Background: Ivacaftor is a modern drug used in the treatment of cystic fibrosis. It is highly lipophilic and exhibits a strong positive food effect. These characteristics can be potentially connected to a pronounced lymphatic transport after oral administration. Methods: A series of studies was conducted to describe the basic pharmacokinetic parameters of ivacaftor in jugular vein cannulated rats when dosed in two distinct formulations: an aqueous suspension and an oil solution. Additionally, an anesthetized mesenteric lymph duct cannulated rat model was studied to precisely assess the extent of lymphatic transport. Results: Mean ± SD ivacaftor oral bioavailability was 18.4 ± 3.2% and 16.2 ± 7.8%, respectively, when administered as an aqueous suspension and an oil solution. The relative contribution of the lymphatic transport to the overall bioavailability was 5.91 ± 1.61% and 4.35 ± 1.84%, respectively. Conclusion: Lymphatic transport plays only a minor role in the process of ivacaftor intestinal absorption, and other factors are, therefore, responsible for its pronounced positive food effect.

1st Faculty of Medicine Institute of Pharmacology General University Hospital Prague Charles University Prague Czechia

3rd Department of Surgery 1st Faculty of Medicine Motol University Hospital Charles University Prague Czechia

Department of Analytical Chemistry Faculty of Science Charles University Prague Czechia

Department of Pediatrics 2nd Faculty of Medicine Motol University Hospital Charles University Prague Czechia

Zentiva K S Prague Czechia

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Boleslavska T., Svetlik S., Zvatora P., Bosak J., Dammer O., Beranek J., et al. (2020). Preclinical evaluation of new formulation concepts for abiraterone acetate bioavailability enhancement based on the inhibition of pH-induced precipitation. Eur. J. Pharm. Biopharm. 151, 81–90. 10.1016/j.ejpb.2020.04.005 PubMed DOI

Caliph S. M., Charman W. N., Porter C. J. (2000). Effect of short-medium-and long-chain fatty acid-based vehicles on the absolute oral bioavailability and intestinal lymphatic transport of halofantrine and assessment of mass balance in lymph-cannulated and non-cannulated rats. J. Pharm. Sci. 89 (8), 1073–1084. 10.1002/1520-6017(200008)89:8<1073::aid-jps12>3.0.co;2-v PubMed DOI

Charman W. N. A., Stella V. J. (1986). Estimating the maximal potential for intestinal lymphatic transport of lipophilic drug molecules. Int. J. Pharm. 34 (1-2), 175–178. 10.1016/0378-5173(86)90027-x DOI

Choo E. F., Boggs J., Zhu C. Q., Lubach J. W., Catron N. D., Jenkins G., et al. (2014). The role of lymphatic transport on the systemic bioavailability of the bcl-2 protein family inhibitors navitoclax (ABT-263) and ABT-199. Drug Metab. Dispos. 42 (2), 207–212. 10.1124/dmd.113.055053 PubMed DOI

Dahan A., Mendelman A., Amsili S., Ezov N., Hoffman A. (2007). The effect of general anesthesia on the intestinal lymphatic transport of lipophilic drugs: comparison between anesthetized and freely moving conscious rat models. Eur. J. Pharm. Sci. 32 (4-5), 367–374. 10.1016/j.ejps.2007.09.005 PubMed DOI

Deeks E. D. (2013). Ivacaftor: a review of its use in patients with cystic fibrosis. Drugs 73 (14), 1595–1604. 10.1007/s40265-013-0115-2 PubMed DOI

Deeks E. D. (2016). Lumacaftor/ivacaftor: a review in cystic fibrosis. Drugs 76 (12), 1191–1201. 10.1007/s40265-016-0611-2 PubMed DOI

EMA (2012). Kalydeco - summary of product characteristics.

EMA (2022). ICH guideline M10 on bioanalytical method validation and study sample analysis.

FDA (2012). Addendum #2 - Pharmacology and toxicology secondary review for NDA 203188.

Grove M., Nielsen J. L., Pedersen G. P., Mullertz A. (2006). Bioavailability of seocalcitol IV: evaluation of lymphatic transport in conscious rats. Pharm. Res-Dordr 23 (11), 2681–2688. 10.1007/s11095-006-9109-z PubMed DOI

Hauss D. J., Fogal S. E., Ficorilli J. V., Price C. A., Roy T., Jayaraj A. A., et al. (1998). Lipid-based delivery systems for improving the bioavailability and lymphatic transport of a poorly water-soluble LTB4 inhibitor. J. Pharm. Sci. 87 (2), 164–169. 10.1021/js970300n PubMed DOI

Hoy S. M. (2019). Elexacaftor/ivacaftor/tezacaftor: first approval. Drugs 79 (18), 2001–2007. 10.1007/s40265-019-01233-7 PubMed DOI

Hrinova E., Skorepova E., Cerna I., Kralovicova J., Kozlik P., Krizek T., et al. (2022). Explaining dissolution properties of rivaroxaban cocrystals. Int. J. Pharm. 622, 121854. 10.1016/j.ijpharm.2022.121854 PubMed DOI

Jelinek P., Rousarova J., Rysanek P., Jezkova M., Havlujova T., Pozniak J., et al. (2022). Application of oil-in-water cannabidiol emulsion for the treatment of rheumatoid arthritis. Cannabis Cannabinoid 2022, 176. 10.1089/can.2022.0176 PubMed DOI PMC

Khoo S. M., Shackleford D. M., Porter C. J., Edwards G. A., Charman W. N. (2003). Intestinal lymphatic transport of halofantrine occurs after oral administration of a unit-dose lipid-based formulation to fasted dogs. Pharm. Res. 20 (9), 1460–1465. 10.1023/a:1025718513246 PubMed DOI

Koziolek M., Alcaro S., Augustijns P., Basit A. W., Grimm M., Hens B., et al. (2019). The mechanisms of pharmacokinetic food-drug interactions - a perspective from the UNGAP group. Eur. J. Pharm. Sci. 134, 31–59. 10.1016/j.ejps.2019.04.003 PubMed DOI

Kralovicova J., Bartunek A., Hofmann J., Krizek T., Kozlik P., Rousarova J., et al. (2022). Pharmacokinetic variability in pre-clinical studies: sample study with abiraterone in rats and implications for short-term comparative pharmacokinetic study designs. Pharmaceutics 14 (3), 643. 10.3390/pharmaceutics14030643 PubMed DOI PMC

Miao Y. F., Zhao S. H., Zuo J., Sun J. Q., Wang J. N. (2022). Reduced the food effect and enhanced the oral bioavailability of ivacaftor by self-nanoemulsifying drug delivery system (SNEDDS) using a new oil phase. Drug Des. Dev. Ther. 16, 1531–1546. 10.2147/DDDT.S356967 PubMed DOI PMC

Padhi D., Salfi M., Harris R. Z. (2007). The pharmacokinetics of cinacalcet are unaffected following consumption of high- and low-fat meals. Am. J. Ther. 14 (3), 235–240. 10.1097/01.mjt.0000212703.71625.26 PubMed DOI

Paterson S. L., Barry P. J., Horsley A. R. (2020). Tezacaftor and ivacaftor for the treatment of cystic fibrosis. Expert Rev. Resp. Med. 14 (1), 15–30. 10.1080/17476348.2020.1682998 PubMed DOI

Porter C. J. H., Trevaskis N. L., Charman W. N. (2007). Lipids and lipid-based formulations: optimizing the oral delivery of lipophilic drugs. Nat. Rev. Drug Discov. 6 (3), 231–248. 10.1038/nrd2197 PubMed DOI

Rysanek P., Grus T., Lukac P., Kozlik P., Krizek T., Pozniak J., et al. (2021). Validity of cycloheximide chylomicron flow blocking method for the evaluation of lymphatic transport of drugs. Brit J. Pharmacol. 178 (23), 4663–4674. 10.1111/bph.15644 PubMed DOI

Rysanek P., Grus T., Sima M., Slanar O. (2020). Lymphatic transport of drugs after intestinal absorption: impact of drug formulation and physicochemical properties. Pharm. Res. 37 (9), 166. 10.1007/s11095-020-02858-0 PubMed DOI

Salamunova P., Krejci T., Rysanek P., Salon I., Kroupova J., Hubatova-Vackova A., et al. (2023). Serum and lymph pharmacokinetics of nilotinib delivered by yeast glucan particles per os . Int. J. Pharm. 634, 122627. 10.1016/j.ijpharm.2023.122627 PubMed DOI

Salem A. H., Agarwal S. K., Dunbar M., Nuthalapati S., Chien D., Freise K. J., et al. (2016). Effect of low- and high-fat meals on the pharmacokinetics of venetoclax, a selective first-in-class BCL-2 inhibitor. J. Clin. Pharmacol. 56 (11), 1355–1361. 10.1002/jcph.741 PubMed DOI

Trevaskis N. L., Hu L., Caliph S. M., Han S., Porter C. J. (2015). The mesenteric lymph duct cannulated rat model: application to the assessment of intestinal lymphatic drug transport. J. Vis. Exp. 97, 52389. 10.3791/52389 PubMed DOI PMC

Valtola A., Kokki H., Gergov M., Ojanpera I., Ranta V. P., Hakala T. (2007). Does coronary artery bypass surgery affect metoprolol bioavailability. Eur. J. Clin. Pharmacol. 63 (5), 471–478. 10.1007/s00228-007-0276-6 PubMed DOI

Watson W. C., Gordon R. S., Jr (1962). Studies on the digestion, absorption and metabolism of castor oil. Biochem. Pharmacol. 11, 229–236. 10.1016/0006-2952(62)90078-3 PubMed DOI

Zhang Y., Huo M. R., Zhou J. P., Xie S. F. (2010). PKSolver: an add-in program for pharmacokinetic and pharmacodynamic data analysis in Microsoft Excel. Comput. Meth Prog. Bio 99 (3), 306–314. 10.1016/j.cmpb.2010.01.007 PubMed DOI