Journal of clinical pharmacology最新文献_第5页

Impact of the Selective Orexin-1 Receptor Antagonist ACT-539313 on the Pharmacokinetics of the CYP3A Probe Drug Midazolam in Healthy Male Subjects. 选择性食欲素-1受体拮抗剂ACT-539313对CYP3A探针药物咪达唑仑在健康男性体内药代动力学的影响

IF 2.9 4区医学

Journal of clinical pharmacology Pub Date : 2020-07-01 Epub Date: 2020-02-08 DOI: 10.1002/jcph.1588

Benjamin Berger, Priska Kaufmann, Annelize Koch, Jasper Dingemanse

{"title":"Impact of the Selective Orexin-1 Receptor Antagonist ACT-539313 on the Pharmacokinetics of the CYP3A Probe Drug Midazolam in Healthy Male Subjects.","authors":"Benjamin Berger, Priska Kaufmann, Annelize Koch, Jasper Dingemanse","doi":"10.1002/jcph.1588","DOIUrl":"https://doi.org/10.1002/jcph.1588","url":null,"abstract":"ACT-539313 is a potent and selective orexin-1 receptor antagonist. CYP3A is the major cytochrome P450 (CYP) enzyme involved in the metabolism and clearance of ACT-539313 in man. The main objective of this study was to investigate the effect of ACT-539313 on the pharmacokinetics of orally administered midazolam. Thereby, this single-center, open-label, fixed-sequence study investigated the CYP3A interaction potential of ACT-539313 following single- (on day 2) and repeated-dose (on day 11) twice-daily administration of 200 mg ACT-539313. Exposure to midazolam was higher during concomitant administration of single as well as after repeated doses of ACT-539313 over 10 days compared to midazolam alone (day 1). In the presence of ACT-539313, the geometric mean ratio of the maximum plasma concentration and the area under the plasma concentration-time curve from time 0 to 24 hours increased by 1.18- and 1.79-fold on day 2, and by 2.13- and 4.54-fold on day 11, respectively. A similar outcome was also shown in the additionally evaluated urinary 6β-hydroxycortisol/cortisol ratio (6β-CR), as the geometric mean ratio of the 6β-CR showed a decrease to 0.78 on day 2 and to 0.61 on day 11. The most commonly reported adverse events (AEs) included somnolence and headache. All AEs were transient and of mild intensity. No treatment-related effects on vital signs, clinical laboratory, and electrocardiogram were observed. In summary, the observed corresponding decrease of both the validated, exogenous (midazolam/1-hydroxymidazolam ratio) and a frequently used endogenous (6β-CR) marker of CYP3A activity is indicative of CYP3A inhibition occurring after ACT-539313 treatment.","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":" ","pages":"931-941"},"PeriodicalIF":2.9,"publicationDate":"2020-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.1588","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37624582","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}

引用次数: 7

Mannuronic Acid in Low-Risk and Intermediate-1-Risk Myelodysplastic Syndromes. 甘露醛酸在低危和中危骨髓增生异常综合征中的作用。

IF 2.9 4区医学

Journal of clinical pharmacology Pub Date : 2020-07-01 Epub Date: 2020-02-16 DOI: 10.1002/jcph.1587

Afshin Ghaderi, Sayyed Reza Safaee Nodehi, Tahereh Bakhtiari, Mona Aslani, Zahra Aghazadeh, Hidenori Matsuo, Bernd H A Rehm, Salvatore Cuzzocrea, Abbas Mirshafiey

{"title":"Mannuronic Acid in Low-Risk and Intermediate-1-Risk Myelodysplastic Syndromes.","authors":"Afshin Ghaderi, Sayyed Reza Safaee Nodehi, Tahereh Bakhtiari, Mona Aslani, Zahra Aghazadeh, Hidenori Matsuo, Bernd H A Rehm, Salvatore Cuzzocrea, Abbas Mirshafiey","doi":"10.1002/jcph.1587","DOIUrl":"https://doi.org/10.1002/jcph.1587","url":null,"abstract":"The discovery of hematologic improvement and bone marrow modification by the drug β-D mannuronic acid (M2000) during treatment of rheumatoid arthritis in phase 1/2/3 clinical trials prompted us to design a new trial to target hematologic deficits in myelodysplastic syndromes (MDS). In this open-label, randomized phase 2 clinical trial, the potential effect and tolerability of drug M2000 was assessed in patients with low- and intermediate-1-risk MDS. The primary efficacy end point was hematologic improvement after 12 weeks of β-D-mannuronic acid therapy. Among 34 enrolled patients, half received their conventional therapy plus β-D-mannuronic acid, and the other half received only conventional drugs. In the conventional + β-D mannuronic acid treatment group, hematologic improvement and development of transfusion independence and/or reduction in transfusion requirements were seen in 12 patients (92.3%) and 1 patient (7.7%), respectively. Moreover, 5 patients (38.5%), 2 patients (15.4%), and 1 patient (7.7%) in the β-D-mannuronic acid-treated group showed hematologic improvement of the major parameters of erythroid, neutrophil, and platelet responses, respectively, based on the International Working Group criteria), whereas in the conventional treatment group as control, no hematologic improvements including erythroid, neutrophil, and platelet response was seen. In this trial, the addition of β-D mannuronic acid to conventional treatment showed promising results in MDS patients with low and intermediate-1 risk with effects on hematologic improvements without significant adverse effect.","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":" ","pages":"879-888"},"PeriodicalIF":2.9,"publicationDate":"2020-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.1587","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37648870","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}

引用次数: 0

Predicting Clinical Effects of CYP3A4 Modulators on Abemaciclib and Active Metabolites Exposure Using Physiologically Based Pharmacokinetic Modeling. 使用基于生理的药代动力学模型预测CYP3A4调节剂对阿贝美昔单抗和活性代谢物暴露的临床影响。

IF 2.9 4区医学

Journal of clinical pharmacology Pub Date : 2020-07-01 Epub Date: 2020-02-20 DOI: 10.1002/jcph.1584

Maria M Posada, Bridget L Morse, P Kellie Turner, Palaniappan Kulanthaivel, Stephen D Hall, Gemma L Dickinson

{"title":"Predicting Clinical Effects of CYP3A4 Modulators on Abemaciclib and Active Metabolites Exposure Using Physiologically Based Pharmacokinetic Modeling.","authors":"Maria M Posada, Bridget L Morse, P Kellie Turner, Palaniappan Kulanthaivel, Stephen D Hall, Gemma L Dickinson","doi":"10.1002/jcph.1584","DOIUrl":"https://doi.org/10.1002/jcph.1584","url":null,"abstract":"Abemaciclib, a selective inhibitor of cyclin-dependent kinases 4 and 6, is metabolized mainly by cytochrome P450 (CYP)3A4. Clinical studies were performed to assess the impact of strong inhibitor (clarithromycin) and inducer (rifampin) on the exposure of abemaciclib and active metabolites. A physiologically based pharmacokinetic (PBPK) model incorporating the metabolites was developed to predict the effect of other strong and moderate CYP3A4 inhibitors and inducers. Clarithromycin increased the area under the plasma concentration-time curve (AUC) of abemaciclib and potency-adjusted unbound active species 3.4-fold and 2.5-fold, respectively. Rifampin decreased corresponding exposures 95% and 77%, respectively. These changes influenced the fraction metabolized via CYP3A4 in the model. An absolute bioavailability study informed the hepatic and gastric availability. In vitro data and a human radiolabel study determined the fraction and rate of formation of the active metabolites as well as absorption-related parameters. The predicted AUC ratios of potency-adjusted unbound active species with rifampin and clarithromycin were within 0.7- and 1.25-fold of those observed. The PBPK model predicted 3.78- and 7.15-fold increases in the AUC of the potency-adjusted unbound active species with strong CYP3A4 inhibitors itraconazole and ketoconazole, respectively; and 1.62- and 2.37-fold increases with the concomitant use of moderate CYP3A4 inhibitors verapamil and diltiazem, respectively. The model predicted modafinil, bosentan, and efavirenz would decrease the AUC of the potency-adjusted unbound active species by 29%, 42%, and 52%, respectively. The current PBPK model, which considers changes in unbound potency-adjusted active species, can be used to inform dosing recommendations when abemaciclib is coadministered with CYP3A4 perpetrators.","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":" ","pages":"915-930"},"PeriodicalIF":2.9,"publicationDate":"2020-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.1584","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37662707","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}

引用次数: 32

Efficacy, Safety, and Tolerability of ONO-4474, an Orally Available Pan-Tropomyosin Receptor Kinase Inhibitor, in Japanese Patients With Moderate to Severe Osteoarthritis of the Knee: A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group Comparative Study. 口服泛原肌球蛋白受体激酶抑制剂ONO-4474在日本中度至重度膝关节骨关节炎患者中的疗效、安全性和耐受性:一项随机、安慰剂对照、双盲、平行组比较研究

IF 2.9 4区医学

Journal of clinical pharmacology Pub Date : 2020-01-01 Epub Date: 2019-07-08 DOI: 10.1002/jcph.1470

Naoki Ishiguro, Shusuke Oyama, Ryunosuke Higashi, Kunio Yanagida

{"title":"Efficacy, Safety, and Tolerability of ONO-4474, an Orally Available Pan-Tropomyosin Receptor Kinase Inhibitor, in Japanese Patients With Moderate to Severe Osteoarthritis of the Knee: A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group Comparative Study.","authors":"Naoki Ishiguro, Shusuke Oyama, Ryunosuke Higashi, Kunio Yanagida","doi":"10.1002/jcph.1470","DOIUrl":"https://doi.org/10.1002/jcph.1470","url":null,"abstract":"We examined the efficacy, safety, and tolerability of ONO-4474 in Japanese patients with osteoarthritis (OA) of the knee. In this multicenter, placebo-controlled, randomized, double-blind, parallel-group comparative study, patients with moderate to severe OA who were refractory to nonsteroidal anti-inflammatory drugs were orally administered 100 mg of ONO-4474 twice daily for 28 days. The primary end point was knee pain during walking, assessed by visual analog scale over 24 hours (VAS24 ). Treatment-emergent adverse events (TEAEs) and adverse drug reactions were reported for safety. In total, 110 patients were randomized (1:1) to receive placebo or ONO-4474. The mean (standard deviation) change in VAS24 scores at week 4 was -26.9 (25.0) mm in the ONO-4474 group and -19.5 (19.6) mm in the placebo group. The difference (ONO-4474 group - placebo group) in posterior mean change in VAS24 at week 4 was -5.8 (posterior standard deviation, 4.4; 95% confidence interval, -14.3 to 2.8) mm. TEAEs were reported in 41.8% of patients in the ONO-4474 group and 18.2% of patients in the placebo group. The most common TEAEs in the ONO-4474 group related to the musculoskeletal system and the peripheral and central nervous systems were myalgia (7.3%), arthralgia (5.5%), dizziness (3.6%), and hypoesthesia (3.6%). Four patients from the ONO-4474 group and 1 patient from the placebo group discontinued treatment because of AEs; however, none were judged to be serious, and all patients recovered or were recovering after discontinuation. ONO-4474 is a novel tropomyosin receptor kinase inhibitor that has an analgesic effect in patients with OA.","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"60 1","pages":"28-36"},"PeriodicalIF":2.9,"publicationDate":"2020-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.1470","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37125458","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}

引用次数: 6

Patisiran Pharmacokinetics, Pharmacodynamics, and Exposure-Response Analyses in the Phase 3 APOLLO Trial in Patients With Hereditary Transthyretin-Mediated (hATTR) Amyloidosis. 帕替西兰药代动力学、药效学和暴露-反应分析在遗传性转甲状腺素介导的 (hATTR) 淀粉样变性患者中的 3 期 APOLLO 试验中的应用。

IF 2.9 4区医学

Journal of clinical pharmacology Pub Date : 2020-01-01 Epub Date: 2019-07-19 DOI: 10.1002/jcph.1480

Xiaoping Zhang, Varun Goel, Husain Attarwala, Marianne T Sweetser, Valerie A Clausen, Gabriel J Robbie

{"title":"Patisiran Pharmacokinetics, Pharmacodynamics, and Exposure-Response Analyses in the Phase 3 APOLLO Trial in Patients With Hereditary Transthyretin-Mediated (hATTR) Amyloidosis.","authors":"Xiaoping Zhang, Varun Goel, Husain Attarwala, Marianne T Sweetser, Valerie A Clausen, Gabriel J Robbie","doi":"10.1002/jcph.1480","DOIUrl":"10.1002/jcph.1480","url":null,"abstract":"Hereditary transthyretin-mediated (hATTR) amyloidosis is an inherited, rapidly progressive, life-threatening disease caused by deposition of abnormal transthyretin protein. Patisiran is an RNA interference therapeutic comprising a novel, small interfering ribonucleic acid (ALN-18328) formulated in a lipid nanoparticle targeted to inhibit hepatic transthyretin protein synthesis. The lipid nanoparticle also contains 2 novel lipid excipients (DLin-MC3-DMA and PEG2000 -C-DMG). Here we report patisiran pharmacokinetics (PK), pharmacodynamics (PD), and exposure-response analyses from the phase 3 APOLLO trial, in which patients with hATTR amyloidosis with polyneuropathy were randomized 2:1 to receive patisiran 0.3 mg/kg or placebo intravenously every 3 weeks over 18 months. In patisiran-treated patients, mean maximum reduction in serum transthyretin level from baseline was 87.8%. Patisiran PK exposure was stable following chronic dosing. There were no meaningful differences in PK exposure, serum transthyretin reduction, and efficacy (change from baseline in modified Neuropathy Impairment Score+7) across all subgroups analyzed (age, sex, race, body weight, genotype status of valine-to-methionine mutation at position 30 [V30M] and non-V30M, prior use of tetramer stabilizers, mild/moderate renal impairment, and mild hepatic impairment). transthyretin reduction and efficacy were similar across the interpatient PK exposure range for ALN-18328. There was no trend in the incidence of adverse events or serious adverse events across the interpatient PK exposure range for all 3 analytes. Incidence of antidrug antibodies was low (3.4%) and transient, with no impact on PK, PD, efficacy, or safety. The patisiran dosing regimen of 0.3 mg/kg every 3 weeks is appropriate for all patients with hATTR amyloidosis.","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"60 1","pages":"37-49"},"PeriodicalIF":2.9,"publicationDate":"2020-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6972979/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50907250","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}

引用次数: 0

Exposure-Response Analysis for Mogamulizumab in Adults With Cutaneous T-Cell Lymphoma. 莫加单抗治疗成人皮肤t细胞淋巴瘤的暴露-反应分析。

IF 2.9 4区医学

Journal of clinical pharmacology Pub Date : 2020-01-01 Epub Date: 2019-12-16 DOI: 10.1002/jcph.1548

Mayumi Mukai, Diane Mould, Hiroshi Maeda, Kazuya Narushima, Douglas Greene

{"title":"Exposure-Response Analysis for Mogamulizumab in Adults With Cutaneous T-Cell Lymphoma.","authors":"Mayumi Mukai, Diane Mould, Hiroshi Maeda, Kazuya Narushima, Douglas Greene","doi":"10.1002/jcph.1548","DOIUrl":"https://doi.org/10.1002/jcph.1548","url":null,"abstract":"Mogamulizumab is a humanized monoclonal antibody against C-C chemokine receptor 4 approved in the United States for the treatment of patients with relapsed/refractory mycosis fungoides or Sézary syndrome, the most common forms of cutaneous T-cell lymphoma (CTCL). The exposure-response relationships for efficacy (progression-free survival [PFS] and overall response rate [ORR]) and safety (the 5 most common treatment-related adverse events by Medical Dictionary for Regulatory Activities [MedDRA] System Organ Class) for 184 patients with CTCL treated with mogamulizumab in a large, registrational clinical trial. Exposure metrics were area under the serum mogamulizumab concentration-time curve over the dose interval at steady state (AUCss ) and minimum serum mogamulizumab concentration after the first dose (Cmin,1st ). PFS by investigator assessment, the primary efficacy objective, and PFS and ORR by independent review were not correlated with exposure metrics; however, there was a statistically significant positive relationship between a secondary objective, ORR by investigator assessment, and AUCss (P = .0168). The frequency of treatment-related adverse events was not related to exposure metrics (Cmin,1st or AUCss ) for any of the MedDRA System Organ Classes examined. Of the covariates that were found to have a statistically significantly effect on the population PK model (ie, albumin, aspartate aminotransferase, body surface area, mild to moderate hepatic impairment, and sex), none was found to impact efficacy or safety, indicating that there is no need to modify dose on the basis of these parameters.","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"60 1","pages":"50-57"},"PeriodicalIF":2.9,"publicationDate":"2020-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.1548","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37460821","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}

引用次数: 2

Effects of Maribavir on P-Glycoprotein and CYP2D6 in Healthy Volunteers. 马里巴韦对健康志愿者P-糖蛋白和CYP2D6的影响

IF 2.9 4区医学

Journal of clinical pharmacology Pub Date : 2020-01-01 Epub Date: 2019-08-06 DOI: 10.1002/jcph.1504

Ivy H Song, Katarina Ilic, Joseph Murphy, Kenneth Lasseter, Patrick Martin

{"title":"Effects of Maribavir on P-Glycoprotein and CYP2D6 in Healthy Volunteers.","authors":"Ivy H Song, Katarina Ilic, Joseph Murphy, Kenneth Lasseter, Patrick Martin","doi":"10.1002/jcph.1504","DOIUrl":"10.1002/jcph.1504","url":null,"abstract":"Maribavir is an investigational drug being evaluated in transplant recipients with cytomegalovirus infection. To understand potential drug-drug interactions, we examined the effects of multiple doses of maribavir on cytochrome P450 (CYP) 2D6 and P-glycoprotein (P-gp) activity using probe substrates in healthy volunteers. During this phase 1 open-label study (NCT02775240), participants received the probe substrates digoxin (0.5 mg) and dextromethorphan (30 mg) before and after maribavir (400 mg twice daily for 8 days). Serial plasma samples were analyzed for digoxin, dextromethorpha, dextrorphan, and maribavir concentrations. Pharmacokinetic parameters were calculated (noncompartmental analysis) and analyzed with a linear mixed-effects model for treatment comparison to estimate geometric mean ratios (GMRs) and 90% confidence intervals (CIs). CYP2D6 polymorphisms were genotyped using polymerase chain reaction. Overall, 17 of 18 participants (94.4%) completed the study. All participants were genotyped as CYP2D6 intermediate/extensive metabolizers. GMR (90%CI) of digoxin Cmax , AUClast , and AUC0-∞ with and without maribavir was 1.257 (1.139-1.387), 1.187 (1.088-1.296), and 1.217 (1.110-1.335), respectively, outside the \"no-effect\" window (0.8-1.25). GMR (90%CI) of dextromethorphan AUClast and AUClast ratio of dextromethorphan/dextrorphan were 0.877 (0.692-1.112) and 0.901 (0.717-1.133), respectively, marginally outside the no-effect window, although large variability was observed in these pharmacokinetic parameters. Pharmacokinetic parameters of dextrorphan were unaffected. Maribavir inhibited P-gp activity but did not affect CYP2D6 activity. Maribavir's effect on the pharmacokinetics of P-gp substrates should be evaluated individually, and caution should be exercised with P-gp substrates with narrow therapeutic windows.","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"60 1","pages":"96-106"},"PeriodicalIF":2.9,"publicationDate":"2020-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6972521/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48324045","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}

引用次数: 0

Effects of Upadacitinib Coadministration on the Pharmacokinetics of Sensitive Cytochrome P450 Probe Substrates: A Study With the Modified Cooperstown 5+1 Cocktail. Upadacitinib共给药对敏感细胞色素P450探针底物药代动力学的影响:改良的Cooperstown 5+1鸡尾酒的研究

IF 2.9 4区医学

Journal of clinical pharmacology Pub Date : 2020-01-01 Epub Date: 2019-08-05 DOI: 10.1002/jcph.1496

Mohamed-Eslam F Mohamed, Tian Feng, Jeffrey V Enejosa, Ogert Fisniku, Ahmed A Othman

{"title":"Effects of Upadacitinib Coadministration on the Pharmacokinetics of Sensitive Cytochrome P450 Probe Substrates: A Study With the Modified Cooperstown 5+1 Cocktail.","authors":"Mohamed-Eslam F Mohamed, Tian Feng, Jeffrey V Enejosa, Ogert Fisniku, Ahmed A Othman","doi":"10.1002/jcph.1496","DOIUrl":"10.1002/jcph.1496","url":null,"abstract":"The aim of this study was to characterize the effects of upadacitinib, a Janus kinase 1 inhibitor, on in vivo activity of different cytochrome P450 (CYP) enzymes using a cocktail approach. Healthy subjects (n = 20) received single oral doses of the modified Cooperstown 5+1 cocktail drugs (midazolam [CYP3A], caffeine [CYP1A2], warfarin + vitamin K [CYP2C9], omeprazole [CYP2C19], and dextromethorphan [CYP2D6]) without upadacitinib and on day 11 (midazolam) or 12 (all other probes) of a 15-day regimen of upadacitinib 30 mg once daily (extended-release formulation). Serial blood samples and 12-hour urine samples were collected for assays of the probe substrates and select metabolites. The ratio (90%CI) of area under the plasma concentration-time curve from time 0 to infinity (AUCinf ) central values when the cocktail drugs were administered with upadacitinib relative to when administered alone were 0.74 (0.68-0.80) for midazolam, 1.22 (1.15-1.29) for caffeine, 1.11 (1.07-1.15) for S-warfarin, 1.07 (0.95-1.22) for dextromethorphan, and 0.82 (0.72-0.94) for omeprazole. The ratio (90%CI) was 1.09 (1.00-1.19) for 5-hydroxy-omeprazole to omeprazole AUCinf ratio and 1.17 (0.97-1.41) for dextromethorphan to dextrorphan 12-hour molar urinary ratio. Upadacitinib 30 mg once daily (a dose that is twice the optimal dose in rheumatoid arthritis based on phase 3 results) has a limited effect on CYP3A activity (26% decrease in exposure of midazolam, a sensitive CYP3A substrate) and no relevant effects on CYP1A2, CYP2C9, CYP2C19, or CYP2D6 activity in vivo. No clinically relevant changes in plasma exposures are expected for drugs that are substrates for the evaluated CYP enzymes when coadministered with upadacitinib.","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"60 1","pages":"86-95"},"PeriodicalIF":2.9,"publicationDate":"2020-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6972567/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47185863","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}

引用次数: 0

Population Pharmacokinetic Modeling of Mogamulizumab in Adults With Cutaneous T-Cell Lymphoma or Adult T-Cell Lymphoma. 莫加珠单抗在成人皮肤t细胞淋巴瘤或成人t细胞淋巴瘤中的群体药代动力学模型。

IF 2.9 4区医学

Journal of clinical pharmacology Pub Date : 2020-01-01 Epub Date: 2019-12-16 DOI: 10.1002/jcph.1564

Mayumi Mukai, Hiroshi Maeda, Kazuya Narushima, Diane R Mould, Douglas Greene

{"title":"Population Pharmacokinetic Modeling of Mogamulizumab in Adults With Cutaneous T-Cell Lymphoma or Adult T-Cell Lymphoma.","authors":"Mayumi Mukai, Hiroshi Maeda, Kazuya Narushima, Diane R Mould, Douglas Greene","doi":"10.1002/jcph.1564","DOIUrl":"https://doi.org/10.1002/jcph.1564","url":null,"abstract":"Cutaneous T-cell lymphoma (CTCL) and adult T-cell leukemia/lymphoma (ATL) are rare non-Hodgkin lymphomas commonly expressing C-C chemokine receptor 4 (CCR4). Mogamulizumab is a humanized monoclonal antibody against CCR4 approved in the United States for the treatment of patients with relapsed/refractory mycosis fungoides or Sézary syndrome, the most common forms of CTCL. Pharmacokinetic (PK) and clinical study data from 444 adult patients with ATL or CTCL collected during 6 clinical trials of mogamulizumab were used to construct a population PK model, which was best described by a 2-compartment model with linear clearance. Albumin, aspartate aminotransferase, mild-to-moderate hepatic impairment, and sex were statistically significant predictors of clearance; albumin was also a statistically significant predictor of peripheral volume of distribution; and body surface area was a statistically significant predictor for central volume of distribution. None of the other covariates-for example, age, body weight, body mass index, bilirubin, creatinine clearance, disease type (ATL and CTCL), ATL subtype (acute, lymphoma, and chronic), CTCL subtype (mycosis fungoides and Sézary syndrome), CCR4 expression (status or degree), race (Japanese and non-Japanese), renal impairment (normal, mild, moderate, and severe), or performance status-had a statistically significant impact. Performance of the final population PK model was acceptable. This model will be valuable for guiding further studies of mogamulizumab.","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"60 1","pages":"58-66"},"PeriodicalIF":2.9,"publicationDate":"2020-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.1564","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37460762","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}

引用次数: 2

Randomized Population Pharmacokinetic Analysis and Safety of Intravenous Acetaminophen for Acute Postoperative Pain in Neonates and Infants 静脉注射对乙酰氨基酚治疗新生儿和婴儿术后急性疼痛的随机人群药动学分析和安全性

IF 2.9 4区医学

Journal of clinical pharmacology Pub Date : 2019-08-25 DOI: 10.1002/jcph.1508

G. Hammer, L. Maxwell, B. Taicher, Mihaela Visoiu, D. Cooper, P. Szmuk, L. Pheng, Nathalie H. Gosselin, Jia Lu, K. Devarakonda

{"title":"Randomized Population Pharmacokinetic Analysis and Safety of Intravenous Acetaminophen for Acute Postoperative Pain in Neonates and Infants","authors":"G. Hammer, L. Maxwell, B. Taicher, Mihaela Visoiu, D. Cooper, P. Szmuk, L. Pheng, Nathalie H. Gosselin, Jia Lu, K. Devarakonda","doi":"10.1002/jcph.1508","DOIUrl":"https://doi.org/10.1002/jcph.1508","url":null,"abstract":"Intravenous administration of acetaminophen is an alternative to the oral and rectal routes, which may be contraindicated in particular clinical settings. This randomized, placebo‐controlled study of intravenous acetaminophen (Ofirmev, Mallinckrodt Pharmaceuticals, Bedminster, New Jersey) in neonate and infant patients with acute postoperative pain assessed pharmacokinetics (PK) and safety, in addition to efficacy and pharmacodynamics of repeated doses administered over 24 hours. Neonate and infant patients (<2 years of age) who were undergoing surgery or had experienced a traumatic injury and were expected to need pain management for at least 24 hours were enrolled. Subjects were randomly assigned to receive intravenous acetaminophen low dose, intravenous acetaminophen high dose, or placebo. A population PK model of intravenous acetaminophen was updated by combining 581 samples from the current study of 158 neonate and infant subjects with results from a previously developed model. The individual predicted‐versus‐observed concentrations plots showed that the structural PK model fit the blood and plasma acetaminophen concentration‐versus‐time profiles in the active and placebo groups. Terminal elimination half‐life was prolonged in neonates and younger infants and in intermediate and older infants similar to values in adults. When compared with placebo, total rescue opioid consumption was similar and significantly fewer intravenous acetaminophen patients prematurely discontinued because of treatment‐emergent adverse events (P < .01). For intravenous acetaminophen, neonates receiving 12.5 mg/kg every 6 hours had PK profiles similar to younger, intermediate, and older infants, adolescents, and adults weighing <50 kg receiving 15 mg/kg every 6 hours and adults ≥ 50 kg receiving 1000 mg every 6 hours.","PeriodicalId":15536,"journal":{"name":"Journal of clinical pharmacology","volume":"60 1","pages":"16 - 27"},"PeriodicalIF":2.9,"publicationDate":"2019-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.1508","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46126096","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}

引用次数: 7