OBJECTIVES Voriconazole exhibits highly variable, non-linear pharmacokinetics and is associated with a narrow therapeutic range. This study aimed to investigate the population pharmacokinetics of voriconazole in adults, including the effect of CYP2C19 genotype and drug-drug interactions. METHODS Non-linear mixed effects modelling (NONMEM) was undertaken of six voriconazole studies in healthy volunteers and patients. Dosing simulations to examine influential covariate effects and voriconazole target attainment (2-5 mg/L) stratified by CYP2C19 phenotype were performed. RESULTS We analysed 3352 voriconazole concentration measurements from 240 participants. A two-compartment pharmacokinetic model with first-order oral absorption with lag time and Michaelis-Menten elimination best described voriconazole pharmacokinetics. Participants with one or more CYP2C19 loss-of-function (LoF) alleles had a 41.2% lower Vmax for voriconazole. Co-administration of phenytoin or rifampicin, St John's wort or glucocorticoids significantly increased voriconazole elimination. Among patients receiving 200 mg of voriconazole twice daily, predicted trough concentrations on day 7 were <2 mg/L for oral and intravenous regimens for 72% and 63% of patients without CYP2C19 LoF alleles, respectively, with 49% and 35% below this threshold with 300 mg twice daily dosing. Conversely, these regimens resulted in 29%, 39%, 57% and 77% of patients with CYP2C19 LoF alleles with voriconazole trough concentrations ≥5 mg/L. CONCLUSIONS Current dosing regimens for voriconazole result in subtherapeutic exposure in many patients without CYP2C19 LoF alleles, suggesting the need for higher doses, whereas these regimens result in supratherapeutic exposure in a high proportion of patients with reduced CYP2C19 activity. These findings support the essential role of therapeutic drug monitoring in ensuring efficacious and safe voriconazole exposure.

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.

To the Editor: The recent approval of the first direct-acting antiviral agents for the hepatitis C virus (HCV), the protease inhibitors telaprevir and boceprevir, represent a substantial advance in the treatment of chronic HCV infection. When used concomitantly with the standard combination of pegylated interferon and ribavirin, these agents have demonstrated significant improvements in the rates of sustained virological response (SVR) for both treatment-naive genotype 1 HCV infection and in previously treated patients who had failed to attain SVR. Indications for the use of therapeutic drug monitoring (TDM) typically include improving or ensuring clinical response to therapy by individualizing dose regimens, preventing or investigating drug-related toxicity, and as an aid to establish patient adherence to prescribed medicines. Initial data indicate that TDM may be useful for several of these indications with telaprevir and boceprevir. Both telaprevir and boceprevir exhibit nonlinear pharmacokinetics, with increasing dose resulting in a less than proportional increase in exposure that is believed to be due to low solubility. High pharmacokinetic variability has been reported with boceprevir, with a range of intersubject variability (percent coefficient of variation) in area under the plasma concentration-time curve (AUC) and trough concentration (Cmin) of 9%–53% and 26%–104%, respectively, reported across trials conducted in healthy volunteers and patients. For telaprevir, food and fat content of coadministered food have a significant influence on drug exposure, with a high-fat meal increasing AUC 4.3-fold compared with fasting, approximately double the exposure that was observed with a low-fat meal. Most importantly, early data on exposure– response (E-R) relationships for efficacy and safety are available for these agents, which are crucial to the utility of TDM. In phase IIb studies, increasing telaprevir Cmin was associated with an increased rate of rapid virological response, a surrogate marker of SVR; in previously treated patients, increasing telaprevir trough concentrations were also associated with a decreased risk of virological breakthrough. In phase III studies, telaprevir AUC was only weakly associated with the primary SVR efficacy end point in treatment-naive patients, although higher rates of SVR were observed at higher telaprevir exposure and telaprevir AUC was a significant predictor of SVR in previously treated patients via logistic regression (P = 0.019). For boceprevir, data from a phase II monotherapy study indicated that boceprevir Cmin is correlated with reductions in HCV-RNA viral load (r = 0.653). In a phase II combination therapy study, a consistent moderate positive correlation between boceprevir Cmin and reduction in viral load was identified; patients with a boceprevir Cmin in the lowest quartile (mean Cmin of 34.9 ng/mL) had a median log10 HCVRNA change from baseline of 21.46, whereas patients with Cmin values in the highest quartile (mean Cmin of 193 ng/mL) had larger reductions in viral load (median log10 HCV-RNA change from baseline of 23.84). However, no significant association between boceprevir exposure (Cmin or AUC) and SVR was identified in a limited pharmacokinetic subset of patients from phase III trials. Although further studies are needed to more accurately define E-R relationships for efficacy for telaprevir and boceprevir, models incorporating pharmacokinetic data with in vitro antiviral potency have identified HCV protease inhibitor Cmin in plasma and the liverto-plasma ratio of these agents as important predictors of decreases in viral load, emphasizing the important connection between adequate drug exposure and antiviral efficacy. With respect to E-R relationships for safety, increases in telaprevir AUC were significantly associated with increased rates of anemia (hemoglobin , 10 g/dL) or hemoglobin toxicity (hemoglobin decrease from baseline. 3.5 g/dL); for boceprevir, a nonsignificant upward trend of increasing anemia incidence was observed with increasing boceprevir AUC. Rash is the most common side effect associated with telaprevir therapy, affecting .50% of patients and leading to discontinuation of therapy in 6%–7% of patients in clinical trials; a correlation was observed between concentrations of the pyrazinoic acid metabolite of telaprevir and the incidence and severity of rash, although low sample size and high variability limited further analysis. An important potential confounding factor for evaluating E-R relationships for telaprevir and boceprevir is the concurrent administration of pegylated interferon and ribavirin with these agents; increasing ribavirin exposure was also associated with anemia in telaprevir and boceprevir studies. Furthermore, a model integrating in vitro antiviral potency, viral kinetics, and human pharmacokinetic data has suggested that resistant HCV variants contribute significantly to treatment failures with HCV protease inhibitors, further complicating the assessment of E-R relationships. Drug interactions causing reduced drug exposure are an additional concern with telaprevir and boceprevir. A number of antiretroviral agents used in HIV treatment have been found to significantly reduce the systemic exposure of telaprevir and boceprevir when used concomitantly (Fig. 1). These interactions are clinically important as HIV/HCV coinfection is relatively common, with HCV prevalence in patients with HIV ranging from 8.9% to 37.2%. These interactions may potentially lead to reduced antiviral efficacy with telaprevir and boceprevir and in some cases also results in reduced antiretroviral drug exposure. Where coadministration of these medicines is necessary, TDM of telaprevir or boceprevir plasma concentration may be useful to monitor the magnitude of effect of these interactions, or where potentially interacting medicines that have not been tested with telaprevir or boceprevir are coadministered, an approach that has been used for other protease inhibitors. In addition, high pill burden and dosing frequency are important concerns with the currently marketed formulations of telaprevir and, particularly, boceprevir, which may contribute to reduced medication adherence. The FDA-approved The authors declare no conflict of interest.

Dolton, Michael J. BPharm; Ray, John E. PhD; McLachlan, Andrew J. PhD Author Information

Fungal peritoneal dialysis (PD)–associated peritonitis is associated with high rates of hospitalization and death (1,2). Standard treatment includes antifungal therapy, removal of the PD catheter, and transfer to hemodialysis (2). In the case of Aspergillus infections, treatment regimens based on amphotericin and flucytosine are complicated by side effects, and so alternative therapies should be explored (1). A 49-year-old man diagnosed with a culture-negative PD-associated peritonitis was treated with intraperitoneal (IP) meropenem and vancomycin for 3 weeks. At the conclusion of treatment, the PD effluent had cleared, and the man embarked on a holiday to Australia. One week after arrival, he presented to hospital with a 2-day history of difficulty with PD exchanges and cloudy effluent, but no abdominal pain or systemic symptoms of infection. Microscopic review of the PD effluent was consistent with PD peritonitis, and empiric IP cephalothin and gentamicin were commenced. Turbidity of the PD fluid was slow to clear, and symptoms of anorexia and lethargy increased. Three days later, Aspergillus flavus was isolated in effluent. Unfortunately, the patient’s travel insurance did not cover treatment of his condition, and the private cost was high. After extensive discussion, he decided to return home for definitive treatment. While awaiting the next flight, treatment included CAPD (2.5-L exchanges, 4 times daily), once-daily IP voriconazole 200 mg (2.5 mg/kg), and careful monitoring. We elected to administer the parenteral formulation IP to maximize the concentration in the peritoneal space. It was highlighted to the patient that, under current standards (2), retaining the PD catheter was suboptimal treatment and that his infection could progress. Further, we were not aware of any published experience with IP administration of voriconazole, and so its use was experimental. The patient was reviewed daily, and a blood sample was obtained before each dose of voriconazole for drug monitoring. Voriconazole administration generated no discomfort, and the PD effluent cleared; however, only a slight symptomatic improvement occurred. The man flew home 72 hours post diagnosis, the PD catheter was removed 72 hours later, and hemodialysis was subsequently commenced and progressed well. Drug monitoring confirmed that voriconazole was absorbed from the peritoneal compartment and also that a therapeutic plasma concentration [>1 mg/L (3)] was achieved by 48 hours after therapy initiation. Before the present report, it was not known whether voriconazole would distribute from the peritoneal space, thereby treating systemic infection or predisposing the patient to adverse effects. Voriconazole has unpredictable pharmacokinetics because of saturable drug metabolism and also drug–drug interactions (although none were present in this patient), and so drug monitoring is recommended. The voriconazole concentration in the effluent was consistently lower than that in the plasma (data not shown), which might reflect protein binding (the protein concentration in the PD effluent was not determined) or slower redistribution from plasma to the peritoneal space, which may limit the efficacy of oral or intravenous therapy. More research is required to determine whether IP voriconazole is effective in the treatment of fungal PD peritonitis. It would also be interesting to confirm our observation that voriconazole may distribute slowly into the peritoneal space from the systemic circulation, because such a finding would further support the requirement for IP administration when the PD catheter is retained.

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.

Voriconazole Pharmacokinetics and Therapeutic Drug Monitoring: A Multi-Center Study 1 2 Michael J Dolton, John E Ray, Sharon C-A Chen, Kingsley Ng, Lisa G Pont, Andrew J 3 McLachlan 4 5 1 Faculty of Pharmacy, University of Sydney, Camperdown, Australia 6 2 Clinical Pharmacology & Toxicology, SydPath, St Vincent’s Hospital, Darlinghurst, 7 Australia 8 3 Centre for Infectious Diseases & Microbiology and the University of Sydney, Westmead 9 Hospital, Westmead, Australia 10 4 Department of Pharmacy, Westmead Hospital, Westmead, Australia 11 5 Centre For Education and Research on Ageing, Concord Repatriation General Hospital, 12 Concord, Australia 13 14 *Corresponding Author: 15 Professor Andrew McLachlan 16 Faculty of Pharmacy 17 University of Sydney NSW 2006 18 Australia 19 Tel: +61 2 9767 7373 20 Fax: +61 2 9351 6950 21 Email: andrew.mclachlan@sydney.edu.au 22 23 Copyright © 2012, American Society for Microbiology. All Rights Reserved. Antimicrob. Agents Chemother. doi:10.1128/AAC.00626-12 AAC Accepts, published online ahead of print on 2 July 2012

Voriconazole is a first-line agent in the treatment of many invasive fungal infections and is known to display highly variable pharmacokinetics. Previous studies of voriconazole therapeutic drug monitoring (TDM) have suggested concentration monitoring to be clinically useful but have been limited by small patient samples at a single institution. This multicenter retrospective study aimed to investigate relationships between voriconazole concentration and clinical outcomes and adverse events and to assess clinical factors and drug interactions that may affect voriconazole concentration. Medical records were reviewed for patients who received voriconazole and had at least 1 concentration measured at seven hospitals in Australia. The study included 201 patients with 783 voriconazole trough concentrations. Voriconazole concentrations of <1.7 mg/liter were associated with a significantly greater incidence of treatment failure (19/74 patients [26%]) than concentrations of ≥1.7 mg/liter (6/89 patients [7%]) (P < 0.01). Neurotoxic adverse events (visual and auditory hallucinations) occurred more frequently at voriconazole concentrations of >5 mg/liter (10/31 patients [32%]) than at concentrations of ≤5 mg/liter (2/170 patients [1.2%]) (P < 0.01). Multiple regression analysis of voriconazole concentration identified associations between increasing patient weight, oral administration of voriconazole, and coadministration of phenytoin or rifampin and significantly reduced concentrations, and associations between increasing patient age and coadministration of proton pump inhibitors and increased concentrations. Coadministration of glucocorticoids was found to significantly reduce voriconazole concentrations, inferring a previously unreported drug interaction between glucocorticoids and voriconazole.

Background: New antiretroviral drug classes provide opportunities to explore novel regimens.Methods: HIV+ adults (<50 copies/mL) receiving atazanavir (ATV) were randomized to raltegravir (RAL) 400 mg + ATV 300 mg twice daily (q12h) for 4 weeks followed by RAL 800 mg + ATV/ritonavir 300/100 mg once daily (q24h) for 4 weeks or vice versa. Validated assays quantitated RAL and ATV plasma concentrations. Primary endpoint was geometric mean ratio (GMR) of ATV minimum concentration (C-min) for q24h/q12h. Equivalence was 90% confidence interval (CI) of GMR lying between 0.80 and 1.25. Participants could consent to a total 48-week follow-up.Results: Twenty-five men, mean age 45 (range, 35-57) years, were evaluated. ATV and RAL demonstrated considerable pharmacokinetic variability. There was no period or sequence effect for pharmacokinetic parameters (P > 0.1 all measures). Ninety percent CIs of ATV GMR C-min [1.30 (90% CI: 1.08 to 1.58)] and RAL GMR C-min [0.48 (90% CI: 0.31 to 0.75)] demonstrated nonequivalence. Seventy-six percent consented to follow-up. There were no serious adverse events and no discontinuations due to adverse events over 48 weeks; HIV RNA remained undetectable.Conclusions: In virologically suppressed adults, regimens comprising ATV plus RAL were efficacious and safe. ATV q12h troughs were lower than ritonavir-boosted atazanavir q24h; RAL q24h troughs were lower than q12h.

ABSTRACT Posaconazole has an important role in the prophylaxis and salvage treatment of invasive fungal infections (IFIs), although poor and variable bioavailability remains an important clinical concern. Therapeutic drug monitoring of posaconazole concentrations has remained contentious, with the use of relatively small patient cohorts in previous studies hindering the assessment of exposure-response relationships. This multicenter retrospective study aimed to investigate relationships between posaconazole concentration and clinical outcomes and adverse events and to assess clinical factors and drug interactions that may affect posaconazole concentrations. Medical records were reviewed for patients who received posaconazole and had ≥1 concentration measured at six hospitals in Australia. Data from 86 patients with 541 posaconazole concentrations were included in the study. Among 72 patients taking posaconazole for prophylaxis against IFIs, 12 patients (17%) developed a breakthrough fungal infection; median posaconazole concentrations were significantly lower than in those who did not develop fungal infection (median [range], 289 [50 to 471] ng/ml versus 485 [0 to 2,035] ng/ml; P < 0.01). The median posaconazole concentration was a significant predictor of breakthrough fungal infection via binary logistic regression ( P < 0.05). A multiple linear regression analysis identified a number of significant drug interactions associated with reduced posaconazole exposure, including coadministration with proton pump inhibitors, metoclopramide, phenytoin or rifampin, and the H 2 antagonist ranitidine ( P < 0.01). Clinical factors such as mucositis, diarrhea, and the early posttransplant period in hematopoietic stem cell transplant recipients were also associated with reduced posaconazole exposure ( P < 0.01). Low posaconazole concentrations are common and are associated with breakthrough fungal infection, supporting the utility of monitoring posaconazole concentrations to ensure optimal systemic exposure.

ABSTRACT Posaconazole has become an important part of the antifungal armamentarium in the prophylaxis and salvage treatment of invasive fungal infections (IFIs). Structurally related to itraconazole, posaconazole displays low oral bioavailability due to poor solubility, with significant drug interactions and gastrointestinal disease also contributing to the generally low posaconazole plasma concentrations observed in patients. While therapeutic drug monitoring (TDM) of plasma concentrations is widely accepted for other triazole antifungal agents such as voriconazole, the utility of TDM for posaconazole is controversial due to debate over the relationship between posaconazole exposure in plasma and clinical response to therapy. This review examines the available evidence for a relationship between plasma concentration and clinical efficacy for posaconazole, as well as evaluating the utility of TDM and providing provisional target concentrations for posaconazole therapy. Increasing evidence supports an exposure-response relationship for plasma posaconazole concentrations for prophylaxis and treatment of IFIs; a clear relationship has not been identified between posaconazole concentration and toxicity. Intracellular and intrapulmonary concentrations have been studied for posaconazole but have not been correlated to clinical outcomes. In view of the high mortality and cost associated with the treatment of IFIs, increasing evidence of an exposure-response relationship for posaconazole efficacy in the prevention and treatment of IFIs, and the common finding of low posaconazole concentrations in patients, TDM for posaconazole is likely to be of significant clinical utility. In patients with subtherapeutic posaconazole concentrations, increased dose frequency, administration with high-fat meals, and withdrawal of interacting medications from therapy are useful strategies to improve systemic absorption.

Metformin is widely used for the treatment of type 2 diabetes mellitus. It is a biguanide developed from galegine, a guanidine derivative found in Galega officinalis (French lilac). Chemically, it is a hydrophilic base which exists at physiological pH as the cationic species (>99.9%). Consequently, its passive diffusion through cell membranes should be very limited. The mean ± SD fractional oral bioavailability (F) of metformin is 55 ± 16%. It is absorbed predominately from the small intestine.

401 EARLY ON-TREATMENT PLASMA RIBAVIRIN CONCENTRATIONS ARE ASSOCIATED WITH ON-TREATMENT ANAEMIA AND TREATMENT OUTCOME IN CHRONIC HEPATITIS C GENOTYPE 1 PATIENTS R.J. Ali, S.K. Roberts, J. Ray, W. Sievert, G. McCaughan, M. Weltman, D. Crawford, W. Cheng, W. Rawlinson, J. Thommes, B. Rizkalla, M. Yoshihara, G.J. Dore, G.V. Matthews, on behalf of the CHARIOT Study Group. National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, St. Vincent’s Hospital, Sydney, NSW, Alfred Hospital, Monash Medical Centre and Monash University, Melbourne, VIC, Royal Prince Alfred Hospital, Nepean Hospital, Sydney, NSW, Greenslopes Hospital, Brisbane, QLD, Royal Perth Hospital, Perth, WA, SEALS Microbiology, Prince of Wales Hospital, Sydney, NSW, Australia; Roche Products, Nutley, NJ, USA; Roche Products, Sydney, NSW, Australia E-mail: rali@nchecr.unsw.edu.au

Background: Posaconazole is an azole antifungal agent with a broad spectrum of activity and a manageable side-effect profile. Although the pharmacokinetics of posaconazole have been described in healthy volunteers who received the drug by means of a nasogastric tube or with nutritional supplements, the pharmacokinetics of posaconazole have not been reported in critically ill patients. Methods: Twenty-seven patients in the general intensive care unit managed according to standard protocols were randomly allocated to dose regimens of either 400 mg twice daily or 200 mg 4 times daily. Plasma samples were collected for pharmacokinetic analysis after the first dose and at steady-state. Posaconazole plasma concentrations were compared with suggested effect targets for prophylaxis and treatment. Results: Mean Cmin steady-state plasma concentrations of posaconazole were low for both regimens (306 and 137 ng/mL for 400 mg twice daily and 200 mg 4 times daily regimens, respectively), as was total exposure to posaconazole in each group [area under the concentration-time curve (AUC0-t) for first dose: 761 and 299 μg·h/L]. Only 17% of patients achieved steady-state Cmin posaconazole plasma concentrations above the suggested target for prophylaxis, and only one patient had a Cmin posaconazole concentration that exceeded the suggested target for treatment effect. Systemic exposure to posaconazole seemed to be subtherapeutic in most patients in this cohort. Poor absorption of posaconazole due to drug interactions may explain the low systemic exposure; however, further investigation is necessary. Conclusions: These data suggest that there is a need for an intraveneous formulation of the drug if it is to be used effectively in critically ill patients, and therapeutic drug monitoring is an essential tool in this setting to identify patients with low systemic exposure to prevent therapeutic failure.

Monitoring of serum voriconazole concentrations has been proposed to optimize therapeutic effect and minimize toxicity. However, little is known about the clinical use of voriconazole therapeutic drug monitoring (TDM) by treating physicians. Four hundred seventy-eight episodes corresponding with 161 adult patients (mean three TDM episodes per patient; range 1-31, at a mean interval 43.6 days [range 1-266] between repetitions) performed at a state reference laboratory in Australia during a 30-month period were reviewed. Information about voriconazole dose was provided on only nine (1.9%) request forms. Timing of voriconazole TDM in relation to the previous dose was stated in 189 (39%) episodes and corresponded with peak measurements in 16; interval measurements (taken on average 3.3 [range 3-10.5] hours from the preceding dose) in 15; and trough measurements in 158 episodes. Of the 158 trough concentration measurements, only 66 (42%) were between 1 and 5.5 mg/L, the suggested therapeutic range. Similarly, only 33% (98 of 298) of all the random TDM episodes achieved voriconazole concentrations greater than 2.05 mg/L, previously associated with favorable outcomes. Compared with trough TDM, random episodes were significantly more likely to result in undetectable (less than 0.1 mg/L) concentrations (45 of 298 [15.1%] versus 12 of 158 [7.6%]; P = 0.021, odds ratio 2.16, 95% confidence interval: 1.11-4.22). Among patients with multiple TDM episodes, there was no correlation between the initial and final trough or between the initial and final random concentrations. Only 44% (eight of 18) of patients with multiple trough TDM had final concentration within 1 to 5.5 mg/L; and only 26% (15 of 58) of patients with multiple random TDM had final concentration greater than 2.05 mg/L. Adoption of consistent and clear guidelines on voriconazole TDM use and education of physicians ordering the test is required because the majority of testing performed was inappropriate and prone to suboptimal interpretation.

The measurement of drug concentrations, for clinical purposes, occurs in many diagnostic laboratories throughout Australia and New Zealand. However, the provision of a comprehensive therapeutic drug monitoring (TDM) service requires the additional elements of pre- and postanalytical advice to ensure that concentrations reported are meaningful, interpretable, and clinically applicable to the individual patient. The aim of this project was to assess the status of TDM services in Australia and New Zealand. A range of professions involved in key aspects of TDM was surveyed by questionnaire in late 2007. Information gathered included: the list of drugs assayed; analytical methods used; interpretation services offered; interpretative methods used; and further monitoring advice provided. Fifty-seven responses were received, of which 42% were from hospitals (public and/or private); 11% a hospital (public and/or private) and pathology provider; and 47% a pathology provider only (public and/or private). Results showed that TDM is applied to a large number of different drugs. Poorly performing assay methods were used in some cases, even when published guidelines recommended alternative practices. Although there was a wide array of assays available, the evidence suggested a need for better selection of assay methods. In addition, only limited advice and/or interpretation of results was offered. Of concern, less than 50% of those providing advice on aminoglycoside dosing in adults used pharmacokinetic tools with six of 37 (16.2%) respondents using Bayesian pharmacokinetic tools, the method recommended in the Australian Therapeutic Guidelines: Antibiotic. In conclusion, the survey highlighted deficiencies in the provision of TDM services, in particular assay method selection and both quality and quantity of postanalytical advice. A range of recommendations, some of which may have international implications, are discussed. There is a need to include measures of impact on clinical decision-making when assessing assay methodologies. Best practice guidelines and professional standards of practice in TDM are needed, supported by an active program of professional development to ensure the benefits of TDM are realized. This will require significant partnerships between the various professions involved.

To assess tobacco, alcohol, cannabis and benzodiazepine use in methadone maintenance treatment (MMT) as potential sources of variability in methadone pharmacokinetics.Trough plasma (R)- and (S)-methadone concentrations were measured on 77 Australian and 74 Swiss MMT patients with no additional medications other than benzodiazepines. Simple and multiple regression analyses were performed for the primary metric, plasma methadone concentration/dose.Cannabis and methadone dose were significantly associated with lower 24-h plasma (R)- and (S)-methadone concentrations/dose. The models containing these variables explained 14-16% and 17-25% of the variation in (R)- and (S)-methadone concentration/dose, respectively. Analysis of 61 patients using only CYP3A4 metabolised benzodiazepines showed this class to be associated with higher (R)-concentration/dose, which is consistent with a potential competitive inhibition of CYP3A4.Cannabis use and higher methadone doses in MMT could in part be a response to-or a cause of-more rapid methadone clearance. The effects of cannabis and benzodiazepines should be controlled for in future studies on methadone pharmacokinetics in MMT.

Therapeutic drug concentrations are measured in many diagnostic laboratories;however, providing a comprehensive therapeutic drug monitoring (TDM) service requires the additional elements of pre- and post-analytical advice to ensure that concentrations reported are meaningful and clinically interpretable. The aim of this project was to assess the status of such TDM services in Australasia. Laboratories were surveyed by questionnaire in late 2007. The results included responses from 57 laboratories of which 42% were from hospital laboratories, 11% hospital pathology providers, 47% as pathology providers. Questions included tests offered, methods adopted, interpretation and further monitoring advice provided. Whilst there was wide array of tests available and support for analytical aspects, there was only limited advice/interpretation of results offered. For example, <50% provided advice on aminoglycoside dosing using pharmacokinetic tools available (tobramycin 42%;gentamicin 28%;vancomycin 24%). In conclusion, the survey reinforces that provision of quality TDM services requires more than issuing just drug concentrations and suggested the need to define appropriate professional practice standards that could potentially be accredited. Therapeutic drug concentrations are measured in many diagnostic laboratories;however, providing a comprehensive therapeutic drug monitoring (TDM) service requires the additional elements of pre- and post-analytical advice to ensure that concentrations reported are meaningful and clinically interpretable. The aim of this project was to assess the status of such TDM services in Australasia. Laboratories were surveyed by questionnaire in late 2007. The results included responses from 57 laboratories of which 42% were from hospital laboratories, 11% hospital pathology providers, 47% as pathology providers. Questions included tests offered, methods adopted, interpretation and further monitoring advice provided. Whilst there was wide array of tests available and support for analytical aspects, there was only limited advice/interpretation of results offered. For example, <50% provided advice on aminoglycoside dosing using pharmacokinetic tools available (tobramycin 42%;gentamicin 28%;vancomycin 24%). In conclusion, the survey reinforces that provision of quality TDM services requires more than issuing just drug concentrations and suggested the need to define appropriate professional practice standards that could potentially be accredited.