Population pharmacokinetics of free flucloxacillin in patients treated with oral flucloxacillin plus probenecid.

Oral flucloxacillin may be coadministered with probenecid to reduce flucloxacillin clearance and increase attainment of pharmacokinetic-pharmacodynamic (PK/PD) targets. The aims of this study were to develop a population PK model of free flucloxacillin when administered orally with probenecid, and to identify optimal dosing regimens for this combination. METHODS: We performed a prospective observational study of adults (45 participants) treated with oral flucloxacillin 1000 mg and probenecid 500 mg 8-hourly for proven or probable staphylococcal infections. Steady-state mid-dose-interval flucloxacillin measurements (45 concentrations) were combined with existing data from a crossover study of healthy participants receiving flucloxacillin with and without probenecid (11 participants, 363 concentrations). We developed a population pharmacokinetic model of free flucloxacillin concentrations within Monolix, and used Monte Carlo simulation to explore optimal dosing regimens to attain PK/PD targets proposed in the literature (free drug time above minimum inhibitory concentration). RESULTS: Flucloxacillin disposition was best described by a 1-compartment model with a lag time and first-order absorption. Free flucloxacillin clearance depended on probenecid, allometrically-scaled fat free mass (FFM) and estimated glomerular filtration rate (eGFR). Predicted PK/PD target attainment was suboptimal with standard dosing regimens with flucloxacillin alone, but substantially improved in the presence of probenecid. CONCLUSION: The simulation results reported can be used to identify dose regimens that optimise flucloxacillin exposure according to eGFR and FFM. Patients with higher FFM and eGFR may require the addition of probenecid and 6-hourly dosing to achieve PK/PD targets. The regimen was well-tolerated, suggesting a potential for further evaluation in controlled clinical trials to establish efficacy.

Compulsory Indications in Hospital Prescribing Software Tested with Antibacterial Prescriptions.

The aim was to assess how making the indication field compulsory in our electronic prescribing system influenced free text documentation and to visualise prescriber behaviour. The indication field was made compulsory for seven antibacterial medicines. Text recorded in the indication field was manually classified as 'indication present', 'other text', 'rubbish text', or 'blank'. The proportion of prescriptions with an indication was compared for four weeks before and after the intervention. Indication provision increased from 10.6% to 72.4% (p<0.01) post-intervention. 'Other text' increased from 7.6% to 25.1% (p<0.01), and 'rubbish text' from 0.0% to 0.6% (p<0.01). Introducing the compulsory indication field increased indication documentation substantially with only a small increase in 'rubbish text'. An interactive report was developed using a live data extract to illustrate indication provision for all medicines prescribed at our tertiary hospital. The interactive report was validated and locally published to support audit and quality improvement projects.

Longitudinal trends in community antibiotic consumption in the Waitaha Canterbury Region of Aotearoa New Zealand over 10 years (2012-2021): an observational study.

AIMS: To investigate community antibiotic consumption in the Waitaha Canterbury Region of Aotearoa New Zealand across 2012-2021. METHODS: This observational study was based on antibiotic dispensing data from Waitaha Canterbury. Outcome measures included number of dispensings/1,000 inhabitants per year and defined daily doses/1,000 inhabitants per day (DIDs), expressed as average annual change (AAC). We stratified antibiotic dispensing per antibiotic group, and per the World Health Organization (WHO) AWaRE (Access, Watch, Reserve) classification. RESULTS: Across 2012-2021, antibiotic dispensing decreased from 867 to 601 dispensings/1,000 inhabitants (AAC -4.2% [95%CI -4.3 to -4.2]). In the pre-COVID period of 2012 to 2019, antibiotic dispensings decreased with AAC of -3.5% (95%CI -3.6 to -3.5). Considering number of dispensings, the largest reductions were observed in quinolones (-14.6%), macrolides/lincosamides (-8.5%) and penicillins with extended spectrum (-4.8%). The number of dispensings increased for nitrofurans (6.0%) and first generation cephalosporins (28.1%), of which 98% comprised cefalexin dispensing. The proportion of Watch antibiotics decreased from 22.0% to 11.9%. CONCLUSIONS: Community antibiotic consumption decreased in Waitaha Canterbury Aotearoa New Zealand from 2012 to 2021, as did use of Watch antibiotics. These changes concord with increasing antimicrobial stewardship guidance for more judicious use of antibiotics. Further research should investigate the factors driving the observed 10-fold rise in cefalexin dispensing.

Allopurinol might improve response to azathioprine and 6-mercaptopurine by correcting an unfavorable metabolite ratio.

BACKGROUND AND AIM: Allopurinol potentiates azathioprine and 6-mercaptopurine (6-MP) by increasing 6-thioguanine nucleotide (6-TGN) metabolite concentrations. The outcome might also be improved by adding allopurinol in individuals who preferentially produce 6-methylmercaptopurine nucleotides (6-MMPN), rather than 6-TGN. The aim of the present study was to investigate the effect of allopurinol on concentrations of 6-MMPN and 6-TGN in individuals with a high ratio of these metabolites (>20), which is indicative of a poor thiopurine response. METHODS: Sixteen individuals were identified who were taking azathioprine or 6-MP, and were commenced on allopurinol to improve a high 6-MMPN:TGN ratio. Metabolite concentrations were compared before and after commencing allopurinol, and markers of disease control were compared. RESULTS: The addition of 100-300 mg allopurinol daily and thiopurine dose reduction (17-50% of the original dose) resulted in a reduction of the median (and range) 6-MMPN concentration, from 11,643 (3,365-27,832) to 221 (55-844) pmol/8×10(8) red blood cells (RBC; P=0.0005), increased 6-TGN from 162 (125-300) to 332 (135-923) pmol/8×10(8) RBC (P=0.0005), and reduced the 6-MMPN:6-TGN ratio from 63 (12-199) to 1 (0.1-4.5) (P=0.0005). There was a significant reduction in steroid dose requirements at 12 months (P=0.04) and trends for improvement in other markers of disease control. One patient developed red cell aplasia that resolved upon stopping azathioprine and allopurinol. CONCLUSIONS: In those with a high 6-MMPN:6-TGN ratio (>20), response to thiopurine treatment might be improved by the addition of allopurinol, together with a reduced thiopurine dose and close hematological monitoring.

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. Standard pharmacokinetic measures and contemporary PK/PD targets were compared. RESULTS: Probenecid increased the mean (95% CI) cephalexin area under the concentration-time curve (AUC0-∞) 1.73-fold (1.61-1.85, p < 0.0001), peak concentration 1.37-fold (1.16-1.58, p < 0.01), time to peak concentration 1.45-fold (1.1-1.8, p < 0.01), and half-life 1.33-fold (1.03-1.62, p < 0.05). The effects resulted in clinically meaningful increases in the probability of PK/PD target attainment (PTA). As an example, the PTA of total concentrations above the minimum inhibitory concentration required to inhibit methicillin-susceptible Staphylococcus aureus isolates (MIC ≤ 8 mg/L) for 70% of a 6 h dose interval approached 100% for cephalexin + probenecid while for cephalexin alone it was <15%. CONCLUSIONS: Probenecid prolonged and flattened the plasma concentration-time curve, enhancing the probability of attaining PK/PD targets. Co-administration of probenecid may expand the clinical benefits of oral cephalexin.

A persuasive approach to antimicrobial stewardship in Christchurch hospitals produced a sustained decrease in intravenous clarithromycin dosing and expenditure via a switch to azithromycin orally.

AIMS: To assess a persuasive multimodel approach to decreasing unnecessary intravenous (IV) clarithromycin use for community-acquired pneumonia (CAP) in Canterbury District Health Board (CDHB) hospitals. METHODS: In December 2013, CDHB guidelines for empiric treatment of CAP changed to prioritise oral azithromycin over IV clarithromycin. The multimodel approach we used to implement this change included obtaining stakeholder agreement, improved guidelines access, education and pharmacist support. The impact of the intervention was evaluated by comparing macrolide usage and expenditure for the four years pre- and post-intervention. RESULTS: Mean annual clarithromycin IV use decreased by 72% from 6.4 to 1.8 defined daily doses (DDDs) per 1,000 occupied bed days (OBDs) post-intervention, while oral azithromycin increased by 833% (4.2 to 39.2 DDDs per 1,000 OBDs). Concurrently, oral clarithromycin use decreased by 91% (32.9 to 2.9 DDDs per 1,000 OBDs), and roxithromycin by 71% (17.0 to 5.0 DDDs per 1,000 OBDs). Mean annual total macrolide use decreased by 21% (68.2 to 53.9 DDDs per 1,000 OBDs), while expenditure decreased by 69% mainly through avoided IV administration. CONCLUSIONS: A persuasive multimodel approach to support adoption of CAP guidelines produced a sustained decrease in IV clarithromycin use, which may have clinical benefits such as reduced occurrence of catheter-related complications.

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. RESULTS: Probenecid, fasting and fed, increased free plasma flucloxacillin area under the concentration-time curve (zero to infinity) ∼1.65-fold (p < 0.01) versus flucloxacillin alone. Probenecid fed prolonged time to peak flucloxacillin concentrations ∼2-fold versus the other two regimens (p < 0.01). Probenecid fasting or fed increased free flucloxacillin concentrations exceeding 30%, 50% and 70% of the first 6, 8 and 12 h post-dose by 1.58- to 5.48-fold compared with flucloxacillin alone. As an example of this pharmacodynamic improvement, the probability of target attainment of free concentrations above the minimum inhibitory concentration for Staphylococcus aureus (0.5 mg/L) for 50% of a 6-hour dose interval was > 80% for flucloxacillin plus probenecid (fasting or fed) and < 20% for flucloxacillin alone. CONCLUSIONS: Probenecid increased flucloxacillin exposure, with predicted pharmacodynamic effects greater than pharmacokinetic effects because of the altered shape of the concentration-time curve. Probenecid may improve the applicability of oral flucloxacillin regimens.

Point prevalence surveys of antimicrobial use in adult inpatients at Canterbury District Health Board Hospitals.

AIMS: To determine the nature and appropriateness of antimicrobial prescribing in adult inpatients at Canterbury District Health Board (CDHB). METHODS: Multidisciplinary teams collected clinical details for all adult inpatients on antimicrobial therapy at three CDHB facilities (~1,100 beds) and made standardised assessments based on the Australian National Antimicrobial Prescribing Survey (http://naps.org.au) against local guidelines and national funding criteria. RESULTS: Antimicrobial therapy was prescribed to 42% of inpatients (322/760), usually to treat infections [377/480 prescriptions (79%)], with amoxicillin+clavulanic acid the agent most commonly prescribed [72/480 prescriptions (15%)]. Of assessable prescriptions, 74% (205/278) were guideline compliant, 98% (469/480) were funding criteria compliant, and 83% (375/451) were appropriate clinically. Prescriptions for the most common indications-surgical prophylaxis [66/480 (14%)] and community-acquired pneumonia [56/480 (12%)]-were often non-compliant with guidelines (32% and 41%, respectively) and inappropriate (18% and 21%, respectively). Overall, the indication was documented in 353/480 (74%) prescriptions, the review/stop date documented in 145/480 (30%) prescriptions, and surgical prophylaxis stopped within 24 hours in 53/66 (80%) prescriptions. CONCLUSIONS: Most antimicrobial prescriptions were appropriate and complied with guidelines. Compliance with key quality indicators (indication documented, review/stop date documented, and surgical prophylaxis ceased within 24 hours) were well below target (>95%) and needs improvement.

Determinants of vancomycin nephrotoxicity when administered to outpatients as a continuous 24-hour infusion.

Vancomycin continuous infusion (VCI) is used to treat serious Gram-positive infections in outpatients. This study was conducted to retrospectively investigate the rate of nephrotoxicity and associated risk factors in out-patients on VCI between May 2013 and November 2018. Vancomycin concentration was monitored twice-weekly to ensure adequate concentrations while avoiding high concentrations linked to nephrotoxicity (a rise in serum creatinine of ≥50% or 44 µmol/L from baseline). The likelihood of developing nephrotoxicity was evaluated using multivariable logistic regression. The 223 patients treated had a mean (standard deviation) age of 61 (16.7) years, baseline serum creatinine of 83.9 (21.2) µmol/L and estimated glomerular filtration rate (eGFR) of 80.6 (20.1) mL/min/1.73m2. Most patients (66%) were treated for bone and joint infections. Eight patients (3.6%) developed nephrotoxicity. In the most parsimonious model, nephrotoxicity was independently associated with an increased median (interquartile range) weighted-average serum vancomycin concentration (28.0 [24.3-32.6] vs. 22.4 [20.2-24.5] mg/L; odds ratio [OR] 1.25; 95% confidence interval [95% CI] 1.09-1.46; P<0.002) and Charlson co-morbidity index (OR 1.62; 95% CI 1.07-2.47; P=0.02). Post-hoc analysis identified 26 patients with a lower nephrotoxicity threshold (rise in serum creatinine of ≥30% or 27 µmol/L). Independent predictors of nephrotoxicity in this group were an increased weighted-average vancomycin concentration, diabetes, con-gestive heart failure and exposure to non-loop diuretics. The nephrotoxicity rate during VCI in this study was lower than previously reported (3.6% vs 15.0-17.0%).  Reducing the weighted-average serum vancomycin concentration may reduce nephrotoxicity while maintaining efficacy.

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 (AUC24/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 AUC24 exposure of around 700 (mg/L).h have been proposed, based on the hypothesis that higher exposures of vancomycin are associated with an unacceptable risk of nephrotoxicity. If AUC24/MIC targets are used, sources of variability in the assessment of both AUC24 and MIC need to be considered. Current consensus guidelines recommend measuring trough vancomycin concentrations during intermittent dosing as a surrogate for the AUC24. Trough concentrations are a misleading surrogate for AUC24 and a poor end-point in themselves. AUC24 estimation using log-linear pharmacokinetic methods based on two plasma concentrations, or Bayesian methods are superior. Alternatively, a single concentration measured during continuous infusion allows simple AUC24 estimation and dose-adjustment. All of these methods have logistical challenges which must be overcome if they are to be adopted successfully.

Thiopurine dose in intermediate and normal metabolizers of thiopurine methyltransferase may differ three-fold.

BACKGROUND & AIMS: Patients with inflammatory bowel disease (IBD) may have different thiopurine dose requirements in relation to thiopurine methyltransferase (TPMT) genotype and/or phenotype. The purpose of this study was to determine thiopurine dose requirements in intermediate versus normal TPMT metabolism status. METHODS: Consecutive patients starting azathioprine or 6-mercaptopurine for IBD were followed up for 9 months. The thiopurine dose was individualized using 6-thioguanine nucleotide (6-TGN) concentrations (range, 235-450 pmol/8 x 10(8) red blood cells [RBCs]) and clinical status. Additional assessments undertaken every three months included measures of disease activity. RESULTS: Eight (10%) of 77 participants were withdrawn because of protocol violation. Fifty-two (75%) of the remaining 69 subjects ( approximately 90% and 10% with the TPMT*1/*1 and *1/*3 genotypes, respectively) completed follow-up on azathioprine (n = 46) or 6-mercaptopurine (n = 6). The mean initial dose (as azathioprine equivalents) was similar ( approximately 1 mg/kg/d) for the 2 TPMT genotypes, but after 9 months the dose was 50% lower in the TPMT*1/*3 group (0.9 vs 1.8 mg/kg/d, P < .0001). Despite dose adjustment, median 6-TGN concentrations still were 2-fold higher in the TPMT*1/*3 group at the end of the follow-up period (505 vs 273 pmol/8 x 10(8) RBCs, P = .02). This difference was 3-fold when the concentration was adjusted for dose (578 vs 183 pmol/8 x 10(8) per mg/kg/d, P = .0007). Results were similar if TPMT phenotype was used instead of genotype. Clinical outcomes did not differ between groups. CONCLUSIONS: Initial target doses to attain therapeutic 6-TGN concentrations (>235 pmol/8 x 10(8) RBCs) in patients with IBD might be 1 and 3 mg/kg/d in intermediate and normal metabolizers, respectively.

Development and validation of a stereoselective liquid chromatography-tandem mass spectrometry assay for quantification of S- and R-metoprolol in human plasma.

A stereoselective liquid chromatography-tandem mass spectrometry assay was developed and validated for quantification of S- and R-metoprolol at concentrations of 0.5-50 microg/L in human plasma. Metoprolol was extracted from plasma by liquid-liquid extraction with ethyl acetate (82% recovery). Chromatographic separation of the enantiomers was achieved on a chiral Chirobiotic T column using an isocratic mobile phase consisting of methanol/acetic acid/ammonia (100/0.15/0.15, v/v/v). An ion trap mass spectrometer with an electrospray interface was used for detection in the positive mode, monitoring the m/z transition 268-->191 for metoprolol. Standard curves for S- and R-metoprolol fitted quadratic functions (r(2)>or=0.9995) over the range 0.5-50 microg/L in plasma, with 0.5 microg/L representing the limit of quantification. In this range, relative standard deviations were <6% for intra-day precision and <10% for inter-day precision. The accuracy was within the range of 92-105%.

Antimicrobial stewardship practice in New Zealand's rural hospitals.

AIMS: We aimed to describe how antimicrobial stewardship (AMS) is practised in New Zealand's diverse rural hospital network. METHODS: Rural hospital medical practitioners were surveyed to estimate the utilisation of prescribing resources and specialist support for AMS, and attitudes towards AMS. Questions reflected recommended strategies for AMS programmes. RESULTS: The response rate was 80.8% (122/151) from 29 rural hospitals (3-114 beds). While 78.7% reported access to local antimicrobial prescribing guidelines, discordant answers from practitioners at the same institution were common. The practice of approval for access to broad-spectrum antimicrobial agents was uncommon. Most respondents had cared for a patient with a multi-drug resistant organism in the preceding 12 months. Only 34.8% of respondents reported receiving formal education on AMS principles, with at least 90% believing it was relevant irrespective of the clinical context considered. Respondents were more likely to believe that antimicrobial overuse and resistance were more relevant at sites distant from the context of rural hospital practice. CONCLUSION: While AMS is perceived as relevant for rural hospital medicine, many of the building blocks of AMS systems are absent in this environment. This presents an opportunity for development as AMS strategies evolve in New Zealand.

Metronidazole stewardship initiative at Christchurch hospitals-achievable with immediate benefits.

AIMS: To evaluate an antimicrobial stewardship (AMS) initiative to change hospital prescribing practice for metronidazole. METHODS: In October 2015, the Canterbury District Health Board (CDHB) AMS committee changed advice for metronidazole to promote two times daily dosing for most indications, prioritisation of the oral route and avoidance of double anaerobic cover. Adoption of the initiative was facilitated via change in prescribing guidelines, education and ongoing pharmacy support. Usage and expenditure on metronidazole for adult inpatients were compared for the five years pre- and two years post-change. Other district health boards (DHBs) were surveyed to determine their dosing recommendation for metronidazole IV. RESULTS: Mean annual metronidazole IV use, as defined daily doses per 1,000 occupied bed days, decreased by 43% post-initiative. Use of non-IV (oral or rectal) formulations increased by 104%. Total savings associated with the initiative were approximately $33,400 in drug costs plus $78,200 per annum in IV giving sets and post-dose flushes. Twelve of 20 (60%) DHBs (including CDHB) endorse twice daily IV dosing. CONCLUSIONS: In addition to financial savings, reduction in IV doses has potential benefits, including avoidance of IV catheter-associated complications such as bloodstream infections. Approaches to metronidazole dosing vary across DHBs and could benefit from national coordination.

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. Flucloxacillin concentrations over 12 hours were measured by liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters, and pharmacodynamic endpoints related to target concentration achievement, were compared in the fed and fasting states. For free flucloxacillin, the fed/fasting area under the concentration-time curve from zero to infinity (AUC0-∞) ratio was 0.80 (p<0.01, 90% CI 0.70-0.92), the peak concentraton (Cmax) ratio 0.51 (p<0.001, 0.42-0.62) and the time to peak concentration (Tmax) ratio 2.2 (p<0.001, 1.87-2.55). The ratios for total flucloxacillin concentrations were similar. The mean (90% CI) fed/fasting ratios of free concentrations exceeded for 30%, 50% and 70% of the first 6 hours post-dose were 0.74 (0.63-0.87, fed inferior p<0.01), 0.95 (0.81-1.11, bioequivalent) and 1.15 (0.97-1.36, fed non-inferior), respectively. Results for 8 hours post-dose and those predicted for steady state were similar. Comparison of probability of target attainments for fed versus fasting across a range of minimum inhibitory concentrations (MICs) were in line with these results. Overall, this study shows that food reduced the AUC0-∞ and Cmax, and prolonged the Tmax of both free and total flucloxacillin concentrations compared with the fasting state, but achievement of free concentration targets associated with efficacy was in most circumstances equivalent. These results suggest that taking flucloxacillin with food is unlikely to compromise efficacy in most circumstances.

Survey of antimicrobial stewardship practices in public hospitals in New Zealand district health boards.

AIMS: To determine what antimicrobial stewardship (AMS) practices exist in New Zealand public hospitals. METHODS: A quantitative survey based on recommended components of hospital AMS programmes was sent to the 20 DHBs in June 2016. RESULTS: Ten of the 20 DHBs had an AMS committee, nine had dedicated AMS pharmacist full-time equivalents (FTEs) and eight had lead clinician FTEs. Only one DHB met FTE recommendations for AMS pharmacists and two for clinicians (0.3 and 0.1 FTEs per 100 acute beds, respectively). All DHBs had conducted at least one antimicrobial audit in the preceding 12 months, most had their own antimicrobial guidelines (19/20) and prescribing policies (18/20), and 12 reported on antimicrobial usage by at least one metric (eg, defined daily doses). Staff education on AMS had been given at most DHBs in the previous year, but only three reported having AMS ward rounds. All DHBs had surveillance programmes for resistant organisms and most produced antibiograms (16/20). All reported barriers to implementation of an AMS programme. CONCLUSIONS: Hospital AMS programmes are in their infancy in New Zealand, with wide variation in practices seen. National co-ordination is required to assist DHBs in developing effective programmes to improve antimicrobial use.

Breastfeeding during tacrolimus therapy.

BACKGROUND: Solid organ transplant recipients are usually advised against breastfeeding because of the questionable safety of immunosuppressants. Limited data suggest that infant exposure to tacrolimus via milk is low. This report characterizes the milk-to-blood ratio for tacrolimus using area under the concentration-time curve analysis in a renal transplant patient. CASE: A 29-year-old woman was exclusively breastfeeding her healthy 3-month-old infant while on tacrolimus 4 mg daily plus other drugs relevant to her transplant. The milk-to-blood ratio was 0.23, and average tacrolimus concentrations in milk were 1.8 microg/L. The baby ingested approximately 0.5% of the maternal dose (weight-adjusted). CONCLUSION: Infant exposure to tacrolimus in milk is very low, suggesting that maternal tacrolimus therapy may be compatible with breastfeeding.

Determination of celecoxib in human plasma and breast milk by high-performance liquid chromatographic assay.

A rapid and simple HPLC assay was developed for the determination of celecoxib in human plasma and breast milk. After proteins were precipitated with acetonitrile, celecoxib was resolved on a C18 column and detected by UV detection at 254 nm. Standard curves were linear over the concentration range 10-2000 microg/L (r(2)>0.99). Bias was

Pharmacoeconomic analyses of azathioprine, methotrexate and prospective pharmacogenetic testing for the management of inflammatory bowel disease.

OBJECTIVES: To compare the cost effectiveness of azathioprine (AZA), methotrexate (MTX) and no immunosuppression for maintaining remission of moderate to severe inflammatory bowel disease (IBD) in New Zealand Caucasians, and to determine whether prospective testing for poor metabolisers of AZA by genotype or phenotype is cost effective. METHODS: Pharmacoeconomic models were developed to compare treatment costs and effects (QALYs) in theoretical populations of 1,000 IBD patients over a 1-year period. Efficacy and tolerability profiles for AZA and MTX were taken from the literature. The costs (year 2004 values) of the drugs and treatment of adverse effects were estimated from New Zealand drug and service costs. Representations of the patients' health-related quality of life (HR-QOL) were obtained from clinicians via the EQ-5D health state classification system and valued using the New Zealand EQ-5D social tariff. The effects of genotyping or phenotyping a population for thiopurine methyltransferase (TPMT) status were compared using the prevalence of TPMT deficiency in Caucasians, the relative risks of neutropenia and the associated costs. RESULTS: Net cost savings (vs no immunosuppressant treatment) of approximately 2.5 million and 1 million New Zealand dollars were realised for AZA and MTX, respectively, for the theoretical 1,000 patients, and AZA generated 877 QALYs compared with 633 for MTX. Phenotype and genotype testing generated net cost savings (vs no testing) of 120,000 and 11,000 New Zealand dollars, respectively. Savings related to phenotype tests were greater because of the lower assay costs of phenotype testing and a greater likelihood of pre-empting neutropenia. CONCLUSION: Our model suggests that both MTX and AZA may generate significant net cost savings and benefits for patients with IBD in New Zealand, with AZA likely to be more cost effective than MTX. Prospective testing for poor metabolisers of AZA may also be cost effective, with phenotype testing likely to be more cost effective than genotype testing.