Probenecid effects on cephalexin pharmacokinetics and pharmacodynamics in healthy volunteers.

Objectives: We evaluated the effects of probenecid on the Pharmaco Kinetics (PK) and pharmacodynamics (PD) of oral cephalexin in healthy volunteers.

Methods: Cephalexin 1000 mg was administered orally to 11 healthy volunteers following a standardized meal, with and without probenecid 500 mg orally, on two separate days one week apart. Total plasma concentrations of cephalexin and probenecid over a 12 h period were measured by liquid chromatography tandem mass spectrometry.

Probenecid and food effects on flucloxacillin pharmacokinetics and pharmacodynamics in healthy volunteers.

Objectives: To measure the effect of probenecid, fasting and fed, on flucloxacillin pharmacokinetic and pharmacodynamic endpoints.

Methods: Flucloxacillin 1000 mg orally was given to 11 volunteers alone while fasting ('flucloxacillin alone'), and with probenecid 500 mg orally while fasting ('probenecid fasting') and with food ('probenecid fed'). Flucloxacillin pharmacokinetic and pharmacodynamic endpoints were compared.

The dosing and monitoring of vancomycin: what is the best way forward?

We have evaluated the literature to review optimal dosing and monitoring of intravenous vancomycin in adults, in response to evolving understanding of targets associated with efficacy and toxicity. The area under the total concentration-time curve (0-24 h) divided by the minimum inhibitory concentration (AUC/MIC) is the most commonly accepted index to guide vancomycin dosing for the treatment of Staphylococcus aureus infections, with a value of 400 h a widely recommended target for efficacy. Upper limits of AUC exposure of around 700 (mg/L).

Simultaneous Determination of Cefalexin, Cefazolin, Flucloxacillin, and Probenecid by Liquid Chromatography-Tandem Mass Spectrometry for Total and Unbound Concentrations in Human Plasma.

Background: Pharmacokinetic studies and therapeutic drug monitoring of antibiotics require a simple, rapid, and reliable analytical method for monitoring the concentrations in plasma, including unbound concentrations for highly protein-bound drugs. The aim of the current work was to develop and validate a liquid chromatography-tandem mass spectrometry method for the simultaneous determination of total and unbound concentrations of 3 widely used β-lactam antibiotics (cefalexin, cefazolin, and flucloxacillin) and the often coadministered drug probenecid in human plasma, suitable for pharmacokinetic studies and for routine use in ordinary, busy hospital laboratories.

Methods: Unbound drug was separated from bound drug by ultrafiltration.

In healthy volunteers, taking flucloxacillin with food does not compromise effective plasma concentrations in most circumstances.

It is usually recommended that flucloxacillin is given on an empty stomach. The aim of this study was to compare total and free flucloxacillin concentrations after oral flucloxacillin, given with and without food, based on contemporary pharmacokinetic and pharmacodynamic targets. Flucloxacillin 1000 mg orally was given to 12 volunteers, after a standardised breakfast and while fasting, on two separate occasions.

Total flucloxacillin plasma concentrations poorly reflect unbound concentrations in hospitalized patients with Staphylococcus aureus bacteraemia.

Aims: Flucloxacillin dosing may be guided by measurement of its total plasma concentrations. Flucloxacillin is highly protein bound with fraction unbound in plasma (f ) of around 0.04 in healthy individuals.

The performance of contemporary cystatin C-based GFR equations in predicting gentamicin clearance.

Aims: We aimed to compare the performances of contemporary cystatin C (Cys)-based GFR equations, and the creatinine only Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation for predicting gentamicin clearance.

Methods: The bias and imprecision of the CKD-EPI, CKD-EPI_Cys and creatinine-cystatin C CKD-EPI (CKD-EPI_CrCys) equations for predicting gentamicin clearances, were assessed in 260 patients treated with gentamicin during 2012-2013. The creatinine-cystatin C Berlin Initiative Study equation (BIS_CrCys) was examined in the ≥70 year subgroup.

Gentamicin and renal function: lessons from 15 years' experience of a pharmacokinetic service for extended interval dosing of gentamicin.

Background: Extended interval dosing (EID) of gentamicin most commonly involves dosing every 24 hours, but patients with impaired renal function may require a longer dose interval. This study examines a large database of patients treated with gentamicin from 1996 to 2010 to see how many patients with renal impairment would have benefited from dose intervals >24 hours and to define the incidence of nephrotoxicity.

Methods: All patients aged ≥ 16 years who had received gentamicin by EID over the 14-year period and had concentration data available were examined.

Correlation between trough plasma dabigatran concentrations and estimates of glomerular filtration rate based on creatinine and cystatin C.

Aims: Dabigatran is largely cleared by renal excretion. Renal function is thus a major determinant of trough dabigatran concentrations, which correlate with the risk of thromboembolic and haemorrhagic outcomes. Current dabigatran dosing guidelines use the Cockcroft-Gault (CG) equation to gauge renal function, instead of contemporary equations including the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations employing creatinine (CKD-EPI_Cr), cystatin C (CKD-EPI_Cys) and both renal biomarkers (CKD-EPI_CrCys).

Population PK modelling and simulation based on fluoxetine and norfluoxetine concentrations in milk: a milk concentration-based prediction model.

Aims: Population pharmacokinetic (pop PK) modelling can be used for PK assessment of drugs in breast milk. However, complex mechanistic modelling of a parent and an active metabolite using both blood and milk samples is challenging. We aimed to develop a simple predictive pop PK model for milk concentration-time profiles of a parent and a metabolite, using data on fluoxetine (FX) and its active metabolite, norfluoxetine (NFX), in milk.

Coagulation assays and plasma fibrinogen concentrations in real-world patients with atrial fibrillation treated with dabigatran.

Aims: In patients with atrial fibrillation prescribed dabigatran, the aim was to examine the correlation between plasma dabigatran concentrations and the three screening coagulation assays [international normalized ratio (INR), activated partial thromboplastin time (aPTT) and thrombin time (TT)] as well as the dilute thrombin time (dTT) and to examine the contribution of plasma fibrinogen concentrations to the variability in TT results.

Methods: Plasma from patients with atrial fibrillation on dabigatran were analysed for clotting times and concentrations of fibrinogen and dabigatran. Correlation plots (and associated r(2) values) were generated using these data.

A proposal for dose-adjustment of dabigatran etexilate in atrial fibrillation guided by thrombin time.

Dabigatran is an oral anticoagulant that is increasingly used for atrial fibrillation (AF). Presently, many authorities state that routine laboratory coagulation monitoring is not required. However, data have recently been published demonstrating that higher trough plasma dabigatran concentrations are associated with lower thromboembolic and higher haemorrhagic event rates.

Thirteen years' experience of pharmacokinetic monitoring and dosing of busulfan: can the strategy be improved?

Background: A busulfan concentration monitoring and dosing service has been provided by Christchurch Hospital since 1998. This study aimed to see (1) the percentage of patients with an area under the concentration time curve (AUC) outside the target range and had dose adjustment, (2) how busulfan clearance (CL) relates to body weight, and (3) if fewer samples could be used to predict doses.

Methods: Blood samples were taken from patients after oral administration, usually at 0.

Transfer of doxazosin into breast milk.

To the best of our knowledge, there have been no published studies of doxazosin transfer into human milk. In rats, milk concentrations twentyfold higher than in plasma have been reported. Based on these animal data, some references advise to avoid breastfeeding during doxazosin therapy.

A simple high-performance liquid chromatography method for simultaneous determination of three triazole antifungals in human plasma.

A rapid and simple high-performance liquid chromatography (HPLC) assay was developed for the simultaneous determination of three triazole antifungals (voriconazole, posaconazole, and itraconazole and the metabolite of itraconazole, hydroxyitraconazole) in human plasma. Sample preparation involved a simple one-step protein precipitation with 1.0 M perchloric acid and methanol.

Determination of imatinib and its active metabolite N-desmethyl imatinib in human plasma by liquid chromatography/tandem mass spectrometry.

Imatinib is a first-line treatment for chronic myelogenous leukaemia (CML). The pharmacokinetics of imatinib in patients with CML are characterised by large interpatient variability. Concentration monitoring of imatinib and its active metabolite N-desmethyl imatinib (DMI) is considered necessary to enhance the safe and effective use of imatinib.

Institutional profile: The Carney Centre for Pharmacogenomics: a New Zealand focus for personalized medicine research.

The integration of genetics and genomics with pharmacology and clinical medicine has enriched our understanding of all of these disciplines and is steadily providing a more complete picture of the etiology, pathophysiology and treatment of disease. To capitalize on this new knowledge requires the ability to evaluate the underlying evidence base and to test the utility of any proposed pharmacogenetic or genomic approaches to personalized medicine, within local or regional healthcare structures. The Carney Centre for Pharmacogenomics is now in its eighth year of operation, and although small by international standards, it has proven to be a valuable focus for research, training and dissemination of such knowledge in New Zealand and beyond.

Influence of adult age on the total and free clearance and protein binding of (R)- and (S)-warfarin.

What Is Already Known About This Subject: Hepatic drug clearance is thought to be reduced with age. However for highly protein bound drugs, which are cleared by capacity-limited metabolism, studies on total clearance have been conflicting. The hypothesis that protein binding decreases with age has been used to explain this.

The pharmacokinetics and pharmacogenetics of the antiemetic cyclizine in palliative care patients.

Context: Cyclizine, an antihistaminic antiemetic, is commonly used in palliative care. Its pharmacokinetics have been poorly studied, and its metabolic pathway is unknown but may involve the genetically controlled cytochrome P450 2D6 (CYP2D6). If this is the case, the metabolic ratio of cyclizine to norcyclizine and efficacy/adverse effects may vary between patients according to their CYP2D6 genotype.