A case of complete atrioventricular block with extremely high blood concentration of azelnidipine

Background Azelnidipine, a dihydropyridine calcium channel blocker (CCB), has less adverse effects (e.g. hot flushes and reflex tachycardia) compared to other dihydropyridine CCBs. Azelnidipine has been reported to reduce heart rate as opposed to inducing tachycardia. No evidence of bradycardia or complete atrioventricular block (CAVB) with azelnidipine treatment has been reported. Case presentation In the present study, a 92-year-old woman was diagnosed with CAVB while taking azelnidipine and simvastatin for an extended period of time, and referred to our medical center. It was thought that the CAVB may have been an adverse effect of azelnidipine treatment. Specifically, it was considered that in this patient, one of the causes might be the concomitant use of simvastatin inhibiting the metabolism of azelnidipine by cytochrome P450 enzyme 3A4. Consequently, it was suggested to the patient’s physician that the patient’s serum azelnidipine levels be measured and treatment with azelnidipine and simvastatin be discontinued. The patient’s serum concentration of azelnidipine at the time of her visit to our center was 63.4 ng/mL, higher than the normal acceptable level. There was no occurrence of CAVB for 4 weeks, to present, following discontinuation of azelnidipine and simvastatin treatment. Conclusions Azelnidipine has a different mechanism of action that other CCBs. In very rare cases, it may cause CAVB when combined with CYP3A4 inhibitors. If a patient taking azelnidipine is diagnosed with CAVB, physicians should suspect that the condition may be an adverse effect of azelnidipine and should consider discontinuing azelnidipine. And, in the elderly, it is necessary to avoid concomitant use of CYP3A4 inhibitors.

Application of Physiologically Based Pharmacokinetic Modeling to Evaluate the Drug–Drug and Drug–Disease Interactions of Apatinib

Aim: Apatinib is an orally administered vascular epidermal growth factor receptor (VEGFR)-tyrosine kinase inhibitors approved for the treatment of advanced gastric adenocarcinoma or gastric esophageal junction adenocarcinoma. Apatinib is predominantly metabolized by CYP3A4/5, followed by CYP2D6. The present study aimed to evaluate the potential drug–drug interaction (DDI) and drug–disease interaction (DDZI) risks of apatinib in Chinese volunteers.Methods: Modeling and simulation were conducted using Simcyp Simulator. The input parameters required for modeling were obtained from literature research or experiments. Then, the developed physiologically based pharmacokinetic (PBPK) models were applied to evaluate single-dose DDI potential in Chinese healthy volunteers with weak and moderate CYP3A inhibitors, strong CYP2D6 inhibitors, as well as CYP3A4 inducers. The DDZI potential was also predicted in patients with hepatic or renal impairment.Results: The developed PBPK models accurately assessed apatinib pharmacokinetics following single-dose administration in Chinese healthy volunteers and cancer patients. The DDI simulation showed 2–4-fold changes in apatinib exposures by moderate CYP3A4 inhibitors and CYP3A4 inducers. A moderate increase of apatinib exposure (1.25–2-fold) was found with strong CYP2D6 inhibitor. In the DDZI simulation with hepatic impairment, the AUC of apatinib was significantly increased by 2.25-fold and 3.04-fold for Child–Pugh B and Child–Pugh C, respectively, with slightly decreased Cmax by 1.54 and 1.67-fold, respectively.Conclusion: The PBPK models developed in the present study would be highly beneficial to quantitatively predict the pharmacokinetic changes of apatinib under different circumstances, which might be difficult to evaluate clinically, so as to avoid some risks in advance.

Do age, fitness and concomitant medications influence management and outcomes of CLL patients treated with ibrutinib?

Functional reserve of organs and systems is known to be relevant in predicting immunochemotherapy tolerance. Age and comorbidities, assessed by the cumulative illness rating scale (CIRS), have been used to address chemotherapy intensity. In ibrutinib era it is still unclear whether age, CIRS and ECOG-PS retain their predictive role on treatment vulnerability. In this 712 CLL patients series treated with ibrutinib outside clinical trials, baseline ECOG-PS and neutropenia, resulted as the most accurate predictors of treatment feasibility and outcomes. Age did not independently influence survival and ibrutinib tolerance, indicating that not age per se, but age-related conditions may affect drug management. We confirmed the role of CIRS>6 as a predictor of a poorer progression and event-free survival (PFS, EFS). The presence of a severe comorbidity was significantly associated with permanent dose reductions (PDR), not translating into worse outcomes. As expected, del(17p) and/or TP53mut and previous therapies affected PFS, EFS and overall survival. No study so far has analyzed the influence of concomitant medications and CYP3A-inhibitors with ibrutinib. In our series, these factors had no impact, though CYP3A4 inhibitors use correlated at Cox regression analysis, with an increased risk of PDR. Despite the limitation of its retrospective nature, this large study confirmed the role of ECOG-PS as the most accurate predictor of ibrutinib feasibility and outcomes and importantly neutropenia emerged as a relevant tool influencing patients vulnerability. Although CIRS>6 retained a significant impact on PFS and EFS its value should be confirmed by prospective studies.

Genetic Polymorphisms Associated With the Pharmacokinetics, Pharmacodynamics and Adverse Effects of Olanzapine, Aripiprazole and Risperidone

Olanzapine, aripiprazole and risperidone are atypical antipsychotics or neuroleptics widely used for schizophrenia treatment. They induce various adverse drug reactions depending on their mechanisms of action: metabolic effects, such as weight gain and alterations of glucose and lipid metabolism; hyperprolactinemia and extrapyramidal effects, such as tremor, akathisia, dystonia, anxiety and distress. In this review, we listed polymorphisms associated with individual response variability to olanzapine, aripiprazole and risperidone. Olanzapine is mainly metabolized by cytochrome P450 enzymes, CYP1A2 and CYP2D6, whereas aripiprazole and risperidone metabolism is mainly mediated by CYP2D6 and CYP3A4. Polymorphisms in these genes and other enzymes and transporters, such as enzymes from the uridine 5'-diphospho-glucuronosyltransferase (UGT) family and ATP-binding cassette sub-family B member 1 (ABCB1), are associated to differences in pharmacokinetics. The three antipsychotics act on dopamine and serotonin receptors, among others, and several studies found associations between polymorphisms in these genes and variations in the incidence of adverse effects and in the response to the drug. Since olanzapine is metabolized by CYP1A2, a lower starting dose should be considered in patients treated with fluvoxamine or other CYP1A2 inhibitors. Regarding aripiprazole, a reduced dose should be administered in CYP2D6 poor metabolizers (PMs). Additionally, a reduction to a quarter of the normal dose is recommended if the patient is treated with concomitant CYP3A4 inhibitors. Risperidone dosage should be reduced for CYP2D6 PMs and titrated for CYPD6 ultrarapid metabolizers (UMs). Moreover, risperidone dose should be evaluated when a CYP2D6, CYP3A4 or ABCB1 inhibitor is administered concomitantly.

Influence of Concomitant Polypharmacy on Docetaxel-induced Febrile Neutropenia

Background/Aim: Docetaxel (DTX) is metabolized by liver cytochromes P450 (CYP) 3A4 (CYP3A4) and 3A5 (CYP3A5) CYP3A4 activity is considered the main factor affecting the effectiveness in DTX clearance. We, therefore, explored the association between DTX-induced febrile neutropenia (FN) and concomitant polypharmacy involving CYP3A4 inhibitors in cancer patients. Patients and Methods: Among patients who received docetaxel, we compared the number of concomitant medications between patients with and without FN, and risk factors associated with FN were identified. Results: The total number of concomitant CYP3A4 inhibitors and substrates used was significantly higher in patients with FN [mean: 2.1 (95% confidence interval (CI)=1.5-2.9)] than in those without FN [mean: 1.4 (95% CI=1.0-1.8)] (p=0.01). The only risk factor for FN was the use of ≥2 concomitant CYP3A4 inhibitors and substrates in total (OR=4.82, 95% CI=1.77-14.1; p=0.002). Conclusion: Polypharmacy involving CYP3A4 inhibitors and substrates increases the risk of DTX-induced FN.

Association of combined phase I/II study of a novel bicyclic peptide and MMAE conjugate BT8009 in patients with advanced malignancies with Nectin-4 expression.

TPS2668 Background: BT8009 is a Bicycle Toxin Conjugate (BTC), a novel class of chemically synthesized molecules, comprising a bicyclic peptide targeting Nectin-4 tumor antigen, linked to cytotoxin (monomethyl auristatin E [MMAE]) via a valine-citrulline (val-cit) cleavable linker. Nectins (Nectin-1, -2, -3, and -4) and nectin-like molecules (Necl) are Ca2+ independent immunoglobulin-like cell adhesion molecules. Recent studies have shown the importance of Nectin-4 in several human cancers, including lung, ovarian, breast and bladder cancer; however, the precise roles and clinical relevance of Nectin-4 in tumors remain largely unknown. The Nectin-4 targeted enfortumab vedotin, linked to MMAE via a val-cit linker, is highly active in late-stage bladder cancer and demonstrates notable additional clinical activity as a single agent and in combination with pembrolizumab1. Skin toxicities, bone marrow suppression, peripheral neuropathy and diabetes have been associated with enfortumab, with some of these toxicities already noted with MMAE-bearing antibody therapies. We anticipate a similar toxicity profile for BT8009 in clinical studies. BT8009 exhibited a favorable preclinical profile and was effective in a range of cell-derived xenograph tumor models. Methods: Study BT8009-100 (NCT04561362) will evaluate safety and tolerability of weekly and every other week BT8009 administration, alone and in combination with q4w nivolumab. Determination of both a realistic phase 2 dose and a sequence will also be key to further exploration of safety and efficacy signals, along with an early examination of the role of baseline immunohistochemistry-ascertained levels of tumor Nectin-4. Patients will be recruited with advanced solid tumors associated with Nectin-4 expression after exhausting SOC options (i.e., bladder, breast, pancreatic, head and neck, gastric, esophageal and ovarian). Patients must have available tumor tissue, acceptable hematologic and other critical organ function and be willing to participate. Appropriate ethical and regulatory approvals and advice will be in place and adhered to. Exclusion criteria include uncontrolled brain metastases, uncontrolled hypertension, concomitant CYP3A4 inhibitors and significant history of autoimmune disease for the nivolumab cohorts. PK serial collections will be taken on D1 through D15. Radiologic tumor assessments for response per RECIST will be taken every two months. 1. Enfortumab Vedotin. FDA_data. 761137Orig1s000MultiDiscliplineR.pdf (fda.gov). Clinical trial information: NCT04561362.

A comprehensive assessment of statin discontinuation among patients who concurrently initiate statins and CYP3A4-inhibitor drugs; a multistate transition model

Aims: To describe the 1-year direct and indirect transition probabilities to premature discontinuation of statin therapy after concurrently initiating statins and CYP3A4-inhibitor drugs. Methods and Results: A retrospective new-user cohort study design was used to identify (N=160828) patients who concurrently initiated CYP3A4-inhibitors (diltiazem, ketoconazole, clarithromycin, others) and CYP3A4-metabolized statins (statin DDI exposed, n = 104774) vs. other statins (unexposed, n = 56054) from the MarketScan Commercial claims database (2012 to 2017). These groups were matched (2:1) through propensity score-matching techniques. We applied a multistate transition model to compare the 1-year transition probabilities involving four distinct states (start, adverse drug events [ADEs], discontinuation of CYP3A4-inhibitor drugs, and discontinuation of statin therapy) between those exposed to statin DDIs, vs. unexposed. Statistically significant differences were assessed by comparing the 95% confidence intervals (CIs) of probabilities. Patients exposed to statin DDIs, vs. unexposed, were significantly less likely to discontinue statin therapy (71.4 [95% CI: 71.1, 71.6] vs. 73.3 [95% CI: 72.9, 73.6]) but more likely to experience an ADE (3.4 [95% CI: 3.3, 3.5] vs. 3.2 [95% CI: 3.1, 3.3]) and discontinue with CYP3A4-inhibitor therapy (21.0 [95% CI: 20.8, 21.3] vs. 19.5 [95% CI: 19.2, 19.8]) directly after concurrently starting stains and CYP3A. Subsequent to experiencing an ADE, those exposed to statin DDIs were still less likely to discontinue statin therapy but were significantly more likely to discontinue CYP3A4-inhibitor therapy. Conclusion: While statin DDI exposure was associated with higher likelihood of ADEs, this did not increase the risk of premature statin discontinuation among patients exposed to statin DDIs, versus unexposed.