Impact Of Drug-drug Interactions Research Articles

Abstract PO1-01-08: The impact of drug-drug interactions between palbociclib and proton pump inhibitors on clinical outcomes of patients with hormone receptor positive, HER2-negative, early breast cancer: an exploratory analysis of the PALLAS study

Abstract Background: Data suggest that concomitant intake of proton pump inhibitors (PPI) may create drug-drug interactions, potentially impacting efficacy of agents including palbociclib, which is widely used in the treatment of metastatic hormone-receptor-positive/HER2-negative (HR+/HER2-) breast cancer. In the open label, randomized, phase 3 PALLAS trial, the addition of palbociclib for two years to standard adjuvant endocrine therapy (ET) in patients with HR+/HER2- early breast cancer (EBC) did not improve invasive disease-free survival (IDFS) compared to adjuvant ET alone. We explored whether concomitant use of PPIs could have affected clinical outcomes in patients treated with palbociclib in PALLAS. Methods: This is an exploratory, unplanned analysis of the PALLAS trial (AFT-05/ABCSG-42/PrE0109/BIG-14-13, NCT02513394), which enrolled 5796 patients with stage II-III HR+/HER2- EBC. Patients were randomized to receive either 2 years of palbociclib (125 mg oral capsules once daily on days 1-21 of a 28-day cycle) with adjuvant ET or ET alone. Primary endpoint was IDFS in the intention-to-treat population. The present exploratory analysis included patients who received at least one dose of palbociclib. Definitions of IDFS, distant relapse-free survival (DRFS) and overall survival (OS) were according to the PALLAS protocol (STEEP criteria), using first day of palbociclib intake as start date. Only PPI concomitant intake during palbociclib treatment was considered. To determine the association of concomitant PPI use with IDFS, DRFS, and OS, uni- and multivariable Cox models with time-dependent PPI (the latter adjusted for age, prior chemotherapy, progesterone receptor, grade, tumor stage, nodal stage, body mass index (BMI)) were used. Also, the association between PPI use and neutropenia was investigated in patients initiating PPI prior to randomization vs never. Odds ratios (OR) unadjusted and adjusted for age and BMI estimated with logistic regression models are reported. Results: Of 2840 patients treated with palbociclib + ET, 533 (18.8%) had concomitant PPI and palbociclib intake. Median duration of PPI intake was 10.8 months (interquartile range 2.3-22.3). Most patients received omeprazole as PPI (n=265, 49.7%). PPI intake was significantly associated with older age, post-menopausal status, use of aromatase inhibitors as ET, higher BMI, and worse ECOG status (all p< 0.001). Concomitant PPI intake was not significantly associated with survival outcomes (Table 1). Unadjusted all grade neutropenia rates were slightly lower in patients who initiated PPI prior study start vs patients never initiating (79% vs 85%, unadjusted OR 0.66, 95%CI 0.50-0.88). After adjustment for BMI and age, the difference between the groups decreased (adjusted OR = 0.77, 95%CI 0.57-1.04). Similar effect sizes were found for grade 3/4 neutropenia rates (54% vs 64%, unadjusted OR 0.66, 95%CI 0.52-0.83, adjusted OR 0.81, 95%CI 0.64-1.03). Conclusions: Our exploratory analysis did not demonstrate a statistically significant relationship between concomitant use of PPIs and palbociclib and survival outcomes of patients in the PALLAS trial. Nonetheless, careful consideration of concomitant medications and of drug-drug interactions is important when studying novel agents in the adjuvant breast cancer setting. Support: AFT, Pfizer; https://acknowledgments.alliancefound.org Table 1. Association between PPI intake and survival outcomes. Citation Format: Elisa Agostinetto, Georg Pfeiler, Dominik Hlauschek, Erica Mayer, Matteo Lambertini, Evandro de Azambuja, Meritxell Bellet- Ezquerra, Jane Meisel, Gabor Rubovszky, Nicholas Zdenkowski, Yelena Novik, Manuel Ruíz - Borrego, Karen Gelmon, Eleftherios Mamounas, Hiroji Iwata, Dongrui Lu, Lidija Sölkner, Christian Fesl, Michael Gnant, Angela DeMichele. The impact of drug-drug interactions between palbociclib and proton pump inhibitors on clinical outcomes of patients with hormone receptor positive, HER2-negative, early breast cancer: an exploratory analysis of the PALLAS study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-01-08.

The Impact of Drug-Drug Interactions on the Toxicity Profile of Combined Treatment with BRAF and MEK Inhibitors in Patients with BRAF-Mutated Metastatic Melanoma.

BRAF and MEK inhibition is a successful strategy in managing BRAF-mutant melanoma, even if the treatment-related toxicity is substantial. We analyzed the role of drug-drug interactions (DDI) on the toxicity profile of anti-BRAF/anti-MEK therapy. In this multicenter, observational, and retrospective study, DDIs were assessed using Drug-PIN software (V 2/23). The association between the Drug-PIN continuous score or the Drug-PIN traffic light and the occurrence of treatment-related toxicities and oncological outcomes was evaluated. In total, 177 patients with advanced BRAF-mutated melanoma undergoing BRAF/MEK targeted therapy were included. All grade toxicity was registered in 79% of patients. Cardiovascular toxicities occurred in 31 patients (17.5%). Further, 94 (55.9%) patients had comorbidities requiring specific pharmacological treatments. The median Drug-PIN score significantly increased when the target combination was added to the patient's home therapy (p-value < 0.0001). Cardiovascular toxicity was significantly associated with the Drug-PIN score (p-value = 0.048). The Drug-PIN traffic light (p = 0.00821) and the Drug-PIN score (p = 0.0291) were seen to be significant predictors of cardiotoxicity. Patients with low-grade vs. high-grade interactions showed a better prognosis regarding overall survival (OS) (p = 0.0045) and progression-free survival (PFS) (p = 0.012). The survival analysis of the subgroup of patients with cardiological toxicity demonstrated that patients with low-grade vs. high-grade DDIs had better outcomes in terms of OS (p = 0.0012) and a trend toward significance in PFS (p = 0.068). DDIs emerged as a critical issue for the risk of treatment-related cardiovascular toxicity. Our findings support the utility of DDI assessment in melanoma patients treated with BRAF/MEK inhibitors.

Assessment of the role of nucleoside transporters, P-glycoprotein, breast cancer resistance protein, and multidrug resistance-associated protein 2 in the placental transport of entecavir using in vitro, ex vivo, and in situ methods

The nucleoside analog entecavir (ETV) is a first-line pharmacotherapy for chronic hepatitis B in adult and pediatric patients. However, due to insufficient data on placental transfer and its effects on pregnancy, ETV administration is not recommended for women after conception. To expand knowledge of safety, we focused on evaluating the contribution of nucleoside transporters (NBMPR sensitive ENTs and Na+ dependent CNTs) and efflux transporters, P-glycoprotein (ABCB1), breast cancer resistance protein (ABCG2), and multidrug resistance-associated transporter 2 (ABCC2), to the placental kinetics of ETV. We observed that NBMPR and nucleosides (adenosine and/or uridine) inhibited [3H]ETV uptake into BeWo cells, microvillous membrane vesicles, and fresh villous fragments prepared from the human term placenta, while Na+ depletion had no effect. Using a dual perfusion study in an open-circuit setup, we showed that maternal-to-fetal and fetal-to-maternal clearances of [3H]ETV in the rat term placenta were decreased by NBMPR and uridine. Net efflux ratios calculated for bidirectional transport studies performed in MDCKII cells expressing human ABCB1, ABCG2, or ABCC2 were close to the value of one. Consistently, no significant decrease in fetal perfusate was observed in the closed-circuit setup of dual perfusion studies, suggesting that active efflux does not significantly reduce maternal-to-fetal transport. In conclusion, ENTs (most likely ENT1), but not CNTs, ABCB1, ABCG2, and ABCC2, contribute significantly to the placental kinetics of ETV. Future studies should investigate the placental/fetal toxicity of ETV, the impact of drug-drug interactions on ENT1, and interindividual variability in ENT1 expression on the placental uptake and fetal exposure to ETV.

Considering the Oral Bioavailability of Protein Kinase Inhibitors: Essential in Assessing the Extent of Drug-Drug Interaction and Improving Clinical Practice.

Protein kinase inhibitors share pharmacokinetic (PK) pathways among themselves. They are all metabolized by several cytochromes P450 (CYP). For most of them, CYP3A4 is the predominant metabolic pathway. However, their oral bioavailability differs. For example, the oral bioavailability of imatinib has been estimated at nearly 100%, but that of ibrutinib averages 3% due to its high hepatic first-pass effect. Overall, the smaller the oral bioavailability, the larger its interindividual PK variability. Indeed, for drugs with low oral bioavailability, the extent of their absorption is an additional cause (along with elimination variability) of differences in drug exposure among patients. The impact of drug-drug interaction (DDI) also differs between drugs with low or high oral bioavailability. We describe and explain why the impact of CYP3A4 inhibitors and inducers is much greater for protein kinase inhibitors with low oral bioavailability. The effect of food on protein kinase inhibitors and DDIs corresponding to plasma protein binding will also be considered. Finally, the benefits of these concepts in clinical practice (including therapeutic drug monitoring) will be discussed. Overall, our main objective was to apply fundamental PK concepts to understanding the main clinical issues of these oral anticancer drugs.

267P AB-ITALY: The impact of drug-drug interaction on abemaciclib treatment in Italian real world experience

Abemaciclib demonstrated a clinical benefit in women affected by HR+/HER2- metastatic breast cancer (mBC). Drug-drug interactions (DDIs) can lead to a reduced treatment efficacy or increased toxicity. Drug-PIN® (Personalized Interactions Network) is a tool recognizing the crucial role of multiple interactions between active and/or pro-drug forms combined with biochemical and demographic patient data. This retro-prospective study aimed to evaluate outcomes, toxicities and DDIs of abemaciclib combined with hormone therapy in a real-world setting. Patients (pts) from 12 referral hospitals in Italy, affected by HR+/HER2- mBC who received abemaciclib were included. Availability of clinical data about comorbidities, concurrent medications, outcomes were inclusion criteria. Drug-PIN® was used to define the Drug-PIN score and Drug-PIN tier (green, yellow, dark yellow, orange, and red) for each pt. Univariate and multivariate analysis were performed to identify early predictors of patients PFS, toxicity or best response (BR). A total of 173 pts were included. Abemaciclib was administered in combination with fulvestrant or with aromatase inhibitors in 92 and 81 pts, respectively. Overall response rate (ORR) was 62.8%. The median PFS was 28.8 months.The most common toxicities were diarrhoea, asthenia and neutropenia in 63%,49%,49% of pts respectively. Median Drug-PIN score was 3.25 (range 0 -114.8) and 150, 6, 8, 6 and 3 pts were in the green, yellow, dark yellow, orange and red tier, respectively. At the univariate analysis, the number of drugs (p=0.003), the best response (p<0.0001), the high values of Drug-PIN score (p=0.015) and the Drug-PIN tier (from dark yellow to red, p=0.039) were associated with decreased PFS. Correcting for significant variables found at univariate analysis, only the association between BR (p<0.0001), Drug-PIN tier (dark yellow to red, p=0.007) and decreased PFS were confirmed at the multivariate analysis (p<0.0001). Our study suggests that the concomitant use of multiple drugs is associated with higher toxicity in pts affected by mBC treated with abemaciclib. Moreover, a statistically significant association between decreased PFS and high Drug-PIN score was shown.

T3 Pharmacogenetic Gene-drug Associations in Pediatric Burn and Surgery Patients

IntroductionManagement of critically ill patients requires simultaneous administration of many medications. These patients may have co-morbidities and drug-drug interactions which may result in decreased drug efficacy or increased risk of adverse reactions. Children are of particular concern as they may be even more sensitive to adverse drug reactions. Current practices rely on a one-size-fits-all approach for most medication dosing. Alternatively, precision medicine evaluates an individual’s genetic profile and adjusts individual therapeutic dosing. Pharmacogenetic testing is not generally implemented but is reserved for addressing an established problem rather than being used proactively to optimize clinical care. A greater understanding of the frequency of clinically significant genetic variants in drug pathways and identification of the drugs most commonly impacted by genetic makeup is needed to incorporate pharmacogenetics into medical care. We hypothesize several patients will have one or more genetic variants in drug metabolizing pathways used by one or more medications administered during hospitalization. The aims of this study are to determine the frequency of abnormal genetic variants in the primary drug pathways and assess what medications may be impacted.MethodsGenetic data from 30 pediatric burn and surgery patients was collected to identify genetic variants in drug metabolizing pathways. We also evaluated drugs potentially impacted by these variants that were administered during the hospitalization. 19 whole exome and 11 whole genome sequencing datasets were analyzed using Aldy allelic decomposition software to identify haplotypes in cytochrome P450 (CYP) metabolizing enzyme genes.Results17 patients were identified with predicted altered function in 1 or more of the following CYP genes: 2C9, 2C19, 2D6, 3A4 and 3A5. The majority had decreased function, except for several patients with CYP2C19 variants with rapid or ultrarapid phenotypes. Drugs administered during hospitalization that rely on these pathways for primary metabolism include hydrocodone, oxycodone, methadone, ibuprofen, ketorolac, celebrex, diazepam, famotidine, diphenhydramine and glycopyrrolate.ConclusionsThis research demonstrates that approximately 1/4 to 1/3 of patients have functionally impactful haplotypes in the primary drug metabolizing pathways. There is great need for future clinical research to further evaluate the clinical relevance of these haplotypes and the additional impact of drug-drug interactions and other clinical confounders that additionally impact drug efficacy.

Impact of Drug-Drug Interaction between CDK4/6 Inhibitors and Proton Pump Inhibitors on Survival Outcomes in the Treatment of Metastatic Breast Cancer—Real World Data from a Portuguese Center

Introduction: Proton pump inhibitors (PPi) are widely prescribed, including in patients undergoing treatment for advanced breast cancer (ABC). Due to the pharmacokinetic characteristics of the CDK4/6 inhibitor (Ci) palbociclib a drug interaction with PPi was hypothesized. It was shown in a retrospective study that this association was an independent predictive factor for worse progression-free survival (PFS). Objective: To verify the impact of concomitant administration of PPi with Ci on overall survival (OS) and PFS. Material and Methods: This is a retrospective cohort study of patients treated with Ci for HR+HER2-ABC in the period from Feb/2017 to Aug/2020. SPSS software was used for data processing. Univariate analysis was done by the Kaplan-Meier method and log-rank test, and multivariate analysis by COX regression. P-value - 75). Treatment with Ci was 1st line for ABC in 68.8%. Choice of Ci was palbociclib in 73.8% (n = 59) and ribociclib in 26.3% (n = 21). The hormone partner was a nonsteroidal aromatase inhibitor in 45.0%, and fulvestrant in 55.0% of cases. 37.5% of patients were on PPi, and 70.0% of them were during the entire treatment (23.3% omeprazole, 73.4% pantoprazole, 3.3% others). Patients taking concomitant PPi and Ci had lower OS (OS-3 years 42.6% vs. 63.4%, p = 0.254) and PFS (PFS med 15 m. vs. 21 m., p = 0.733), although with no statistically significant difference. Discussion: In the sample, there was a numerical difference, without the statistical significance in the use of PPi in the survival of patients under Ci. This difference could be more evident with a longer follow-up and a larger sample size. This study intends to alert to the growing importance of checking for drug interactions. Polymedication, advanced age and the presence of several comorbidities are real problems in patients with ABC. Conclusion: Real-world data from this center demonstrate a negative, non-statistically significant impact of PPi treatment on survival outcomes, in patients treated with Ci for HR+HER2-ABC.

Prevalence, beliefs and impact of drug-drug interactions between antiretroviral therapy and illicit drugs among people living with HIV in Spain.

Drug use implies important challenges related to HIV management, particularly due to an increased risk of potential interactions between antiretroviral therapy (ART) and illicit drugs (pDDIs). This study analyses the prevalence and severity of pDDIs among people living with HIV (PLHIV). It also explores their awareness of pDDIs and their beliefs about the toxicity that they may cause, as well as the impact of pDDIs on selected health variables. We conducted an on-line cross-sectional survey across 33 Spanish hospitals and NGOs to collect demographics and clinical data. pDDIs were checked against the Interaction Checker developed by Liverpool University. The sample of the present study was composed of 694 PLHIV who used illicit drugs. They represented 49.5% of the 1,401 PLHIV that participated in the survey. After excluding 38 participants due to lack of information on their ART or illicit drug use, 335 (51.1%) participants consuming drugs presented with some potentially significant pDDIs between their ART and illicit drugs, with a mean of 2.1±1.7 (1–10) pDDIs per patient. The drugs most frequently involved in pDDIs were cocaine, cannabis, MDMA and nitrates ("poppers"). The prevalence of pDDIs across ART regimens was: protease inhibitors (41.7%); integrase inhibitor-boosted regimens (32.1%), and non-nucleoside reverse transcriptase inhibitors (26.3%). An awareness of pDDIs and beliefs about their potential toxicity correlated positively with intentional non-adherence (p<0.0001). Participants with pDDIs exhibited a higher prevalence of intentional non-adherence (2.19±1.04 vs. 1.93±0.94; p = 0.001). The presence of pDDIs was not associated with poorer results in the clinical variables analysed. A significant proportion of PLHIV who use drugs experience pDDIs, thereby requiring close monitoring. pDDIs should be considered in the clinical management of HIV patients. Adequate information about pDDIs and indicators about how to manage ART when PLHIV use drugs could improve ART non-adherence.

Abstract PS5-16: Impact of drug-drug interaction on palbociclib serum levels: Interest of therapeutic drug monitoring

Abstract Background: The CDK4/6 inhibitors palbociclib is prescribed in association with hormonal therapy for the management of metastatic breast cancer patients. Like most oral targeted drug, therapeutic drug monitoring may be used for personalize their dosage. Using a recently published dosing technique (LC-MS/MS), we aimed at evaluating the correlation between first-cycle palbociclib plasma exposition and co-medications in order to evaluate drug-drug interaction (DDI) impact under palbociclib treatment.Methods: This is an open-label phase 4 study conducted in female subjects with first-line metastatic breast cancer (NCT04025541) treated with a palbociclib-aromatase inhibitor association. Plasma concentration of palbociclib was assessed at 24 hours postdose (plasma trough concentration Ctrough) at day 15 of first cycle of treatment. A dedicated pharmacist consultation allowed the determination of clinical covariates of interest, such as weight, body surface area, ethnicity, food intake, co-medications use and DDI before Palbociclib initiation and retrospectively at the end of clinical trial. Patients were classified then according to their risk of DDI potentially leading to inhibition of CYP3A4 and/or P-glycoprotein and gastric pH increase by gastric acid-suppressive (GAS) agents (such as proton pump inhibitors, histamine H2-receptor blockers or alginic acid). Relevant drug known to have an inhibition of CYP3A4 and/or P-glycoprotein or pH-modification activity were checked in databases (e.g. DDI predictor®, Drugs.com®, Pubmed®). Results: To date, after Ctrough analysis of the 35 first cases, the geometric mean (± standard deviation [min-max]) of palbociclib plasma Ctrough was 79.5 ng/ml (± 26.1% [43.6 ng/mL - 133 ng/mL]) at day 15, similar to what reported in the PALOMA trials. No correlation between plasma concentration and body weight, body area or also age of the patients was found in our cohort. Regarding ethnicity, all the included patients were from Caucasian origin. 31% of patients (11/35) were identified of taking drugs that could cause DDI CYP3A4 and P-glycoprotein inhibition mediated (amlodipine n=3, simvastatin n=3, losartan n=2, fluconazole n=1, atorvastatin n=1, ivabradine n=1). These potential DDI interactions were associated with a significantly higher palbociclib concentration DDI subgroup (102 ng/mL vs 69 ng/mL) (p=0.000272) (Table 1). No CYP3A4 and/or P-glycoprotein inductor were reported in cohort. 1.4% of patients (5/35) were identified of taking GAS agents (pantoprazole n=2, ranitidine n=2, alginic acid n=1). We found a significantly reduction of palbociclib concentration (59.2 ng/mL vs 79.8 ng/mL) (p=0.048) in patients taking GAS medications (Table 1). Conclusion : These preliminary results, in real-life settings, obtained with our recently-published HPLC-MS/MS method, give important information on palbociclib monitoring and pharmacokinetic variability. DDI appear to have a significant impact on palbociclib plasma exposure, GAS agents are already know to modified palbociclib absorption. Additional studies are needed to characterize palbociclib plasma concentration variations between patients, and their clinical impact on efficacy and safety. The study is ongoing and will evaluate additional potential clinical and biological impact of DDI on neutropenia occurrence, on a larger population of patients. Table 1: Patients’ plasma palbociclib concentration (day 15 of cycle 1 of treatment).Plasma palbociclib concentrations (ng/ml), global cohort (n=35)Geometric mean (CV%) (min;max)79.5 (26.1%) (43.6;133)Plasma palbociclib concentrations (ng/ml), cohort with DDI CYP3A4 and P-gp mediated (n=11)Geometric mean (CV%)102 (24.3%)Plasma palbociclib concentrations (ng/ml), cohort without DDI CYP3A4 and P-gp mediated (n=24)Geometric mean (CV%)69 (19.8%)Plasma palbociclib concentrations (ng/ml), cohort with GAS treatment (n=5)Geometric mean (CV%)59.2 (15.9%)Plasma palbociclib concentrations (ng/ml), cohort without GAS treatment (n=30)Geometric mean (CV%)82.9 (26.1%) Citation Format: Fanny Leenhardt, Matthieu Gracia, Catherine Perrin, Claudia Muracciole-Bich, Bénédicte Marion, Celine Roques, Marie Alexandre, Nelly Firmin, Stephane Pouderoux, Litaty Mbatchi, Celine Gongora, William Jacot, Alexandre Evrard. Impact of drug-drug interaction on palbociclib serum levels: Interest of therapeutic drug monitoring [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-16.

Physiologically based pharmacokinetic modeling of altered tizanidine systemic exposure by CYP1A2 modulation: Impact of drug-drug interactions and cigarette consumption

Tizanidine is an alpha2-adrenergic agonist, used to treat spasticity associated with multiple sclerosis and spinal injury. Tizanidine is primarily metabolized by CYP1A2 and is considered a sensitive index substrate for this enzyme. The physiologically based pharmacokinetic (PBPK) modeling platform Simcyp® was used to evaluate the impact of CYP1A2 modulation on tizanidine exposure through drug-drug interactions (DDIs) and host-dependent habits (cigarette smoking). A PBPK model was developed to predict tizanidine disposition in healthy volunteers following oral administration. The model was verified based on agreement between model-simulated and clinically observed systemic exposure metrics (Cmax, AUC). The model was then used to carry-out DDI simulations to predict alterations in tizanidine systemic exposure when co-administered with various CYP1A2 perpetrators including competitive inhibitors (fluvoxamine, ciprofloxacin), a mechanism-based inhibitor (rofecoxib), and an inducer (rifampin). Additional simulations were performed to evaluate the impact of cigarette smoking on systemic exposure. Under each scenario, the PBPK model was able to capture the observed fold changes in tizanidine Cmax and AUC of tizanidine when coadministered with CYP1A2 inhibitors or inducers. These results add to the available research findings in the literature on PBPK predictions of drug-drug interactions and illustrate the potential application in drug development, specifically to support product labeling.

Drug-Drug Interactions with Direct Oral Anticoagulants.

A large body of evidence suggests that not only direct anticoagulant effects but also major bleeding events and stroke prevention depend on plasma concentrations of direct oral anticoagulants (DOACs). Concomitant drugs that cause drug–drug interactions (DDIs) alter DOAC exposure by increasing or decreasing DOAC bioavailability and/or clearance; hence, they might affect the efficacy and safety of DOAC therapy. Patients with renal impairment already receive smaller DOAC maintenance doses because avoidance of elevated DOAC exposure might prevent serious bleeding events. For other causes of increased exposure such as DDIs, management is often less well-defined. Considering that DOAC patients are often older and have multiple co-morbidities, polypharmacy is highly prevalent. However, the effect of multiple drugs on DOAC exposure, and especially the impact of DDIs when concurring with drug–disease interactions as observed in renal impairment, has not been thoroughly elucidated. In order to provide effective and safe anticoagulation with DOACs, understanding the mechanisms and magnitude of DDIs appears relevant. Instead of avoiding drug combinations with DOACs, more DDI trials should be conducted and new strategies such as dose adjustments based on therapeutic drug monitoring should be investigated. However, dose adjustments based on concentration measurements cannot currently be recommended because evidence-based data are missing.

Adverse drug reactions caused by drug–drug interactions in cardiovascular disease patients: introduction of a simple prediction tool using electronic screening database items

Objective: Cardiovascular disease (CVD) drugs have been frequently implicated in adverse drug reaction (ADR)-related hospitalizations. Drug–drug interactions (DDIs) are common preventable cause of ADRs, but the impact of DDIs in the CVD population has not been investigated. Hence, the primary aim of the study was to identify DDIs associated with ADRs in CVD patients at hospital admission. The second aim was to develop a simple tool to identify high-risk patients for DDI-related adverse events.Methods: An observational study was conducted on the Cardiology Ward of University Clinical Hospital Center. Data were obtained from medical charts. A clinical panel identified DDIs implicated in ADRs, using LexiInteract database and Drug Interaction Probability Scale. Statistics were performed using PASW 22 (SPSS Inc.).Results: DDIs contributed to hospital admission with a total prevalence of 9.69%. DDI-related ADRs affected mainly cardiac function (heart rate or rhythm, 41.07%); bleeding and effect on blood pressure were equally distributed (17.86%). Non-cardiovascular ADRs were found in 23.21% of DDIs. After admission, 73% of the identified DDIs led to changes in prescription. Prediction ability of calculated DDI adverse event probability scores was rated as good (AUC = 0.80, p < .001).Conclusions: CVD patients are highly exposed to adverse DDIs; about one in ten patients hospitalized with CVD might have a DDI contributing to the hospitalization. Given the high prevalence of CVD, DDI-related harm might be a significant burden worldwide. Identification of patients with high DDI adverse event risk might ease the recognition of DDI-related harm and improve the use of electronic databases in clinical practice.

A Clinical Quantitative Evaluation of Hepatobiliary Transport of [11C]Dehydropravastatin in Humans Using Positron Emission Tomography.

Various positron emission tomography (PET) probes have been developed to assess in vivo activities in humans of drug transporters, which aid in the prediction of pharmacokinetic properties of drugs and the impact of drug-drug interactions. We developed a new PET probe, sodium (3R, 5R)-3, 5-dihydroxy-7-((1S, 2S, 6S, 8S)-6-hydroxy-2-methyl-8- ((1-[11C]-(E)-2-methyl-but-2-enoyl) oxy) -1, 2, 6, 7, 8, 8a-hexahydronaphthalen-1-yl) heptanoate ([11C]DPV), and demonstrated its usefulness for the quantitative investigation of Oatps (gene symbol SLCO) and Mrp2 (gene symbol ABCC2) in rats. To further analyze the species differences and verify the pharmacokinetic parameters in humans, serial PET scanning of the abdominal region with [11C]DPV was performed in six healthy volunteers with and without an OATP1Bs and MRP2 inhibitor, rifampicin (600 mg, oral), in a crossover fashion. After intravenous injection, [11C]DPV rapidly distributed to the liver and kidney followed by secretion into the bile and urine. Rifampicin significantly reduced the liver distribution of [11C]DPV 3-fold, resulting in a 7.5-fold reduced amount of excretion into the bile and the delayed elimination of [11C]DPV from the blood circulation. The hepatic uptake clearance (CLuptake, liver) and canalicular efflux clearance (CLint, bile) of [11C]DPV (544 ± 204 and 10.2 ± 3.5 µl/min per gram liver, respectively) in humans were lower than the previously reported corresponding parameters in rats (1800 and 298 µl/min per gram liver, respectively) (Shingaki et al., 2013). Furthermore, rifampicin treatment significantly reduced CLuptake, liver and CLint, bile by 58% and 44%, respectively. These results suggest that PET imaging with [11C]DPV is an effective tool for quantitatively characterizing the OATP1Bs and MRP2 functions in the human hepatobiliary transport system.

How Informative Are Drug-Drug Interactions of Gene-Drug Interactions?

FDA recommendations to manage polymorphic CYP-mediated drug-drug interactions (DDIs) and gene-drug interactions (GDIs) are typically similar. However, DDIs may not always reliably predict GDIs because the victim drug may have multiple metabolic pathways and the perpetrator drug may affect multiple enzymes or transporters. Consequently, it is of great interest to both the pharmaceutical industry and regulatory agencies to determine if DDI studies can be leveraged to inform GDIs or vice versa for dose adjustment and labeling. The objective of this study was to investigate under what circumstances DDIs can be used to predict GDIs for prototypical CYP2C9, CYP2C19, and CYP2D6 substrates. We investigated model substrates for CYP2D6 (metoprolol, dextromethorphan, atomoxetine, and vortioxetine), CYP2C9 (warfarin, flurbiprofen, and celecoxib), and CYP2C19 (omeprazole and clopidogrel). Data on drug exposure for poor metabolizers (GDI) and for DDIs mediated by strong/moderate inhibitors in extensive metabolizers were collected. The impact of DDIs and GDIs on drug exposure was compared using: (1) a descriptive and (2) a physiologically based pharmacokinetic convergence analysis. Results from both approaches indicate that information on DDIs can be used to reliably predict GDIs for CYP2D6 substrates. The situation is more complex for CYP2C9 and CYP2C19 substrates because dose of the inhibitor (CYP2C9) and potency of the inhibitor (CYP2C19) impact the extent to which perpetrator drugs phenotypically convert extensive metabolizers to poor(er) metabolizers.

Majority of HIV/HCV Patients Need to Switch Antiretroviral Therapy to Accommodate Direct Acting Antivirals.

The impact of drug-drug interactions (DDIs) between interferon-free direct acting antiviral (DAA) regimens and antiretrovirals (ART) among HIV/HCV co-infected individuals in clinical practice settings is unknown. A single-center, retrospective chart review of co-infected patients was conducted from June 2014 to February 2015. Significant interactions between simeprevir (SMV), ledipasvir (LDV), and paritaprevir/ritonavir/ombitasvir plus dasabuvir (3D regimen) with ART were identified based on available literature. SMV had the largest number of DDIs and was further investigated to determine the feasibility of ART switch to allow for DAA use. Of 127 subjects, 23% had advanced liver disease; 86% of those with known HCV genotype were HCV genotype 1. An ART switch allowing use of SMV, LDV, and 3D regimen was recommended in 97/127 (76%), 81/127 (64%), and 91/127 (72%) patients, respectively. Subjects on PI/r regimens had limited options for ART switch, with 40% of these patients unable to be switched to an ART regimen that avoided the use of a PI. In conclusion, the majority of HIV/HCV co-infected patients will be recommended to switch ART prior to use of interferon-free, DAA regimens, and an ART switch may not be feasible for more than a third of patients on a boosted PI. DDIs between ART and DAAs represent an additional barrier to treatment efficacy in clinical practice settings that are unaccounted for in clinical trials.

Antiplatelet resistance in outpatients with monitored adherence

Antiplatelet resistance with aspirin and clopidogrel has been associated with clinical, cellular and pharmacogenetic factors; and non-adherence has been considered as a major contributor to resistance in outpatients. We aimed at assessing factors to resistance when adherence to the antiplatelet drugs and all other oral solid drugs was controlled for. In a pilot study, we tested arachidonic acid and/or ADP-induced in vitro platelet aggregation of 82 outpatients with chronic aspirin and/or clopidogrel treatment before and after a one-week period of measuring the patient’s adherence with the polymedication electronic monitoring system (POEMS). Resistance was found in 20% (aspirin; n = 69) and 25% (clopidogrel; n = 32) of the patients after monitored adherence. Mean platelet aggregation was not (aspirin) or non-significantly (clopidogrel) lowered when compared to baseline. Diabetes mellitus and inflammation were consistently associated with resistance to both drugs, but CYP2C19 polymorphisms could not be confirmed as predictors of clopidogrel response. Electronically compiled multidrug dosing histories allowed the concomitant intake of high-dose lipophilic statins to be identified as a risk factor of impaired response to clopidogrel and revealed that exposure to further potential drug–drug interactions (DDIs) was too low for analysis. Multidrug adherence monitoring allowed thus dismissing non-adherence as a major contributor to resistance and inter-individual response variability in an outpatient setting. Additionally, it allowed analysing the impact of DDIs according to the actual exposure to the potentially interfering drugs. Further studies based on this methodology are essential to prevent misleading results due to incomplete adherence and gain additional insight into the impact of timing adherence on antiplatelet drug response.

Impact of Hepatic Uptake Transporters on Pharmacokinetics and Drug−Drug Interactions: Use of Assays and Models for Decision Making in the Pharmaceutical Industry

The ability to predict hepatic metabolic clearance is a key component in the design and selection of small molecule drug candidates within the pharmaceutical industry. The recognition that metabolism-transporter interplay can influence hepatic metabolic clearance has presented new challenges, both in terms of the creation of experimental systems suitable for an industry setting and also in developing an understanding of the pharmacokinetic concepts that underpin them. This paper reviews the pharmacokinetic principles that govern the kinetics of uptake transporter substrates. In addition, new data are presented from a range of test systems for assessing hepatic drug clearance and the impact of drug-drug interactions (DDIs).

An Interaction Between Aspirin and Valproate: The Relevance of Plasma Protein Displacement Drug-Drug Interactions

Despite the ubiquity and severity of drug-drug interactions, this problem is one of the most poorly recognized and poorly understood issues within clinical medicine (1, 2). The impact of drug-drug interactions on patient safety is finally being elucidated, and the magnitude of the problem is vast (3, 4). Detection and anticipation of these interactions is a daunting task, given the breadth of pharmacodynamic and pharmacokinetic variables with which clinicians must grapple. Physicians are finding it increasingly necessary to become acquainted with the workings of the cytochrome P450 system, phase II metabolism, and even mediators of absorption and distribution, such as the P-glycoprotein transporter. It is not surprising that addressing the subtle and complex drug-drug interactions arising from exotic regimens exceeds the capabilities of most clinicians. However, as the following case illustrates, even well-known and commonplace drug-drug interactions may elude detection and produce significant patient morbidity.

An Interaction Between Aspirin and Valproate: The Relevance of Plasma Protein Displacement Drug-Drug Interactions

An Interaction Between Aspirin and Valproate: The Relevance of Plasma Protein Displacement Drug-Drug Interactions