Shortcomings and limitations of current PPIs

Currently available proton pump inhibitors (PPIs), which are the standard of care for acid-related disease, have a well-established efficacy and safety profile, but they are still far from the ideal antisecretory compound. An ideal drug should allow full acid control around the clock as well as dose dependent and predictable pharmacokinetic and pharmacodynamic properties. Moreover, an ideal agent should display high oral bioavailability, a rapid onset of action and few, if any, clinically relevant interactions with food or concomitantly administered drugs [1-2]. At variance with the above considerations, the so-called first generation PPIs (omeprazole, pantoprazole, and lansoprazole) have remarkable limitations, because their half-life is relatively short (0.5 to 2.1 hours) and consequently, the onset of their pharmacological action is rather slow. Furthermore, they are not able to achieve 24-hour suppression of gastric acid secretion and nocturnal acid breakthrough may occur even in patients receiving PPIs twice daily [3]. Also, the efficacy may vary among individuals due to cytochrome P450 polymorphism [4]. All the above shortcomings limit their usefulness as ondemand GERD therapy and their benefit in the control of symptoms occurring during the night. The so-called second-generation PPIs (rabeprazole and esomeprazole) offer several key advantages over the previously mentioned molecules of the same class in terms of a quicker acid inhibition, higher potency, and longer duration of action. However, despite these improvements, they do not permit to obtain clinical results which are significantly better than those achievable with the first-generation PPIs [5].

Ilaprazole chemistry

Recently, a new benzimidazole compound, ilaprazole {2-[[(4- methoxy-3-methyl)-2-pyridinylmethylsulfinyl-5-(1 H-pyrrol-1- yl)-1 H-benzimidazole, CAS 172152–36-2)}, designated also as IY81149, was synthesized at Il-Yang Pharmacy Co. (Seoul, Korea) and is presently developed by Livzon Pharmaceutical Group Inc. (Zhuhai, China). It clearly shows that this molecule belongs, like first-generation (omeprazole, lansoprazole and pantoprazole) and second-generation (rabeprazole and esomeprazole) PPIs, to benzimidazole compounds (Figure 1). After intestinal absorption, they accumulate specifically and selectively in the secretory canaliculus of the parietal cell and block the H⁺-K⁺ATPase, which is the final step of acid secretion. Its Indication inclues gastroesophageal reflux disease, both erosive and non-erosive[1].

Pharmacokinetic and pharmacodynamics properties 

Preliminary data from in vivo preclinical studies and clinical investigations have shown that ilaprazole can elicit a marked and dose-dependent suppression of gastric acid secretion,together with more prolonged plasma half-life and similar safety as compared to omeprazole and therefore it can be of help in improving and overtaking the above described limitations of traditional PPIs [6]. 

The main plasma pharmacokinetic parameters, after daily oral administration of 10 mg for 7 days, can be summarized as follows: the area under the curve of plasma concentration over time from 0 to 24 h (AUC_{0–24 h}) ranges between 1766.6 and 2243.t ng h/mL; the peak concentration at steady state (C_ss,max) ranges between 236 and 292 (ng/mL); the time to reach C_ss,max (tmax), that can be estimated by direct inspection read of the plasma concentration– time curves, ranges between 3.4 and 3.7 h; the elimination halflife (t_1/2) ranges between 8.1 and 10.1 h [7]. The impact of the hepatic cytochrome P450 (CYP) polymorphism on the pharmacokinetics of ilaprazole deserves careful consideration. In fact, two major CYP3A5 polymorphic alleles (CYP3A5*1 and *3) have been identified in the Chinese population [8] and, of note, in Chinese healthy subjects, Li et al. [9] observed no significant correlation between CYP3A5 genetic variations and disposition after administration of 10 mg ilaprazole as a single oral dose. In particular, there were no significant variations in the plasma AUC and peak plasma concentration (Cmax) of ilaprazole in individuals with CYP3A5*1 or CYP3A5*3 genotypes. Moreover, in the same study, there was no correlation between ilaprazole metabolism and CYP2C19 genotypes. Overall, based on current knowledge, genotype variations of CYP3A5 or CYP2C19 do not appear to affect ilaprazole metabolism. 

As the extension of plasma half-life is a critical factor in accelerating the onset of action, compounds with a half-life longer than that of current PPIs may be expected to display first-day efficacy. Indeed, a mean half-life of 3.6 h has been reported for ilaprazole in healthy volunteers and this is far longer than that estimated for both first- and second-generation PPIs (0.5–2 hours), thus contributing to a more rapid control of acid-related symptoms. 

Moreover, by examining the metabolites of ilaprazole, it has been found that it is predominantly metabolized by CYP3A and only partially by CYP2C19 [10]. So, the impact of CYP450 polymorphism on the pharmacokinetics of ilaprazole is lower than that of previous PPIs and this property combined with the prolonged elimination half-life is expected to impact positively, in terms of both lower inter-individual variability and longer-lasting acid inhibition, on the control of gastric acid secretion by this new PPI. 

Several in vivo investigations evaluated the antisecretory activity of this compound, which proved to be 2-3 times stronger than that of omeprazole. The high antisecretory activity of ilaprazole was confirmed in GERD patients where the drug, given at 10 and 20 mg daily, provided a greater and prolonged suppression of acid secretion compared with omeprazole 20 mg. In another study, significant differences were found between ilaprazole and omeprazole in terms of intragastric mean pH values. In fact, given at the dose of 20 mg daily, ilaprazole allowed to obtain significantly higher mean pH values than omeprazole 20 mg on day 1 (7.78 vs. 6.67, p < 0.05) and 5, 10, and 20 mg of ilaprazole were all superior to omeprazole 20 mg on day 5 (7.51, 8.14, and 7.95 vs. 7.44, respectively, p < 0.05). The authors concluded that ilaprazole was comparable to omeprazole at relatively low dosage on day 5 of administration, but, using equivalent dosages as high as 20 mg of the two PPIs, ilaprazole had quicker onset of action on day 1 compared to omeprazole. So, the improved pharmacodynamic activity of ilaprazole may reflect its improved pharmacokinetic properties in comparison to other PPIs.[1]

Clinical application

Many studies were not performed exclusively in GERD patients, but their results seemed to be highly predictive of a good success of ilaprazole, even at low dosages, in patients with both ERD and NERD, and therefore further clinical trials are urgently needed to confirm this expectation. Two 4-week studies on the treatment of peptic ulcer, showed that ilaprazole, given at both 5 and 10 mg daily, was as tolerable and safe as omeprazole 20 mg daily.

Conclusions

Up to date, ilaprazole has been shown to induce an irreversible inhibition of gastric H⁺-K⁺-ATPase in a dose-dependent manner with greater acid suppression as compared with omeprazole. These improved pharmacodynamic features are the mirror of the peculiar pharmacokinetic properties of ilaprazole, which are characterized by an extended plasma elimination half-life, as compared to current PPIs. This longer half-life may contribute in speeding the relief of symptoms, particularly in patients with NERD.

References

[1] Savarino E, Ottonello A, Martinucci I, Dulbecco P, Savarino V. Ilaprazole for the treatment of gastro-esophageal reflux. Expert Opin Pharmacother. 2016;17(15):2107-2113.

[2] Scarpignato C, Pelosini I, Di Mario F. Acid suppression therapy: where do we go from here? Dig Dis. 2006;24:11-46.

[3] Tytgat GN. Shortcomings of the first-generation proton pump inhibitors. Eur J Gastroenterol Hepatol. 2001;13(Suppl 1):S29-33.

[4] Klotz U, Schwab M, Treiber G. CYP2C19 polymorphism and proton pump inhibitors. Basic Clin Pharmacol Toxicol. 2004;95:2-8.

[5] Savarino V, Di Mario F, Scarpignato C. Proton pump inhibitors in GORD. An overview of their pharmacology, efficacy and safety. Pharmacol Res. 2009;59:135-153.

[6] Kim EJ, Lee RK, Lee SM, et al. General pharmacology of IY-81149, a new proton pump inhibitor. Arzneimittelforschung. 2001;51:51-59.

[7] De Bortoli N, Martinucci I, Giacchino M, et al. The pharmacokinetics of ilaprazole for gastro-esophageal reflux treatment. Exp Opin Drug Metab Toxicol. 2013;9:1361-1369.

[8] Liu CH, Peck K, Huang JD, et al. Screening CYP3A single nucleotide polymorphisms in a Han Chinese population with a genotyping chip. Pharmacogenomics. 2005;6:731–747.

[9] Li Y, Zhang W, Guo D, et al. Pharmacokinetics of the new proton pump inhibitor ilaprazole in Chinese healthy subjects in relation to CYP3A5 and CYP2C19 genotypes. Clin Chim Acta. 2008;391:60–67.

[10] Cho H, Choi MK, Cho DY, et al. Effect of CYP2C19 genetic polymorphism on pharmacokinetics and pharmacodynamics of a new proton pump inhibitor, ilaprazole. J Clin Pharmacol. 2012;52:976-984.