Abstract
Aims
The aim was to assess potential interaction between methotrexate (MTX) and proton pump inhibitors (PPIs) in patients receiving high-dose MTX.
Methods
Records of 56 adults receiving 201 cycles of MTX were reviewed to determine effects of PPI administration on MTX elimination. Repeated-measures logistic regressions and Cox regressions were performed to evaluate the possible drug interaction.
Results
Despite a significant difference between those receiving a PPI and not receiving a PPI in median MTX levels at 24 (8.0 vs. 3.9 μmol l−1, respectively, P = 0.013) and 72 h after MTX administration (0.08 vs. 0.05 μmol l−1, respectively, P = 0.037), there was no difference between those receiving a PPI and not receiving a PPI in the proportion of patients experiencing delayed elimination at 24 (19.2% vs. 20.2%, respectively, P = 1.000) and 72 h (36.2% vs. 33.7%, respectively, P = 0.765). When data were analysed using Cox regression, controlling for multiple cycles of MTX per patient, PPI use was not a significant predictor of time to MTX < 0.1 μmol l−1. When the clustering effect of multiple cycles of MTX per patient was controlled for, co-administration of PPIs was not a significant predictor of MTX level (P = 0.969). A comparison of patients with delayed elimination at any time point and those without delayed elimination indicated that PPI use was not a significant predictor of delayed elimination (P = 0.607).
Conclusions
This study does not support previous findings of a significant interaction between PPIs and MTX. Based on these results, the clinical significance of any potential interaction is likely to be small.
Keywords: drug interaction, methotrexate, proton pump inhibitor
What is Already Known about this Subject —
Case reports and retrospective studies have implicated that concomitant administration of methotrexate (MTX) and proton pump inhibitors (PPIs) may decrease the elimination of MTX.
Many cancer patients receive PPIs as supportive care for symptoms related to either their cancer and its treatment or a common primary diagnosis of gastro-oesophageal reflux disease.
Prior studies did not control for clustering of multiple cycles per patient and included a relatively low proportion (≤21%) of patients receiving PPIs concomitantly with MTX.
What this Study Adds —
Almost half of the patients (47.3%) received PPIs concomitantly with MTX.
Use of PPIs did not have a significant effect on the proportion of patients who experienced delayed MTX elimination and, after controlling for the effects of clustering, PPI use was not a significant predictor of MTX level or delayed elimination.
The clinical significance of any potential interaction between MTX and PPIs is likely to be small.
Introduction
Methotrexate (MTX) is an antifolate chemotherapeutic agent that inhibits dihydrofolate reductase. High doses of MTX are often used in the treatment regimens for multiple malignancies, including acute leukaemia, aggressive lymphomas and osteosarcoma. Leucovorin rescue after high-dose MTX and monitoring of drug levels is essential when administering these high doses in order to detect elevated plasma drug concentrations and direct routine ancillary measures to prevent toxicity (i.e. leucovorin dosing, urinary alkalinization, etc.). Additionally, through therapeutic drug monitoring, early recognition of those patients with renal impairment and at risk for severe toxicity secondary to methotrexate can allow the early administration of glucarpidase to treat toxic methotrexate levels in those with significantly delayed elimination.
Methotrexate is primarily eliminated through renal excretion, with 95% recovered in the urine unchanged within 30 h of administration 1. Numerous factors are known to influence MTX elimination, including urinary pH, renal function, oedema/fluid third spacing and concomitant administration of drugs known to interact with methotrexate elimination (sulfamethoxazole/trimethoprim, aspirin, nonsteroidal anti-inflammatory drugs, probenecid, cephalosporins, dantrolene and penicillins) 1,2.
Several case reports, as well as some retrospective studies, have implicated that concomitant administration of MTX and proton pump inhibitors (PPIs) may decrease the elimination of MTX, leading to elevated plasma drug concentrations 3–11. However, not all reports have shown that co-administration of MTX and PPIs results in delayed MTX elimination 2,12. In addition to reports of a possible interaction, the prescribing information for MTX and the PPIs in the USA has been updated with a warning of this possible interaction 13,14. The proposed mechanisms for the interaction include inhibition of renal H+/K+-ATPase involved in active tubular secretion of MTX or the inhibition of breast cancer resistance protein, which is also involved in mediating MTX transport 15.
Many patients, especially those with serious illnesses such as a malignancy, receive adjunct medications, such as PPIs. This class of medications is believed to be relatively safe and free from interactions outside of decreasing the bioavailability of some orally administered medications that rely on lower gastric pH levels for absorption. Clinically, a significant drug interaction between MTX and PPIs could have devastating effects on cancer patients given the narrow therapeutic index of MTX. Delays in elimination could lead to significant adverse effects, such as mucositis and enhanced myelosuppression. Despite literature supporting a possible interaction between these medications, effects of delayed MTX elimination are rarely observed given the high frequency of PPI use in the cancer population. The purpose of this study was to determine whether an interaction exists between MTX and PPIs that results in delayed MTX elimination.
Methods
Study design
Patients admitted to our institution between 1 January 2008 and 1 August 2012 who received high-dose MTX [≥1000 mg m−2 intravenously (IV) over 3–4 h or ≥200 mg m−2 IV bolus followed by ≥800 mg m−2 IV over 22–24 h] were identified via the pharmacy’s electronic database. If a patient was admitted more than once during this time period, data from each admission were collected. Therefore, it was possible for patients with more than one admission to have data collected on multiple cycles of MTX. Patients were excluded if they were <18 years of age, pregnant or did not have MTX levels monitored. Patient information and data were extracted from the electronic medical records. Study methods were reviewed and approved by the local institutional review board.
Data collection
Medical records of included patients were reviewed for the duration of the MTX infusion and the time until plasma MTX levels were ≤0.1 μmol l−1. Baseline demographics (diagnosis, sex, age, height, weight and body surface area) were collected for all patients, together with MTX dose/infusion time, baseline serum creatinine (Scr), aspartate aminotransferase (AST), alanine aminotransferase (ALT), urine pH, use of urinary alkalinization, presence of pleural effusions or ascites and leucovorin administration. Serum creatinine together with patient age, height, weight, and gender were used to calculate creatinine clearance (CrCl) via the Cockroft–Gault formula. The use of drugs known to interact with methotrexate was also noted, including sulfamethoxazole/trimethoprim, aspirin, nonsteroidal anti-inflammatory drugs, probenicid, penicillins, cephalosporins and dantrolene. Methotrexate levels and Scr were collected until MTX levels were nontoxic (MTX level <0.1 umol l−1). The standard of care at the institution was to check MTX levels at 24, 48 and 72 h after the start of the MTX infusion and every morning thereafter, until MTX level was ≤0.1 μmol l−1. Lastly, the use of a PPI was noted.
End-points
The primary end-point of the study was to determine whether the use of PPIs in conjunction with MTX resulted in delayed MTX elimination in comparison to those patients not receiving PPIs. Delayed MTX elimination was defined as plasma MTX concentrations of >10 μmol l−1 at 24 h after the start of MTX therapy if receiving bolus infusion (i.e. over 3–4 h) or >20 μmol l−1 at 24 h after the start of MTX therapy if receiving infusional MTX (i.e. over 22–24 h), >1 μmol l−1 at 48 h and >0.1 μmol l−1 at 72 h. Patients receiving their dose over 3–4 h were classified as having a short infusion time, while those receiving their dose over 22–24 h were classified as having a long infusion time. Secondary end-points included a comparison of the time taken to reach an MTX level of <0.1 μmol l−1 in patients receiving PPIs with those patients not receiving PPIs and a comparison of PPI use among those with and without delayed elimination.
Statistical analysis
Differences in patient characteristics, MTX dose, MTX infusion time (short/long) and incidence of delayed elimination were compared using Fisher’s exact test or the Mann–Whitney U test, as appropriate. To control for variables affecting MTX elimination and clustering effects of multiple cycles of MTX per patient, a repeated-measures regression analysis using mixed procedures was conducted on MTX level, a repeated-measures logistic regression using GLIMMIX procedure was conducted on the nominal variable delayed elimination, and time to MTX level <0.1 μmol l−1 was analysed using the Cox regression PHREG procedure. The following variables were included in the repeated measures and Cox regression analyses: patient demographics (age, gender, height, weight); PPI administration; receipt of additional interacting medications; MTX level (24, 48 and 72 h postinfusion); MTX dose; MTX infusion time (short/long); baseline Scr and CrCl; baseline AST/ALT; and urinary pH (<7). Data were analysed using IBM SPSS Statistics for Windows, version 20.0 (IBM Corp., Armonk, NY, USA) and SAS, version 9.1 (Cary, NC, USA). A P value <0.05 was considered to be statistically significant.
Results
Patient characteristics
A total of 56 patients receiving 201 cycles of high-dose MTX were identified and included in this analysis. Proton pump inhibitors were co-administered with MTX in 95 (47%) of the cycles. Of the 56 patients, 18 (32.1%) did not receive a PPI with any MTX cycle, 23 (41.1%) received a PPI with every MTX cycle, and 15 (26.8%) received a PPI during at least one MTX cycle and did not receive a PPI during at least one MTX cycle. Results are reported per MTX cycle and not by patient.
The majority of baseline characteristics were similar between patients who received a PPI compared with those who did not receive a PPI, including renal function as represented by Scr levels and methotrexate dosing (Table 1). There were two differences between the groups, with patients who received concomitant PPIs being more likely to have a long MTX infusion time compared with those not receiving a PPI (50.5 vs. 34.0%, P = 0.022) and those receiving PPIs also receiving more medications known to interact with MTX. The difference in infusion time (short vs. long) between groups remained significant even when logistic regression using the GLIMMIX procedure was used to control for clustering (P = 0.017).
Table 1.
Baseline characteristics (unadjusted for clustering)
| Baseline characteristic | Without PPI (n = 106) | With PPI (n = 95) | P value |
|---|---|---|---|
| Male [n (%)] | 79 (54.5) | 66 (45.5) | 0.436 |
| Age [years; median (IQR)] | 53 (19) | 57 (23) | 0.063 |
| Body surface area [m2; median (IQR)] | 1.99 (0.34) | 2.06 (0.47) | 0.847 |
| Baseline serum creatinine [mg dl−1; median (IQR)] | 1.00 (0.26) | 1.0 (0.36) | 0.313 |
| AST baseline [units l−1; median (IQR)] | 20.5 (15) | 21.0 (13) | 0.690 |
| ALT baseline [units l−1; median (IQR)] | 42.5 (22) | 45.0 (44) | 0.179 |
| Diagnosis [n (%)] | |||
| Central nervous system lymphoma | 54 (51) | 43 (45) | |
| Burkitt’s lymphoma | 12 (11) | 14 (15) | |
| Mantle cell lymphoma | 9 (8) | 7 (7) | |
| Non-Hodgkin’s lymphoma | 15 (14) | 9 (9) | |
| Non-Hodgkin’s lymphoma (testicular) | 3 (3) | 0 (0) | |
| T-Cell lymphoblastic lymphoma | 5 (5) | 6 (6) | |
| Acute lymphoblastic leukaemia | 5 (5) | 10 (12) | |
| Osteosarcoma | 3 (3) | 6 (6) | |
| MTX dose [mg m−2; median (IQR)] | 3500 (2500) | 3500 (3000) | 0.170 |
| Total MTX dose [mg; median (IQR)] | 6850 (5000) | 6000 (6000) | 0.516 |
| Long MTX infusion time (22–24 h) [n (%)] | 36 (34) | 48 (50.5) | 0.022 |
| Number of interacting medications [n (%)] | 0.002 | ||
| 0 | 93 (88) | 64 (67) | |
| 1 | 10 (9) | 23 (24) | |
| 2 | 3 (3) | 8 (9) | |
| Pleural effusion [n (%)] | 0 (0) | 0 (0) | NA |
| Ascites [n (%)] | 0 (0) | 1 (0.5) | 0.473 |
Abbreviations are as follows: ALT, alanine aminotransferase; AST, aspartate aminotransferase; IQR, interquartile range; MTX, methotrexate; NA, not assessed; PPI, proton pump inhibitor.
Supportive management of methotrexate therapy
Patients in both groups received the same supportive care, with all patients receiving urinary alkalinization and leucovorin rescue. Urine pH was ≥7 in the majority of patients receiving high-dose MTX at baseline, 24, 48 and 72 h, with no differences between groups seen in those with urinary pH results available at those time points (Table 2). A statistically significant difference was found in the 24 h serum creatinine between those receiving a PPI and those not receiving a PPI (0.8 vs. 0.9 mg dl−1, respectively, P = 0.028); however, this difference was not present at 48 and 72 h (Table 2).
Table 2.
Methotrexate management and monitoring (unadjusted for clustering)
| Condition | Serum creatinine [mg dl−1; median (IQR)] | Urine pH ≥ 7 [n (% of those with available results)] | ||||||
|---|---|---|---|---|---|---|---|---|
| No PPI | 24 h | 48 h | 72 h | Baseline | 24 h | 48 h | 72 h | |
| Number with result available | 81 | 78 | 58 | 100 | 95 | 99 | 64 | |
| Result | 0.9 (0.40) | 1.0 (0.31) | 1.1 (0.30) | 91 (91.0) | 91 (95.8) | 97 (98.0) | 62 (96.9) | |
| PPI | Number with result available | 62 | 76 | 63 | 94 | 82 | 91 | 71 |
| Result | 0.8 (1.0) | 0.9 (0.30) | 1.0 (0.30) | 90 (95.7) | 79 (96.3) | 88 (96.7) | 69 (97.2) | |
| P value | 0.028 | 0.860 | 0.484 | 0.253 | 1.000 | 0.672 | 1.000 | |
Abbreviations are as follows: IQR, interquartile range; PPI, Proton pump inhibitor. Times (in hours) are the times after the start of the methotrexate infusion.
Methotrexate level
Patients who received a PPI had significantly higher MTX levels at 24 and 72 h compared with patients who did not receive a PPI (Table 3). However, when data were analysed to control for the clustering effect of multiple cycles of MTX per patient, using repeated-measures mixed procedures, co-administration of PPIs was not a significant predictor of MTX level (P = 0.969). Significant predictors identified included height (P = 0.010), CrCl (P = 0.003) and time (P < 0.001). Patients who were taller had higher MTX levels, whereas those with a higher CrCl had lower MTX levels. Similar to the effect of CrCl, time also showed a negative correlation with the MTX level.
Table 3.
Methotrexate elimination (unadjusted for clustering)
| MTX level [μmol l−1; median (IQR)] | Delayed elimination (%) | Time to MTX level <0.1 μmol l−1 [h; median (IQR)] | ||||||
|---|---|---|---|---|---|---|---|---|
| Condition | 24 h | 48 h | 72 h | 24 h | 48 h | 72 h | ||
| No PPI | Number with results available | 99 | 105 | 100 | ||||
| Result | 3.940 (13.94) | 0.215 (0.52) | 0.050 (0.135) | 20.2 | 11.3 | 33.7 | 72 (24) | |
| PPI | Number with results available | 76 | 94 | 93 | ||||
| Result | 8.005 (12.06) | 0.280 (0.52) | 0.075 (0.1675) | 19.2 | 20.0 | 36.2 | 72 (18) | |
| P value | 0.013 | 0.056 | 0.037 | 1.000 | 0.117 | 0.765 | 0.030 | |
Abbreviations are as follows: IQR, interquartile range; MTX, methotrexate; PPI, proton pump inhibitor. Times (in hours) are the times after the start of the MTX infusion.
Methotrexate elimination
There was a statistical difference between groups in the time taken to reach a nontoxic MTX level based on observed drug levels at 24, 48 and 72 h, as represented by the differences in interquartile ranges, even though the median time to reach an MTX level <0.1 μmol l−1 was 72 h in both groups (Table 3). When data were analysed using Cox regression, controlling for multiple cycles of MTX per patient, PPI use was not a significant predictor of the time taken to reach an MTX level <0.1 μmol l−1. The only significant predictor was baseline CrCl (P = 0.008). The higher the CrCl value, the less time it took to achieve an MTX level <0.1 μmol l−1. Additionally, the proportion of patients experiencing delayed elimination was not different between groups at any time point (Table 3).
Delayed methotrexate elimination
When patients with delayed elimination at any time point after the MTX infusion were compared with those without delayed elimination, the only statistically significant differences between the groups were patient age and baseline Scr (Table 4). When data were analysed using repeated-measures logistic regression with the GLIMMIX procedure to control for possible clustering, there was not an association between PPI use and delayed elimination of MTX (P = 0.607). Patient age and time were the only significant predictors of delayed MTX elimination (P = 0.008 and P < 0.001, respectively). Older patients had an increased risk of delayed elimination while, as one would expect, the risk of delayed elimination lessened over time.
Table 4.
Comparison of delayed vs. no delayed elmination (unadjusted for clustering)
| Baseline characteristic | No delayed elimination (n = 119) | Delayed elimination (n = 82) | P value |
|---|---|---|---|
| Age [years; median (IQR)] | 50 (21) | 60 (14) | 0.003 |
| Body surface area [m2; median (IQR)] | 2.00 (0.37) | 1.99 (0.41) | 0.420 |
| Baseline serum creatinine [mg dl−1; median (IQR)] | 0.9 (0.3) | 1.1 (0.3) | 0.001 |
| AST baseline [units l−1; median (IQR)] | 21 (13) | 19 (15) | 0.733 |
| ALT baseline [units l−1; median (IQR)] | 45 (26) | 42 (31) | 0.283 |
| Diagnosis [n (%)] | |||
| Central nervous system lymphoma | 59 (50) | 38 (46) | |
| Burkitt’s lymphoma | 13 (11) | 13 (16) | |
| Mantle cell lymphoma | 11 (9) | 5 (6) | |
| Non-Hodgkin’s lymphoma | 15 (13) | 9 (11) | |
| Non-Hodgkin’s lymphoma (testicular) | 1 (<1) | 2 (2) | |
| T-Cell lymphoblastic lymphoma | 8 (7) | 3 (4) | |
| Acute lymphoblastic leukaemia | 8 (7) | 7 (9) | |
| Osteosarcoma | 4 (3) | 5 (6) | |
| MTX dose [mg m−2; median (IQR)] | 3500 (2500) | 3500 (2500) | 0.934 |
| Total MTX dose [mg; median (IQR)] | 6900 (5000) | 6055 (4833) | 0.857 |
| Number of interacting medications [n (%)] | 0.603 | ||
| 0 | 91 (77) | 66 (81) | |
| 1 | 23 (19) | 10 (12) | |
| 2 | 5 (4) | 6 (7) | |
| Receiving a concomitant PPI [n (%)] | 57 (48) | 38 (47) | 0.886 |
Abbreviations are as follows: ALT, alanine aminotransferase; AST, aspartate aminotransferase; IQR, interquartile range; MTX, methotrexate.
Discussion
Delayed elimination of MTX after administration of high doses could have devastating effects on patients, including increased risk for serious adverse effects. It is particularly important for practitioners to evaluate a patient’s risk for delayed MTX elimination critically and take the necessary precautions during MTX administration, including altering the home drug regimen to minimize drug–drug interactions. Proton pump inhibitors have relatively few known pharmacokinetic drug interactions; however, there have been multiple reports of delayed MTX elimination when co-administered with PPIs. Results from our study showed that once the data were controlled for confounders and possible clustering, PPI use was not a significant predictor of MTX level, delayed elimination or the time taken to reach an MTX level <0.1 μmol l−1, despite the fact that the PPI group had a significantly longer infusion time and were more likely to receive other interacting medications.
Results of the present study echo those of a recent evaluation of the effect of drug interactions on MTX elimination and toxicity 2. The retrospective, case–control study identified 73 patients receiving MTX (23 cases with delayed elimination and 50 control patients without delayed elimination). It was determined that, along with other potential interacting medications, PPIs were not significantly associated with delayed MTX elimination [odds ratio (95% confidence interval), 1.50 (0.55–4.06), P = 0.454]. Use of PPIs occurred in 11 case patients (47.8%) and 19 control patients (38.0%). The present study also did not observe any differences in the use of PPIs between those with and without delayed elimination. Additionally, when the present study used an alternative method to analyse the data, in that patients were grouped and compared based on whether or not they received a PPI during their admissions for MTX administration, the results were similar, in that PPIs were not a significant predictor of MTX levels or elimination.
Multiple reports have shown an association between PPI co-administration and delayed MTX elimination. Five case reports describing a possible interaction between PPIs and MTX were identified 3–7. Four reports described increased levels while receiving PPIs concomitantly with high-dose MTX, while the fifth described a case of increased toxicity (myalgia) with low-dose weekly intramuscular MTX. An additional case report that did not find an interaction with omeprazole was also identified 12. This case described a patient who had identical MTX clearance during two cycles of high-dose MTX for osteosarcoma despite receiving omeprazole only during the first cycle.
In addition to the multiple case reports described above, a case series, two retrospective clinical studies and a pharmacokinetic study described an association between delayed MTX elimination and concomitant PPI use 8–11. The case series included five patients who received glucarpidase for delayed MTX elimination 8. All patients received a PPI during the course of MTX therapy; however, in previous and subsequent cycles without PPI co-administration, delayed elimination was not observed. In the two retrospective clinical studies, PPI use was associated with delayed elimination 10,11. These studies included 171 and 177 cycles of high-dose MTX, and 18 and 21% of the patients in each study received PPIs, respectively. This is significantly less than the proportion of patients receiving PPIs in the present study (47.3%). For the published studies, data were primarily analysed comparing patients with delayed elimination with those without delayed elimination, which differs from how data were analysed in the present study. Moreover, previous studies did not control for multiple cycles in the same patient. In the present study, a statistically significant difference was found in MTX levels and the time to achieve MTX levels <0.1 μmol l−1 between patients who received and did not receive PPIs when data were compared without adjusting for potential clustering. However, after controlling for clustering, a statistically significant difference was not found. It is possible that had earlier published studies controlled for multiple cycles of MTX, they would not have found the increased use of PPIs in patients with delayed elimination to be significant. Another consideration is the clinical significance of differences in MTX elimination observed between groups. Although median MTX levels at 24 and 72 h were higher in the PPI group prior to adjusting for clustering, this is likely to be clinically insignificant given the fact that the median levels in both groups were below the generally accepted thresholds for 24 and 72 h methotrexate levels (24 h, ≤10–20 μmol l−1; and 72 h, ≤1 μmol l−1). Likewise, the difference in the time to reach a nontoxic MTX level is likely to be of little clinical significance given the fact that the medians were the same and that this effect disappeared upon controlling for clustering.
The lack of an association of PPI use with MTX elimination in this study differs from previous studies and may be related to the greater number of patients receiving PPIs in our study. Additionally, methods used for data analysis differed from previous studies. Similar to the other studies describing a possible interaction, the present study is limited by its retrospective nature. Another limitation is that our study did not assess adverse effects associated with MTX. It is possible that patients experience increased adverse effects when receiving the combination of MTX and PPIs without a noticeable change in elimination, as described in the case report of myalgia with low-dose MTX 5. However, this is unlikely given the strong association between MTX drug levels/duration of exposure and adverse effects 1. There were two differences between groups in baseline characteristics; however, these were unlikely to influence the results of the study given the fact both would tend to lead to increased MTX levels in the PPI group (patients receiving PPIs also received more interacting medications and had longer infusion times). These would benefit the group not receiving PPIs; however, such a benefit was not observed in the analysis. Additionally, repeated measures, logistic regression and Cox regression did not identify use of interacting medications and infusion time as having a significant effect on PPI use, MTX levels or MTX elimination. Another difference between groups was in the 24 h serum creatinine, with those not receiving a PPI having a slightly higher median serum creatinine (Table 2). This difference would favour the PPI group. Creatinine clearance was taken into account in the Cox regression and repeated-measures testing.
Conclusion
Our study suggests that there is not an association between concomitant use of PPI and MTX level, time to elimination, or delayed elimination of MTX, despite the fact that patients receiving PPIs had significantly longer infusion times and received more interacting medications. Although the presence of an interaction between MTX and PPIs cannot be ruled out by this study alone, the clinical significance of any potential interaction between MTX and PPIs is likely to be small, especially in those at low risk for delayed elimination. Future studies should include a large prospective trial to allow for the control of multiple cycles of MTX per patient and other possible confounders, such as MTX infusion time and patient characteristics.
Competing Interests
All authors have completed the Unified Competing Interest form at http://www.icmje.org/conflicts-of-interest/ (available on request from the corresponding author) and declare: no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work.
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