Population pharmacokinetic modelling of febuxostat in healthy subjects and people with gout.

AIMS: To investigate and characterise the pharmacokinetics of febuxostat and the effect of the covariates of renal function and body size descriptors on the pharmacokinetics of the drug. METHODS: Blood samples (n = 239) were collected using sparse and rich sampling strategies from healthy (n = 9) and gouty (n = 29) subjects. Febuxostat plasma concentrations were measured by a validated high-performance liquid chromatography method. Population pharmacokinetic analysis was performed using NONMEM. A common variability on bioavailability (FVAR) approach was used to test the effect of fed status on absorption parameters. Covariates were modelled using a power model. RESULTS: The time course of the plasma concentrations of febuxostat is best described by a two-compartment model. In the final model, the population mean for apparent clearance (CL/F), apparent central volume of distribution (Vc/F), apparent peripheral volume of distribution (Vp/F), absorption rate constant (ka) and apparent intercompartmental clearance (Q/F) were 6.91 l h-1 , 32.8 l, 19.4 l, 3.6 h-1 and 1.25 l h-1 , respectively. The population parmater variability (coefficient of variation) for CL/F, Vc/F and Vp/F were 13.6, 22 and 19.5%, respectively. Food reduced the relative biovailability and ka by 67% and 87%, respectively. Renal function, as assessed by creatinine clearance, was a significant covariate for CL/F while body mass index was a significant covariate for Vc/F. CONCLUSIONS: Renal function and body mass index were significant covariates. Further work is warranted to investigate the clinical relevance of these results, notably as renal impairment and obesity are common occurrences in people with gout.

Are vancomycin dosing guidelines followed? A mixed methods study of vancomycin prescribing practices.

AIMS: Despite the availability of international consensus guidelines, vancomycin dosing and therapeutic drug monitoring (TDM) remain suboptimal. This study aimed to assess concordance of vancomycin dosing and TDM with institutional guidelines and to identify factors taken into consideration by clinicians when prescribing vancomycin. METHODS: A retrospective audit of 163 patients receiving vancomycin therapy (≥48 hours) was undertaken. Data collected included patient characteristics, dosing history and plasma vancomycin and creatinine concentrations. Concordance of dosing and TDM with institutional guidelines was evaluated. Semi-structured interviews, including simulated prescribing scenarios, were undertaken with prescribers (n = 17) and transcripts analysed. RESULTS: Plasma vancomycin concentrations (n = 1043) were collected during 179 courses of therapy. Only 24% of courses commenced with a loading dose with 72% lower than recommended. The initial maintenance dose was concordant in 42% of courses with 34% lower than recommended. Only 14% of TDM samples were trough vancomycin concentrations. Dose was not adjusted for 60% (21/35) of subtherapeutic and 43% (18/42) of supratherapeutic trough vancomycin concentrations, respectively. Interview participants reported that patient characteristics (including renal function), vancomycin concentrations, guidelines and expert advice influenced vancomycin prescribing decisions. Despite referring to guidelines when completing simulated prescribing scenarios, only 37% of prescribing decisions aligned with guideline recommendations. CONCLUSION: Poor compliance with institutional vancomycin guidelines was observed, despite prescriber awareness of available guidelines. Multifaceted strategies to support prescriber decision-making are required to improve vancomycin dosing and monitoring.

Honorary Professor Garry Graham.

An appreciation of the contribution of Professor Gary Graham to anti-inflammatory and antirheumatic pharmacology and clinical pharmacology.

Assessing the accuracy of two Bayesian forecasting programs in estimating vancomycin drug exposure.

BACKGROUND: Current guidelines for intravenous vancomycin identify drug exposure (as indicated by the AUC) as the best pharmacokinetic (PK) indicator of therapeutic outcome. OBJECTIVES: To assess the accuracy of two Bayesian forecasting programs in estimating vancomycin AUC0-∞ in adults with limited blood concentration sampling. METHODS: The application of seven vancomycin population PK models in two Bayesian forecasting programs was examined in non-obese adults (n = 22) with stable renal function. Patients were intensively sampled following a single (1000 mg or 15 mg/kg) dose. For each patient, AUC was calculated by fitting all vancomycin concentrations to a two-compartment model (defined as AUCTRUE). AUCTRUE was then compared with the Bayesian-estimated AUC0-∞ values using a single vancomycin concentration sampled at various times post-infusion. RESULTS: Optimal sampling times varied across different models. AUCTRUE was generally overestimated at earlier sampling times and underestimated at sampling times after 4 h post-infusion. The models by Goti et al. (Ther Drug Monit 2018. 40: 212-21) and Thomson et al. (J Antimicrob Chemother 2009. 63: 1050-7) had precise and unbiased sampling times (defined as mean imprecision <25% and <38 mg·h/L, with 95% CI for mean bias containing zero) between 1.5 and 6 h and between 0.75 and 2 h post-infusion, respectively. Precise but biased sampling times for Thomson et al. were between 4 and 6 h post-infusion. CONCLUSIONS: When using a single vancomycin concentration for Bayesian estimation of vancomycin drug exposure (AUC), the predictive performance was generally most accurate with sample collection between 1.5 and 6 h after infusion, though optimal sampling times varied across different population PK models.

Voriconazole: an audit of hospital-based dosing and monitoring and evaluation of the predictive performance of a dose-prediction software package.

BACKGROUND: Therapeutic drug monitoring (TDM) is recommended to guide voriconazole therapy. OBJECTIVES: To determine compliance of hospital-based voriconazole dosing and TDM with the Australian national guidelines and evaluate the predictive performance of a one-compartment population pharmacokinetic voriconazole model available in a commercial dose-prediction software package. METHODS: A retrospective audit of voriconazole therapy at an Australian public hospital (1 January to 31 December 2016) was undertaken. Data collected included patient demographics, dosing history and plasma concentrations. Concordance of dosing and TDM with Australian guidelines was assessed. Observed concentrations were compared with those predicted by dose-prediction software. Measures of bias (mean prediction error) and precision (mean squared prediction error) were calculated. RESULTS: Adherence to dosing guidelines for 110 courses of therapy (41% for prophylaxis and 59% for invasive fungal infections) was poor, unless oral formulation guidelines recommended a 200 mg dose, the most commonly prescribed dose (56% of prescriptions). Plasma voriconazole concentrations were obtained for 82% (90/110) of courses [median of 3 (range: 1-27) obtained per course]. A minority (27%) of plasma concentrations were trough concentrations [median concentration: 1.5 mg/L (range: <0.1 to >5.0 mg/L)]. Of trough concentrations, 57% (58/101) were therapeutic, 37% (37/101) were subtherapeutic and 6% (6/101) were supratherapeutic. The dose-prediction software performed well, with acceptable bias and precision of 0.09 mg/L (95% CI -0.08 to 0.27) and 1.32 (mg/L)2 (95% CI 0.96-1.67), respectively. CONCLUSIONS: Voriconazole dosing was suboptimal based on published guidelines and TDM results. Dose-prediction software could enhance TDM-guided therapy.

A pharmacokinetic-pharmacodynamic study of a single dose of febuxostat in healthy subjects.

AIMS: To examine the pharmacokinetic-phamacodynamic (PK-PD) relationships of plasma febuxostat and serum urate and the effect of a single dose of the drug on renal excretion and fractional clearance of urate (FCU). METHODS: Blood and urine samples were collected at baseline and up to 145 hours following administration of febuxostat (80 mg) to healthy subjects (n = 9). Plasma febuxostat and serum and urinary urate and creatinine concentrations were determined. Febuxostat pharmacokinetics were estimated using a two-compartment model with first-order absorption. An Emax PK-PD model was fitted to mean febuxostat and urate concentrations. Urinary urate excretion and FCU were calculated pre- and post-dose. RESULTS: Maximum mean plasma concentration of febuxostat (2.7 mg L-1 ) was observed 1.2 hours after dosage. Febuxostat initial and terminal half-lives were 2.0 ± 1.0 and 14.0 ± 4.7 hours (mean ± SD), respectively. The majority (81%) of the drug was eliminated in the 9 hours after dosing. Serum urate declined slowly achieving mean nadir (0.20 mmol L-1 ) at 24 hours. The IC50 (plasma febuxostat concentration that inhibits urate production by 50%) was 0.11 ± 0.09 mg L-1 (mean ± SD). Urinary urate excretion changed in parallel with serum urate. There was no systematic or significant change in FCU from baseline. CONCLUSION: The PK-PD model could potentially be used to individualise febuxostat treatment and improve clinical outcomes. A single dose of febuxostat does not affect the efficiency of the kidney to excrete urate. Further investigations are required to confirm the present results following multiple dosing with febuxostat.

Is the use of metformin in patients undergoing dialysis hazardous for life? A systematic review of the safety of metformin in patients undergoing dialysis.

AIMS: Metformin may have clinical benefits in dialysis patients; however, its safety in this population is unknown. This systematic review evaluated the safety of metformin in dialysis patients. METHODS: MEDLINE, Embase, CENTRAL, PsycINFO and the Cochrane Library were searched for randomised controlled trials and observational studies evaluating metformin use in dialysis patients. Three authors reviewed the studies and extracted data. The primary outcomes were mortality, occurrence of lactic acidosis and myocardial infarction (MI) in patients taking metformin during dialysis treatment for ≥12 months (long term). Risk of bias was assessed using Risk Of Bias In Nonrandomised Studies of Interventions (ROBINS-1). Overall quality of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation (GRADE). RESULTS: Fifteen observational studies were eligible; 7 were prospective observational studies and 8 were case reports/case series. No randomised controlled trials were identified. The 7 prospective observational studies (n = 194) reported on cautious metformin use in patients undergoing maintenance dialysis. Only 3 provided long-term follow-up data. In 2 long-term studies of metformin therapy (≤1000 mg/d) in patients undergoing peritoneal dialysis (PD), 1 reported 6 deaths (6/83; 7%) due to major cardiovascular events (3 MI) and the other reported no deaths (0/35). One long-term study of metformin therapy (250 mg to 500 mg thrice weekly) in patients undergoing haemodialysis reported 4 deaths (4/61; 7%) due to major cardiovascular events (2 MI). These findings provide very low-quality evidence as they come from small observational studies. CONCLUSION: The evidence regarding the safety of metformin in people undergoing dialysis is inconclusive. Appropriately designed randomised controlled trials are needed to resolve this uncertainty.

Individualising the dose of allopurinol in patients with gout.

AIMS: The aims of the study were to: 1) determine if a plasma oxypurinol concentration-response relationship or an allopurinol dose-response relationship best predicts the dose requirements of allopurinol in the treatment of gout; and 2) to construct a nomogram for calculating the optimum maintenance dose of allopurinol to achieve target serum urate (SU) concentrations. METHODS: A nonlinear regression analysis was used to examine the plasma oxypurinol concentration- and allopurinol dose-response relationships with serum urate. In 81 patients (205 samples), creatinine clearance (CLCR ), concomitant diuretic use and SU concentrations before (UP ) and during (UT ) treatment were monitored across a range of allopurinol doses (D, 50-700 mg daily). Plasma concentrations of oxypurinol (C) were measured in 47 patients (98 samples). Models (n = 47 patients) and predictions from each relationship were compared using F-tests, r2 values and paired t-tests. The best model was used to construct a nomogram. RESULTS: The final plasma oxypurinol concentration-response relationship (UT = UP - C*(UP - UR )/(ID50 + C), r2  = 0.64) and allopurinol dose-response relationship (UT = UP - D* (UP - UR )/(ID50 + D), r2  = 0.60) did not include CLCR or diuretic use as covariates. There was no difference (P = 0.87) between the predicted SU concentrations derived from the oxypurinol concentration- and allopurinol dose-response relationships. The nomogram constructed using the allopurinol dose-response relationship for all recruited patients (n = 81 patients) required pretreatment SU as the predictor of allopurinol maintenance dose. CONCLUSIONS: Plasma oxypurinol concentrations, CLCR and diuretic status are not required to predict the maintenance dose of allopurinol. Using the nomogram, the maintenance dose of allopurinol estimated to reach target concentrations can be predicted from UP .

Hyperuricaemia: contributions of urate transporter ABCG2 and the fractional renal clearance of urate.

OBJECTIVE: To investigate the contributions towards hyperuricaemia of known risk factors, focusing on fractional (renal) clearance of urate (FCU) and variation in the ATP-binding cassette transporter, sub-family G 2 (ABCG2) gene. METHODS: The contributions of age, sex, ancestry, Q141K genotype for ABCG2, FCU, sugar-sweetened beverage and alcohol consumption, metabolic syndrome disorders and measures of renal function to the risk of hyperuricaemia were evaluated by comparing hyperuricaemic (serum urate≥0.42 mmol/L, n=448) with normouricaemic (serum urate<0.42 mmol/L, n=344) participants using stepwise logistic regression. Model performance was evaluated using the area under the receiver operator characteristic curve (AUROC). RESULTS: ABCG2 genotype, FCU, male sex, body mass index, serum triglyceride concentrations, estimated glomerular filtration rate and consumption of alcohol were the best predictors of hyperuricaemia (AUROC 0.90, 81% accuracy). Homozygosity in the 141K variant for ABCG2 conferred an adjusted OR of 10.5 for hyperuricaemia (95% CI 2.4 to 46.2). For each 1% decrease of FCU, the adjusted OR increased by 51% (OR 1.51, 95% CI 1.37 to 1.66). There was no association between ABCG2 genotype and FCU (r=0.02, p=0.83). CONCLUSIONS: The ABCG2 141K variant and the FCU contribute strongly but independently to hyperuricaemia. These findings provide further evidence for a significant contribution of ABCG2 to extra-renal (gut) clearance of urate.

Xanthine oxidoreductase and its inhibitors: relevance for gout.

Xanthine oxidoreductase (XOR) is the rate-limiting enzyme in purine catabolism and converts hypoxanthine to xanthine, and xanthine into uric acid. When concentrations of uric acid exceed its biochemical saturation point, crystals of uric acid, in the form of monosodium urate, emerge and can predispose an individual to gout, the commonest form of inflammatory arthritis in men aged over 40 years. XOR inhibitors are primarily used in the treatment of gout, reducing the formation of uric acid and thereby, preventing the formation of monosodium urate crystals. Allopurinol is established as first-line therapy for gout; a newer alternative, febuxostat, is used in patients unable to tolerate allopurinol. This review provides an overview of gout, a detailed analysis of the structure and function of XOR, discussion on the pharmacokinetics and pharmacodynamics of XOR inhibitors-allopurinol and febuxostat, and the relevance of XOR in common comorbidities of gout.

Insights into the poor prognosis of allopurinol-induced severe cutaneous adverse reactions: the impact of renal insufficiency, high plasma levels of oxypurinol and granulysin.

OBJECTIVE: Allopurinol, an antihyperuricaemic agent, is one of the common causes of life-threatening severe cutaneous adverse reactions (SCAR), including drug rash with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN). The prognostic factors for allopurinol-related SCAR remain unclear. This study aimed to investigate the relationship of dosing, renal function, plasma levels of oxypurinol and granulysin (a cytotoxic protein of SJS/TEN), the disease severity and mortality in allopurinol-SCAR. METHODS: We prospectively enrolled 48 patients with allopurinol-SCAR (26 SJS/TEN and 22 DRESS) and 138 allopurinol-tolerant controls from 2007 to 2012. The human leucocyte antigen (HLA)-B*58:01 status, plasma concentrations of oxypurinol and granulysin were determined. RESULTS: In this cohort, HLA-B*58:01 was strongly associated with allopurinol-SCAR (p<0.001, OR (95% CI) 109 (25 to 481)); however, the initial/maintenance dosages showed no relationship with the disease. Poor renal function was significantly associated with the delayed clearance of plasma oxypurinol, and increased the risk of allopurinol-SCAR (p<0.001, OR (95% CI) 8.0 (3.9 to 17)). Sustained high levels of oxypurinol after allopurinol withdrawal correlated with the poor prognosis of allopurinol-SCAR. In particular, the increased plasma levels of oxypurinol and granulysin linked to the high mortality of allopurinol-SJS/TEN (p<0.01), and strongly associated with prolonged cutaneous reactions in allopurinol-DRESS (p<0.05). CONCLUSIONS: Impaired renal function and increased plasma levels of oxypurinol and granulysin correlated with the poor prognosis of allopurinol-SCAR. Allopurinol prescription is suggested to be avoided in subjects with renal insufficiency and HLA-B*58:01 carriers. An early intervention to increase the clearance of plasma oxypurinol may improve the prognosis of allopurinol-SCAR.

Understanding the dose-response relationship of allopurinol: predicting the optimal dosage.

AIMS: The aim of the study was to identify and quantify factors that control the plasma concentrations of urate during allopurinol treatment and to predict optimal doses of allopurinol. METHODS: Plasma concentrations of urate and creatinine (112 samples, 46 patients) before and during treatment with various doses of allopurinol (50-600 mg daily) were monitored. Non-linear and multiple linear regression equations were used to examine the relationships between allopurinol dose (D), creatinine clearance (CLcr) and plasma concentrations of urate before (UP) and during treatment with allopurinol (UT). RESULTS: Plasma concentrations of urate achieved during allopurinol therapy were dependent on the daily dose of allopurinol and the plasma concentration of urate pre-treatment. The non-linear equation: UT = (1 - D/(ID50 + D)) × (UP - UR) + UR , fitted the data well (r(2) = 0.74, P < 0.0001). The parameters and their best fit values were: daily dose of allopurinol reducing the inhibitable plasma urate by 50% (ID50 = 226 mg, 95% CI 167, 303 mg), apparent resistant plasma urate (UR = 0.20 mmol l(-1), 95 % CI 0.14, 0.25 mmol l(-1)). Incorporation of CLcr did not significantly improve the fit (P = 0.09). CONCLUSIONS: A high baseline plasma urate concentration requires a high dose of allopurinol to reduce plasma urate below recommended concentrations. This dose is dependent on only the pre-treatment plasma urate concentration and is not influenced by CLcr .

Antifungal use and therapeutic monitoring of plasma concentrations of itraconazole in heart and lung transplantation patients.

BACKGROUND: The prophylactic use of itraconazole has dramatically reduced the incidence of fungal infections in patients after solid-organ transplantation. To further reduce this incidence, it has been suggested that plasma concentrations of itraconazole be monitored and maintained above a putative minimum target concentration of 500 ng/mL. METHODS: A retrospective audit was undertaken of patients who had had a heart or lung transplant over a 14-month period (between January 1, 2010 and March 31, 2011). The itraconazole prophylaxis regimen (dose, time of last dose, time of blood collection) and plasma concentrations were recorded together with the use of concomitant antacid medication. Details of breakthrough fungal infections were documented. RESULTS: Eighty-four heart or lung organ transplantations were undertaken in the study period; 57 were treated prophylactically with itraconazole. Plasma concentrations of itraconazole were monitored in 56% (n = 32) of these cases. Considerable interpatient (range, 50-2000 ng/mL) and intrapatient variability in plasma concentrations was observed. The putative target was not achieved consistently in the majority of cases. All patients were taking a proton pump inhibitor. Six of the cohort developed an invasive fungal infection. None of the 3 patients for whom plasma concentrations were monitored was above the target concentration. CONCLUSIONS: Further clinical studies, involving monitoring of the active metabolite and attention to the importance of the stereoisomers of itraconazole, may give better insight into the appropriateness of the currently suggested minimum target concentration, whose validity remains uncertain. Formulations with improved absorption characteristics could reduce the variability of absorption with the goal of further reducing the incidence of infrequent, but life-threatening, invasive fungal infections.

An audit of a therapeutic drug monitoring service for allopurinol therapy.

BACKGROUND: Oxypurinol, the active metabolite of allopurinol, is the major determinant of the hypouricemic effect of allopurinol. Monitoring oxypurinol concentrations is undertaken to determine adherence to therapy, to investigate reasons for continuing attacks of acute gout and/or insufficiently low plasma urate concentrations despite allopurinol treatment, and to assess the risk of allopurinol hypersensitivity, an adverse effect that has been putatively associated with elevated plasma oxypurinol concentrations. METHODS: An audit of request forms requesting plasma oxypurinol concentration measurements received by the pathology service (SydPath) at St Vincent's Hospital, Darlinghurst, Sydney was undertaken for the 7-year period January 2005-December 2011. Patient demographics, biochemical data, including plasma creatinine and uric acid concentrations, comorbidities, and concomitant medications were recorded. RESULTS: There were 412 requests for determination of an oxypurinol concentration. On 48% of occasions, the time of allopurinol dosing was recorded, while just 79 (19%) blood samples were collected 6-9 hours postdosing, the time window used to establish the therapeutic range for oxypurinol. For these optimally interpretable concentrations, 32 (8%) were within the putative therapeutic range (5-15 mg/L), while 5 (1%) were below and 41 (10%) above this range. The daily dose of allopurinol was documented on only one-third of the request forms. Individually, plasma urate and creatinine concentrations were requested concomitantly with plasma oxypurinol concentrations in 66% and 58% of the cases, respectively; while plasma oxypurinol, urate, and creatinine concentrations were requested concomitantly in 49% of the cases. CONCLUSIONS: Requesting clinicians and blood specimen collectors often fail to provide relevant information (dose, times of last dose, and blood sample collection) to allow the most useful interpretation of oxypurinol concentrations. Concomitant plasma urate and creatinine concentrations should be requested to allow more complete interpretation of the data.

The pharmacokinetics of oxypurinol in people with gout.

AIMS: Our aim was to identify and quantify the sources of variability in oxypurinol pharmacokinetics and explore relationships with plasma urate concentrations. METHODS: Non-linear mixed effects modelling was applied to concentration-time data from 155 gouty patients with demographic, medical history and renal transporter genotype information. RESULTS: A one compartment pharmacokinetic model with first order absorption best described the oxypurinol concentration-time data. Renal function and concomitant medicines (diuretics and probenecid), but not transporter genotype, significantly influenced oxypurinol pharmacokinetics and reduced the between subject variability in the apparent clearance of oxypurinol (CL/F(m)) from 65% to 29%. CL/F(m) for patients with normal, mild, moderate and severe renal impairment was 1.8, 0.6, 0.3 and 0.18 l h(-1), respectively. Model predictions showed a relationship between plasma oxypurinol and urate concentrations and failure to reach target oxypurinol concentrations using suggested allopurinol dosing guidelines. CONCLUSIONS: In conclusion, this first established pharmacokinetic model provides a tool to achieve target oxypurinol plasma concentrations, thereby optimizing the effectiveness and safety of allopurinol therapy in gouty patients with various degrees of renal impairment.

Lack of effect of hydrochlorothiazide and low-dose aspirin on the renal clearance of urate and oxypurinol after a single dose of allopurinol in normal volunteers.

AIMS: To determine whether low-dose aspirin and hydrochlorothiazide (HCTZ) affect the renal clearance of oxypurinol and/or urate. METHODS: Healthy volunteers (n = 8) were treated with allopurinol (600 mg, control), and allopurinol (600 mg) co-administered with single doses of aspirin (100 mg) or HCTZ (25 mg) or a combination of the two. RESULTS: Hydrochlorothiazide, low-dose aspirin or a combination of the two, when co-administered with allopurinol, did not significantly alter (P > 0.05) the renal clearance of oxypurinol or urate. In particular, aspirin and HCTZ, when taken together and with allopurinol, did not change (P > 0.05) oxypurinol fractional renal clearance (allopurinol alone: 0.217, 0.173-0.262; combined: 0.202, 0.155-0.250) or urate fractional renal clearance (allopurinol alone: 0.066, 0.032-0.099; combined: 0.058, 0.038-0.078). CONCLUSIONS: A single, low-dose of aspirin or an anti-hypertensive dose of hydrochlorothiazide, when administered alone or together with allopurinol, are unlikely to alter the hypouricaemic effect of allopurinol. The effect of chronic aspirin and HCTZ dosing taken together upon the efficacy of chronic allopurinol therapy in patients with hyperuricaemia needs to be investigated.

Use of NSAIDs for osteoarthritis amongst older-aged primary care patients: engagement with information and perceptions of risk.

BACKGROUND: non-steroidal anti-inflammatory drugs (NSAIDs) are used commonly to treat osteoarthritis in older patients. OBJECTIVE: to explore the understandings of risk that older-aged primary care patients have in the context of the use of oral NSAIDs to treat osteoarthritis. METHOD: semi-structured interviews were conducted with 15 patients who were recruited from four general practices located in Sydney, Australia. Patients were aged at least 65 years and were currently taking, or in the past 2 years had taken, an NSAID for osteoarthritis. Emergent themes were identified from the transcripts and were compared within and across transcripts to develop more abstract concepts. RESULTS: patients demonstrated three key 'modes of disengagement' from medication-specific risk information, each of which could also be a mode of modulating a sense of danger and each of which would demand a unique clinical response. These were: 'transference of responsibility'-transferring the responsibility to their GP, 'general versus specific risk'-considering the risk of taking medicine in general as opposed to the specific risk of taking an NSAID, and 'personal immunity'-some patients with a long history of NSAID use without apparent toxicity believed they were, therefore, not at risk of future adverse effects, while a few patients believed they were immune to adverse effects of drugs in general. CONCLUSION: there is a need for greater recognition of these 'modes of disengagement'/'hazard modulation' in order to attain a clinical response leading to safer, more effective and more ethical use of medicines.

Pharmacokinetic and pharmacodynamic interactions of echinacea and policosanol with warfarin in healthy subjects.

AIMS: This study investigated the pharmacokinetic and pharmacodynamic interactions of echinacea and policosanol with warfarin in healthy subjects. METHODS: This was an open-label, randomized, three-treatment, cross-over, clinical trial in healthy male subjects (n= 12) of known CYP2C9 and VKORC1 genotype who received a single oral dose of warfarin alone or after 2 weeks of pre-treatment with each herbal medicine at recommended doses. Pharmacodynamic (INR, platelet activity) and pharmacokinetic (warfarin enantiomer concentrations) end points were evaluated. RESULTS: The apparent clearance of (S)-warfarin (90% CI of ratio; 1.01, 1.18) was significantly higher during concomitant treatment with echinacea but this did not lead to a clinically significant change in INR (90% CI of AUC of INR; 0.91, 1.31). Policosanol did not significantly affect warfarin enantiomer pharmacokinetics or warfarin response. Neither echinacea nor policosanol had a significant effect on platelet aggregation after 2 weeks of pre-treatment with the respective herbal medicines. CONCLUSION: Echinacea significantly reduced plasma concentrations of S-warfarin. However, neither echinacea nor policosanol significantly affected warfarin pharmacodynamics, platelet aggregation or baseline clotting status in healthy subjects.

The safety and pharmacokinetics of metformin in patients with chronic liver disease.

BACKGROUND: The FDA approved 'label' for metformin lists hepatic insufficiency as a risk for lactic acidosis. Little evidence supports this warning. AIMS: To investigate the safety and pharmacokinetics of metformin in patients with chronic liver disease (CLD). METHODS: Chronic liver disease patients with and without type 2 diabetes mellitus (T2DM) were studied by a cross-sectional survey of patients already prescribed metformin (n = 34), and by a prospective study where metformin (500 mg, immediate release, twice daily) for up to 6 weeks was prescribed (n = 24). Plasma metformin and lactate concentrations were monitored. Individual pharmacokinetics were obtained and compared to previously published values from healthy and T2DM populations without CLD. RESULTS: All plasma metformin and lactate concentrations remained below the putative safety thresholds (metformin, 5 mg/L; lactate, 5 mmol/L). Lactate concentrations were unrelated to average steady-state metformin concentrations. In patients with CLD, T2DM was associated with higher plasma lactate concentrations (48% higher than those without T2DM, P < 0.0001). CLD patients with cirrhosis had 23% higher lactate concentrations than those without cirrhosis (P = 0.01). The pharmacokinetics of metformin in CLD patients were similar to patients with T2DM and no liver disease. The ratio of apparent metformin clearance (CLMet /F) to creatinine clearance was marginally lower in CLD patients compared to healthy subjects (median, interquartile range; 12.6, 9.5-15.9 vs 14.9, 13.4-16.4; P = 0.03). CONCLUSIONS: The pharmacokinetics of metformin are not altered sufficiently in CLD patients to raise concerns regarding unsafe concentrations of metformin. There were no unsafe plasma lactate concentrations observed in CLD patients receiving metformin (ACTRN12619001292167; ACTRN12619001348145).