Abstract:
BACKGROUND AND OBJECTIVES:Abemaciclib, a dual inhibitor of cyclin-dependent kinases 4 and 6, has demonstrated clinical activity in a number of different cancer types. The objectives of this study were to characterize the pharmacokinetics of abemaciclib in cancer patients using population pharmacokinetic (popPK) modeling, and to evaluate target engagement at clinically relevant dose levels. METHODS:A phase I study was conducted in cancer patients which incorporated intensive pharmacokinetic sampling after single and multiple oral doses of abemaciclib. Data were analyzed by popPK modeling, and patient demographics contributing to pharmacokinetic variability were explored. Target engagement was evaluated by combining the clinical popPK model with a previously developed pre-clinical pharmacokinetic/pharmacodynamic model. RESULTS:The pharmacokinetic analysis incorporated 4012 plasma concentrations from 224 patients treated with abemaciclib at doses ranging from 50 to 225 mg every 24 h and 75 to 275 mg every 12 h. A linear one-compartment model with time- and dose-dependent relative bioavailability (F rel) adequately described the pharmacokinetics of abemaciclib. Serum albumin and alkaline phosphatase were the only significant covariates identified in the model, the inclusion of which reduced inter-individual variability in F rel by 10.3 percentage points. By combining the clinical popPK model with the previously developed pre-clinical pharmacokinetic/pharmacodynamic model, the extent of target engagement in skin in cancer patients was successfully predicted. CONCLUSION:The proportion of abemaciclib pharmacokinetic variability that can be attributed to patient demographics is negligible, and as such there are currently no dose adjustments recommended for adult patients of different sex, age, or body weight. TRIAL REGISTRATION:NCT01394016 (ClinicalTrials.gov).
journal_name
Clin Pharmacokinetjournal_title
Clinical pharmacokineticsauthors
Tate SC,Sykes AK,Kulanthaivel P,Chan EM,Turner PK,Cronier DMdoi
10.1007/s40262-017-0559-8subject
Has Abstractpub_date
2018-03-01 00:00:00pages
335-344issue
3eissn
0312-5963issn
1179-1926pii
10.1007/s40262-017-0559-8journal_volume
57pub_type
杂志文章,多中心研究abstract::Antipyrine pharmacokinetics were studied in 6 healthy women before and 2, 8 and 12 weeks after administering the injectable progestagen (progestin), norethisterone (norethindrone) enanthate 200mg intramuscularly. Additionally, antipyrine kinetics in 5 women who had previously used the injectable contraceptive for 8 to...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章
doi:10.2165/00003088-198611020-00007
更新日期:1986-03-01 00:00:00
abstract:INTRODUCTION:Renal impairment may have a significant impact on the pharmacokinetics of drugs. Ad hoc studies in subjects with renal impairment are required by the regulatory authorities to propose dose adjustments in these subjects, to find a dosing regimen able to provide a systemic exposure similar to those in subjec...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章
doi:10.1007/s40262-017-0574-9
更新日期:2018-04-01 00:00:00
abstract::Vigabatrin is a structural analogue of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). It is supplied as a racemic mixture, with the S(+) enantiomer possessing pharmacological activity. [R,S]-Vigabatrin plasma concentrations can be estimated using high-performance liquid chromatographic methods. Only g...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.2165/00003088-199223040-00003
更新日期:1992-10-01 00:00:00
abstract::Although individualised antihypertensive therapy is widely recommended, prospective methods for optimising treatment are hampered by the paucity of basic information about dose-plasma concentration-response relationships for commonly used drugs. Concentration-effect analysis has been applied to a number of therapeutic...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.2165/00003088-199426060-00005
更新日期:1994-06-01 00:00:00
abstract::Clinical pharmacokinetics emerged as a clinical discipline in the late 1960s and early 1970s. Clinical pharmacokinetic monitoring (CPM) helped many pharmacists to enter the clinical arena, but the focus was more on the pharmacists and tools. With the widespread acceptance of pharmaceutical care and patient-focused pha...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.2165/00003088-199834040-00001
更新日期:1998-04-01 00:00:00
abstract:BACKGROUND AND OBJECTIVE:Febuxostat is a xanthine oxidase inhibitor indicated for gout and hyperuricemia. This work investigates potential clinically relevant covariates for febuxostat pharmacokinetics with a special focus on Asian race and bodyweight. METHODS:Febuxostat plasma concentrations from 141 male subjects we...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章
doi:10.1007/s40262-020-00943-6
更新日期:2020-09-19 00:00:00
abstract::Morphine, morphine-6-glucuronide (M6G), morphine-3-glucuronide (M3G) and normorphine were analysed with high performance liquid chromatography in plasma and urine, collected over 72 h after administration of single intravenous 5 mg and oral 20 mg doses of morphine to 7 healthy volunteers. Systemic plasma clearance of ...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章
doi:10.2165/00003088-199324040-00007
更新日期:1993-04-01 00:00:00
abstract::A method is presented for the simultaneous estimation of functional hepatic blood flow and intrinsic clearance. The method uses pharmacokinetic data of a therapeutically employed drug and one of its primary metabolites following intravenous and oral administration of the parent compound. When the disposition of the dr...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章
doi:10.2165/00003088-199223010-00006
更新日期:1992-07-01 00:00:00
abstract::Models of tolerance are commonly derived on empirical grounds, because of lack of knowledge about the mechanism of tolerance or because of the difficulty of appropriately simplifying complex physiological processes. The present study was performed to evaluate the interchangeability of tolerance models used in the lite...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.2165/00003088-199936020-00005
更新日期:1999-02-01 00:00:00
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 ...
journal_title:Clinical pharmacokinetics
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doi:10.1007/s40262-016-0441-0
更新日期:2017-03-01 00:00:00
abstract::The pharmacokinetic effect of extracorporeal elimination can be evaluated from the extracorporeal elimination rate constant, from the amount of drug removed, and from extracorporeal clearance. To compare the validity of these approaches in clinical practice, the effect of multiple plasma exchanges on the steady-state ...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章
doi:10.2165/00003088-198510060-00004
更新日期:1985-11-01 00:00:00
abstract::According to recent clinical consensus, pharmacotherapy of inflammatory bowel disease (IBD) is, or should be, personalized medicine. IBD treatment is complex, with highly different treatment classes and relatively few data on treatment strategy. Although thorough evidence-based international IBD guidelines currently e...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.1007/s40262-018-0639-4
更新日期:2018-09-01 00:00:00
abstract:BACKGROUND AND OBJECTIVE:Tegafur is an oral fluorouracil prodrug used in the treatment of colorectal cancer. The aim of this phase II, crossover, bioequivalence study was to compare the pharmacokinetics (primary objective) and tolerability (secondary objective) of tegafur-uracil (UFT) given as three daily doses (tid, r...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,随机对照试验
doi:10.2165/00003088-200746110-00003
更新日期:2007-01-01 00:00:00
abstract::Histamine H2-receptor antagonists are a unique class of compounds. Pharmacologically they are characterised as a family by their ability to inhibit the secretion of gastric acid, and kinetically they are classified as a family by their similarity in absorption, distribution and elimination. All the H2-receptor antagon...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.2165/00003088-199120030-00004
更新日期:1991-03-01 00:00:00
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 ...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章
doi:10.1007/s40262-017-0614-5
更新日期:2018-08-01 00:00:00
abstract:OBJECTIVE:The aims of this study were to (1) determine whether opportunistically collected data can be used to develop physiologically based pharmacokinetic (PBPK) models in pediatric patients; and (2) characterize age-related maturational changes in drug disposition for the renally eliminated and hepatically metaboliz...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章
doi:10.1007/s40262-018-00733-1
更新日期:2019-07-01 00:00:00
abstract::Inadequate pain control in the postoperative period not only contributes to patient discomfort, but also causes physiological changes that may result in increased risk of myocardial ischaemia, deep vein thrombosis and pulmonary embolism. These events complicate postoperative recovery and may lead to longer hospital st...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.2165/00003088-200544001-00002
更新日期:2005-01-01 00:00:00
abstract::The effects of diabetes mellitus on the pharmacokinetics and pharmacodynamics of drugs have been well described in experimental animal models; however, only minimal data exist for humans and the current knowledge regarding the effects of diabetes on these properties remains unclear. Nevertheless, it has been observed ...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.2165/11631900-000000000-00000
更新日期:2012-08-01 00:00:00
abstract::With the use of combination chemotherapy as well as a wide range of symptomatic therapies (e.g. analgesics and antiemetics) for the treatment of patients with cancer, the field of oncology practises polypharmacy to an extreme degree. The risk for a drug interaction under these conditions is high, and the pharmacologic...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.2165/00003088-198611030-00004
更新日期:1986-05-01 00:00:00
abstract::Dilevalol and labetalol are examples of a growing number of new beta-blockers which combine nonselective beta-adrenoceptor antagonism with vasodilator activity. Dilevalol is one of the 4 stereoisomers of labetalol, and is estimated to form approximately 25% of the racemic drug. Labetalol itself is an alpha 1-antagonis...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.2165/00003088-199121020-00002
更新日期:1991-08-01 00:00:00
abstract:OBJECTIVE:A prospective pharmacokinetic study was performed in Caucasian patients from an intensive care unit with respiratory support to evaluate the influence of this circumstance on the pharmacokinetic behaviour of levofloxacin. PATIENTS AND METHODS:A standard dosage regimen of 500 mg/day was administered to nine C...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章
doi:10.2165/00003088-200544060-00004
更新日期:2005-01-01 00:00:00
abstract::Since up to 90% of a theophylline dose is biotransformed, drugs influencing microsomal enzyme systems in the liver may affect the elimination of theophylline. Other integrated mechanisms (e.g. hepatic uptake) may also be altered by concurrent administration of other drugs. Whatever the mechanism, the interaction may b...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.2165/00003088-198409040-00002
更新日期:1984-07-01 00:00:00
abstract::The hypolipidaemic agent pravastatin differs from other US Food and Drug Administration (FDA)-approved HMG-CoA reductase inhibitors (e.g. lovastatin and simvastatin) because it has greater hydrophilicity, as a result of the hydroxyl group attached to its decalin ring. The hydrophilic nature of pravastatin accounts for...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.2165/00003088-199427020-00002
更新日期:1994-08-01 00:00:00
abstract::Ketoprofen, a potent nonsteroidal anti-inflammatory drug (NSAID) of the 2-arylpropionic acid class, has been used clinically for over 15 years in Europe, and has recently been introduced in the United States. Although it possesses a chiral centre, with only the S-enantiomer possessing beneficial pharmacological activi...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.2165/00003088-199019030-00004
更新日期:1990-09-01 00:00:00
abstract::Since its discovery in 1970, and introduction into clinical practice in 1978, cyclosporin has become the most important immunosuppressive drug used to prevent organ transplant rejection. This has been achieved by virtue of the improved graft survival rates and adverse effect profiles in patients when compared with tha...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.2165/00003088-199732050-00002
更新日期:1997-05-01 00:00:00
abstract::Many antiarrhythmic drugs introduced into the market during the past three decades have a chiral centre in their structure and are marketed as racemates. Most of these agents, including disopyramide, encainide, flecainide, mexiletine, propafenone and tocainide, belong to class I antiarrhythmics, whereas verapamil is a...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.2165/00003088-200241080-00001
更新日期:2002-01-01 00:00:00
abstract:BACKGROUND AND OBJECTIVE:Taurolidine is known to have antimicrobial activity. Furthermore, at lower concentrations, it has been found to exert a selective antineoplastic effect in vitro and in vivo. The aim of this study was to investigate the pharmacokinetics of taurolidine in vivo following repeated intravenous infus...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章
doi:10.2165/00003088-200746060-00005
更新日期:2007-01-01 00:00:00
abstract::Buspirone is an anxiolytic drug given at a dosage of 15 mg/day. The mechanism of action of the drug is not well characterised, but it may exert its effect by acting on the dopaminergic system in the central nervous system or by binding to serotonin (5-hydroxytryptamine) receptors. Following a oral dose of buspirone 20...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.2165/00003088-199936040-00003
更新日期:1999-04-01 00:00:00
abstract::The half-life of a drug, which expresses a change in concentration in units of time, is perhaps the most easily understood pharmacokinetic parameter and provides a succinct description of many concentration-time profiles. The calculation of a half-life implies a linear, first-order, time-invariant process. No drug per...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章
doi:10.2165/00003088-200140040-00001
更新日期:2001-01-01 00:00:00
abstract::The use of liposomal carriers and the modification of therapeutic molecules through the attachment of poly(ethylene glycol) [PEG] moieties ('pegylation') are the most common approaches for enhancing the delivery of parenteral agents. Although 'classical' liposomes (i.e. phospholipid bilayer vehicles) have been effecti...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.2165/00003088-200140070-00005
更新日期:2001-01-01 00:00:00