Co-administration Of Proton Pump Inhibitors Research Articles

Development of physiologically-based pharmacokinetic models to predict food effects and co-administration of proton pump inhibitors on the pharmacokinetics of sonidegib and vismodegib

Development of physiologically-based pharmacokinetic models to predict food effects and co-administration of proton pump inhibitors on the pharmacokinetics of sonidegib and vismodegib

Proton Pump Inhibitors Do Not Affect the Bioavailability of a Novel Liquid Formulation of Levothyroxine

ObjectiveThis study evaluates the impact of a representative proton pump inhibitor (PPI) (omeprazole), administered simultaneously or staggered, on the pharmacokinetics of levothyroxine (LT4) solution (Tirosint-SOL). MethodsThis was a randomized, 3-way crossover, comparative bioavailability study in 36 healthy adults under fasting conditions.Omeprazole 40 mg delayed-release capsule was administered once daily from Day 1 to 6 (mornings, Treatment-A; evenings, Treatment-B; none, Treatment-C) to increase and stabilize gastric pH. In the morning of Day 5, a single dose of LT4 solution 600 mcg was administered. Blood samples were collected 0 to 48 hours post-LT4 administration. Noncompartmental pharmacokinetic parameters were calculated for total serum thyroxine using baseline-corrected data. Maximum concentration (Cmax) and area under the concentration-time curve (AUC0-48) were included in an analysis of variance to obtain geometric mean ratios and 90% confidence intervals. ResultsFor both comparisons (A/C and B/C), geometric mean ratios and 90% confidence intervals for all parameters were within the equivalence boundaries (80%-125%), indicating bioequivalence: for A/C, AUC0-48 98.98% [94%-104%], and Cmax 91.68% [87%-97%]; for B/C, AUC0-48 98.94% [95%-103%], and Cmax 94.90% [90%-100%]. Median Tmax (time associated with Cmax) was similar across treatments. ConclusionThis study demonstrated that Tirosint-SOL bioavailability is unaffected by coadministration of a representative PPI, given simultaneously or staggered by about 12 hours, compared to administration of LT4 solution alone. For hypothyroid patients on PPI therapy, administration of LT4 solution may reduce variations in thyroid stimulating hormone levels related to intermittent use of acid-reducing drugs and consequently the need for dose adjustments.

Analysis of Risk Factors for Febrile Neutropenia in Patients with Small-Cell Lung Cancer Receiving Carboplatin Plus Etoposide Therapy

Introduction: Febrile neutropenia (FN) is an oncologic emergency requiring immediate empiric antibiotic therapy. Although carboplatin plus etoposide combination chemotherapy is associated with a relatively high frequency of FN, the risk factors are unclear. Hence, this retrospective study aimed to identify predictive markers of carboplatin/etoposide-induced FN. Methods: We conducted a retrospective cohort analysis of patients with previously untreated small-cell lung cancer (SCLC) who received combination chemotherapy with carboplatin (area under the concentration curve: 5 mg/mL·min, day 1) and etoposide (80 or 100 mg/m2, days 1–3) between July 2007 and June 2022. FN was assessed during the 21 days after initiation of carboplatin and etoposide therapy according to the Japanese Society of Medical Oncology’s definition. Fisher’s exact test for categorical variables and Mann-Whitney U test for continuous variables were used to compare the two groups. Statistical significance was set at p values p values Results: Among the 176 eligible patients, the incidence of FN during the first cycle of chemotherapy was 25.0% (44/176). Multivariate analysis revealed that co-administration of proton pump inhibitors (PPIs) or potassium-competitive acid blockers (PCABs) and body mass index (BMI) were significantly associated with FN (p = 0.0035 and 0.0011, respectively). Patients with both co-administration of PPIs or PCABs and a BMI ≤22.509 kg/m2 presented with significantly higher frequencies of FN compared with the other patients (13/24 [54.2%] vs. 31/152 [20.4%] patients; odds ratio: 4.56, 95% confidence interval: 1.70–12.48; p = 0.00147). Conclusion: Patients who received carboplatin plus etoposide for SCLC with co-administration of PPIs or PCABs and a BMI ≤22.509 kg/m2 more frequently present with FN than those without the two factors.

Conversion of raltegravir carrying a 1,3,4-oxadiazole ring to a hydrolysis product upon pH changes decreases its antiviral activity.

Raltegravir (RAL), a human immunodeficiency virus (HIV)-1 integrase inhibitor, has been administered as part of antiretroviral therapy. Studies in patients with HIV-1 have shown high variability in the pharmacokinetics of RAL, and in healthy volunteers, coadministration of proton-pump inhibitors has been shown to increase the plasma RAL concentrations. Here, we found that RAL containing a 1,3,4-oxadiazole ring is converted to a hydrolysis product (H-RAL) with a cleaved 1,3,4-oxadiazole ring at pH 1.0 and 13.0 conditions in vitro, thereby reducing the anti-HIV activity of the drug. The inclusion of cyclodextrins (beta-cyclodextrin [βCD], random methyl-βCD [RAM-βCD], and hydroxypropyl-βCD [HP-βCD]) can protect RAL from pH-induced changes. The conversion of RAL to H-RAL was detected by using various mass spectrometry analyses. The chromatogram of H-RAL increased in a time-dependent manner similar to another 1,3,4-oxadiazole-containing drug, zibotentan, using high-performance liquid chromatography. Oral bioavailability and target protein interactions of H-RAL were predicted to be lower than those of RAL. Moreover, H-RAL exhibited significantly reduced anti-HIV-1 activity, whereas combinations with βCD, RAM-βCD, and HP-βCD attenuated this effect in cell-based assays. These findings suggest that βCDs can potentially protect against the conversion of RAL to H-RAL under acidic conditions in the stomach, thereby preserving the anti-HIV-1 effect of RAL. Although clinical trials are needed for evaluation, we anticipate that protective devices such as βCDs may improve the pharmacokinetics of RAL, leading to better treatment outcomes, including reduced dosing, long-term anti-HIV-1 activity, and deeper HIV-1 suppression.

Knowledge, Attitude and Practices of Resident Doctors Towards use of Proton Pump Inhibitors in A Tertiary Care Hospital in Pune, India: A Cross-Sectional Survey

Background and Objectives: The most commonly prescribed drugs in healthcare systems are proton pump inhibitors (PPIs). Several studies have found that globally PPIs are frequently used without proper justification. Appropriate and updated knowledge about PPI among medical professionals is essential to enhance the rationale of PPI application. The present study with this goal was initiated to evaluate the understanding and behavioral practices toward PPI use among resident doctors in a tertiary care teaching hospital in Pune, western India. Method: A cross sectional survey using structured questionnaire. Results: The questionnaire was completed by 137 resident doctors. 82.5% of them prescribed acid-suppressing drugs for acute gastritis and other drugs in combination with them as the most common indications for the majority of their patients. These prescriptions were based on the consultant's or unit's policy, and resident doctors were not given the liberty to breach this policy. 71.5% of the respondents chose PPIs as their first choice, and 75.1% preferred the oral route. 10.2% of them claimed to have encountered a PPI-related adverse event. Despite the fact that 75.9% of the respondents preferred to prescribe PPIs for short durations, a lack of awareness about the possible risks associated with chronic PPI use was noted. 58.4% of resident doctors preferred using the step-down strategy, but 19.7% of participants were unaware of step up or step down when prescribing PPIs. The concept of drug interactions with the co-administration of PPI was also less understood by study participants. Conclusion: In the present survey study participants had less knowledge on correct indications for PPI usage as they fared PPI over any other acid-reducing medications to majority of their patients. There was also a lack of understanding of PPI adverse drug reactions, drug-drug interactions, and specific PPI administration approaches.

Co prescription of anti-acid therapy reduces the bioavailability of mycophenolate mofetil in systemic sclerosis patients: A crossover trial

ObjectiveMycophenolate mofetil (MMF) is an effective treatment option for interstitial lung disease (ILD) in systemic sclerosis (SSc). Many patients require co-administration of proton pump inhibitors (PPI) or H2 receptor blockers (HRB) because of various gastrointestinal (GI) manifestations in SSc. Co-treatment with PPI or HRB have shown to reduce serum drug levels in post-transplant patients. We wanted to see if there is a similar phenomenon for Mycophenolate in SSc. MethodsTwenty SSc patients, who were on a stable dose of MMF (1.5-3 g) underwent a sequential cross over study with MMF alone in the first month, followed by co-treatment with Ranitidine and then Esomeprazole in the second and third month respectively. Estimation of 12-hour area under curve (AUC) of Mycophenolic Acid (MPA) levels and total GI score were calculated at the end of each month and compared between the treatment arms. [Trial registration: CTRI/2020/06/025,939] ResultsCo-administration of esomeprazole was associated with 32.7% (mean difference = 22.28 μg h ml–1) reduction in mean AUC MPA, whereas ranitidine caused a reduction of 21.97% (mean difference = 14.93 μg h ml–1) in MPA AUC when compared to MMF without anti-acid therapies. The addition of ranitidine or esomeprazole resulted in significant reduction in the total GI score. ConclusionCo-administration of PPI or HRB can significantly reduce the bioavailability of MMF in patients with SSc. To avoid therapeutic failure of MMF drug level monitoring is essential when these agents are co-prescribed with MMF.

Model based assessment of food and acid reducing agent effects on oral absorption of mezigdomide (CC-92480), a novel cereblon E3 ligase modulator.

Mezigdomide is a novel cereblon E3 ligase modulator (CELMoD) agent with enhanced autonomous cell-killing activity in multiple myeloma (MM) cells, and promising immunomodulatory and antitumor activity in patients with MM. We developed a population pharmacokinetics (PKs) model for mezigdomide in healthy subjects (HSs), and quantified effects of high-fat meal and proton pump inhibitor (PPI) on human disposition parameters. Plasma concentrations from 64 HS in two phase I clinical studies (NCT03803644 and NCT04211545) were used to develop a population PK model. The HSs received single oral doses of 0.4-3.2 mg mezigdomide with full PK profiles collected. A two-compartment linear PK model with first-order absorption and lag time best described mezigdomide PK profiles in HSs. The population PK parameters of absorption rate constant, lag time, central volume of distribution, clearance, peripheral volume of distribution, and intercompartmental clearance were estimated to be 1.18 h-1 (interoccasion variability [IOV]: 65%), 0.423 h (IOV: 31%), 440 L (interindividual variability [IIV]: 63%), 35.1 L/h (IIV: 40%), 243 L (IIV: 26%), and 36.8 L/h (IIV: 26%), respectively. High-fat meal increased oral bioavailability by ~30% and PPI co-administration decreased oral bioavailability by ~64%. Mezigdomide demonstrated a linear dose-exposure relationship in HSs. The PK model suggests a modest effect of high-fat meal, and a substantial effect of PPIs on mezigdomide oral bioavailability. This population PK model enables data integration across studies to identify important covariate effects and is being used to guide dose selection in clinical study designs for mezigdomide in patients with MM.

Effect of morning versus night-time administration of proton pump inhibitor (pantoprazole) on thyroid function test in levothyroxine-treated primary hypothyroidism: a prospective cross-over study

BackgroundOne of the common causes of suboptimal control of thyroid stimulating hormone (TSH) in levothyroxine-treated hypothyroidism is coadministration of proton pump inhibitors (PPIs). Morning administration of pantoprazole has been shown to suppress intragastric pH to a greater extent. We therefore aimed to determine the effect of pantoprazole at different time points of the day on thyroid function test (TFT) in levothyroxine-treated overt primary hypothyroidism.MethodsIn this single centre, hospital based, prospective, two arm cross-over study (AB, BA), participants were randomized into 2 groups based on morning (6:00 am – 7:00 am simultaneously with the scheduled levothyroxine tablet) (group M) and evening (30 min before dinner) intake of 40 mg pantoprazole tablet (group N). After the initial 6 weeks (period 1), a washout period of 1 week for pantoprazole was given, and then both the groups crossed over for another 6 weeks (period 2). Patients were instructed to continue the same brand of levothyroxine tablet at empty stomach 1-hour before breakfast. Serum TSH was measured at baseline, week 6, and week 13.ResultsData from 30 patients, who completed the study with 100% compliance, were analysed. Mean TSH values of the study participants were significantly higher both at week 6 and week 13 compared to the baseline. Mean baseline serum TSH concentrations for groups M and N were 2.70 (± 1.36), and 2.20 (± 1.06) µlU/mL, respectively. Mean serum TSH concentrations at the end periods 1 and 2 for group M were 3.78 (± 4.29), and 3.76 (± 2.77) while the levels in group N were 3.30 (± 1.90), and 4.53 (± 4.590) µlU/mL, respectively. There was a significant rise in serum TSH concentration across periods 1 and 2 in both the groups (F2, 58 = 3.87, p = 0.03). Within group changes in TSH across periods 1 and 2 were not statistically significant. Similarly difference in TSH between the groups, either at 6 weeks or at 13 weeks, were also not statistically significant.ConclusionsConcomitant use of pantoprazole, even for 6 weeks, leads to significant elevation in serum TSH in levothyroxine-treated patients who are biochemically euthyroid, irrespective of timing of pantoprazole intake. Early morning and night-time administration of pantoprazole have similar effect on TFT in these patients.

Aspirin vs Clopidogrel: Antiplatelet Agent of Choice for Those With Recent Bleeding or at Risk for Gastrointestinal Bleed.

Antiplatelet agents are used worldwide mainly for primary and secondary prevention of cardiovascular events on a long-term basis for mortality benefit. Gastrointestinal bleeding is a well-known adverse effect. Various factors are to be considered while choosing antiplatelet agents to prevent the risk of bleedand rebleed incidents. These range from deciding on the agent, timing of therapy, underlying indications, coadministration of proton pump inhibitor, etc. At the same time, one must weigh the risks of cardiovascular events secondary to the stoppage of antiplatelet therapy. With this review, we have tried to guide the clinician on decision-making regarding the care of patients on management of acute upper and lower gastrointestinal bleeding, stoppage, restarting of agents, and measures to prevent a recurrence. We have focused on aspirin and clopidogrel as they are among the most widely used antiplatelet agents.

Effect of co-medications and potential risk factors of high-dose methotrexate-mediated acute hepatotoxicity in patients with osteosarcoma.

Taiwanese patients frequently experience severe hepatotoxicity associated with high-dose methotrexate (HD-MTX) treatment, which interferes with subsequent treatment. Drug-drug interactions occur when MTX is used in combination with proton pump inhibitors (PPIs), trimethoprim-sulfamethoxazole (TMP-SMX), or non-steroidal anti-inflammatory drugs (NSAIDs). In East Asia, real-world analyses on the effects of co-medication and other potential risk factors on the clinical course of HD-MTX-mediated acute hepatotoxicity in patients with osteogenic sarcoma (OGS) are limited. This cohort study included patients with newly diagnosed OGS who were treated with HD-MTX between 2009 and 2017 at Taipei Veterans General Hospital. We collected data on the clinical course of HD-MTX-mediated acute hepatotoxicity, co-medications, and other potential risk factors, and analyzed the effects of these factors on the clinical course of HD-MTX-mediated acute hepatotoxicity. Almost all patients with OGS treated with HD-MTX developed acute hepatotoxicity with elevated alanine aminotransferase (ALT) levels. Most patients with Grade 3-4 ALT elevation failed to recover to Grade 2 within 7 days. Women and children are high-risk subgroups for HD-MTX-mediated elevation of ALT levels. Age is a factor that contributes to the pharmacokinetic differences of HD-MTX. However, the concurrent use of PPIs, TMP-SMX, or NSAIDs did not affect the elimination of MTX when administered with adequate supportive therapy. Co-administration of PPIs, TMP-SMX, or NSAIDs may have limited effects on acute hepatotoxicity in well-monitored and adequately pre-medicated patients with OGS undergoing chemotherapy with HD-MTX. Clinicians should pay particular attention to ALT levels when prescribing HD-MTX to children and women.

Abstract PD13-10: PD13-10 Impact of Proton Pump Inhibitors (PPI) on Palbociclib (PAL) Outcomes in Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer (HR+/HER2- ABC): Exploratory Analysis of the PARSIFAL Trial

Abstract Background The use of PPI among cancer patients (pts) is quite frequent. PAL is an oral, cyclin-dependent kinase 4 and 6 inhibitor recommended to be taken under fed conditions. PAL showed a reduced solubility when gastric pH is >4.5, a level commonly achieved by PPI. Observational, retrospective studies on concomitant PPI with PAL or ribociclib showed a shorter progression-free survival (PFS) among PPI users than nonusers. In the randomized, phase 2 PARSIFAL trial, PAL plus fulvestrant demonstrated no improvement in PFS and overall survival (OS) versus PAL plus letrozole as frontline treatment in HR+/HER2- ABC pts (Llombart-Cussac et al, JAMA Oncol 2021). Here we assessed the impact of PPI on PAL efficacy and safety in pts included in the PARSIFAL study. Methods Pts with endocrine-sensitive HR+/HER2- ABC and no prior therapy in advanced setting were randomly assigned to receive PAL (hard capsule formulation) plus either fulvestrant or letrozole. Pts with ≥1 PPI received over the entire PAL-based regimen were defined as PPI users, or PPI naïve (N-PPI) if no PPI was administered over the whole study treatment. We carried out two analyses considering early PPI users (E-PPI) –composed by pts who were receiving PPI since the PAL-based regimen initiation– and long-term PPI users (LT-PPI) –composed by pts who received PPI over the entire or ≥⅔ of the PAL-based regimen. PPI users defined as neither E-PPI nor LT-PPI were excluded from the analysis to avoid biases due to the PPI limited exposition. PFS, OS, and safety were compared among groups. Landmark analysis at 3, 6, 12, 18, 24, and 30 months (mo) was used for survival estimates conditional on surviving to certain time points and adjust for immortality bias in comparison between N-PPI and PPI users. Analyses were adjusted by stratification factors and patient characteristics. Results Of 486 pts included in the study, 325 (66.9%) were N-PPI. Among 161 (33.1%) PPI users, 64 (13.2%) were E-PPI and 91 (18.7%) were LT-PPI. Omeprazole was the most prescribed PPI in 80.7% (130 of 161) of PPI users. Median exposition to PPI for PPI users, E-PPI, and LT-PPI was 13.6, 15.9, and 19.4 mo, respectively. Compared with N-PPI, E-PPI and LT-PPI were older (median age, 60.5 vs 66.5 vs 67.0 years, respectively; P< 0.001) and had a worse functional status (ECOG PS of 0, 60.0% vs 34.0% vs 43.0%, respectively; P=0.002). Median follow-up for the whole population was 32 mo. Median PFS was 28.7 mo in N-PPI compared with 23.0 mo in E-PPI (HR 1.5; 95%CI 1.1–2.2; P=0.024) and 23.0 mo in LT-PPI (HR 1.4; 95%CI 1.0–1.9; P=0.035). Both PPI groups had poorer median PFS than N-PPI by landmark analysis at 3 and 12 mo. Subgroup analysis showed a consistent trend regardless of endocrine partner. Three-year OS rate was 81.1% in N-PPI compared with 63.5% in E-PPI (HR 2.2; 95%CI 1.3–3.7; P=0.003) and 62.0% in LT-PPI (HR 2.1; 95%CI 1.4–3.4; P=0.001). Both PPI groups had poorer 3-year OS rate than N-PPI by landmark analysis at 3, 6, 12, and 18 mo. Grade ≥3 hematological adverse events (AEs) occurred in 71.7% (233 of 325 pts) of N-PPI compared with 57.8% (37 of 64 pts; P=0.021) of E-PPI and 54.9% (50 of 91 pts; P=0.003) of LT-PPI. Dose reductions and delays due to hematological AEs were reported in 70.8% (230 of 325 pts) of N-PPI compared with 56.3% (36 of 64 pts; P=0.018) of E-PPI and 52.7% (48 of 91 pts; P=0.002) of LT-PPI. At 3 mo, 45.8% (149 of 325 pts) of N-PPI required a dose reduction or delay due to hematological AEs compared with 39.1% (25 of 64 pts; P=0.42) of E-PPI. Conclusions Early and sustained coadministration of PPI with PAL and endocrine therapy were associated with lower efficacy, hematological toxicities, and dose modifications. Despite the post-hoc nature of the study, these findings suggest pharmacokinetic interactions between PPI and PAL capsules. Further confirmatory studies including the tablet formulation of PAL, which is expected to assure its optimal absorption, are needed. Citation Format: Serena Di Cosimo, José Manuel Pérez-García, Meritxell Bellet Ezquerra, Florence Dalenc, Miguel Gil Gil, Manuel Ruiz Borrego, Joaquín Gavilá, Miguel Sampayo-Cordero, Elena Aguirre, Peter Schmid, Frederik Marmé, Joseph Gligorov, Andreas Schneeweiss, Joan Albanell, Pilar Zamora, Duncan Wheatley, Eduardo Martínez De Dueñas, Vicente Carañana, Kepa Amillano, Andrea Malfettone, Javier Cortés, Antonio Llombart-Cussac. PD13-10 Impact of Proton Pump Inhibitors (PPI) on Palbociclib (PAL) Outcomes in Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer (HR+/HER2- ABC): Exploratory Analysis of the PARSIFAL Trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD13-10.

Use of Gastrointestinal Simulator, Mass Transport Analysis, and Absorption Simulation to Investigate the Impact of pH Modifiers in Mitigating Weakly Basic Drugs' Performance Issues Related to Gastric pH: Palbociclib Case Study.

It is well known that reduced gastric acidity, for example with concomitant administration of acid reducing agents, can result in variable pharmacokinetics and decreased absorption of weakly basic drugs. It is important to identify the risk of reduced and variable absorption early in development, so that product design options to address the risk can be considered. This article describes the utilization of in vitro and in silico tools to predict the effect of gastric pH, as well as the impact of adding pH modifiers, in mitigating the effect of acid reducing agents on weak base drugs' dissolution and absorption. Palbociclib, a weakly basic drug, was evaluated in low and high gastric pH conditions in a multicompartmental dissolution apparatus referred to as a gastrointestinal simulator (GIS). The GIS permits the testing of pharmaceutical products in a way that better assesses dissolution under physiologically relevant conditions of pH, buffer concentration, formulation additives, and physiological variations including GI pH, buffer concentrations, secretions, stomach emptying rate, residence time in the GI, and aqueous luminal volume. To predict drug dissolution in the GIS, a hierarchical mass transport model was used and validated using in vitro experimental data. Dissolution results were then compared to observed human clinical plasma data with and without proton pump inhibitors using a GastroPlus absorption model to predict palbociclib plasma profiles and pharmacokinetic parameters. The results showed that the in silico model successfully predicted palbociclib dissolution in the GIS under low and high gastric pH conditions with and without pH modifiers. Furthermore, the GIS data coupled with the in silico tools anticipated (1) the reduced palbociclib exposure due to proton pump inhibitor coadministration and (2) the mitigating effect of a pH-modifying agent. This study provides tools to help in the development of orally administered formulations to overcome the effect of elevated gastric pH, especially when formulating with pH modifiers.

Population Pharmacokinetics of Palbociclib and Its Correlation with Clinical Efficacy and Safety in Patients with Advanced Breast Cancer.

Neutropenia is the most frequent dose-limiting toxicity reported in patients with metastatic breast cancer receiving palbociclib. The objective of this study was to investigate the pharmacokinetic–pharmacodynamic (PK/PD) relationships for toxicity (i.e., absolute neutrophil count, ANC) and efficacy (i.e., progression-free survival, PFS). A semi-mechanistic PK/PD model was used to predict neutrophils’ time course using a population approach (NONMEM). Influence of demographic and clinical characteristics was evaluated. Cox proportional hazards models were developed to evaluate the influence of palbociclib PK on PFS. A two-compartment model with first-order absorption and a lag time adequately described the 255 palbociclib concentrations provided by 44 patients. The effect of the co-administration of proton-pump inhibitors in fasting conditions increased palbociclib clearance by 56%. None of the tested covariates affected the PD parameters. Model-based simulations confirmed the concentration-dependent and non-cumulative properties of palbociclib-induced neutropenia, reversible after treatment withdrawal. The ANC nadir occurred approximately at day 24 of each cycle. Cox analyses revealed a trend for better PFS with increasing palbociclib exposure in older patients. By characterizing palbociclib-induced neutropenia, this model offers support to clinicians to rationally optimize treatment management through patient-individualized strategies.

Proton pump inhibitors affect capecitabine efficacy in patients with stage II\u2013III colorectal cancer: a multicenter retrospective study

The association between capecitabine efficacy and proton pump inhibitors (PPIs) is controversial. Here, we determined whether co-administration of PPIs affects the real-world effectiveness of capecitabine. This retrospective observational study included consecutive patients with stage II–III colorectal cancer (CRC) who received adjuvant capecitabine monotherapy or CapeOX (capecitabine and oxaliplatin) between January 2009 and December 2014 at nine participating institutions. The primary endpoint was the difference in relapse-free survival (RFS) between patients who received PPIs and those who did not and was estimated using the Kaplan–Meier method. Overall survival (OS) was the secondary endpoint. Multivariable analysis of RFS and OS was performed using a Cox proportional hazards model, propensity score adjustment, and inverse probability of treatment weighting (IPTW) analyses. Data from 606 patients were evaluated, 54 of whom had received a PPI. PPI-treated patients tended to have poorer RFS and OS than patients treated without PPIs. The hazard ratio for RFS with capecitabine monotherapy was 2.48 (95% confidence interval: 1.22–5.07). These results were consistent with sensitivity analyses performed using propensity score adjustment and IPTW methods. Co-administration of PPIs may reduce the effectiveness of capecitabine and negatively impact patients with stage II–III CRC.

Effect of proton pump inhibitors on the development of hypomagnesemia induced by panitumumab.

Panitumumab, a therapeutic agent for unresectable advanced/recurrent colorectal cancer, is a human IgG2 monoclonal antibody that binds to and inhibits the activity of the epidermal growth factor receptor (EGFR). The onset of hypomagnesemia is a known side effect of anti-EGFR inhibitors, including panitumumab, and it is thought that inhibition of reabsorption of Mg in renal tubules is one of the causes. In addition, recent reports have shown that long-term administration of proton pump inhibitors (PPIs) reduces serum magnesium levels. Therefore, in this study, 102 patients who received oral PPIs treated with panitumumab were classified into a PPI combination group and a PPI non-combination group, and the effect of PPIs on the development of grade 2 or higher hypomagnesemia was investigated. The incidence of hypomagnesemia in the PPI combination group (46.9%, 15/32) was higher than that in the PPI non-combination group (25.7%, 18/70). A comparison of the backgrounds of the two groups of patients showed a significant difference in serum albumin levels. PPI administration was significantly associated with panitumumab-induced hypomagnesemia development when adjusted for known risk factors, serum albumin level, renal function, and oral magnesium oxide tablets in Cox proportional hazards regression analysis (hazard ratio 2.09; 95% confidence interval 1.03-4.22; P =0.040). These results indicate that detailed monitoring of serum magnesium levels is recommended for patients treated with panitumumab and co-administration of PPIs.

Population Pharmacokinetics Analysis of Pemigatinib in Patients With Advanced Malignancies.

Pemigatinib is a fibroblast growth factor receptor 1–3 inhibitor used to treat cholangiocarcinoma. A compartmental population pharmacokinetics model was developed using data from 318 patients with cancer enrolled in a phase 1 dose‐escalation/dose‐expansion study, a phase 1 Japanese PK bridging study, and a phase 2 cholangiocarcinoma study. The final model for pemigatinib was a 2‐compartment disposition model with first‐order absorption and linear elimination. All fixed‐ and random‐effect parameters were estimated with good precision, and no apparent biases in the overall model fit were observed. For females, the estimated typical pemigatinib absorption rate constant (ka) and oral clearance (CL/F) were estimated (1.49 L/h and 10.3 L/h, respectively). For males, the typical apparent clearance and ka are 19.0% higher and 56.5% lower, respectively, compared with females. Typical apparent volume of distribution of the central compartment (Vc/F) and peripheral compartment for a 73.3‐kg patient was estimated to be 122.0 L and 80.1 L, respectively; both increased with body weight. Phosphate binder coadministration decreases typical pemigatinib CL/F by 14.1%. Proton pump inhibitor coadministration increases typical pemigatinib apparent Vc/F by 24.4%. Phosphate binders and sex contribute a <20% change to CL/F. The impact of the investigated covariates on pemigatinib pharmacokinetics are not clinically significant.

Analysis of Combined Effect of CYP2C19 Genetic Polymorphism and Proton Pump Inhibitors Coadministration on Trough Concentration of Voriconazole.

PurposeTo analyze the combined effect of CYP2C19 genetic polymorphism and PPIs coadministration on voriconazole trough concentration (VCZ-Ctrough) in Chinese patients with hematological disorders.Patients and MethodsA prospective observational study involved 250 plasma samples from 114 adult patients receiving voriconazole with or without PPIs were analyzed. Demographics and clinical characteristics were obtained from patient’s records. A validated LC-MS/MS was used to quantify the plasma VCZ-Ctrough. Genotyping for CYP2C19*2 and CYP2C19*3 variant alleles was performed by PCR-RFLP followed by DNA sequencing. The combined total score (from 2 to 5) was calculated for each patient. The higher the score, the lesser the metabolism of the patient.FindingsFifty percent of patients administered with voriconazole were coadministered with PPIs, predominantly omeprazole or esomeprazole. Patients exhibiting CYP2C19 poor metabolizer phenotype showed a significantly higher median VCZ-Ctrough, (4.31µg/mL [IQR, 1.64µg/mL–7.36µg/mL]) than patients with normal metabolizer (1.38µg/mL, [IQR, 0.79µg/mL–2.14µg/mL], p < 0.0001). Similarly, patients co-administration with PPIs had higher median VCZ-Ctrough (2.86µg/mL [IQR 1.33µg/mL–4.66µg/mL]), than PPIs non-users (1.71µg/mL, [IQR, 0.86µg/mL–3.48µg/mL], p = 0.001). However, we noted that the median VCZ-Ctrough for each factor was ranging within the normal recommended therapeutic range in the Chinese population (0.5µg/mL–5µg/mL). But when the two factors were combined, the median VCZ-Ctrough was steadily increasing as the metabolic capacity (reflected by combined total score) was increasing. Importantly, the median VCZ-Ctrough in PM/PPIs user (total score 5) was significantly elevated to supra-therapeutic levels compared to NM/PPI non-user group (total score 2) (5.83µg/mL [IQR, 2.19µg/mL–9.51µg/mL] versus 1.13µg/mL [IQR, 0.67µg/mL–1.82µg/mL]), respectively, P < 0.0001. Furthermore, we observed that the elevation of median VCZ-Ctrough to supra-therapeutic levels was largely contributed by omeprazole or esomeprazole compared to lansoprazole or pantoprazole.ConclusionCoadministration with PPIs significantly increased voriconazole trough concentrations and there was an additive effect in CYP2C19 PMs, who were most likely to have supra-therapeutic levels.

The Clinical Impact of Proton Pump Inhibitors When Co-Administered With Dual Antiplatelet Therapy in Patients Having Acute Myocardial Infarction With Low Risk of Gastrointestinal Bleeding: Insights From the China Acute Myocardial Infarction Registry.

Background: The latest guidelines recommend the use of proton pump inhibitors (PPIs) to minimize gastrointestinal bleeding (GIB) in patients receiving dual antiplatelet therapy (DAPT), even though this co-administration may increase the risk of ischemia due to drug interactions. We have noticed that there are few studies conducted on patients with a lower risk of GIB. Therefore, we investigated the clinical effect of co-administration of PPI on DAPT patients with low GIB risk.Methods and Results: From January 2013 to September 2014, a total of 17,274 consecutive patients on DAPT from 108 hospitals with low risk for GIB in the China Acute Myocardial Infarction (CAMI) registry were analyzed. The primary endpoints were GIB and major adverse cardiovascular and cerebrovascular events (MACCE). Multivariate logistic regression analysis and Cox proportional hazard models were used to assess the effect of PPIs use. Of the analyzed patients, 66.6% (n = 11,487) were treated with PPIs. PPI use did not show an extra gastrointestinal protective effect in patients with low risk for GIB who were hospitalized and on follow-up after 2 years. Moreover, it was associated with an increased risk of stroke during the 2-year follow-up [hazard ratio (HR) 2.072, 95% confidence interval (CI) 1.388–3.091, p = 0.0003] and an increased risk of MI after 6 months (HR 1.580, 95% CI 1.102–2.265, p = 0.0119). We found the same results after propensity score matching.Conclusion: PPI use is prevalent in DAPT patients with low GIB risk. PPIs did not show an extra gastrointestinal protective effect, while an increased risk of stroke was observed during the 2-year follow-up.Clinical Trial Registration:www.clinicaltrials.gov, identifier NCT01874691.

498P Association between capecitabine efficacy and proton pump inhibitors in patients with stage II-III colorectal cancer: A retrospective multicenter study

The association between capecitabine efficacy and coadministration of proton pump inhibitors (PPIs) has currently been controversial issue. The present study aimed to clarify whether coadministration of PPIs affects the real-world effectiveness of capecitabine in postoperative patients with early-stage colorectal cancer (CRC) receiving adjuvant chemotherapy.

Improved characterization of the pharmacokinetics of acalabrutinib and its pharmacologically active metabolite, ACP-5862, in patients with B-cell malignancies and in healthy subjects using a population pharmacokinetic approach.

This analysis aimed to describe the pharmacokinetics (PK) of acalabrutinib and its active metabolite, ACP‐5862. A total of 8935 acalabrutinib samples from 712 subjects and 2394 ACP‐5862 samples from 304 subjects from 12 clinical studies in patients with B‐cell malignancies and healthy subjects were analysed by nonlinear mixed‐effects modelling. Acalabrutinib PK was characterized by a 2‐compartment model with first‐order elimination. The large variability in absorption was adequately described by transit compartment chain and first‐order absorption, with between‐occasion variability on the mean transit time and relative bioavailability. The PK of ACP‐5862 was characterized by a 2‐compartment model with first‐order elimination, and the formation rate was defined as the acalabrutinib clearance multiplied by the fraction metabolized. Health status, Eastern Cooperative Oncology Group performance status, and coadministration of proton‐pump inhibitors were significant covariates. However, none of the investigated covariates led to clinically meaningful changes in exposure, supporting a flat dosing of acalabrutinib.