Abstract:
BACKGROUND AND AIMS:In this study, we evaluate the performance of allometric concepts to predict the implications of age and size on the pharmacokinetics of lamotrigine, and assess the dose rationale across different age groups from 0.2 to 91 years. METHODS:An allometrically scaled pharmacokinetic model was developed using adolescent and adult data, taking into account the effect of comedications. Model parameters were then used to extrapolate lamotrigine pharmacokinetics to older adults (> 65 years), children (4-12 years) and infants and toddlers (0.2-2.0 years). In addition, simulations were performed to identify the implication of different doses and dosing regimens for each population, so as to ensure steady-state concentrations within a predefined reference range. RESULTS:The pharmacokinetics of lamotrigine was best described using a one-compartment model with first-order absorption and elimination. Carbamazepine, phenytoin, and valproic acid changed systemic clearance (CL) by + 76.5, + 129, and - 47.4%, respectively. Allometric principles allowed accurate extrapolation of disposition parameters to older adults and children older than 4 years of age. A maturation function was required to describe changes in exposure in younger patients. Compared with adults, a child aged 1.7 years has a 31.5% higher CL, after correcting for body weight. Patients > 65 years of age showed a decrease in CL of approximately 15%. CONCLUSION:Population pharmacokinetic models are usually limited to a subgroup of patients, which may mask the identification of factors contributing to interindividual variability. The availability of an integrated model including the whole patient population provides insight into the role of age-related changes in the disposition of lamotrigine, and potential implications for maintenance dose optimisation in any future trials. TRIAL REGISTRATION:According to GlaxoSmithKline's Clinical Trial Register, data from the GlaxoSmithKline studies LAM100034 and LEP103944, corresponding to ClinicalTrials.gov identifiers NCT00113165 and NCT00264615, used in this work, have been used in previous publications (doi: https://doi.org/10.1212/01.wnl.0000277698.33743.8b , https://doi.org/10.1111/j.1528-1167.2007.01274.x ).
journal_name
Clin Pharmacokinetjournal_title
Clinical pharmacokineticsauthors
van Dijkman SC,de Jager NCB,Rauwé WM,Danhof M,Della Pasqua Odoi
10.1007/s40262-017-0614-5subject
Has Abstractpub_date
2018-08-01 00:00:00pages
1039-1053issue
8eissn
0312-5963issn
1179-1926pii
10.1007/s40262-017-0614-5journal_volume
57pub_type
杂志文章abstract:BACKGROUND AND OBJECTIVE:Losmapimod is an orally available, potent p38 mitogen-activated protein kinase inhibitor. It is in development as an anti-inflammatory drug in different therapeutic areas. Clinical studies have shown that losmapimod is well tolerated and safe in humans and several studies have shown its pharmac...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,随机对照试验
doi:10.1007/s40262-012-0025-6
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abstract::For propofol clearance, allometric scaling has been applied successfully for extrapolations between species (rats and humans) and within the human bodyweight range (children and adults). In this analysis, the human bodyweight range is explored to determine for which range an allometric model with a fixed or estimated ...
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abstract:BACKGROUND:For imatinib, a relationship between systemic exposure and clinical outcome has been suggested. Importantly, imatinib concentrations are not stable and decrease over time, for which several mechanisms have been suggested. In this study, we investigated if a decrease in alpha-1 acid glycoprotein (AGP) is the ...
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doi:10.1007/s40262-016-0441-0
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abstract::Thienopyridines are inactive prodrugs that are converted in vivo to active metabolites, which irreversibly bind to and inactivate platelet P2Y(12) receptors, and inhibit platelet activation and aggregation. Prasugrel is a third-generation thienopyridine, recently approved for prevention of thrombotic cardiovascular co...
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journal_title:Clinical pharmacokinetics
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abstract::There are many pathological changes in patients with cystic fibrosis (CF) which can lead to alterations in drug disposition. Although, in patients with CF, the extent of drug absorption varies widely and the rate of absorption is slower, bioavailability is not altered. Plasma protein binding for the majority of drugs ...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.2165/00003088-199835040-00004
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abstract:OBJECTIVE:Although amikacin is primarily eliminated via glomerular filtration, drug concentrations are not consistently predicted in all patients. To better describe the relationship between amikacin clearance and both age and renal function, we used a new heuristic approach involving statistical analysis of dependence...
journal_title:Clinical pharmacokinetics
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abstract::Dasabuvir is a nonstructural (NS) 5B non-nucleoside inhibitor of the hepatitis C virus (HCV) used in combination with ombitasvir/paritaprevir/ritonavir for the treatment of chronic HCV infection. It is primarily metabolized by cytochrome P450 (CYP) 2C8, with a minor contribution from CYP3A. Biotransformation of dasabu...
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更新日期:1988-06-01 00:00:00
abstract:BACKGROUND AND OBJECTIVES:Upadacitinib is a janus kinase (JAK) 1 inhibitor being developed for the treatment of rheumatoid arthritis (RA) and other inflammatory diseases. This work characterized upadacitinib population pharmacokinetics in healthy subjects and RA patients and the effects of covariates on upadacitinib ex...
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pub_type: 杂志文章,评审
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更新日期:2018-08-01 00:00:00
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abstract::18 hypertensive patients with a glomerular filtration rate (GFR) between 3.8 and 113ml/min received guanfacine as single intravenous and multiple oral dose treatment. Mean plasma concentrations of guanfacine on the fifth day or oral treatment ranged from 6.5 to 8.6ng/ml in patients with normal renal function (GFR > 90...
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pub_type: 杂志文章,多中心研究,随机对照试验
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journal_title:Clinical pharmacokinetics
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doi:10.2165/00003088-198308020-00004
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abstract::Cisapride, a prokinetic agent, has been used for the treatment of a number of gastrointestinal disorders, particularly gastro-oesophageal reflux disease in adults and children. Since 1993, 341 cases of ventricular arrhythmias, including 80 deaths, have been reported to the US Food and Drug Administration. Marketing of...
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abstract::The combination of hepatic artery infusion (HAI) of irinotecan, 5-fluorouracil and oxaliplatin with intravenous cetuximab has safely achieved prolonged survival in colorectal cancer patients with extensive liver metastases and prior treatment. Systemic exposure to the drugs or their main metabolites was determined dur...
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pub_type: 临床试验,杂志文章,多中心研究
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abstract::Dorzolamide is a carbonic anhydrase inhibitor for topical ophthalmic application. It is used in the treatment of glaucoma to lower the intraocular pressure. After absorption via the cornea and stroma, it inhibits carbonic anhydrase in the ciliary process, which leads to a reduction of aqueous humour production and the...
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journal_title:Clinical pharmacokinetics
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journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.2165/00003088-198917060-00004
更新日期:1989-12-01 00:00:00
abstract:BACKGROUND AND OBJECTIVES:Bayesian forecasting (BF) methods for tobramycin dose individualisation has not seen widespread clinical adoption, despite being endorsed by clinical practice guidelines. Several freeware and commercial programmes using BF methods are available to support personalised dosing. This study evalua...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章
doi:10.1007/s40262-017-0610-9
更新日期:2018-08-01 00:00:00
abstract:OBJECTIVE:To obtain a pharmacokinetic profile of cyclosporin microemulsion formulation in patients with inflammatory bowel disease. PATIENTS AND PARTICIPANTS:58 consecutive patients (19 women and 39 men), aged 16 to 64 years (mean age 38 years), with a diagnosis of ulcerative colitis (29 patients) or Crohn's disease (...
journal_title:Clinical pharmacokinetics
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更新日期:2001-01-01 00:00:00