Impacts of genetic polymorphisms and cancer cachexia on naldemedine pharmacokinetics and bowel movements in patients receiving opioid analgesics.

Publisher: Blackwell Science Country of Publication: England NLM ID: 8710411 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1472-8206 (Electronic) Linking ISSN: 07673981 NLM ISO Abbreviation: Fundam Clin Pharmacol Subsets: MEDLINE

Publication: <2001->: Oxford : Blackwell Science
Original Publication: Paris ; New York : Elsevier, c1987-

Cachexia*/genetics ; Cachexia*/drug therapy ; Cachexia*/etiology ; Analgesics, Opioid*/pharmacokinetics ; Analgesics, Opioid*/adverse effects ; Analgesics, Opioid*/administration & dosage ; Naltrexone*/analogs & derivatives ; Naltrexone*/pharmacokinetics ; Naltrexone*/therapeutic use ; Naltrexone*/adverse effects ; Cytochrome P-450 CYP3A*/genetics ; Polymorphism, Genetic* ; Cancer Pain*/drug therapy ; Cancer Pain*/genetics; Humans ; Male ; Female ; Middle Aged ; Prospective Studies ; Aged ; Neoplasms/drug therapy ; Neoplasms/genetics ; Neoplasms/complications ; Genotype ; ATP Binding Cassette Transporter, Subfamily B/genetics ; Adult ; Opioid-Induced Constipation/genetics ; Opioid-Induced Constipation/drug therapy ; Defecation/drug effects

Background/objectives: Clinical responses to naldemedine vary between individuals with advanced cancer. This is a prospective, single-center, observational study aimed to evaluate the influence of genetic polymorphisms and cachexia status on plasma naldemedine and clinical responses.
Methods: Forty-eight patients being treated with naldemedine for opioid-induced constipation under treatment of cancer pain were enrolled. Plasma naldemedine concentrations were determined on the fourth day or later after administration of naldemedine, and the associations with genotypes, cachexia status, and clinical responses were assessed.
Results: Cancer patients exhibited a large variation in the plasma naldemedine concentrations, and it was correlated with serum total protein level. Patients who were homozygous CYP3A5*3 had a higher plasma concentration of naldemedine than those with the *1 allele. ABCB1 genotypes tested in this study were not associated with plasma naldemedine. A negative correlation was observed between the plasma naldemedine concentration and 4β-hydroxycholesterol level. The plasma naldemedine concentration was lower in patients with refractory cachexia than in those with precachexia and cachexia. While serum levels of interleukin-6 (IL-6) and acute-phase proteins were higher in patients with refractory cachexia, they were not associated with plasma naldemedine. A higher plasma concentration of naldemedine, CYP3A5*3/*3, and an earlier naldemedine administration after starting opioid analgesics were related to improvement of bowel movements.
Conclusion: Plasma naldemedine increased under deficient activity of CYP3A5 in cancer patients. Cachectic patients with a higher serum IL-6 had a lower plasma naldemedine. Plasma naldemedine, related to CYP3A5 genotype, and the initiation timing of naldemedine were associated with improved bowel movements.
(© 2024 The Authors. Fundamental & Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of Société Française de Pharmacologie et de Thérapeutique.)

Uritsky TJ. Methylnaltrexone: peripherally acting μ‐opioid receptor antagonist. J Adv Pract Oncol. 2019;10(1):62‐67.
Kalso E, Edwards JE, Moore AR, McQuay HJ. Opioids in chronic non‐cancer pain: systematic review of efficacy and safety. Pain. 2004;112(3):372‐380. doi:10.1016/j.pain.2004.09.019.
Chey WD, Webster L, Sostek M, Lappalainen J, Barker PN, Tack J. Naloxegol for opioid‐induced constipation in patients with noncancer pain. N Engl J Med. 2014;370(25):2387‐2396. doi:10.1056/NEJMoa1310246.
Bell TJ, Panchal SJ, Miaskowski C, Bolge SC, Milanova T, Williamson R. The prevalence, severity, and impact of opioid‐induced bowel dysfunction: results of a US and European patient survey (PROBE 1). Pain Med. 2009;10(1):35‐42. doi:10.1111/j.1526‐4637.2008.00495.x.
Katakami N, Oda K, Tauchi K, et al. Phase IIb, randomized double‐blind, placebo‐controlled study of naldemedine for the treatment of opioid‐induced constipation in patients with cancer. J Clin Oncol. 2017;35(17):1921‐1928. doi:10.1200/JCO.2016.70.8453.
Product information for Symproic. The Japan Pharmaceuticals and Medical Devices Agency https://www.pmda.go.jp/ (last accessed on 9 April 2023).
Prescribing information for SYMPROIC (Reference ID: 4074014). The US Food and Drug Administration https://www.accessdata.fda.gov/ (last accessed on 9 April 2023).
Rizmoic: EPAR—product information. The European Medicines Agency https://www.ema.europa.eu/ (last accessed on 9 April 2023).
Björkhem‐Bergman L, Bäckström T, Nylén H, et al. Comparison of endogenous 4β‐hydroxycholesterol with midazolam as markers for CYP3A4 induction by rifampicin. Drug Metab Dispos. 2013;41(8):1488‐1493. doi:10.1124/dmd.113.052316.
Diczfalusy U, Nylén H, Elander P, Bertilsson L. 4β‐Hydroxycholesterol, an endogenous marker of CYP3A4/5 activity in humans. Br J Clin Pharmacol. 2011;71(2):183‐189. doi:10.1111/j.1365‐2125.2010.03773.x.
Ishida T, Naito T, Sato H, Kawakami J. Relationship between the plasma fentanyl and serum 4β‐hydroxycholesterol based on CYP3A5 genotype and gender in patients with cancer pain. Drug Metab Pharmacokinet. 2016;31(3):242‐248. doi:10.1016/j.dmpk.2016.04.001.
Fukumura K, Kawaguchi N, Ishibashi T, Kubota R, Tada Y, Ogura E. Clinical drug‐drug interaction studies to evaluate the effects of a P‐glycoprotein inhibitor, CYP3A inhibitors, and a CYP3A inducer on the pharmacokinetics of naldemedine in healthy subjects. Clin Drug Investig. 2020;40(6):529‐540. doi:10.1007/s40261‐020‐00902‐w.
Sun H, Dai H, Shaik N, Elmquist WF. Drug efflux transporters in the CNS. Adv Drug Deliv Rev. 2003;55(1):83‐105. doi:10.1016/s0169‐409x(02)00172‐2.
Kim KA, Park PW, Park JY. Effect of ABCB1 (MDR1) haplotypes derived from G2677T/C3435T on the pharmacokinetics of amlodipine in healthy subjects. Br J Clin Pharmacol. 2007;63(1):53‐58. doi:10.1111/j.1365‐2125.2006.02733.x.
Turiján‐Espinoza E, Ruíz‐Rodríguez VM, Uresti‐Rivera EE, et al. Clinical utility of ABCB1 and ABCG2 genotyping for assessing the clinical and pathological response to FAC therapy in Mexican breast cancer patients. Cancer Chemother Pharmacol. 2021;87(6):843‐853.
Yu Z, Wen L, Shen X, Zhang H. Effects of the OPRM1 A118G polymorphism (rs1799971) on opioid analgesia in cancer pain: a systematic review and meta‐analysis. Clin J Pain. 2019;35(1):77‐86.
Hooten WM, Biernacka JM, O'Brien TG, Cunningham JM, Black JL. Associations of catechol‐O‐methyltransferase (rs4680) single nucleotide polymorphisms with opioid use and dose among adults with chronic pain. Pain. 2019;160(1):263‐268.
Trobec K, Kos MK, von Haehling S, et al. Pharmacokinetics of drugs in cachectic patients: a systematic review. PLoS ONE. 2013;8(11):e79603.
McNamara MJ, Alexander HR, Norton JA. Cytokines and their role in the pathophysiology of cancer cachexia. JPEN J Parenter Enteral Nutr. 1992;16(6 Suppl):50S‐55S.
Tanaka H, Naito T, Sato H, Hiraide T, Yamada Y, Kawakami J. Impact of CYP genotype and inflammatory markers on the plasma concentrations of tramadol and its demethylated metabolites and drug tolerability in cancer patient. Eur J Clin Pharmacol. 2018;74(11):1461‐1469.
Takeshita Y, Fujikawa S, Serizawa K, et al. New BBB model reveals that IL‐6 blockade suppressed the BBB disorder, preventing onset of NMOSD. Neurol Neuroimmunol Neuroinflamm. 2021;8(6):e1076.
Fukumura K, Yokota T, Baba Y, Arjona Ferreira JC. Phase 1, randomized, double‐blind, placebo‐controlled studies on the safety, tolerability, and pharmacokinetics of naldemedine in healthy volunteers. Clin Pharmacol Drug Dev. 2018;7(5):474‐483.
Drug development and drug interactions. Table of substrates, inhibitors and inducers. The US Food and Drug Administration https://www.fda.gov/ (last accessed on 21 January 2023).
Joshi P, Vishwakarma RA, Bharate SB. Natural alkaloids as P‐gp inhibitors for multidrug resistance reversal in cancer. Eur J Med Chem. 2017;138:273‐292.
Fearon K, Strasser F, Anker SD, et al. Definition and classification of cancer cachexia: an international consensus. Lancet Oncol. 2011;12(5):489‐495.
Forrest LM, McMillan DC, McArdle CS, Angerson WJ, Dunlop DJ. Evaluation of cumulative prognostic scores based on the systemic inflammatory response in patients with inoperable non‐small‐cell lung cancer. Br J Cancer. 2003;89(6):1028‐1030.
Kubota R, Fukumura K, Wajima T. Population pharmacokinetics and exposure‐response relationships of naldemedine. Pharm Res. 2018;35(11):225.
Hsyu PH, Pignataro DS, Matschke K. Effect of aprepitant, a moderate CYP3A4 inhibitor, on bosutinib exposure in healthy subjects. Eur J Clin Pharmacol. 2017;73(1):49‐56.
Takashina Y, Naito T, Mino Y, Yagi T, Ohnishi K, Kawakami J. Impact of CYP3A5 and ABCB1 gene polymorphisms on fentanyl pharmacokinetics and clinical responses in cancer patients undergoing conversion to a transdermal system. Drug Metab Pharmacokinet. 2012;27(4):414‐421.
Hirano K, Naito T, Mino Y, Takayama T, Ozono S, Kawakami J. Impact of CYP3A5 genetic polymorphism on cross‐reactivity in tacrolimus chemiluminescent immunoassay in kidney transplant recipients. Clin Chim Acta. 2012;414:120‐124.
Fukuen S, Fukuda T, Maune H, et al. Novel detection assay by PCR‐RFLP and frequency of the CYP3A5 SNPs, CYP3A5*3 and *6, in a Japanese population. Pharmacogenetics. 2002;12(4):331‐334.
Naito T, Mino Y, Aoki Y, et al. ABCB1 genetic variant and its associated tacrolimus pharmacokinetics affect renal function in patients with rheumatoid arthritis. Clin Chim Acta. 2015;445:79‐84.
Hawwa AF, McKiernan PJ, Shields M, Millership JS, Collier PS, McElnay JC. Influence of ABCB1 polymorphisms and haplotypes on tacrolimus nephrotoxicity and dosage requirements in children with liver transplant. Br J Clin Pharmacol. 2009;68(3):413‐421.
Salama NN, Yang Z, Bui T, Ho RJ. MDR1 haplotypes significantly minimize intracellular uptake and transcellular P‐gp substrate transport in recombinant LLC‐PK1 cells. J Pharm Sci. 2006;95(10):2293‐2308.
Gesenberg C, Mathias NR, Xu Y, et al. Utilization of in vitro, in vivo and in silico tools to evaluate the pH‐dependent absorption of a BCS class II compound and identify a pH‐effect mitigating strategy. Pharm Res. 2019;36(12):164.
Morgan ET, Goralski KB, Piquette‐Miller M, et al. Regulation of drug‐metabolizing enzymes and transporters in infection, inflammation, and cancer. Drug Metab Dispos. 2008;36(2):205‐216.
Saib S, Delavenne X. Inflammation induces changes in the functional expression of P‐gp, BCRP, and MRP2: an overview of different models and consequences for drug disposition. Pharmaceutics. 2021;13(10):1544.
Dickmann LJ, Patel SK, Rock DA, Wienkers LC, Slatter JG. Effects of interleukin‐6 (IL‐6) and an anti‐IL‐6 monoclonal antibody on drug‐metabolizing enzymes in human hepatocyte culture. Drug Metab Dispos. 2011;39(8):1415‐1422.
Legakis I, Stathopoulos J, Matzouridis T, Stathopoulos G. Decreased plasma ghrelin levels in patients with advanced cancer and weight loss in comparison to healthy individuals. Anticancer Res. 2009;29(10):3949‐3952.
Hwang IC, Park JY, Myung SK, Ahn HY, Fukuda K, Liao Q. OPRM1 A118G gene variant and postoperative opioid requirement: a systematic review and meta‐analysis. Anesthesiology. 2014;121(4):825‐834.
Mitchell JM, O'Neil JP, Jagust WJ, Fields HL. Catechol‐O‐methyltransferase genotype modulates opioid release in decision circuitry. Clin Transl Sci. 2013;6(5):400‐403.
Kanbayashi Y, Shimizu M, Ishizuka Y, Sawa S, Yabe K, Uchida M. Factors associated with non‐response to naldemedine for opioid‐induced constipation in cancer patients: a subgroup analysis. PLoS ONE. 2022;17(12):e0278823.

21H04204 JSPS KAKENHI; 21K06664 JSPS KAKENHI; 22H04287 JSPS KAKENHI

Keywords: cachexia; genetic polymorphism; naldemedine; opioid‐induced constipation; pharmacokinetics

0 (Analgesics, Opioid)
5S6W795CQM (Naltrexone)
EC 1.14.14.1 (Cytochrome P-450 CYP3A)
03KSI6WLXH (naldemedine)
EC 1.14.14.1 (CYP3A5 protein, human)
0 (ATP Binding Cassette Transporter, Subfamily B)
0 (ABCB1 protein, human)

Date Created: 20240109 Date Completed: 20240514 Latest Revision: 20240521

20240521

10.1111/fcp.12976

38192190