidémiologie, Institut Bergonié, Bordeaux, France. 5. Département d'Oncologie Médicale, Centre Jean Perrin, Clermont Ferrand, France. 6. Département d'Oncologie Médicale, IUCT Oncopole, Toulouse, France. 7. Département d'Oncologie Médicale, Centre François Baclesse, Caen, France. 8. Laboratoire de Biochimie et Biologie Moléculaire, CHU Nîmes, Hôpital Carémeau, Place du Professeur Robert Debré, 30029, Nîmes, Cedex 9, France. alexandre.evrard@umontpellier.fr. 9. IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, 34298, Montpellier, France. alexandre.evrard@umontpellier.fr. 10. Laboratoire de Pharmacocinétique, Faculté de Pharmacie, Université de Montpellier, Montpellier, France. alexandre.evrard@umontpellier.fr. 11. Département d'Oncologie Médicale, CHU Nîmes, Hôpital Carémeau, Nîmes, France.
Abstract
PURPOSE: Temsirolimus is a mammalian target of rapamycin (mTOR) inhibitor that exhibits antitumor activity in renal cell carcinoma and mantle cell lymphoma. The metabolism of temsirolimus and its active metabolite sirolimus mainly depends on cytochrome P450 3A4/5 (CYP3A4/A5) and the ABCB1 transporter. Differently from sirolimus, no pharmacogenetic study on temsirolimus has been conducted. Therefore, the aim of this pilot study was to identify genetic determinants of the inter-individual variability in temsirolimus pharmacokinetics and toxicity. METHODS: Pharmacokinetic profiles were obtained for 16 patients with bladder cancer after intravenous infusion of 25 mg temsirolimus. Non-compartmental analysis was performed to calculate the pharmacokinetic parameters of temsirolimus and sirolimus, its main metabolite. The presence of single nucleotide polymorphisms (SNPs) in CYP3A5, ABCB1 and in their transcriptional regulator NR1I2 (PXR) was assessed by genotyping. Non-parametric statistical tests were used to assess associations between candidate SNPs and temsirolimus pharmacokinetics and toxicity. RESULTS: The ratio between sirolimus AUC and temsirolimus AUC was 1.6-fold higher in patients who experienced serious toxic events (p = 0.034). The frequency of adverse events was significantly higher in patients homozygous for the NR1I2-rs6785049 A allele (OR = 0.065, p = 0.04) or NR1I2-rs3814055 C allele (OR = 0.032, p = 0.006). These NR1I2 SNPs were also predictive of temsirolimus half-life and global exposure to temsirolimus and sirolimus. Finally, the effect of the ABCB1-rs1128503, ABCB1-rs2032582 and CYP3A5*3 SNPs on sirolimus pharmacokinetics was confirmed. CONCLUSIONS: Our findings suggest that SNPs of NR1I2 and its target genes CYP3A5 and ABCB1 are genetic determinants of temsirolimus pharmacokinetics and toxicity in patients with bladder cancer.
PURPOSE:Temsirolimus is a mammalian target of rapamycin (mTOR) inhibitor that exhibits antitumor activity in renal cell carcinoma and mantle cell lymphoma. The metabolism of temsirolimus and its active metabolite sirolimus mainly depends on cytochrome P450 3A4/5 (CYP3A4/A5) and the ABCB1 transporter. Differently from sirolimus, no pharmacogenetic study on temsirolimus has been conducted. Therefore, the aim of this pilot study was to identify genetic determinants of the inter-individual variability in temsirolimus pharmacokinetics and toxicity. METHODS: Pharmacokinetic profiles were obtained for 16 patients with bladder cancer after intravenous infusion of 25 mg temsirolimus. Non-compartmental analysis was performed to calculate the pharmacokinetic parameters of temsirolimus and sirolimus, its main metabolite. The presence of single nucleotide polymorphisms (SNPs) in CYP3A5, ABCB1 and in their transcriptional regulator NR1I2 (PXR) was assessed by genotyping. Non-parametric statistical tests were used to assess associations between candidate SNPs and temsirolimus pharmacokinetics and toxicity. RESULTS: The ratio between sirolimus AUC and temsirolimus AUC was 1.6-fold higher in patients who experienced serious toxic events (p = 0.034). The frequency of adverse events was significantly higher in patients homozygous for the NR1I2-rs6785049 A allele (OR = 0.065, p = 0.04) or NR1I2-rs3814055 C allele (OR = 0.032, p = 0.006). These NR1I2 SNPs were also predictive of temsirolimus half-life and global exposure to temsirolimus and sirolimus. Finally, the effect of the ABCB1-rs1128503, ABCB1-rs2032582 and CYP3A5*3 SNPs on sirolimus pharmacokinetics was confirmed. CONCLUSIONS: Our findings suggest that SNPs of NR1I2 and its target genes CYP3A5 and ABCB1 are genetic determinants of temsirolimus pharmacokinetics and toxicity in patients with bladder cancer.
Authors: Taimour Langaee; Mohammad H Al-Shaer; Yan Gong; Elizabeth Lima; Sampson Antwi; Anthony Enimil; Albert Dompreh; Hongmei Yang; Wael A Alghamdi; Lubbe Wiesner; Charles A Peloquin; Awewura Kwara Journal: Infect Genet Evol Date: 2021-04-08 Impact factor: 3.342