The concomitant use of tyrosine kinase inhibitors and proton pump inhibitors: Prevalence, predictors, and impact on survival and discontinuation of therapy in older adults with cancer

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Abstract

The concomitant use of tyrosine kinase inhibitors (TKI) and proton pump inhibitors (PPI) is a significant concern due to potential drug-drug interaction that reduces TKI absorption, thus potentially reducing effectiveness of TKI. This study evaluated the prevalence and predictors of concomitant use of TKI-PPI and its impact on survival and therapy discontinuation in older adults with cancer. This retrospective study used linked SEER-Medicare data for the years 2007-2012. We included 12,538 patients with lung, renal cell, chronic myelogenous leukemia, liver or pancreatic cancer. The primary exposure variable was concomitant use of TKI-PPI defined as at least 30 days of PPI use in the first 90 days from the start of the TKI (exposure period). Outcomes were overall survival and discontinuation of therapy in 90 days and one year following the end of the exposure period. Inverse probability of treatment weight adjusted Cox proportional hazards regression evaluated the association between exposure and outcome. Overall prevalence of TKI-PPI use was 22.7%. Predictors associated with increased use included polypharmacy and prior PPI use. TKI-PPI use decreased survival (HR = 1.16; 95% CI = 1.05, 1.28) in 90 days and in one year (HR=1.10; 95% CI = 1.04,1.18) but was not associated with discontinuation. Nearly one in four older adults with cancer taking TKI used PPI concomitantly, and concomitant use was associated with an increased risk of death. Concerted medication therapy management efforts are needed to identify and reduce PPI use when TKIs are initiated. Nearly one in four older adults with cancer received interacting drugs tyrosine kinase inhibitors (TKI) and proton pump inhibitors (PPI) concomitantly. The concomitant use of TKI and PPI was associated with an increased risk of death.

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Role of tyrosine kinase inhibitors in cancer therapy.

Amit Arora, Eric M Scholar (2005)

Cancer chemotherapy has been one of the major medical advances in the last few decades. However, the drugs used for this therapy have a narrow therapeutic index, and often the responses produced are only just palliative as well as unpredictable. In contrast, targeted therapy that has been introduced in recent years is directed against cancer-specific molecules and signaling pathways and thus has more limited nonspecific toxicities. Tyrosine kinases are an especially important target because they play an important role in the modulation of growth factor signaling. This review focuses on small molecule inhibitors of tyrosine kinase. They compete with the ATP binding site of the catalytic domain of several oncogenic tyrosine kinases. They are orally active, small molecules that have a favorable safety profile and can be easily combined with other forms of chemotherapy or radiation therapy. Several tyrosine kinase inhibitors (TKIs) have been found to have effective antitumor activity and have been approved or are in clinical trials. The inhibitors discussed in this manuscript are imatinib mesylate (STI571; Gleevec), gefitinib (Iressa), erlotinib (OSI-1774; Tarceva), lapatinib (GW-572016), canertinib (CI-1033), semaxinib (SU5416), vatalanib (PTK787/ZK222584), sorafenib (BAY 43-9006), sutent (SU11248), and leflunomide (SU101). TKIs are thus an important new class of targeted therapy that interfere with specific cell signaling pathways and thus allow target-specific therapy for selected malignancies. The pharmacological properties and anticancer activities of these inhibitors are discussed in this review. Use of these targeted therapies is not without limitations such as the development of resistance and the lack of tumor response in the general population. The availability of newer inhibitors and improved patient selection will help overcome these problems in the future.

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The performance of inverse probability of treatment weighting and full matching on the propensity score in the presence of model misspecification when estimating the effect of treatment on survival outcomes

Peter C Austin, Elizabeth A. Stuart (2015)

There is increasing interest in estimating the causal effects of treatments using observational data. Propensity-score matching methods are frequently used to adjust for differences in observed characteristics between treated and control individuals in observational studies. Survival or time-to-event outcomes occur frequently in the medical literature, but the use of propensity score methods in survival analysis has not been thoroughly investigated. This paper compares two approaches for estimating the Average Treatment Effect (ATE) on survival outcomes: Inverse Probability of Treatment Weighting (IPTW) and full matching. The performance of these methods was compared in an extensive set of simulations that varied the extent of confounding and the amount of misspecification of the propensity score model. We found that both IPTW and full matching resulted in estimation of marginal hazard ratios with negligible bias when the ATE was the target estimand and the treatment-selection process was weak to moderate. However, when the treatment-selection process was strong, both methods resulted in biased estimation of the true marginal hazard ratio, even when the propensity score model was correctly specified. When the propensity score model was correctly specified, bias tended to be lower for full matching than for IPTW. The reasons for these biases and for the differences between the two methods appeared to be due to some extreme weights generated for each method. Both methods tended to produce more extreme weights as the magnitude of the effects of covariates on treatment selection increased. Furthermore, more extreme weights were observed for IPTW than for full matching. However, the poorer performance of both methods in the presence of a strong treatment-selection process was mitigated by the use of IPTW with restriction and full matching with a caliper restriction when the propensity score model was correctly specified.

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Drug absorption interactions between oral targeted anticancer agents and PPIs: is pH-dependent solubility the Achilles heel of targeted therapy?

N R Budha, A Frymoyer, G Smelick … (2012)

A majority of the novel orally administered, molecularly targeted anticancer therapies are weak bases that exhibit pH-dependent solubility, and suppression of gastric acidity with acid-reducing agents could impair their absorption. In addition, a majority of cancer patients frequently take acid-reducing agents to alleviate symptoms of gastroesophageal reflux disease, thereby raising the potential for a common but underappreciated drug-drug interaction (DDI) that could decrease the exposure of anticancer medication and result in subsequent failure of therapy. This article is a review of the available clinical literature describing the extent of the interaction between 15 orally administered, small-molecule targeted anticancer therapies and acid-reducing agents. The currently available clinical data suggest that the magnitude of this DDI is largest for compounds whose in vitro solubility varies over the pH range 1-4. This range represents the normal physiological gastric acidity (pH ~1) and gastric acidity while on an acid-reducing agent (pH ~4).