Journal of clinical pharmacology最新文献

{"title":"Results From the First-in-Human Study With Ozanimod, a Novel, Selective Sphingosine-1-Phosphate Receptor Modulator.","authors":"Jonathan Q Tran,&nbsp;Jeffrey P Hartung,&nbsp;Robert J Peach,&nbsp;Marcus F Boehm,&nbsp;Hugh Rosen,&nbsp;Heather Smith,&nbsp;Jennifer L Brooks,&nbsp;Gregg A Timony,&nbsp;Allan D Olson,&nbsp;Sheila Gujrathi,&nbsp;Paul A Frohna","doi":"10.1002/jcph.887","DOIUrl":"https://doi.org/10.1002/jcph.887","url":null,"abstract":"<p><p>The sphingosine-1-phosphate 1 receptor (S1P_1R ) is expressed by lymphocytes, dendritic cells, and vascular endothelial cells and plays a role in the regulation of chronic inflammation and lymphocyte egress from peripheral lymphoid organs. Ozanimod is an oral selective modulator of S1P_1R and S1P_5R receptors in clinical development for the treatment of chronic immune-mediated, inflammatory diseases. This first-in-human study characterized the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of ozanimod in 88 healthy volunteers using a range of single and multiple doses (7 and 28 days) and a dose-escalation regimen. Ozanimod was generally well tolerated up to a maximum single dose of 3 mg and multiple doses of 2 mg/d, with no severe adverse events (AEs) and no dose-limiting toxicities. The most common ozanimod-related AEs included headache, somnolence, dizziness, nausea, and fatigue. Ozanimod exhibited linear PK, high steady-state volume of distribution (73-101 L/kg), moderate oral clearance (204-227 L/h), and an elimination half-life of approximately 17 to 21 hours. Ozanimod produced a robust dose-dependent reduction in total peripheral lymphocytes, with a median decrease of 65% to 68% observed after 28 days of dosing at 1 and 1.5 mg/d, respectively. Ozanimod selectivity affected lymphocyte subtypes, causing marked decreases in cells expressing CCR7 and variable decreases in subsets lacking CCR7. A dose-dependent negative chronotropic effect was observed following the first dose, with the dose-escalation regimen attenuating the first-dose negative chronotropic effect. Ozanimod safety, PK, and PD properties support the once-daily regimens under clinical investigation.</p>","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"57 8","pages":"988-996"},"PeriodicalIF":2.9,"publicationDate":"2017-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.887","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34905865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Electrophysiological Adverse Effects of Direct-Acting Antivirals in Patients With Chronic Hepatitis C.","authors":"Roberto Rossotti,&nbsp;Lucio Jesus Garcia-Fraile Fraile,&nbsp;Chiara Baiguera,&nbsp;Massimo Puoti","doi":"10.1002/jcph.905","DOIUrl":"https://doi.org/10.1002/jcph.905","url":null,"abstract":"Dear Editor, We read with great interest the article by DuranteMangoni et al.1 Sofosbuvir (SOF) has recently been correlated with bradyarrhythmias, especially if coadministered with amiodarone. In this study, DuranteMangoni et al assessed several electrocardiographic (ECG) parameters in 26 subjects who were consecutively treated with various SOF-based regimens. They did not observe significant changes in ECG parameters except a transient increase of QTc duration during the first week that returned to baseline values afterward. In contrast to what was reported by Renet et al2 and Fontaine et al,3 the authors concluded that SOF-based regimens could be considered safe. HIV/HCV coinfected patients are often treated with methadone and antiretrovirals, such as atazanavir and rilpivirine, which have an effect on QTc duration. Thus, we performed a similar evaluation of ECG parameters in 58 coinfected individuals treated with different SOFbased regimens from January 2015 to July 2016. ECG parameters were prospectively collected at baseline, after 1 and 4 weeks, and at the end of therapy. Compared to the study by Durante-Mangoni and colleagues, our population is larger and has several differences, especially in terms of liver fibrosis severity (Table 1). In the overall analysis, QTc duration did not change significantly over treatment (P= .31). Patients receiving atazanavir or rilpivirine had stable QTc intervals during treatment. No difference was noted for any directacting antiviral combination. At baseline, F3 (defined by a stiffness between 10 and 14 kPa) and cirrhotic subjects had comparable QTc values (408 milliseconds vs 422 milliseconds for F4 [defined by a stiffness >14 kPa] overall, 421 milliseconds for Child-Pugh-Turcotte class [CPT] A and 425 for CPT B/C), but such difference was not significant (P = .16). At week 4, F3 individuals maintained the same QTc value (407 milliseconds), but F4 patients had a slight increase to 424 milliseconds (P = 0.01). If we consider F3, CPT A (423 milliseconds), and CPT B/C Table 1. Baseline Features of Study Population","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"57 7","pages":"931-932"},"PeriodicalIF":2.9,"publicationDate":"2017-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.905","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34962945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alternative Treatment Regimens With the PCSK9 Inhibitors Alirocumab and Evolocumab: A Pharmacokinetic and Pharmacodynamic Modeling Approach.","authors":"Nina Scherer,&nbsp;Christiane Dings,&nbsp;Michael Böhm,&nbsp;Ulrich Laufs,&nbsp;Thorsten Lehr","doi":"10.1002/jcph.866","DOIUrl":"https://doi.org/10.1002/jcph.866","url":null,"abstract":"<p><p>Alirocumab and evolocumab are 2 human monoclonal antibodies that inhibit the proprotein convertase subtilisin/kexin type 9 (PCSK9). These antibodies can potently lower low-density lipoprotein cholesterol (LDLc) serum concentrations. The aims of this analysis were to develop a pharmacokinetic (PK) and pharmacodynamic (PD) model for both antibodies, to simulate and investigate different dosage and application regimens, and finally, to note the effects on LDLc levels. Alirocumab was clinically studied and approved with 2 doses, 75 and 150 mg every 2 weeks (Q2W), whereas evolocumab was tested and approved with 2 dosing intervals, 140 mg Q2W and 420 mg Q4W. Data were digitized from published studies describing alirocumab and evolocumab PK, as well as LDLc levels in humans for various single and multiple doses. Alirocumab dosages ranged between 75 and 300 mg and evolocumab from 7 to 420 mg. The analysis was performed using a nonlinear mixed-effects modeling technique. A 2-compartment model with first-order absorption and saturable elimination described the PK of both antibodies best. LDLc levels were described by a turnover model with zero-order synthesis rate decreased by the antibodies and a first-order degradation rate that was increased by the antibodies. Simulations show a comparable effectiveness for alirocumab 75 mg Q2W and 150 mg Q3W as well as evolucmab 140 mg Q2W and 420 mg Q5W, respectively. This is the first PK/PD model describing the link between alirocumab and evolocumab PK and LDLc concentrations. The model may serve as an important tool to simulate different dosage regimens in order to optimize therapy.</p>","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"57 7","pages":"846-854"},"PeriodicalIF":2.9,"publicationDate":"2017-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.866","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34785806","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population Pharmacokinetic Modeling of Secukinumab in Patients With Moderate to Severe Psoriasis.","authors":"Gerard Bruin,&nbsp;Christian Loesche,&nbsp;Judit Nyirady,&nbsp;Oliver Sander","doi":"10.1002/jcph.876","DOIUrl":"https://doi.org/10.1002/jcph.876","url":null,"abstract":"<p><p>Secukinumab is a human monoclonal antibody with demonstrated efficacy for moderate to severe psoriasis; it binds to and neutralizes interleukin (IL)-17A. The pharmacokinetic (PK) parameters of secukinumab were best described by a 2-compartment model. Only weight was included in the final model, as other covariates did not affect clinical relevance. The estimated serum clearance of secukinumab was 0.19 L/day, with interindividual variability (IIV) of 32% coefficient of variation (CV), and low total volume of distribution (central compartment volume, 3.61 L with IIV of 30% CV; peripheral compartment volume, 2.87 L with IIV of 18% CV). The bioavailability of secukinumab after subcutaneous dosing was approximately 73%, with an absorption rate of 0.18/day with IIV of 35% CV. The PK profile of secukinumab was linear, with no evidence of a dose dependence of clearance. Clearance and volume of secukinumab varied with body weight in an allometric relationship. The time to maximum serum concentration at steady state occurred approximately 6 days after dosing for both secukinumab 300 mg and secukinumab 150 mg. Overall, the PK properties of secukinumab were typical of a 150-kDa human IgG1 antibody interacting with a soluble target.</p>","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"57 7","pages":"876-885"},"PeriodicalIF":2.9,"publicationDate":"2017-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.876","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34794766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Brivaracetam: An Adjunctive Treatment for Partial-Onset Seizures.","authors":"John A Kappes,&nbsp;William J Hayes,&nbsp;Joe D Strain,&nbsp;Debra K Farver","doi":"10.1002/jcph.900","DOIUrl":"https://doi.org/10.1002/jcph.900","url":null,"abstract":"<p><p>Brivaracetam is an analogue of levetiracetam that is Food and Drug Administration-approved for adjunctive treatment of partial-onset seizures in patients 16 years and older. In placebo-controlled trials adjunct brivaracetam demonstrated efficacy in reducing the frequency of seizures. The most commonly reported adverse effects are somnolence, dizziness, and fatigue. Clinical trials have evaluated brivaracetam for safety and efficacy in adjunctive treatment of partial-onset seizures in patients 16 years and older for up to 16 weeks. Brivaracetam's mechanism is similar to that of levetiracetam but with greater receptor binding affinity on synaptic vesicle protein 2A and inhibitory effects on sodium channels. Clinically significant differences between these agents are undetermined. Brivaracetam is available as oral tablets, oral solution, and intravenous solution. The Food and Drug Administration-approved dose is 50 mg twice daily, and titration is not required. Brivaracetam does not need dose adjustment for renal impairment and has minimal drug-drug interactions. Current limitations of brivaracetam include lack of head-to-head trials, limited long-term safety and efficacy data, and cost. Overall, brivaracetam is a viable adjunct therapeutic option for refractory partial-onset seizures in those who have failed conventional therapies.</p>","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"57 7","pages":"811-817"},"PeriodicalIF":2.9,"publicationDate":"2017-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.900","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34899908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Generic Docetaxel.","authors":"Dominique Levêque,&nbsp;Guillaume Becker","doi":"10.1002/jcph.893","DOIUrl":"https://doi.org/10.1002/jcph.893","url":null,"abstract":"We read with great interest the article by N. Al Faqeer et al on the retrospective comparison of generic and branded formulations of docetaxel in terms of incidence of febrile neutropenia resulting in hospital admission.1 The authors found a higher incidence of febrile neutropenia with generic formulations compared with branded docetaxel and stated that the lower cost of generics should be balanced with the expenditure relative to complications. This kind of study is rather uncommon because approved generics and branded drugs have the same clinical activity. The approval of intravenous generic drugs is based on pharmaceutical equivalence, and clinical trials are not required by drug regulatory agencies. In fact, they are useless because the active entity is the same. In short, comparing generic drugs and their branded reference is the same as comparing various batches of the branded drug.2 Suspicion about generic drugs is often related to case reports or isolated observations. We do not think that this study proves than docetaxel generics are clinically different from the branded reference because of the several limitations highlighted by the authors (retrospective design, no check of drug–drug interactions). Docetaxel is cleared by CYP3A-mediated metabolism, and huge variations of elimination have been found among patients.3,4 In addition, docetaxel clearance has been related to CYP3A activity5 and has also been found to be an independent predictor of febrile neutropenia.3 So the difference of febrile neutropenia might have been simply related to the variations of metabolic elimination and not to the source of the docetaxel. At last, if a higher incidence of severe neutropenia really exists between the different formulations of docetaxel, it suggests that the generic vials are overdosed. Consequently, the drug agencies and the manufacturers should be alerted and the vials checked and eventually withdrawn. Otherwise, what can we do with this information, apart from casting doubts on generics and fear among patients?","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"57 7","pages":"935"},"PeriodicalIF":2.9,"publicationDate":"2017-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.893","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34963645","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Use of Simvastatin and Risk of Acute Pancreatitis: A Nationwide Case-Control Study in Taiwan.","authors":"Chih-Ming Lin,&nbsp;Kuan-Fu Liao,&nbsp;Cheng-Li Lin,&nbsp;Shih-Wei Lai","doi":"10.1002/jcph.881","DOIUrl":"https://doi.org/10.1002/jcph.881","url":null,"abstract":"<p><p>The correlation between simvastatin use and acute pancreatitis is explored. A case-control study was conducted to analyze claim data from the Taiwan National Health Insurance Program. The case group comprising a total of 3882 subjects aged 20 to 84 years with their first acute pancreatitis episode occurring between 1998 and 2011 formed the case group, against 3790 randomly selected controls matched for sex, age, comorbidities, and index year of acute pancreatitis diagnosis. Recent use of simvastatin was defined as subjects whose last remaining simvastatin tablet was noted ≤7 days before the date of acute pancreatitis diagnosis. Remote use of simvastatin was defined as subjects whose last remaining 1 tablet for simvastatin was noted >7 days before the date of acute pancreatitis diagnosis. Never use of simvastatin was defined as subjects who had never been prescribed simvastatin. A multivariable unconditional logistic regression model was used to estimate the odds ratio and 95%CI to explore the correlation between simvastatin use and acute pancreatitis. After adjustment for confounders, multivariable logistic regression analysis revealed that the adjusted odds ratio of acute pancreatitis was 1.3 for subjects with recent use of simvastatin (95%CI 1.02, 1.73), when compared with those with never use of simvastatin. The crude odds ratio decreased to 1.1 for those with remote use of simvastatin (95%CI 0.93, 1.34) but without statistical significance. Recent use of simvastatin is associated with acute pancreatitis. Clinicians should consider the possibility of simvastatin-associated acute pancreatitis for patients presenting for acute pancreatitis without known cause.</p>","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"57 7","pages":"918-923"},"PeriodicalIF":2.9,"publicationDate":"2017-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.881","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34818084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Generic and Branded Docetaxel.","authors":"Nour Al Faqeer,&nbsp;Lama Nazer","doi":"10.1002/jcph.914","DOIUrl":"https://doi.org/10.1002/jcph.914","url":null,"abstract":"We thank Leveque et al for their thoughtful comments regarding our study comparing generic and branded formulations of docetaxel. We agree that the generic formulations are expected to be comparable to the branded drugs in terms of quality and clinical activity. However, several studies have raised the concern about clinically significant differences between generic and branded formulations with both chemotherapy and nonchemotherapy products.1–4 Furthermore, the differences between brand and generic formulations of docetaxel were previously addressed and were attributed to insufficient active ingredients and/or high level of impurities that may affect the efficacy and safety of the drug.5,6 Poirier et al compared the adverse event profile of generic docetaxel to the branded product and reported results that were consistent with those reported in our study. The incidence of febrile neutropenia was more serious with generic docetaxel despite increased G-CSF use.5 We agree that the presence or absence of drug– drug interactions in the study patients may have had an impact on the findings, and we agree that the unavailability of this information for the patients included is a limitation to the study. However, we predict that the large sample size and the similarities between the groups in several patient-related characteristics may haveminimized the impact of this limitation on the final results. The findings of this study and other similar studies are important for clinicians when they switch patients from branded to generic formulations or vice versa. In fact, our study was conducted as a result of the clinical observations reported to the pharmacy after patients had been switched from the branded docetaxel to the generic. The studywas generated to answer the question of whether the change in docetaxel formulation was associated with the observed increased incidence of febrile neutropenia.","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"57 7","pages":"936"},"PeriodicalIF":2.9,"publicationDate":"2017-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.914","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34962963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reply to Letter: Influence of Liver and Kidney Disease on Sofosbuvir Electrophysiological Effects.","authors":"Martina Vitrone,&nbsp;Antonio Parrella,&nbsp;Emanuele Durante-Mangoni","doi":"10.1002/jcph.915","DOIUrl":"https://doi.org/10.1002/jcph.915","url":null,"abstract":"We thank Drs Rossotti, Puoti, and colleagues for further reasoning on the electrophysiological effects of sofosbuvir for hepatitis C. Indeed, they analyze 2 important variables that we did not assess in our study,1 namely antiretroviral therapy for HIV coinfection and liver cirrhosis. None of our patients had HIV coinfection, but many had cirrhosis, a condition that can affect both cardiac electrical parameters and drug metabolism. A high frequency of mostly nonsignificant electrophysiological abnormalities occurs in patients with cirrhosis, including chronotropic incompetence, electromechanical uncoupling, and QT interval prolongation progressing from Child-Pugh-Turcotte (CPT) stage A to C.2 We therefore analyzed QTc duration in 18 cirrhotic and 8 noncirrhotic advanced fibrosis (F3) patients, all treated with sofosbuvir-based regimens. At week 1 of therapy, cirrhotic patients had no significant variation of QTc values compared with baseline (431.2 milliseconds vs 424.3 milliseconds, P = .480). Similar results were observed comparing QTc changes at week 4 (422.7 milliseconds vs 424.3 milliseconds at baseline, P = .554). When the same analysis was performed in CPT A patients (n = 15), the results were similar: 423.3 milliseconds at baseline, 429.9 milliseconds at week 1 and 421.5 milliseconds at week 4 (T0 to TW1 P = .575; T0 to TW4 P = .826). F3 patients similarly showed stable QTc values (424.4, 430.8, and 423.5 milliseconds at baseline, week 1, and week 4, respectively; T0 to TW1 P = .463; T0 to TW4 P = .161). Results confirm the overall conclusions of our study. We did not perform the same analysis in the CPT B group, due to the small number of patients (N = 3). The area under the concentration-time curve (AUC) of sofosbuvir given at 400 mg/day increased after 7 days of dosing by 126% and 143% in CPT B and CPT C patients, respectively, consistent with a potentially stronger electrophysiological effect. However, there are other conditions that can influence AUC. In patients with mild or moderate renal insufficiency, sofosbuvir AUC values were elevated by 61% and 107%, respectively, compared to controls.3 In this setting, sofosbuvir has demonstrated a favorable safety profile that did not appear to contribute any additional significant toxicity. Furthermore, no clinically significant electrocardiogram abnormalities and no meaningful changes in Fridericia-corrected QT intervals were observed in patients with a glomerular filtration rate &lt;30 mL/min, although AUC increased by 171%.4 In light of the common occurrence of renal functional impairment in HIV infection, results of Rossotti et al in this specific clinical setting could be explained by the double effect of liver and kidney impairment. Accordingly, we further assessed the influence of renal function on QTc duration. We divided sofosbuvirtreated patients in 2 groups according to the median value of the estimated glomerular filtration rate. Comparing patients with higher estimated glomerular ","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"57 7","pages":"933-934"},"PeriodicalIF":2.9,"publicationDate":"2017-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.915","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34963642","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetics of Venetoclax, a Novel BCL-2 Inhibitor, in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia or Non-Hodgkin Lymphoma.","authors":"Ahmed Hamed Salem,&nbsp;Suresh K Agarwal,&nbsp;Martin Dunbar,&nbsp;Sari L Heitner Enschede,&nbsp;Rod A Humerickhouse,&nbsp;Shekman L Wong","doi":"10.1002/jcph.821","DOIUrl":"https://doi.org/10.1002/jcph.821","url":null,"abstract":"<p><p>Venetoclax is a selective BCL-2 inhibitor that is approved in the United States for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion who have received at least 1 prior therapy. The aim of this analysis was to characterize venetoclax pharmacokinetics in the plasma and urine of patients with hematological malignancies and evaluate the effect of dose proportionality, accumulation, weak and moderate CYP3A inhibitors, as well as low- and high-fat meals on venetoclax pharmacokinetics. Patients received a once-daily venetoclax dose of 20 to 1200 mg. Pharmacokinetic parameters were estimated using noncompartmental methods. Venetoclax peak exposures were achieved at 5 to 8 hours under low-fat conditions, and the mean terminal-phase elimination half-life ranged between 14.1 and 18.2 hours at different doses. Venetoclax steady-state exposures showed minimal accumulation and increased proportionally over the dose range of 300 to 900 mg. Low-fat and high-fat meals increased venetoclax exposures by approximately 4-fold relative to the fasting state. Moderate CYP3A inhibitors increased venetoclax exposures by 40% to 60%, whereas weak CYP3A inhibitors had no effect. A negligible amount of venetoclax was excreted in the urine. In summary, venetoclax exhibits a pharmacokinetic profile that is compatible with once-daily dosing with food regardless of fat content. Concomitant use of venetoclax with moderate CYP3A inhibitors should be avoided or venetoclax dose should be reduced during the venetoclax initiation and ramp-up phase in CLL patients. Renal excretion plays a minimal role in the elimination of venetoclax.</p>","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"57 4","pages":"484-492"},"PeriodicalIF":2.9,"publicationDate":"2017-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.821","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34334471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}