Drug transporters are critically important for the absorption, distribution, metabolism, and excretion (ADME) of many drugs and endogenous compounds. Therefore, disruption of these pathways by ...inhibition, induction, genetic polymorphisms, or disease can have profound effects on overall physiology, drug pharmacokinetics, drug efficacy, and toxicity. This white paper provides a review of changes in transporter function associated with acute and chronic disease states, describes regulatory pathways affecting transporter expression, and identifies opportunities to advance the field.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Telemonitoring (TM) can improve heart failure (HF) outcomes by facilitating patient self-care and clinical decisions. The Medly program enables patients to use a mobile phone to record daily HF ...readings and receive personalized self-care messages generated by a clinically validated algorithm. The TM system also generates alerts, which are immediately acted upon by the patients' existing care team. This program has been operating for 3 years as part of the standard of care in an outpatient heart function clinic in Toronto, Canada.
This study aimed to evaluate the 6-month impact of this TM program on health service utilization, clinical outcomes, quality of life (QoL), and patient self-care.
This pragmatic quality improvement study employed a pretest-posttest design to compare 6-month outcome measures with those at program enrollment. The primary outcome was the number of HF-related hospitalizations. Secondary outcomes included all-cause hospitalizations, emergency department visits (HF related and all cause), length of stay (HF related and all cause), and visits to the outpatient clinic. Clinical outcomes included bloodwork (B-type natriuretic peptide BNP, creatinine, and sodium), left ventricular ejection fraction, and predicted survival score using the Seattle Heart Failure Model. QoL was measured using the Minnesota Living with Heart Failure Questionnaire (MLHFQ) and the 5-level EuroQol 5-dimensional questionnaire. Self-care was measured using the Self-Care of Heart Failure Index (SCHFI). The difference in outcome scores was analyzed using negative binomial distribution and Poisson regressions for the health service utilization outcomes and linear regressions for all other outcomes to control for key demographic and clinical variables.
Available data for 315 patients enrolled in the TM program between August 2016 and January 2019 were analyzed. A 50% decrease in HF-related hospitalizations (incidence rate ratio IRR=0.50; P<.001) and a 24% decrease in the number of all-cause hospitalizations (IRR=0.76; P=.02) were found when comparing the number of events 6 months after program enrollment with the number of events 6 months before enrollment. With regard to clinical outcomes at 6 months, a 59% decrease in BNP values was found after adjusting for control variables. Moreover, 6-month MLHFQ total scores were 9.8 points lower than baseline scores (P<.001), representing a clinically meaningful improvement in HF-related QoL. Similarly, the MLHFQ physical and emotional subscales showed a decrease of 5.4 points (P<.001) and 1.5 points (P=.04), respectively. Finally, patient self-care after 6 months improved as demonstrated by a 7.8-point (P<.001) and 8.5-point (P=.01) increase in the SCHFI maintenance and management scores, respectively. No significant changes were observed in the remaining secondary outcomes.
This study suggests that an HF TM program, which provides patients with self-care support and active monitoring by their existing care team, can reduce health service utilization and improve clinical, QoL, and patient self-care outcomes.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Acid-reducing agents (ARAs) are the most commonly prescribed medications in North America and Western Europe. There are currently no data describing the prevalence of their use among cancer patients. ...However, this is a paramount question due to the potential for significant drug–drug interactions (DDIs) between ARAs, most commonly proton pump inhibitors (PPIs), and orally administered cancer therapeutics that display pH-dependent solubility, which may lead to decreased drug absorption and decreased therapeutic benefit. Of recently approved orally administered cancer therapeutics, >50% are characterized as having pH-dependent solubility, but there are currently no data describing the potential for this ARA-DDI liability among targeted agents currently in clinical development. The objectives of this study were to (1) determine the prevalence of ARA use among different cancer populations and (2) investigate the prevalence of orally administered cancer therapeutics currently in development that may be liable for an ARA-DDI. To address the question of ARA use among cancer patients, a retrospective cross-sectional analysis was performed using two large healthcare databases: Thomson Reuters MarketScan (N = 1,776,443) and the U.S. Department of Veterans Affairs (VA, N = 1,171,833). Among all cancer patients, the total prevalence proportion of ARA use (no. of cancer patients receiving an ARA/total no. of cancer patients) was 20% and 33% for the MarketScan and VA databases, respectively. PPIs were the most commonly prescribed agent, comprising 79% and 65% of all cancer patients receiving a prescription for an ARA (no. of cancer patients receiving a PPI /no. of cancer patients receiving an ARA) for the MarketScan and VA databases, respectively. To estimate the ARA-DDI liability of orally administered molecular targeted cancer therapeutics currently in development, two publicly available databases, (1) Kinase SARfari and (2) canSAR, were examined. For those orally administered clinical candidates that had available structures, the pKa’s and corresponding relative solubilities were calculated for a normal fasting pH of 1.2 and an “ARA-hypochlorhydric” pH of 4. Taking calculated pKa’s and relative solubilities into consideration, clinical candidates were classified based on their risk for an ARA-DDI. More than one-quarter (28%) of the molecules investigated are at high risk for an ARA-DDI, and of those high risk molecules, nearly three-quarters (73%) are being clinically evaluated for at least one of five cancer types with the highest prevalence of ARA use (gastrointestinal, pancreatic, lung, glioblastoma multiforme, gastrointestinal stromal tumor (GIST)). These data strongly suggest that with the clinical development of ARA-DDI-susceptible cancer therapeutics will come continued challenges for drug-development scientists, oncologists, and regulatory agencies in ensuring that patients achieve safe and efficacious exposures of their cancer therapeutics and thus optimal patient outcomes.
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IJS, KILJ, NUK, PNG, UL, UM
Breast cancer resistance protein (BCRP; ABCG2) limits intestinal absorption of low-permeability substrate drugs and mediates biliary excretion of drugs and metabolites. Based on clinical evidence of ...BCRP-mediated drug-drug interactions (DDIs) and the c.421C>A functional polymorphism affecting drug efficacy and safety, both the US Food and Drug Administration and European Medicines Agency recommend preclinical evaluation and, when appropriate, clinical assessment of BCRP-mediated DDIs. Although many BCRP substrates and inhibitors have been identified in vitro, clinical translation has been confounded by overlap with other transporters and metabolic enzymes. Regulatory recommendations for BCRP-mediated clinical DDI studies are challenging, as consensus is lacking on the choice of the most robust and specific human BCRP substrates and inhibitors and optimal study design. This review proposes a path forward based on a comprehensive analysis of available data. Oral sulfasalazine (1000 mg, immediate-release tablet) is the best available clinical substrate for intestinal BCRP, oral rosuvastatin (20 mg) for both intestinal and hepatic BCRP, and intravenous rosuvastatin (4 mg) for hepatic BCRP. Oral curcumin (2000 mg) and lapatinib (250 mg) are the best available clinical BCRP inhibitors. To interrogate the worst-case clinical BCRP DDI scenario, study subjects harboring the BCRP c.421C/C reference genotype are recommended. In addition, if sulfasalazine is selected as the substrate, subjects having the rapid acetylator phenotype are recommended. In the case of rosuvastatin, subjects with the organic anion-transporting polypeptide 1B1 c.521T/T genotype are recommended, together with monitoring of rosuvastatin's cholesterol-lowering effect at baseline and DDI phase. A proof-of-concept clinical study is being planned by a collaborative consortium to evaluate the proposed BCRP DDI study design.
Membrane transporters in drug development Giacomini, Kathleen M; Huang, Shiew-Mei; Tweedie, Donald J ...
Nature reviews. Drug discovery,
03/2010, Volume:
9, Issue:
3
Journal Article
Peer reviewed
Open access
Membrane transporters can be major determinants of the pharmacokinetic, safety and efficacy profiles of drugs. This presents several key questions for drug development, including which transporters ...are clinically important in drug absorption and disposition, and which in vitro methods are suitable for studying drug interactions with these transporters. In addition, what criteria should trigger follow-up clinical studies, and which clinical studies should be conducted if needed. In this article, we provide the recommendations of the International Transporter Consortium on these issues, and present decision trees that are intended to help guide clinical studies on the currently recognized most important drug transporter interactions. The recommendations are generally intended to support clinical development and filing of a new drug application. Overall, it is advised that the timing of transporter investigations should be driven by efficacy, safety and clinical trial enrolment questions (for example, exclusion and inclusion criteria), as well as a need for further understanding of the absorption, distribution, metabolism and excretion properties of the drug molecule, and information required for drug labelling.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
This first-in-human dose-escalation trial evaluated the safety, tolerability, maximal-tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics, pharmacodynamics, and preliminary ...clinical activity of pictilisib (GDC-0941), an oral, potent, and selective inhibitor of the class I phosphatidylinositol-3-kinases (PI3K).
Sixty patients with solid tumors received pictilisib at 14 dose levels from 15 to 450 mg once-daily, initially on days 1 to 21 every 28 days and later, using continuous dosing for selected dose levels. Pharmacodynamic studies incorporated (18)F-FDG-PET, and assessment of phosphorylated AKT and S6 ribosomal protein in platelet-rich plasma (PRP) and tumor tissue.
Pictilisib was well tolerated. The most common toxicities were grade 1-2 nausea, rash, and fatigue, whereas the DLT was grade 3 maculopapular rash (450 mg, 2 of 3 patients; 330 mg, 1 of 7 patients). The pharmacokinetic profile was dose-proportional and supported once-daily dosing. Levels of phosphorylated serine-473 AKT were suppressed >90% in PRP at 3 hours after dose at the MTD and in tumor at pictilisib doses associated with AUC >20 h·μmol/L. Significant increase in plasma insulin and glucose levels, and >25% decrease in (18)F-FDG uptake by PET in 7 of 32 evaluable patients confirmed target modulation. A patient with V600E BRAF-mutant melanoma and another with platinum-refractory epithelial ovarian cancer exhibiting PTEN loss and PIK3CA amplification demonstrated partial response by RECIST and GCIG-CA125 criteria, respectively.
Pictilisib was safely administered with a dose-proportional pharmacokinetic profile, on-target pharmacodynamic activity at dose levels ≥100 mg and signs of antitumor activity. The recommended phase II dose was continuous dosing at 330 mg once-daily.
Telemonitoring (TM) can improve heart failure (HF) outcomes by facilitating patient self-care and clinical decision support. However, these outcomes are only possible if patients consistently adhere ...to taking prescribed home readings.
The objectives of this study were to (1) quantify the degree to which patients adhered to taking prescribed home readings in the context of a mobile phone-based TM program and (2) explain longitudinal adherence rates based on the duration of program enrollment, patient characteristics, and patient perceptions of the TM program.
A mixed-methods explanatory sequential design was used to meet the 2 research objectives, and all explanatory methods were guided by the unified theory of acceptance and use of technology 2 (UTAUT2). Overall adherence rates were calculated as the proportion of days patients took weight, blood pressure, heart rate, and symptom readings over the total number of days they were enrolled in the program up to 1 year. Monthly adherence rates were also calculated as the proportion of days patients took the same 4 readings over each 30-day period following program enrollment. Next, simple and multivariate regressions were performed to determine the influence of time, age, sex, and disease severity on adherence rates. Additional explanatory methods included questionnaires at 6 and 12 months probing patients on the perceived benefits and ease of use of the TM program, an analysis of reasons for patients leaving the program, and semistructured interviews conducted with a purposeful sampling of patients (n=24) with a range of adherence rates and demographics.
Overall average adherence was 73.6% (SD 25.0) with average adherence rates declining over time at a rate of 1.4% per month (P<.001). The multivariate regressions found no significant effect of sex and disease severity on adherence rates. When grouping patients' ages by decade, age was a significant predictor (P=.04) whereby older patients had higher adherence rates over time. Adherence rates were further explained by patients' perceptions with regard to the themes of (1) performance expectancy (improvements in HF management and peace of mind), (2) effort expectancy (ease of use and technical issues), (3) facilitating conditions (availability of technical support and automated adherence calls), (4) social influence (support from family, friends, and trusted clinicians), and (5) habit (degree to which taking readings became automatic).
The decline in adherence rates over time is consistent with findings from other studies. However, this study also found adherence to be the highest and most consistent over time in older age groups and progressively lower over time for younger age groups. These findings can inform the design and implementation of TM interventions that maximize patient adherence, which will enable a more accurate evaluation of impact and optimization of resources.
RR2-10.2196/resprot.9911.
Purpose To evaluate the in vivo efficacy of curcumin as an inhibitor of the multidrug-resistance-linked ATP Binding Cassette (ABC) drug transporter, ABCG2. Methods Photoaffinity labeling with ...¹²⁵I-iodoarylazidoprazosin was used to characterize the interaction of sulfasalazine, a substrate of the mouse ABCG2, with human ABCG2. In addition, the inhibitory effect of curcumin on ABCG2 was evaluated in brain capillaries from rats. Furthermore, the effect of curcumin on absorption of orally administered sulfasalazine in wild-type and abcg2 ⁻/⁻ mice was also determined. Results Sulfasalazine interacted at the drug-substrate site(s) of human ABCG2. Curcumin inhibited ABCG2 activity at nanomolar concentrations at the rat blood-brain barrier in the ex vivo assay. Based on studies in wild type and abcg2 ⁻/⁻ mice, we observed that oral curcumin increased C max and relative bioavailability of sulfasalazine by selectively inhibiting ABCG2 function. Conclusions This study validates our previous in vitro results with human ABCG2 (Chearwae et al., Mol. Cancer Ther. 5:1995-2006, 2006) and provides the first in vivo evidence for the inhibition by curcumin of ABCG2-mediated efflux of sulfasalazine in mice. Based on these studies, we propose that non-toxic concentrations of curcumin may be used to enhance drug exposure when the rate-limiting step of drug absorption and/or tissue distribution is impacted by ABCG2.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Taselisib is a potent and selective tumor growth inhibitor through PI3K pathway suppression. Thirty-four patients with locally advanced or metastatic solid tumors were treated (phase I study, ...modified 3+3 dose escalation; 5 cohorts; 3-16 mg taselisib once-daily capsule). Taselisib pharmacokinetics were dose-proportional; mean half-life was 40 hours. Frequent dose-dependent, treatment-related adverse events included diarrhea, hyperglycemia, decreased appetite, nausea, rash, stomatitis, and vomiting. At 12 and 16 mg dose levels, dose-limiting toxicities (DLT) were observed, with an accumulation of higher-grade adverse events after the cycle 1 DLT assessment window. Pharmacodynamic findings showed pathway inhibition at ≥3 mg in patient tumor samples, consistent with preclinical
-mutant tumor xenograft models. Confirmed response rate was 36% for
-mutant tumor patients with measurable disease 5/14: 4 breast cancer (3 patients at 12 mg); 1 non-small cell lung cancer, where responses started at 3 mg, and 0% in patients with tumors without known
hotspot mutations (0/15).
Preliminary data consistent with preclinical data indicate increased antitumor activity of taselisib in patients with
-mutant tumors (in comparison with patients with tumors without known activating
hotspot mutations) starting at the lowest dose tested of 3 mg, thereby supporting higher potency for taselisib against
-mutant tumors.
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To the best of our knowledge, this study is the first to compare dual inhibition of PI3K/mammalian target of rapamycin (mTOR) by apitolisib (GDC-0980) against single inhibition of mTORC1 by ...everolimus in metastatic renal cell carcinoma (mRCC).
Patients with clear-cell mRCC who progressed on or after vascular endothelial growth factor-targeted therapy were randomly assigned to apitolisib 40 mg once per day or to everolimus 10 mg once per day. End points included progression-free survival, safety, overall survival, and objective response rate. Biomarker assessments were conducted.
Eighty-five patients were randomly assigned. After 67 events, stratified analysis revealed that median progression-free survival was significantly shorter for apitolisib than for everolimus (3.7 v 6.1 months; hazard ratio, 2.12 95% CI, 1.23 to 3.63; P < .01); apitolisib was not favored in any stratification subgroup. Median overall survival was not significantly different but trended in favor of everolimus (16.5 v 22.8 months; hazard ratio, 1.77 95% CI, 0.97 to 3.24; P = .06). The objective response rate was 7.1% for apitolisib and 11.6% for everolimus. Patients administered apitolisib with a greater incidence of grade 3 to 4 adverse events were more likely to discontinue treatment (31% v 12% for everolimus). No drug-related deaths were observed. Apitolisib in comparison with everolimus was associated with substantially more high-grade hyperglycemia (40% v 9%) and rash (24% v 2%). Apitolisib pharmacokinetics suggested a relationship between exposure, and rash and hyperglycemia. Retrospective biomarker analyses revealed a relationship between VHL mutation status and outcome with everolimus but not with apitolisib. High hypoxia-inducible factor 1α protein expression was associated with better outcome in both arms.
This study demonstrated that dual PI3K/mTOR inhibition by apitolisib was less effective than was everolimus in mRCC, likely because full blockade of PI3K/mTOR signaling resulted in multiple on-target adverse events. VHL mutation and hypoxia-inducible factor 1α expression may be predictive of an mTOR inhibitor benefit, although prospective validation is required.
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