2.1 Modulation of Gastric pH
Group-specific interactions between PPIs and other drugs may result from a PPI-induced increase in gastric pH, which can decrease the soluble amount of other drug substances, alter drug release from products with pH-dependent dissolution properties, or indirectly impact bioavailability by changing the kinetics of pro-drugs. Examples of drug pharmacokinetics that are affected by gastric pH have been discussed extensively in the 2006 review [
10]. These include the reduced bioavailability of oral ketoconazole when co-administered with omeprazole 60 mg [
11], and the reduced mean area under the concentration-time curve at 24 hours (AUC
24) and peak plasma concentration (
C
max) of oral itraconazole 200-mg capsules administered with concomitant omeprazole 40 mg [
12].
Of importance since the publication of the 2006 review, new data are available for the interaction of PPIs and mycophenolate mofetil. Administration of PPIs increases intragastric pH, which slows down the hydrolysis of mycophenolate mofetil resulting in decreased maximum exposure and availability of mycophenolic acid, at least at early time points. Compared with mycophenolate mofetil alone, coadministration of mycophenolate mofetil with pantoprazole-Na resulted in persistently lower plasma concentrations of mycophenolic acid in heart transplant recipients [
13] and a significant decrease in total and maximum exposure in patients with autoimmune disease. This correlated with a 42 % increase (
p < 0.01) in the area of inosine monophosphate dehydrogenase activity [
14]. However, coadministration of pantoprazole-Na and enteric-coated mycophenolate sodium did not result in any significant changes in pharmacokinetic parameters in heart or lung transplant recipients [
15]. These findings from steady-state studies confirmed results from an earlier study in healthy individuals [
16]. Being in steady state for pantoprazole-Na (40 mg/day) significantly lowered total and maximum exposure of mycophenolic acid after administration of mycophenolate mofetil, but had no relevant effect after administration of enteric-coated mycophenolate sodium. Other pharmacokinetic parameters were not affected [
16], suggesting that interaction on the enzymatic level is unlikely.
Other interactions not discussed in the previous review include changes in the contact of the PPIs themselves to the gastric environment, which will change the exposure to the PPI. This predominantly results from the instability of PPIs at low pH and makes administration of PPIs by means of gastro-resistant formulations a necessity. Consistent with this, concomitant intake of the prokinetic mosapride led to increases of about 50 % in total and maximum exposure after administration of rabeprazole, which was explained by the increased transport time to the intestine [
17]. These results substantiated earlier results for the combination of omeprazole and mosapride [
18] and suggested that such an interaction would also benefit all other PPIs. However, this explanation does not address the fact that administration as a gastro-resistant formulation means no contact of PPI and gastric acid, suggesting that an undiscovered pharmacokinetic interaction with mosapride is also possible.
A group effect with clear clinical implications is assumed for several protease inhibitors that can have significantly altered bioavailability if coadministered with PPIs. For example, total and maximum exposure to single-dose atazanavir 400 mg was reduced by more than 90 % when administered with lansoprazole 60 mg [
19]. The loss in solubility for atazanavir at increased pH values is considered responsible for this effect, as a CYP-mediated interaction is unlikely for this drug combination. For other combinations, the situation may be more complex. Exposure to nelfinavir, which is comparably pH-dependently soluble, was reduced at steady state after nelfinavir 1,250 mg twice daily for 4 days by about 35 % if coadministered with omeprazole 40 mg once daily for 4 days, but terminal elimination and clearance remained unaltered [
20]. Nevertheless, nelfinavir is metabolised by CYP 2C19, whose inhibition by omeprazole probably counteracts the loss in exposure caused by solubility effects. This would also explain the decrease in the metabolic ratio of the main metabolite and nelfinavir.
In contrast, total and maximum exposure to single-dose raltegravir 400 mg are increased by a factor of 3 and 4, respectively, if administered with omeprazole 20 mg once daily for 4 days [
21]. Enzyme-based interactions are unlikely given the metabolic pathway of raltegravir; however, raltegravir has greatly increased solubility at increased pH and is a substrate to P-glycoprotein, which is at least modestly inhibited by omeprazole, both effects probably being synergistic. As shown here, in addition to possible group effects of PPIs, individual interactions of each compound remain possible and should be considered.
The situation for protease inhibitors becomes even more complex with the common concomitant use of the booster ritonavir. Ritonavir itself has better solubility at a lower pH, boosts other protease inhibitors by inhibiting CYP3A4, is metabolised by CYP3A4 (similar to PPIs) and is a substrate and inhibitor of P-glycoprotein [
22‐
24].
Total and maximum exposure of the non-ionizable lopinavir and ritonavir at steady state were both increased by about 25 % when administered with omeprazole, without obvious changes in the elimination [
22]. These findings were explained by an increase in exposure to ritonavir resulting from inhibition of P-glycoprotein by omeprazole and a subsequent stronger inhibitory effect on CYP3A4 by ritonavir. Separation of protease inhibitor and omeprazole administration by 2 hours in another study largely prevented this effect; the increase in total and maximum exposure to ritonavir after dose separation was lowered from 14 to 3 % and from 16 to 8 %, respectively [
23]. In contrast, exposure to concomitantly administered saquinavir remained increased by 50–70 % and, thus, was obviously not triggered by the change for ritonavir (i.e., another more systemic effect should account for this effect). Consistent with this, in another study, the increase in exposure to ritonavir was negligible, but exposure to saquinavir was increased by about 80 %, with a concomitant increase of omeprazole dose [
24].
The combined effect of several factors was demonstrated in a study with a single dose of indinavir 800 mg, in which exposure to indinavir was decreased by 35 and 45 % with constant treatment with omeprazole 20 and 40 mg but was increased by 55 % when a single dose of ritonavir 200 mg was added to high-dose omeprazole [
25].
2.3 The Cytochrome P450 Enzyme System
Discussion of interactions with intestinal and liver CYPs was extensive in the 2006 review [
10] and is not reiterated here, except to remind readers that PPIs are predominantly metabolised in the liver by CYP2C19 and CYP3A4 [
27].
Of significance since the previous review, there have been extensive discussions in recent reviews and meta-analyses on the drug interactions between certain PPIs and clopidogrel [
28‐
34]. These interactions appear to be mediated by CYP2C19 and are of utmost clinical relevance. Although recent retrospective studies have suggested an attenuation of the beneficial effects of clopidogrel when administered concomitantly with PPIs in general, stratification of the analysis has indicated that such effects are not present in patients receiving pantoprazole-Na compared with those receiving omeprazole [
35,
36]. Several studies demonstrated that being in steady state for omeprazole significantly increased total exposure to clopidogrel and decreased exposure to the active metabolite [
37]. These effects continued to persist even after separating administrations of the drugs by 12 hours, or after administration of doubled doses of clopidogrel. However, differences became clearly smaller after substitution of omeprazole by pantoprazole-Na [
37].
This is consistent with the finding that clopidogrel must be activated by CYP2C19, an enzyme inhibited by omeprazole but not pantoprazole-Na [
38]. It is further confirmed by data showing that exposure to the active metabolite after administration of clopidogrel was significantly decreased, and inhibition of platelet function diminished, under coadministration of omeprazole or esomeprazole [
39]. The relevance of CYP2C19 is further stressed by a study showing that only a small effect was observed from coadministration of lansoprazole with prasugrel, the latter being activated more dominantly by CYP isoenzymes other than CYP2C19 [
40].
The situation for lansoprazole seems more complex; however, unlike for rabeprazole, at least some information, including pharmacokinetic data, is available. Coadministration of lansoprazole with clopidogrel had no effect on the formation of clopidogrel’s inactive carboxylic acid metabolite. Nonetheless, the pharmacodynamic effect was significantly lowered in good responders to clopidogrel, probably as a result of inhibition of clopidogrel activation via CYP2C19, which is without relevance for the formation of the carboxylic acid derivative via esterases [
40]. However, evaluation of the total population in this study did not show more than a trend to a lowered efficacy of clopidogrel. This is consistent with findings reported from another study which found lansoprazole or dexlansoprazole exhibited no significant effect on the exposure to clopidogrel’s active metabolite or its pharmacodynamics [
39].
In summary an interaction between clopidogrel and PPIs seems to exist for omeprazole and esomeprazole, whereas there are only limited data for rabeprazole. Dexlansoprazole, lansoprazole and pantoprazole-Na had less effect on the antiplatelet activity of clopidogrel than did omeprazole or esomeprazole, which is supported by the Plavix label [
41].