Journal of Clinical Pharmacology最新文献

{"title":"Assessment of pharmacokinetic drug-drug interaction between pradigastat and atazanavir or probenecid.","authors":"Anisha Mendonza,&nbsp;Imad Hanna,&nbsp;Dan Meyers,&nbsp;Phillip Koo,&nbsp;Srikanth Neelakantham,&nbsp;Bing Zhu,&nbsp;Tapan Majumdar,&nbsp;Sam Rebello,&nbsp;Gangadhar Sunkara,&nbsp;Jin Chen","doi":"10.1002/jcph.595","DOIUrl":"https://doi.org/10.1002/jcph.595","url":null,"abstract":"<p><p>Pradigastat, a novel diacylglycerol acyltransferase-1 inhibitor, has activity in common metabolic diseases associated with abnormal accumulation of triglycerides. In vitro studies suggest that glucuronidation is the predominant metabolism pathway for elimination of pradigastat in humans and confirmed the role of uridine 5'-diphosphoglucuronosyltransferase (UGT) enzymes, UGT1A1, -1A3, and -2B7. The in vitro studies using atazanavir as a selective inhibitor of UGT1A1 and -1A3 indicated that these enzymes contribute ∼55% toward the overall glucuronidation pathway. Therefore, a clinical study was conducted to assess the potential for drug interaction between pradigastat and probenecid (purported general UGT inhibitor) or atazanavir (selective UGT1A1, -1A3 inhibitor). The study included 2 parallel cohorts, each with 3 sequential treatment periods and 22 healthy subjects per cohort. The 90%CI of the geometric mean ratios for Cmax,ss and AUCτ,ss of pradigastat were within 0.80-1.25 when administered in combination with probenecid. However, the Cmax,ss and AUCτ,ss of pradigastat decreased by 31% (90%CI: 0.62-0.78) and 26% (0.67-0.82), respectively, when administered in combination with atazanavir. This magnitude of decrease in pradigastat steady-state exposure is not considered clinically relevant. Pradigastat was well tolerated by all subjects, either alone or in combination with atazanavir or probenecid. </p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"56 3","pages":"355-64"},"PeriodicalIF":2.9,"publicationDate":"2016-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.595","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34019786","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, safety, and tolerability of paliperidone palmitate 3-month formulation in patients with schizophrenia: A phase-1, single-dose, randomized, open-label study.","authors":"Paulien Ravenstijn,&nbsp;Bart Remmerie,&nbsp;Adam Savitz,&nbsp;Mahesh N Samtani,&nbsp;Isaac Nuamah,&nbsp;Cheng-Tao Chang,&nbsp;Marc De Meulder,&nbsp;David Hough,&nbsp;Srihari Gopal","doi":"10.1002/jcph.597","DOIUrl":"https://doi.org/10.1002/jcph.597","url":null,"abstract":"<p><p>This multicenter, randomized, open-label, parallel-group, phase-1 study assessed the pharmacokinetics (PK), safety, and tolerability of the investigational intramuscular paliperidone palmitate 3-month (PP3M) formulation in patients with schizophrenia or schizoaffective disorder. A total of 328 patients (men or women, aged 18-65 years) were enrolled in 1 of 4 separately conducted panels (A to D). Each panel had 2 single-dose treatment periods (period 1, 1 mg intramuscular paliperidone immediate release [IR]; period 2, intramuscular PP3M 75-525 mg eq) separated by a washout of 7-21 days. Overall, 245 of 308 (79.5%) PP3M-dosed patients completed the study. Because the PK studies of panels A and C were compromised by incomplete injection in some patients, PK data from only panels B and D are presented. Safety data from all panels are presented. Peak paliperidone plasma concentration was achieved between 23 and 34 days, and apparent half-life was ∼2-4 months. Mean plasma AUC∞ and Cmax of paliperidone appeared to be dose-proportional. Relative bioavailability in comparison with paliperidone was ∼100% independent of the dose and injection site. Headache and nasopharyngitis were the most common (>7%) treatment-emergent adverse events. Overall, safety and tolerability were similar to those of the 1-month formulation. Results support a once-every-3-months dosing interval in patients with schizophrenia or schizoaffective disorder. </p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"56 3","pages":"330-9"},"PeriodicalIF":2.9,"publicationDate":"2016-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.597","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34019793","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 meropenem in children receiving continuous renal replacement therapy: Validation of clinical trial simulations.","authors":"Edward J Nehus,&nbsp;Tomoyuki Mizuno,&nbsp;Shareen Cox,&nbsp;Stuart L Goldstein,&nbsp;Alexander A Vinks","doi":"10.1002/jcph.601","DOIUrl":"https://doi.org/10.1002/jcph.601","url":null,"abstract":"<p><p>Meropenem is frequently prescribed in critically ill children receiving continuous renal replacement therapy (CRRT). We previously used clinical trial simulations to evaluate dosing regimens of meropenem in this population and reported that a dose of 20 mg/kg every 12 hours optimizes target attainment. Meropenem pharmacokinetics were investigated in this prospective, open-label study to validate our previous in silico predictions. Seven patients received meropenem (13.8-22 mg/kg) administered intravenously every 12 hours as part of standard care. A mean dose of 18.6 mg/kg of meropenem was administered, resulting in a mean peak concentration of 80.1 μg/mL. Meropenem volume of distribution was 0.35 ± 0.085 L/kg. CRRT clearance was 40.2 ± 6.6 mL/(min · 1.73 m(2) ) and accounted for 63.4% of the total clearance of 74.8 ± 36.9 mL/(min · 1.73 m(2) ). Simulations demonstrated that a dose of 20 mg/kg every 12 hours resulted in a time above the minimum inhibitory concentration (%fT > MIC) of 100% in 5 out of 7 subjects, with a %fT > MIC of 93% and 43% in the remaining 2 subjects. We conclude that CRRT contributed significantly to the total clearance of meropenem. A dosing regimen of 20 mg/kg achieved good target attainment in critically ill children receiving CRRT, which is consistent with our previously published in silico predictions. </p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"56 3","pages":"291-7"},"PeriodicalIF":2.9,"publicationDate":"2016-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.601","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34047742","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":"Drug-metabolism mechanism: Knowledge-based population pharmacokinetic approach for characterizing clobazam drug-drug interactions.","authors":"Dwain Tolbert,&nbsp;Ihor Bekersky,&nbsp;Hui-May Chu,&nbsp;Ene I Ette","doi":"10.1002/jcph.603","DOIUrl":"https://doi.org/10.1002/jcph.603","url":null,"abstract":"<p><p>A metabolic mechanism-based characterization of antiepileptic drug-drug interactions (DDIs) with clobazam in patients with Lennox-Gastaut syndrome (LGS) was performed using a population pharmacokinetic (PPK) approach. To characterize potential DDIs with clobazam, pharmacokinetic (PK) data from 153 patients with LGS in study OV-1012 (NCT00518713) and 18 healthy participants in bioavailability study OV-1017 were pooled. Antiepileptic drugs (AEDs) were grouped based on their effects on the cytochrome P450 (CYP) isozymes responsible for the metabolism of clobazam and its metabolite, N-desmethylclobazam (N-CLB): CYP3A inducers (phenobarbital, phenytoin, and carbamazepine), CYP2C19 inducers (valproic acid, phenobarbital, phenytoin, and carbamazepine), or CYP2C19 inhibitors (felbamate, oxcarbazepine). CYP3A4 inducers-which did not affect the oral clearance of clobazam-significantly increased the formation of N-CLB by 9.4%, while CYP2C19 inducers significantly increased the apparent elimination rate of N-CLB by 10.5%, resulting in a negligible net change in the PK of the active metabolite. CYP2C19 inhibitors did not affect N-CLB elimination. Because concomitant use of AEDs that are either CYP450 inhibitors or inducers with clobazam in the treatment of LGS patients had negligible to no effect on clobazam PK in this study, dosage adjustments may not be required for clobazam in the presence of the AEDs investigated here. </p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"56 3","pages":"365-74"},"PeriodicalIF":2.9,"publicationDate":"2016-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.603","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33946903","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":"A personal perspective of orphan drug development for rare diseases: A golden opportunity or an unsustainable future?","authors":"Charles Oo,&nbsp;Lorraine M Rusch","doi":"10.1002/jcph.599","DOIUrl":"https://doi.org/10.1002/jcph.599","url":null,"abstract":"1. Tiwari J. Navigating through orphan medicinal product regulations in EU and US—similarities and differences. Regul Toxicol Pharmacol. 2015;71(1):63–67. 2. Tambuyzer E. Rare diseases, orphan drugs and their regulation: questions and misconceptions. Nat Rev Drug Discov. 2010;9(12): 921–929. 3. Kakkis ED, O’Donovan M, Cox G, et al. Recommendations for the development of rare disease drugs using the accelerated approval pathway and for qualifying biomarkers as primary endpoints. Orphanet J Rare Dis. 2015;10:16. doi:10.1186/s13023-014-0195-4 4. Gaddipati H, Liu K, Pariser A, Pazdur R. Rare cancer trial design: lessons from FDA approvals. Clin Cancer Res. 2012;18: 5172–5178. 5. Dupont AG, Van Wilder PB. Access to orphan drugs despite poor quality of clinical evidence. Br J Clin Pharmacol. 2011;71(4): 488–496. 6. Braun MM, Farag-El-Massah S, Xu K, Cot e TR. Emergence of orphan drugs in the United States: a quantitative assessment of the first 25 years. Nat Rev Drug Discov. 2010;9:519–522. 7. Meekings KN, Williams CSM, Arrowsmith JE. Orphan drug development: an economically viable strategy for biopharma R&D. Drug Discov Today. 2012;17(13–14):660–664. 8. Haffner ME, Whitley J, Moses M. Two decades of orphan product development. Nat Rev Drug Discov. 2002;1(10):821–825. 9. Orphan Drug Act. 21 CFR Part 316 Orphan Drugs. US Food Drug Admin. 2013;78(113):15–33. 10. Simoens S. Pricing and reimbursement of orphan drugs: the need for more transparency. Orphanet J Rare Dis. 2011;6(1):42. 11. Bashaw ED, Huang S-M, Cot e TR, et al. Clinical pharmacology as a cornerstone of orphan drug development. Nat Rev Drug Discov. 2011;10(11):795–796. 12. Abrahamyan L, Diamond IR, Johnson SR, Feldman BM. A new toolkit for conducting clinical trials in rare disorders. J Popul Ther Clin Pharmacol. 2014;21(1):66–78. 13. Oo C, Tsai J-C, Kao HD. There is no better time than the present: nanotechnology as a disruptive innovation for drug development. Drug Discov Today. 2015;20(6):645–647. 14. Dunoyer M. Accelerating access to treatments for rare diseases. Nat Rev Drug Discov. 2011;10(7):475–476. Oo and Rusch 3 Drug Interactions","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"56 3","pages":"257-9"},"PeriodicalIF":2.9,"publicationDate":"2016-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.599","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33868376","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 pharmacokinetics of meropenem during continuous infusion in surgical ICU patients.","authors":"Martin G Kees,&nbsp;Iris K Minichmayr,&nbsp;Stefan Moritz,&nbsp;Stefanie Beck,&nbsp;Sebastian G Wicha,&nbsp;Frieder Kees,&nbsp;Charlotte Kloft,&nbsp;Thomas Steinke","doi":"10.1002/jcph.600","DOIUrl":"https://doi.org/10.1002/jcph.600","url":null,"abstract":"<p><p>Continuous infusion of meropenem is a candidate strategy for optimization of its pharmacokinetic/pharmacodynamic profile. However, plasma concentrations are difficult to predict in critically ill patients. Steady-state concentrations of meropenem were determined prospectively during continuous infusion in 32 surgical ICU patients (aged 21-85 years, body weight 55-125 kg, APACHE II 5-29, measured creatinine clearance 22.7-297 mL/min). Urine was collected for the quantification of renal clearance of meropenem and creatinine. Cystatin C was measured as an additional marker of renal function. Population pharmacokinetic models were developed using NONMEM(®) , which described total meropenem clearance and its relationship with several estimates of renal function (measured creatinine clearance CLCR , Cockcroft-Gault formula CLCG , Hoek formula, 1/plasma creatinine, 1/plasma cystatin C) and other patient characteristics. Any estimate of renal function improved the model performance. The strongest association of clearance was found with CLCR (typical clearance = 11.3 L/h × [1 + 0.00932 × (CLCR  - 80 mL/min)]), followed by 1/plasma cystatin C; CLCG was the least predictive covariate. Neither age, weight, nor sex was found to be significant. These models can be used to predict dosing requirements or meropenem concentrations during continuous infusion. The covariate CLCR offers the best predictive performance; if not available, cystatin C may provide a promising alternative to plasma creatinine. </p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"56 3","pages":"307-15"},"PeriodicalIF":2.9,"publicationDate":"2016-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.600","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33945572","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 and bioequivalence of a liquid formulation of hydroxyurea in children with sickle cell anemia.","authors":"Jeremie H Estepp,&nbsp;Chiara Melloni,&nbsp;Courtney D Thornburg,&nbsp;Paweł Wiczling,&nbsp;Zora Rogers,&nbsp;Jennifer A Rothman,&nbsp;Nancy S Green,&nbsp;Robert Liem,&nbsp;Amanda M Brandow,&nbsp;Shelley E Crary,&nbsp;Thomas H Howard,&nbsp;Maurine H Morris,&nbsp;Andrew Lewandowski,&nbsp;Uttam Garg,&nbsp;William J Jusko,&nbsp;Kathleen A Neville","doi":"10.1002/jcph.598","DOIUrl":"https://doi.org/10.1002/jcph.598","url":null,"abstract":"<p><p>Hydroxyurea (HU) is a crucial therapy for children with sickle cell anemia, but its off-label use is a barrier to widespread acceptance. We found HU exposure is not significantly altered by liquid vs capsule formulation, and weight-based dosing schemes provide consistent exposure. HU is recommended for all children starting as young as 9 months of age with sickle cell anemia (SCA; HbSS and HbSβspan(0) thalassemia); however; a paucity of pediatric data exists regarding the pharmacokinetics (PK) or the exposure-response relationship of HU. This trial aimed to characterize the PK of HU in children and to evaluate and compare the bioavailability of a liquid vs capsule formulation. This multicenter; prospective; open-label trial enrolled 39 children with SCA who provided 682 plasma samples for PK analysis following administration of HU. Noncompartmental and population PK models are described. We report that liquid and capsule formulations of HU are bioequivalent; weight-based dosing schemes provide consistent drug exposure; and age-based dosing schemes are unnecessary. These data support the use of liquid HU in children unable to swallow capsules and in those whose weight precludes the use of fixed capsule formulations. Taken with existing safety and efficacy literature; these findings should encourage the use of HU across the spectrum of age and weight in children with SCA; and they should facilitate the expanded use of HU as recommended in the National Heart; Lung; and Blood Institute guidelines for individuals with SCA. </p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"56 3","pages":"298-306"},"PeriodicalIF":2.9,"publicationDate":"2016-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.598","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33860721","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":"Genetic variation of CYP3A5 influences paclitaxel/carboplatin-induced toxicity in Chinese epithelial ovarian cancer patients.","authors":"Lei Hu,&nbsp;Qiao-Li Lv,&nbsp;Ying Guo,&nbsp;Lin Cheng,&nbsp;Na-Yiyuan Wu,&nbsp;Chong-Zhen Qin,&nbsp;Hong-Hao Zhou","doi":"10.1002/jcph.587","DOIUrl":"https://doi.org/10.1002/jcph.587","url":null,"abstract":"<p><p>Combination chemotherapy with platinum and taxane is the first-line treatment for ovarian cancer. The dose-limiting toxicities of these drugs include neuropathy, leukopenia, and neutropenia, but they exhibit substantial interindividual variability. This study investigated the relationship between CYP3A5 polymorphisms and paclitaxel/carboplatin-induced toxicity in Chinese epithelial ovarian cancer patients. Seventy-five patients with epithelial ovarian cancer were recruited. After combination chemotherapy, genotype analysis was conducted, and toxic effects were evaluated according to the Common Toxicity Criteria. A significant association was found between myelosuppression and the CYP3A5*3 genotype. CYP3A5*3/*1 patients showed a significantly higher risk of developing leukopenia (P < .001; Pearson's χ(2) test) and neutropenia (P < .001; Pearson's χ(2) test) than CYP3A5*3*3 patients. CYP3A5*3/*3 patients had significantly higher median leukocyte and neutrophil nadir counts than CYP3A5*3*1 patients (P < .001, Mann-Whitney U test). However, we did not observe an association between neuropathy and CYP3A5*3 in this study (P =.64; Pearson's χ(2) test). This is the first study to verify the influence of CYP3A5 polymorphisms on paclitaxel/carboplatin-induced toxicity in Chinese epithelial ovarian cancer patients. Our findings suggest that interindividual variability in paclitaxel/carboplatin-induced myelosuppression can be predicted by CYP3A5*3 genotyping and that incorporation of CYP3A5*3 genetic data in treatment selection could help to reduce myelosuppression events, thereby individualizing paclitaxel/carboplatin pharmacotherapy. </p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"56 3","pages":"349-54"},"PeriodicalIF":2.9,"publicationDate":"2016-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.587","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34011070","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 high-dose intravenous melatonin in humans.","authors":"Lars P H Andersen,&nbsp;Mads U Werner,&nbsp;Mette M Rosenkilde,&nbsp;Andreas Q Fenger,&nbsp;Marian C Petersen,&nbsp;Jacob Rosenberg,&nbsp;Ismail Gögenur","doi":"10.1002/jcph.592","DOIUrl":"https://doi.org/10.1002/jcph.592","url":null,"abstract":"<p><p>This crossover study investigated the pharmacokinetics and adverse effects of high-dose intravenous melatonin. Volunteers participated in 3 identical study sessions, receiving an intravenous bolus of 10 mg melatonin, 100 mg melatonin, and placebo. Blood samples were collected at baseline and 0, 60, 120, 180, 240, 300, 360, and 420 minutes after the bolus. Quantitative determination of plasma melatonin concentrations was performed using a radioimmunoassay technique. Pharmacokinetic parameters were estimated by a compartmental pharmacokinetic analysis. Adverse effects included assessments of sedation and registration of other symptoms. Sedation, evaluated as simple reaction times, was measured at baseline and 120, 180, 300, and 420 minutes after the bolus. Twelve male volunteers completed the study. Median (IQR) Cmax after the bolus injections of 10 mg and 100 mg of melatonin were 221,500.0 (185,637.5-326,175.0) pg/mL and 1,251,500.0 (864,375.0-1,770,500.0) pg/mL, respectively; mean (SD) t1/2 was 42.3 (5.6) minutes and 46.2 (6.2) minutes; mean (SD) Vd was 1.6 (0.9) L/kg and 2.0 (0.8) L/kg; mean (SD) CL was 0.0253 (0.0096) L/min · kg and 0.0300 (0.0120) L/min · kg; and median (IQR) AUC0- ∞ , 8,997,633.0 (6,071,696.2-11,602,811.9) pg · min/mL and 54,685,979.4 (36,028,638.6-105,779,612.0) pg · min/mL. High-dose intravenous melatonin did not induce sedation, evaluated as simple reaction times. No adverse effects were reported in the study. </p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"56 3","pages":"324-9"},"PeriodicalIF":2.9,"publicationDate":"2016-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.592","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34015239","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":"Pilot evaluation of the population pharmacokinetics of bumetanide in term newborn infants with seizures.","authors":"Vincent Jullien,&nbsp;Ronit M Pressler,&nbsp;Geraldine Boylan,&nbsp;Mats Blennow,&nbsp;Neil Marlow,&nbsp;Catherine Chiron,&nbsp;Gerard Pons","doi":"10.1002/jcph.596","DOIUrl":"https://doi.org/10.1002/jcph.596","url":null,"abstract":"<p><p>Recent experimental data suggest bumetanide as a possible therapeutic option in newborn infants with seizures after birth asphyxia. Because pharmacokinetic (PK) data are lacking in this population, who very often benefit from therapeutic cooling, which can modify the PK behavior of a drug, a PK study was conducted in term infants with seizures caused by hypoxic-ischemic encephalopathy. Fourteen infants were included, 13 of them being cooled. Forty-nine blood samples were available for the determination of the plasma concentration of bumetanide. Concentration-time data were analyzed by the use of a population approach performed with Monolix Software. Bumetanide was found to follow a 2-compartment model. The mean values were 0.063 L/h for clearance, 0.28 and 0.44 L for the central and peripheral distribution volumes, respectively, and 0.59 L/h for the distribution clearance. Birth body weight explained the interindividual variability of bumetanide clearance via an allometric model. No relationship was found between bumetanide exposure and its efficacy (reduction in seizure burden) or its toxicity (hearing loss). This study describes the first PK model of bumetanide in hypothermia-treated infants with seizures. </p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"56 3","pages":"284-90"},"PeriodicalIF":2.9,"publicationDate":"2016-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.596","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34019788","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}