Evidence Of Drug-drug Interaction Research Articles

Drug Interactions in People on Cannabidiol: Is There Cause for Concern?

Introduction: Cannabidiol (CBD) exhibits multiple therapeutic properties, but its use in advanced cancer patients raises concerns about potential drug-drug interactions (DDIs) due to polypharmacy. This study aims to look for evidence of DDIs between concomitant medications and CBD oil in a randomized placebo-controlled trial of CBD oil for symptom control (MedCan-1 parent study). Materials and Methods: Surrogate measures were used to identify possible drug interactions: (1) the maximum mL of oil self-selected by patients in CBD or placebo groups in relation to opioids, specific drug groups, or individual agents; (2) the occurrence of any new or worse adverse effect in relation to the study arm and the concomitant medication classes/medications of interest. Results: The dose of CBD self-selected by participants was not related to opioid use or medications, including benzodiazepines and antipsychotics. The likelihood of developing an adverse effect while on study or when taking specific medications was not increased by CBD. Participants on paracetamol tolerated a higher dose of CBD. Discussion: Concerns regarding the development of clinically significant drug interactions when taking CBD in the context of anti-cancer and other concomitant medications at least in the short term may be unfounded.

Icaritin exhibits potential drug-drug interactions through the inhibition of human UDP-glucuronosyltransferase in vitro.

Icaritin is a prenylflavonoid derivative of the genus Epimedium (Berberidaceae) and has a variety of pharmacological actions. Icaritin is approved by the National Medical Products Administration as an anticancer drug that exhibits efficacy and safety advantages in patients with hepatocellular carcinoma cells. This study aimed to evaluate the inhibitory effects of icaritin on UDP-glucuronosyltransferase (UGT) isoforms. 4-Methylumbelliferone (4-MU) was employed as a probe drug for all the tested UGT isoforms using in vitro human liver microsomes (HLM). The inhibition potentials of UGT1A1 and 1A9 in HLM were further tested by employing 17β-estradiol (E2) and propofol (PRO) as probe substrates, respectively. The results showed that icaritin inhibits UGT1A1, 1A3, 1A4, 1A7, 1A8, 1A10, 2B7, and 2B15. Furthermore, icaritin exhibited a mixed inhibition of UGT1A1, 1A3, and 1A9, and the inhibition kinetic parameters (Ki) were calculated to be 3.538, 2.117, and 0.306 (μM), respectively. The inhibition of human liver microsomal UGT1A1 and 1A9 both followed mixed mechanism, with Ki values of 2.694 and 1.431 (μM). This study provides supporting information for understanding the drug-drug interaction (DDI) potential of the flavonoid icaritin and other UGT-metabolized drugs in clinical settings. In addition, the findings provide safety evidence for DDI when liver cancer patients receive a combination therapy including icaritin.

Discovering clinical drug-drug interactions with known pharmacokinetics mechanisms using spontaneous reporting systems and electronic health records

ObjectiveAlthough the mechanisms behind pharmacokinetic (PK) drug-drug interactions (DDIs) are well-documented, bridging the gap between this knowledge and clinical evidence of DDIs, especially for serious adverse drug reactions (SADRs), remains challenging. While leveraging the FDA Adverse Event Reporting System (FAERS) database along with disproportionality analysis tends to detect a vast number of DDI signals, this abundance complicates further investigation, such as validation through clinical trials. Our study proposed a framework to efficiently prioritize these signals and assessed their reliability using multi-source Electronic Health Records (EHR) to identify top candidates for further investigation. MethodsWe analyzed FAERS data spanning from January 2004 to March 2023, employing four established disproportionality methods: Proportional Reporting Ratio (PRR), Reporting Odds Ratio (ROR), Multi-item Gamma Poisson Shrinker (MGPS), and Bayesian Confidence Propagating Neural Network (BCPNN). Building upon these models, we developed four ranking models to prioritize DDI-SADR signals and cross-referenced signals with DrugBank. To validate the top-ranked signals, we employed longitudinal EHRs from Vanderbilt University Medical Center and the All of Us research program. The performance of each model was assessed by counting how many of the top-ranked signals were confirmed by EHRs and calculating the average ranking of these confirmed signals. ResultsOut of 189 DDI-SADR signals identified by all four disproportionality methods, only two were documented in the DrugBank database. By prioritizing the top 20 signals as determined by each of the four disproportionality methods and our four ranking models, 58 unique DDI-SADR signals were selected for EHR validations. Of these, five signals were confirmed. The ranking model, which integrated the MGPS and BCPNN, demonstrated superior performance by assigning the highest priority to those five EHR-confirmed signals. ConclusionThe fusion of disproportionality analysis with ranking models, validated through multi-source EHRs, presents a groundbreaking approach to pharmacovigilance. Our study's confirmation of five significant DDI-SADRs, previously unrecorded in the DrugBank database, highlights the essential role of advanced data analysis techniques in identifying ADRs.

Initial results from a phase 1b study of ORIC-101, a glucocorticoid receptor antagonist, in combination with nab-paclitaxel in patients with advanced solid tumors.

2553 Background: ORIC-101 is a potent and selective, orally bioavailable, small molecule antagonist of the glucocorticoid receptor (GR). Preclinical studies have demonstrated that activation of GR signaling leads to decreased responsiveness to chemotherapeutics (eg, taxanes) and antiandrogens across multiple tumor types. Mechanistically, ORIC-101 inhibits GR transcriptional activity and blocks the prosurvival signals mediated by the activated nuclear hormone receptor. Methods: A 3+3 dose escalation design was used to assess safety, pharmacokinetics (PK), pharmacodynamics (PD), and select the Recommended Phase 2 Dose (RP2D) of ORIC-101 in combination with nab-paclitaxel (nab-pac; NCT03928314). ORIC-101 doses ranging from 80 to 240 mg once daily, given either intermittently or in a continuous dosing regimen, were evaluated in combination with weekly nab-pac at 75 or 100 mg/m2. Plasma PK and PD biomarkers were assessed on day 1 and after repeat dosing. PD modulation in blood-derived peripheral blood mononuclear cells (PBMCs) was assessed by RT-qPCR for GR target genes. Antitumor activity was assessed by RECIST v1.1. Results: 21 patients with 10 different solid tumors, with and without a prior taxane, were treated in 5 cohorts. ORIC-101 exposure increased with dose, with no evidence for drug-drug interaction with nab-pac. In the initial cohort at 240 mg ORIC-101 and 100 mg/m2 nab-pac, 2 patients experienced dose limiting toxicities (DLTs) of Grade 3 fatigue and Grade 4 neutropenia/thrombocytopenia, respectively. No further DLTs were observed in subsequent cohorts and the RP2D was established as 160 mg ORIC-101 dosed once daily continuously for 21 days with nab-pac 75 mg/m2 given on days 1, 8, and 15 of each 28-day cycle, without requirement for prophylactic granulocyte colony-stimulating factor (G-CSF). The most common (> 15%), all grade treatment-related adverse events (AEs) were nausea (38%), diarrhea (33%), fatigue (29%), leukopenia (29%), neutropenia (29%), anemia (24%), and 19% of patients had increased liver function tests and alopecia. Biomarker data demonstrated ORIC-101-induced reduction in GR target gene expression in PBMCs, indicating PD modulation at all dose levels of ORIC-101. Preliminary antitumor activity was observed in 3 taxane-refractory patients with breast, endometrial, and pancreatic cancers. Conclusions: The combination of ORIC-101 and nab-paclitaxel demonstrated an acceptable tolerability profile and does not require prophylactic G-CSF. PK and PD showed no evidence of drug-drug-interaction and demonstrated GR target inhibition. Preliminary antitumor activity was observed in patients with solid tumors that previously progressed on a taxane-containing regimen. Dose expansion is ongoing at the RP2D in dedicated pancreatic, ovarian, triple negative breast cancers, and tissue-agnostic cohorts. Clinical trial information: NCT03928314.

Abstract P1-19-46: A phase Ib dose escalation study evaluating the mutant selective PI3K-alpha inhibitor GDC-0077 (G) in combination with letrozole (L) with and without palbociclib (P) in patients with PIK3CA-mutant HR+/HER2- breast cancer

Abstract Background: Dysregulation of the PI3K/AKT/mTOR signaling pathway occurs in solid tumor malignancies. GDC-0077 (G) is a potent p110α-selective, p110α-mutant degrading inhibitor with anti-tumor activity in PIK3CA-mutant breast cancer xenograft models as a single agent and in combination with endocrine therapies (ET) with or without a CDK4/6 inhibitor (i). An open-label, Phase I dose escalation study of Galone and in combination with ET and P is underway in patients (pts) with locally advanced or metastatic PIK3CA-mutant solid tumors. Data from the combinations of G and L with and without P in pts with PIK3CA-mutant HR+/HER2- breast cancer are presented herein. Methods: This study (NCT03006172) assesses the safety (NCI-CTCAE v4), pharmacokinetics (PK), and preliminary anti-tumor activity (RECIST v1.1) of G administered daily (QD) orally at 6 or 9 mg with L (G+L) or at 3, 6, or 9 mg in combination with P+L (G+P+L). L is administered QD orally at 2.5 mg. P is administered QD orally at 125 mg on Days 1-21 followed by 7 days off in 28-day cycles. For dose expansion, prior CDK4/6i was prohibited (G+P+L) and up to one prior metastatic chemotherapy allowed (G+L and G+P+L). Tumor and ctDNA samples (collected before and after 2 weeks of G) are profiled for relevant signaling and pharmacodynamic (PD) biomarkers. Results: As of 29 March 2019, 70 pts had enrolled (G+L: 37 pts [7 at 6 mg and 30 at 9 mg]; G+P+L: 33 pts [3 at 3 mg, 3 at 6 mg, and 27 at 9 mg]). Overall, 33 pts in G+L and 31 pts in G+P+L received ≥ 1 prior metastatic therapy; 70% and 21% of pts received prior CDK4/6i in G+L and G+P+L arms, respectively. No DLTs were reported in pts receiving either combination with G. In G+L, the most frequent treatment-related AEs (TRAEs) occurring in ≥10 (27%) pts included hyperglycemia (25 pts, 68%), nausea (14 pts, 38%), and diarrhea (10 pts, 27%). Grade ≥3 TRAEs in ≥2 (5%) pts included hyperglycemia (7 pts, 19%), and fatigue and hypokalemia (2 pts each, 5%). In G+P+L, the most frequent TRAEs occurring in ≥13 (41%) pts included neutropenia (25 pts, 78%), hyperglycemia (17 pts, 52%), anemia (17 pts, 52%), diarrhea (16 pts, 49%), and nausea and thrombocytopenia (13 pts each, 39%). Grade ≥3 TRAEs in ≥2 (6%) pts included neutropenia (21 pts, 64%), hyperglycemia (5 pts, 15%), lymphopenia (3 pts, 15%), and leukopenia and thrombocytopenia (2 pts each, 6%). Hyperglycemia was manageable with oral anti-hyperglycemic medication. Stomatitis (grouped term) occurred in 11 pts (30%) in G+L and 21 pts (64%) in G+P+L and responded to treatment with dexamethasone mouthwash. 46 pts discontinued treatment, mainly due to disease progression; one due to Grade 3 hyperglycemia in G+P+L (no discontinuation due to AE in G+L). Median G treatment duration: 5.7 months (range 0.2-14.5) in G+L and 9.7 months (range 1.3-23.1) in G+P+L, with a cumulative G dose intensity of 98% for both. In G+ L, PR was reported in 6 pts (16%), confirmed PR in 3 pts (8%) and CBR 35% (13 pts). In G+P+L, PR was reported in 14 pts (42%), confirmed PR in 12 pts (36%) and CBR 76% (25 pts). G PK parameters were similar to those observed as a single agent, and P and L showed exposures comparable with historical data, suggesting an absence of PK drug-drug interaction (DDI). Robust PD downregulation of PI3K pathway effectors (pAKT, pS6) was observed in available paired biopsies and PIK3CA mutant allele frequency decreased in ctDNA on-treatment in most patients. Conclusion: This Phase Ib study of GDC-0077 in combination with letrozole with and without pabocicilb demonstrated a manageable safety profile combining GDC-0077 at its single agent recommended Phase II dose of 9 mg with letrozole with and without palbociclib at standard doses, with no evidence for DDI, high GDC-0077 dose intensity, and promising preliminary anti-tumor activity. Citation Format: Komal Jhaveri, Kevin Kalinsky, Philippe Bedard, Andres Cervantes, Cristina Saura, Ian Krop, Erika Hamilton, Peter Schmid, Andrea Varga, Nick Turner, Antoine Italiano, Valentina Gambardella, Zachary Veitch, Mafalda Oliveira, Leslie Dickmann, Naoki Kotani, Amy Kapp, Katie Hutchinson, Stephanie Royer-Joo, Anjali Vaze, Jennifer Schutzman, Dejan Juric. A phase Ib dose escalation study evaluating the mutant selective PI3K-alpha inhibitor GDC-0077 (G) in combination with letrozole (L) with and without palbociclib (P) in patients with PIK3CA-mutant HR+/HER2- breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-46.

Translational Knowledge Discovery Between Drug Interactions and Pharmacogenetics.

Clinical translation of drug-drug interaction (DDI) studies is limited, and knowledge gaps across different types of DDI evidence make it difficult to consolidate and link them to clinical consequences. Consequently, we developed information retrieval (IR) models to retrieve DDI and drug-gene interaction (DGI) evidence from 25 million PubMed abstracts and distinguish DDI evidence into in vitro pharmacokinetic (PK), clinical PK, andclinical pharmacodynamic (PD) studies for US Food and Drug Administration (FDA) approved and withdrawn drugs. Additionally, information extraction models were developed to extract DDI-pairs and DGI-pairs from the IR-retrieved abstracts. An overlapping analysis identified 986unique DDI-pairs between all 3 types of evidence. Another 2,157 and 13,012 DDI-pairs and 3,173 DGI-pairs were identified from known clinical PK/PD DDI, clinical PD DDI, and DGI evidence, respectively. By integrating DDI and DGI evidence, we discovered 119 and 18 new pharmacogenetic hypotheses associated with CYP3A and CYP2D6, respectively. Some of these DGI evidence can also aid us in understanding DDI mechanisms.

Testing the face validity and inter-rater agreement of a simple approach to drug-drug interaction evidence assessment.

A convenience sample of participants with professional experience evaluating DDI evidence was recruited. Participants independently evaluated pre-selected evidence items for 5 drug pairs using the new instrument. For each drug pair, participants labeled each evidence item as sufficient or insufficient to establish the existence of a DDI based on the evidence categories provided by the instrument. Participants also decided if the overall body of evidence supported a DDI involving the drug pair. Agreement was computed both at the evidence item and drug pair levels. A cut-off of≥70% was chosen as the agreement threshold for percent agreement, while a coefficient>0.6 was used as the cut-off for chance-corrected agreement. Open ended comments were collected and coded to identify themes related to the participants' experience using the novel approach. The face validity of the new instrument was established by two rounds of evaluation involving a total of 6 experts. Fifteen experts agreed to participate in the reliability assessment, and 14 completed the study. Participant agreement on the sufficiency of 22 of the 34 evidence items (65%) did not exceed the a priori agreement threshold. Similarly, agreement on the sufficiency of evidence for 3 of the 5 drug pairs (60%) was poor. Chance-corrected agreement at the drug pair level further confirmed the poor interrater reliability of the instrument (Gwet's AC1=0.24, Conger's Kappa=0.24). Participant comments suggested several possible reasons for the disagreements including unaddressed subjectivity in assessing an evidence item's type and study design, an infeasible separation of evidence evaluation from the consideration of clinical relevance, and potential issues related to the evaluation of DDI case reports. Even though the key findings were negative, the study's results shed light on how experts approach DDI evidence assessment, including the importance situating evidence assessment within the context of consideration of clinical relevance. Analysis of participant comments within the context of the negative findings identified several promising future research directions including: novel computer-based support for evidence assessment; formal evaluation of a more comprehensive evidence assessment approach that requires consideration of specific, explicitly stated, clinical consequences; and more formal investigation of DDI case report assessment instruments.

Dimethyl Fumarate in Psoriasis Therapy

This presentation by Dr Weisenseel considered the role of fumaric acid esters (FAE) in plaque psoriasis. FAE, first developed in 1959 and approved in 1994, are available in two forms: dimethyl fumarate (DMF) alone (e.g. Skilarence®; Almirall Ltd., Uxbridge, UK) or DMF together with calcium, zinc, and magnesium salts of monoethyl fumarate (Fumaderm®). Up-titration is recommended for FAE/DMF dosing. The BRIDGE study demonstrated that Skilarence has comparable efficacy, safety, and tolerability to Fumaderm, while the retrospective FUTURE study demonstrated that the efficacy of FAE increase over time. Additionally, in separate studies combining FAE with ultraviolet therapy, FAE were shown to achieve a faster clinical response and required a lower mean maximum daily dose in the up-titration period. FAE side effects, such as flushing and gastrointestinal effects, can usually be handled by individualising patient doses, involving both up and down-titration. Dr Weisenseel explained how patients are required to have their lymphocyte levels monitored every 3 months, with lymphocyte counts <700 cells/µL in two consecutive tests considered the criterion for stopping DMF therapy due to the increased risk of progressive multifocal leukoencephalopathy (PML). There is no evidence of drug-drug interactions with FAE, although retinoids, cyclosporin, immune suppressants, and cytostatics should be avoided.

Abstract CT026: Phase I study of AZD6738, an inhibitor of ataxia telangiectasia Rad3-related (ATR), in combination with olaparib or durvalumab in patients (pts) with advanced solid cancers

Abstract Background: AZD6738 is a potent selective oral ATR inhibitor. Therapeutic combinations aim to inhibit ATR-dependent cycle arrest and repair induced by the PARP inhibitor Olaparib (Ola), and to exploit DNA damage-induced immune responses with the anti-PD-L1 antibody Durvalumab (Durva). Here we present the results of the ongoing Phase I study D5330C00004 (NCT02264678) dose escalation combinations of AZD6738 with Ola or Durva. Methods: A trial assessing AZD6738 in combination with continuous Ola tablets or Durva IV infusion per 28-day cycle. Pharmacokinetic (PK) and pharmacodynamic evaluations were conducted. Results: 70 pts with advanced cancer were treated with +Ola (45 pts) or +Durva (25 pts). Tumor types included breast, ovary, prostate, pancreas, lung, HNSCC and gastric cancers. +Ola: AZD6738 was assessed in 10 cohorts from 60 mg od to 240 mg bd for 5-14 days (D), co-dosing with Ola 100-300 mg bd continuously. All causality toxicity occurring in ≥20% subjects (pts with ≥G3 events) included: thrombocytopenia (5 pts), anemia (7 pts), neutropenia (6 pts), fatigue (1 pt), decreased appetite (1 pt), nausea, vomiting, constipation, diarrhea and cough. Thrombocytopenia and neutropenia were dose- and schedule limiting toxicities (DLTs). The Recommended Phase 2 Dose is AZD6738 160 mg od D1-7 + Ola 300 mg bd D1-28. Of 39 evaluable pts, 1 RECIST complete response (CR), 5 partial responses (PR) and 1 unconfirmed (uPR) were observed in pts with advanced breast (3 pts), ovarian, prostate, pancreatic and ampullary cancer and BRCA1/2 mutations independent of ATM status. Dose expansions are ongoing in pts with advanced gastric and breast cancer. +Durva: AZD6738 was evaluated in 5 cohorts with 1-2 weeks monotherapy run-in, followed by Durva 1500 mg on D1 + AZD6738 80-240 mg od or bd for 1 (D22-28) or 2 (D15-28) weeks. Toxicity occurring in ≥20% subjects included: anemia (≥G3 in 1 pt), fatigue, nausea, decreased appetite, cough, vomiting, dizziness, pruritus, constipation, diarrhea, musculoskeletal chest pain and dyspnea. One DLT of thrombocytopenia was observed. Of 21 pts, 1 RECIST CR, 2 PRs and 1 uPR were observed in pts with advanced NSCLC (3 pts) and HNSCC (1 pt), independent of tumor PD-L1 expression. Peripheral monocytes and proliferating T-cells were suppressed; both rebounding to levels ≥ baseline during the off-drug interval. GM-CSF increased reciprocally to on-target decreases in monocytes. Preliminary PK data showed rapid absorption of AZD6738 with peak plasma concentration ≈1.5h post dose, a biphasic decline with an elimination half-life of 11h. Despite ≈45% variability in clearance, there was dose proportionality and no evidence of drug-drug interaction with Ola or Durva. Conclusions: The combinations of AZD6738 with Ola or Durva were tolerated in dose escalation with preliminary signals of antitumor activity in pts with advanced solid tumors. Citation Format: Matthew G. Krebs, Juanita Lopez, Anthony El-Khoueiry, Yung-Jue Bang, Sophie Postel-Vinay, Wassim Abida, Louise Carter, Wen Xu, Seock-Ah Im, Andrew Pierce, Paul Frewer, Alienor Berges, S.Y. Amy Cheung, Christine Stephens, Brunella Felicetti, Emma Dean, Simon J. Hollingsworth. Phase I study of AZD6738, an inhibitor of ataxia telangiectasia Rad3-related (ATR), in combination with olaparib or durvalumab in patients (pts) with advanced solid cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT026.

Use of a Caco-2 permeability assay to evaluate the effects of several Kampo medicines on the drug transporter P-glycoprotein

In modern medical care in which Kampo and Western drugs are often combined, it is extremely important to clarify drug–drug interaction (DDI) to ensure safety and efficacy. However, there is little evidence of DDI in Kampo medicines. Therefore, as part of our studies to clarify the DDI risk for Kampo medicines, we evaluated the effects of five Kampo medicines [yokukansan (YKS), rikkunshito (RKT), shakuyakukanzoto (SKT), hangeshashinto (HST), and goshajinkigan (GJG)] that are widely used in Japan, on drug transporter P-glycoprotein (P-gp) using a Caco-2 permeability assay. These Kampo medicines inhibited the P-gp transport of digoxin through a Caco-2 cell monolayer. The IC50 values were 1.94–10.80 mg/ml. Of the five Kampo medicines, YKS showed the strongest inhibition (IC50 = 1.94 mg/ml), which was attributed to Uncariae Uncis Cum Ramulus. Unfortunately, we could not find the active ingredients responsible for its action. Finally, the Igut/IC50 values for the five Kampo medicines were calculated, and the DDI risk was objectively evaluated according to the criteria in the DDI guidance issued by the Japanese Ministry of Health, Labor, and Welfare and the US Food and Drug Administration. The Igut/IC50 values for the five Kampo medicines were ≤3.4. As these values were <10, they were evaluated as having a weak P-gp inhibitory effect that does not require further verification in humans, suggesting that the DDI risk due to P-gp inhibition for these Kampo medicines is low. The results should provide useful clinical information on the safety and efficacy of the combined use of Kampo and Western medicines.

P165 HIV inpatient experience

Introduction‘Standards of care for people living with HIV 2013’ provides recommendations for the clinical care of HIV positive patients, including inpatients. We conducted an audit to describe patterns of service use with particular reference to time to diagnosis of HIV, presenting illness, medication, length of stay and follow up.MethodsData was collected retrospectively from notes of 36 inpatients from 1stJanuary to 31stDecember 2014.Results4 patients were newly diagnosed with HIV, of which, 3(75%) presented with an AIDS defining illness. HIV test was performed in MAU on 2 patients (50%). In the remaining 32 patients, 8 presented with AIDS defining illness. 11% had evidence of drug-drug interactions. 37% had no evidence of HIV Team inpatient review. 25 patients were discharged within 7 days, however, 4 stayed for more than 28 days. Only 41% were seen in HIV Outpatients within 4 weeks after discharge. After admission with AIDS defining diagnosis, all patients were alive at 30 days and 72% alive at 6 months.DiscussionComplex care accounted for a sizeable proportion of our inpatient work. Current BHIVA recommendation of immediate commencement of HAART will significantly reduce disease progression and inpatient admission. This audit highlights the need for continued effort to raise awareness of HIV testing among non-HIV specialists and GP’s.

Phase I study to evaluate the tolerability, pharmacokinetics (PK) and pharmacodynamic (PD) of PM01183 (Lurbinectedin) in combination with olaparib in patients with advanced solid tumors.

5573 Background: PM01183 (Lurbinectedin) is a new anticancer drug that exerts antitumor activity through inhibition of trans-activated transcription and modulation of tumor microenvironment and is highly active in platinum resistant ovarian cancer. (Poveda A et al. ASCO 2014.abstr #5505). Olaparib (AZD2281, KU-0059436) is a polyadenosine 5’diphosphoribose (poly [ADP ribose]) polymerase (PARP) inhibitor of PARP-1,-2 and-3 with proven antitumoral activity in homologous recombination deficient tumors. The combination of PM01183 and Olaparib has shown synergistic activity in cell-lines, independent of BRCA mutation status. Methods: This phase I study evaluates the safety, PK and PD of PM1183 in combination with short course of Olaparib tablet formulation [days (d) 1-5] a cycle of 21 d, through a 3+3 dose escalation design (NCT02684318) Patients with advanced or metastatic solid tumors without established standard therapeutic alternatives were selected. Primary endpoints: safety (MTD, DLT and RP2D). Secondary endpoints: PK and PD (western blot analysis of RAD51 and p-gH2AX) profiles at 0h,4.5h, 6.5h and 24h at first cycle of treatment. Results: 20 patients were enrolled from Nov 2015 to Sep 2016 (15 ovarian, 5 endometrial) to 5 dose levels. 19/20 were evaluable for toxicity. Two dose limiting toxicities (DLTs) (both grade 4 neutropenia ≥ 4 days) occurred at the highest dose level (PM01183 2 mg/m2 iv d1 + Olaparib 250 mg [BID] oral on d 1-5. Grade 3 toxicities occurred in 30% of patients, including grade 3 neutropenia (6%) and grade 3 asthenia (10%). PK data are available from 19 patients. Median of PM01183 total clearance (11.0 L/h) is the same as when PM01183 is given as single agent. Clearance of Olaparib (7 L/h) is consistent with results reported elsewhere (5.1 – 8.6 L/h). PD: An overall increase of RAD51 and p-gH2AX was observed, being particularly evident in 56% of patients. Conclusions: The Recommended Dose for Phase II (RP2D) was PM01183 1,5 mg/m2 iv d1 + Olaparib 250 mg BID on d 1-5. This combination is feasible and without evidence of drug-drug interactions. A phase-II study at RP2D is ongoing. Clinical trial information: NCT02684318.

A phase IB study of CX-4945 in combination with gemcitabine plus cisplatin in the frontline systemic treatment of patients with advanced cholangiocarcinoma.

294 Background: CX-4945 is a first-in-class casein kinase-2 (CK2) threonine kinase small molecule inhibitor. CK2 is pleiotropic and regulates key cellular processes such as proliferation and DNA damage repair, and has been shown to enhance efficacy of gemcitabine (G) and cisplatin (C) in cell line and xenograft CCA model systems. A Phase IB study of G+C with CX-4945 was conducted in advanced cholangiocarcinoma (CCA) patients. Methods: A multi-center “3+3” dose escalation study was conducted in advanced CCA patients. Eligible patients had ECOG PS 0-1 and adequate hematologic, hepatic, and renal function. Primary endpoints were maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D). Secondary endpoints included pharmacokinetic (PK) analyses, overall toxicity evaluation and preliminary assessment of efficacy. Routine clinical dosing for G (1000 mg/m2) and C (25 mg/m2), both on days 1 and 8 every 21 days, was used. Dose escalation cohort were CX-4945 given twice daily on days 0,1,2 and 7,8,9 at 200 mg (DL1), 400mg (DL2), 600 mg (DL3), 800 mg (DL4) and 1000 (DL5) mg. NCI CTCAE v4.03 was used for toxicity assessment and RECIST v1.1 for efficacy evaluation. Results: Nineteen patients were enrolled (DL1:n = 3; DL2:n = 4 DL3:n = 3; DL4:n = 4; DL5:n = 5). No dose limiting toxicities were encountered. MTD and RP2D were ascertained to be DL5. No grade 3 or 4 toxicities at prevalence &gt; 10% were encountered and the overall toxicity profile of the combination was reflective of standard G+C toxicity profile. At data cut-off, preliminary efficacy evaluation demonstrated disease control rate (CR+PR+SD) of 64% (PR:32%, SD:32% and CR:0%), along with median progression-free survival (PFS) of 5 months (range 0-14 months). PK analyses showed no evidence of drug-drug interactions between G, C and CX-4945. Conclusions: RP2D for G+C with CX-4945 is DL5 (CX-4945 dosed on days 0,1,2 and 7,8,9 at 1000 mg PO bid with standard G and C dosing). Preliminary clinical efficacy and tolerability of the regimen support planned controlled, randomized Phase 2 evaluation. Clinical trial information: NCT02128282.

Extracting drug-enzyme relation from literature as evidence for drug drug interaction.

BackgroundInformation about drug–drug interactions (DDIs) is crucial for computational applications such as pharmacovigilance and drug repurposing. However, existing sources of DDIs have the problems of low coverage, low accuracy and low agreement. One common type of DDIs is related to the mechanism of drug metabolism: a DDI relation may be caused by different interactions (e.g., substrate, inhibit) between drugs and enzymes in the drug metabolism process. Thus, information from drug enzyme interactions (DEIs) serves as important supportive evidence for DDIs. Further, potential DDIs present implicitly could be detected by inference and reasoning based on DEIs.MethodsIn this article, we propose a hybrid approach to combining machine learning algorithm with trigger words and syntactic patterns, for DEI relation extraction from biomedical literature. The extracted DEI relations are used for reasoning to infer potential DDI relations, based on a defined drug-enzyme ontology incorporating biological knowledge.ResultsEvaluation results demonstrate that the performance of DEI relation extraction is promising, with an F-measure of 84.97 % on the in vivo dataset and 65.58 % on the in vitro dataset. Further, the inferred DDIs achieved a precision of 83.19 % on the in vivo dataset and 70.94 % on the in vitro dataset, respectively. A further examination showed that the overlaps between our inferred DDIs and those present in DrugBank were 42.02 % on the in vivo dataset and 19.23 % on the in vitro dataset, respectively.ConclusionsThis paper proposed an effective approach to extract DEI relations from biomedical literature. Potential DDIs not present in existing knowledge bases were then inferred based on the extracted DEIs, demonstrating the capability of the proposed approach to detect DDIs with scientific evidence for pharmacovigilance and drug repurposing applications.

Abstract P6-13-21: Phase 1 study of GR antagonist mifepristone (M) in combination with eribulin (E) in advanced solid tumors, with dose expansion in patients (pts) with GR-positive triple-negative breast cancer (TNBC)

Abstract Background: High tumor GR expression is associated with poor prognosis in estrogen receptor (ER) negative early-stage breast cancer. Co-treatment with M, a GR antagonist, potentiates effects of chemotherapy in ER- breast cancer xenograft studies. Herein we describe results of a phase 1 dose-escalation study of M plus E, with an ongoing dose expansion cohort in pts with GR+ TNBC. Objectives: Determine 1) safety and tolerability, 2) recommended phase 2 dose (RP2D) of M + E, and 3) characterize pharmacokinetics (PK) and clinical activity of M in pts with GR+ TNBC. Methods: Eligibility: 1) relapsed/refractory breast, ovarian, prostate, urothelial, sarcoma, or non-small cell lung cancer; 2) 2-5 prior chemotherapy regimens for advanced disease; 3) ECOG PS 0-1; and 4) adequate end-organ function. Study used a 3 + 3 dose escalation scheme. After a 7 day lead-in of M alone, M was administered by mouth daily in combination with E given IV on days 1 and 8 of a 21 day cycle. Results: 13 pts in Part 1 Dose escalation with metastatic breast cancer (MBC) were treated with M+E: 5 TNBC, 8 GR+ tumors, 2 GR- tumors, and 3 of unknown GR status. Pts were treated at 3 dose levels (DL)[M mg/d, E mg/m2]: 3 at DL1 [600, 1.1] 4 at DL-1a [300, 1.4], and 6 at DL-1 [300, 1.1]. Median duration of treatment was 90+ days. Neutropenia leading to delay of E was dose limiting in 4 pts. CTAE Grade 3/4 neutropenia was observed in 10 pts over all DL, but easily managed (9 pts with growth factor support). Other grade 3+ toxicities were neuropathy (2 pts) and onycholysis (1 pt). No other significant toxicity was noted. RP2D was determined as 300mg/d M and 1.1mg/m2 E. At this DL there were no DLTs. PK of M and E were as predicted from published literature with no evidence of drug-drug interaction (DDI). A total of 6 pts received this dose (3 TNBC; 3 MBC). All 3 TNBC were GR+. 1 had partial response, 1 had stable disease, and 1 had progressive disease. A phase I/II study of M+E is now in progress. To date, 3 GR+ TNBC pts have been treated for a median of 28+ days. Conclusion: M + E is a novel combination designed to improve antitumor activity. It is well tolerated with evidence of clinical activity and no evidence of DDI. RP2D is 300mg M + E 1.1mg/m2. Study is ongoing in expansion phase where recruitment is limited to pts with GR+ TNBC. Additional PK and clinical data will be presented. Citation Format: Wilks S, Modiano M, Spira A, Becerra C, Walling J, Nguyen D, Baker G, Conzen SD, Nanda R. Phase 1 study of GR antagonist mifepristone (M) in combination with eribulin (E) in advanced solid tumors, with dose expansion in patients (pts) with GR-positive triple-negative breast cancer (TNBC). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-13-21.

Abstract CT303: A phase I pharmacokinetic and pharmacodynamic evaluation of the combination of everolimus and buparlisib for concurrent mTOR and PI3K pathway blockade in patients with advanced solid tumors

Abstract Background: Preclinical work showed improved anticancer efficacy with the combination of an mTOR and a PI3K inhibitor over either agent alone. We conducted a phase I study to determine the recommended phase II dose (RP2D) of the combination of everolimus (E), an mTOR inhibitor and buparlisib or BKM120 (B), a pan-PI3K inhibitor. Methods: Patients with advanced solid malignancies who have exhausted standard treatment options were enrolled. Main eligibility criteria include ECOG performance status 0-2, adequate end organ function and absence of glucose intolerance, uncontrolled hepatitis, anxiety or depression. Dose escalation was performed using a Bayesian Escalation with Overdose Control (EWOC) design to evaluate different doses of E (5mg or 10mg) and B (20, 40, 60 and 80 mg,) once daily continuously. Eligible patients were enrolled in cohorts of 3 patients. Pharmacokinetic (PK) assessment was conducted in cycle 1 on day 8 using peripheral blood samples collected at time 0, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours and prior to dosing on cycle 1 D day 15. Pharmacodynamic (PD) impact on mTOR/PI3K pathway modulation was evaluated in skin punch biopsies collected at baseline and at end of cycle 1. Results: We enrolled 35 patients: Median age 63yrs (range:40-79), 21 females (58%); 2 Latinos (6%), 7 Blacks (20%) and 26 Caucasians (74%); with cancers of the lung (8), colorectal (7), sarcomas (3), salivary gland (3), breast (3), thyroid (3), thymic (2), bladder (2), ovarian (2), head and neck (1) and PNET (1). The safety of 6 different dose combinations of E and B (5/20; 10/20; 5/40; 5/60; 10/60; 5/80) was assessed. The most frequent toxicities were: hyperglycemia, diarrhea, nausea, fatigue and AST elevation. The dose limiting toxicities observed in 6 patients were: fatigue (3), hyperglycemia (1), mucositis (1), acute renal failure (1) and urinary tract infection (1). The 5/60 combination was defined as the RP2D. The median number of cycles completed was 2 (range: 0-20). Of the 25 patients evaluable for efficacy, 8 (32%) had disease progression while 17 (68%) achieved stable disease (SD). Median duration of SD was 18 weeks (range: 2-83) and 7 patients had SD lasting ≥6 months. Steady-state PK data for both agents in 24 evaluable patients showed no evidence of drug-drug interaction, with dose-normalized maximum concentrations (Cmax) and area-under-the-curve (AUC0-∞) values for E and B in combination being comparable to single agent data. Preliminary signal of efficacy for the combination was observed in patients with thymic, breast and lung cancer. PD analysis is ongoing and will be presented at the meeting. Conclusion: The safety profile of the combination of everolimus plus buparlisib is well tolerated and the RP2D is 5mg/day and 60mg/day respectively on a continuous daily schedule. The efficacy data are encouraging and warrant further evaluation in phase II studies. Citation Format: Taofeek Kunle Owonikoko, R.Donald Harvey, Colleen Lewis, Zhengjia Chen, John S. Kauh, Meredith Renfroe, Rijalda Deovic, Gabriel L. Sica, Bradley C. Carthon, Wayne Bernard Harris, Bassel F. El-Rayes, Suresh S. Ramalingam, Fadlo R. Khuri. A phase I pharmacokinetic and pharmacodynamic evaluation of the combination of everolimus and buparlisib for concurrent mTOR and PI3K pathway blockade in patients with advanced solid tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT303. doi:10.1158/1538-7445.AM2015-CT303

Extraction of pharmacokinetic evidence of drug-drug interactions from the literature.

Drug-drug interaction (DDI) is a major cause of morbidity and mortality and a subject of intense scientific interest. Biomedical literature mining can aid DDI research by extracting evidence for large numbers of potential interactions from published literature and clinical databases. Though DDI is investigated in domains ranging in scale from intracellular biochemistry to human populations, literature mining has not been used to extract specific types of experimental evidence, which are reported differently for distinct experimental goals. We focus on pharmacokinetic evidence for DDI, essential for identifying causal mechanisms of putative interactions and as input for further pharmacological and pharmacoepidemiology investigations. We used manually curated corpora of PubMed abstracts and annotated sentences to evaluate the efficacy of literature mining on two tasks: first, identifying PubMed abstracts containing pharmacokinetic evidence of DDIs; second, extracting sentences containing such evidence from abstracts. We implemented a text mining pipeline and evaluated it using several linear classifiers and a variety of feature transforms. The most important textual features in the abstract and sentence classification tasks were analyzed. We also investigated the performance benefits of using features derived from PubMed metadata fields, various publicly available named entity recognizers, and pharmacokinetic dictionaries. Several classifiers performed very well in distinguishing relevant and irrelevant abstracts (reaching F1≈0.93, MCC≈0.74, iAUC≈0.99) and sentences (F1≈0.76, MCC≈0.65, iAUC≈0.83). We found that word bigram features were important for achieving optimal classifier performance and that features derived from Medical Subject Headings (MeSH) terms significantly improved abstract classification. We also found that some drug-related named entity recognition tools and dictionaries led to slight but significant improvements, especially in classification of evidence sentences. Based on our thorough analysis of classifiers and feature transforms and the high classification performance achieved, we demonstrate that literature mining can aid DDI discovery by supporting automatic extraction of specific types of experimental evidence.

Abstract P5-19-05: Combination vorinostat and lapatinib reverses epithelial-mesenchymal transition, inhibits the cancer stem cell population of HER2+ breast cancer cells and is effective in heavily pretreated advanced tumors

Abstract Although strides have been made in the treatment of breast cancer, patients often relapse due to recurrence or metastasis. The targeting of these cellular processes has become essential in the quest for a cancer cure. Previously, we have demonstrated the efficacy of histone deacetylase inhibitors (HDACi) in inducing differentiation and inhibiting metastasis in triple negative breast cancer cells. In addition, we have shown that HER2 regulates the cancer stem cell (CSC) population in AI resistant cells. Based on these previous results, we hypothesize that the combination of both HDACi and HER2 inhibition may be synergistic and further reduce CSC. In this study, we treated a panel of HER2+ breast cancer cell lines with the combination of 1µM vorinostat (HDACi) and 1µM lapatinib (a dual EGFR/HER2 inhibitor) for 72 hours and examined its effects on cell number, mesenchymal and epithelial markers, migratory potential, and cancer stem cell characteristics. The combination reduced cell number when compared to either agent alone (p&amp;lt;0.01 compared to vehicle). Cells treated with the combination exhibited a more epithelial morphology when compared to vehicle treated cells. Furthermore, when compared to vehicle treatment, the combination downregulated the expression of mesenchymal proteins: Twist (p&amp;lt;0.001), Snail (n.s.), and Vimentin (p&amp;lt;0.001) and concurrently upregulated epithelial proteins: cytokeratin 18 (p&amp;lt;0.001) and E-cadherin (n.s.), suggesting that the combination may reverse EMT (epithelial-mesenchymal transition). The combination was also able to inhibit the migratory potential of cells as measured using xCELLigence. In addition to its effects on EMT and migration, the combination also significantly reduced markers of the CSC population. Cellular markers of CSC, including mammary stem cell markers CD49f (p&amp;lt;0.01), CD24lo/CD44hi (p&amp;lt;0.01), and aldehyde dehydrogenase activity (p&amp;lt;0.001) were decreased following treatment with the combination. The self-renewal capability of cells was also affected by the combination, as evidenced by decreased expression of pluripotency proteins BMI-1 (p&amp;lt;0.05) and β-catenin (n.s.), as well as reduction of both primary (p&amp;lt;0.05) and secondary (p&amp;lt;0.05) mammosphere formation. We further conducted a phase I/II clinical trial of vorinostat in combination with lapatinib. There were 12 patients enrolled (9 in phase I and 3 in phase II). The treatment was fairly well tolerated with no DLT observed in phase I. PK analysis showed no evidence of drug-drug interaction. Among 8 patients with HER2-positive (HER2+) breast cancer, the clinical benefit rate (CR, PR, and SD) was 37.5% (1 PR, 2 SD). Intriguingly, we observed that none of the HER2+ breast cancer patients developed metastasis at a new site during the treatment. Their disease progression was due to the enlargement of previously existing lesions. Taken together, these results suggest that the combination of vorinostat and lapatinib may target both metastasis and CSC and that the combination is well tolerated and effective in patients with advanced HER2+ disease. Citation Format: Amanda J Schech, Saranya Chumsri, Preeti Shah, Stephen L Yu, Nancy S Tait, Kenneth S Bauer, Jane C Lewis, Ting Bao, Martin J Edelman, Katherine H Tkaczuk, Angela H Brodie. Combination vorinostat and lapatinib reverses epithelial-mesenchymal transition, inhibits the cancer stem cell population of HER2+ breast cancer cells and is effective in heavily pretreated advanced tumors [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-19-05.

Consensus recommendations for systematic evaluation of drug-drug interaction evidence for clinical decision support.

Healthcare organizations, compendia, and drug knowledgebase vendors use varying methods to evaluate and synthesize evidence on drug-drug interactions (DDIs). This situation has a negative effect on electronic prescribing and medication information systems that warn clinicians of potentially harmful medication combinations. The aim of this study was to provide recommendations for systematic evaluation of evidence for DDIs from the scientific literature, drug product labeling, and regulatory documents. A conference series was conducted to develop a structured process to improve the quality of DDI alerting systems. Three expert workgroups were assembled to address the goals of the conference. The Evidence Workgroup consisted of 18 individuals with expertise in pharmacology, drug information, biomedical informatics, and clinical decision support. Workgroup members met via webinar 12 times from January 2013 to February 2014. Two in-person meetings were conducted in May and September 2013 to reach consensus on recommendations. We developed expert consensus answers to the following three key questions. (i) What is the best approach to evaluate DDI evidence? (ii) What evidence is required for a DDI to be applicable to an entire class of drugs? (iii) How should a structured evaluation process be vetted and validated? Evidence-based decision support for DDIs requires consistent application of transparent and systematic methods to evaluate the evidence. Drug compendia and clinical decision support systems in which these recommendations are implemented should be able to provide higher-quality information about DDIs.

Evidence of Drug-Drug Interactions through Uptake and Efflux Transport Systems in Rat Hepatocytes: Implications for Cellular Concentrations of Competing Drugs

For drugs with hepatobiliary transport across hepatocytes, the interplay between uptake and efflux transporters determines hepatic concentrations of drugs, but the evolution over time of these concentrations is difficult to measure in humans other than with magnetic resonance imaging contrast agents in the liver. Gadobenate dimeglumine (BOPTA) is a contrast agent used in liver magnetic resonance imaging that enters into human hepatocytes through organic anion transporting polypeptides (OATP) and exits unchanged into bile through the multiple resistance-associated protein 2 (MRP2). Rifampicin (RIF) is transported by the same membrane proteins and may compete with BOPTA for hepatic uptake. Simultaneous drug-drug interactions through uptake and efflux transport systems in hepatocytes according to the cellular concentrations of competing drugs were never investigated. In perfused rat liver preparations, we demonstrate how the drug-drug interactions through transporters determine cellular concentrations of the competing drugs BOPTA and RIF, and we show that the cellular concentrations by modulating transport through membranes regulate the rat Oatp-Mrp2 interplay. Moreover, drug interactions through transporters change greatly over time.