A cross-sectional study of hydroxychloroquine concentrations and effects in people with systemic lupus erythematosus.

BACKGROUND/AIMS: To investigate the pharmacokinetics of hydroxychloroquine (HCQ) and relationships of HCQ concentration with disease activity variables (concentration-effect relationships) in patients with systemic lupus erythematosus (SLE). METHODS: HCQ concentration and disease activity were measured at a single time point in 60 patients with SLE receiving HCQ for at least 6 months. Some retrospective objective data on disease activity prior to HCQ commencement were available. Correlations were sought between HCQ blood concentrations and disease variables (Systemic Lupus Activity Measure (SLAM) scores, joint scores, morning stiffness, pain, well-being, general improvement, other medication use (including corticosteroids), and physician and patient assessments). Blood HCQ concentrations were also dichotomised into 'more' and 'less/no' disease activity, and mean blood concentrations in the two groups for each disease activity measure were compared. RESULTS: The pharmacokinetics (dose-concentration relationships) of HCQ were highly variable in people with SLE. Apparent total clearance of HCQ from blood was 316 (± 319) mL/min (mean (± standard deviation). There was no correlation between SLAM score, patient global assessment or physician global assessment, and blood HCQ concentrations (r(2) = 0.2, 0.04 and 0.13, respectively; P > 0.05). However, during HCQ therapy, 64% (14 of 22 patients) had a reduction in prednisolone dose of 50% or more compared with pre-HCQ therapy. CONCLUSIONS: No significant concentration-effect relationship for HCQ in the treatment of SLE was observed perhaps because consistently high enough blood HCQ concentrations were not achieved. Pharmacokinetic variability led to a wide range of blood HCQ concentrations. A concentration-targeting study for HCQ in SLE would be timely.

Validity of self-reported osteoporosis in mid-age and older women.

UNLABELLED: The validity of self-reported osteoporosis is often questioned, but validation studies are lacking. We validated self-reported prevalence and incidence of osteoporosis against self-reported and administrative data on medications. The concurrent validity was moderate to good for self-reported prevalent osteoporosis, but only poor to moderate for self-reported incident osteoporosis in mid-age and older women, respectively. Construct validity was acceptable for self-reported prevalent but not for incident osteoporosis. INTRODUCTION: The validity of self-reported osteoporosis is often questioned, but validation studies are lacking. The aim was to examine the validity of self-reported prevalence and incidence of osteoporosis against self-reported and administrative data on medications. METHODS: Data were from mid-age (56-61 years in 2007) and older (79-84 years in 2005) participants in the Australian Longitudinal Study on Women's Health. Self-reported diagnosis was compared with medication information from (1) self-report (n(mid) = 10,509 and n(old) = 7,072), and (2) pharmaceutical prescription reimbursement claims (n(mid) = 6,632 and n(old) = 4,668). Concurrent validity of self-report was examined by calculating agreement, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). Construct validity was tested by examining associations of self-reported diagnosis with osteoporosis-related characteristics (fracture, weight, bodily pain, back pain, and physical functioning). RESULTS: Agreement, sensitivity and PPV of self-reported prevalent diagnosis were higher when compared with medication claims (mid-age women: kappa = 0.51, 95% confidence interval [CI] = 0.46-0.56; older women: kappa = 0.65, 95% CI = 0.63-0.68) than with self-reported medication (mid-age women: kappa = 0.41, 95% CI = 0.37-0.45; older women: kappa = 0.57, 95% CI = 0.55-0.59). Sensitivity, PPV and agreement were lower for self-reported incident diagnosis (mid-age women: kappa = 0.39, 95% CI = 0.32-0.47; older women: kappa = 0.55, 95% CI = 0.51-0.61). Statistically significant associations between self-reported diagnosis and at least four of five characteristics were found for prevalent diagnosis in both age groups and for incident diagnosis in older women. CONCLUSIONS: The concurrent validity was moderate to good for self-reported prevalent osteoporosis, but only poor to moderate for self-reported incident osteoporosis in mid-age and older women, respectively. Construct validity was acceptable for self-reported prevalent but not for incident osteoporosis.

Towards concordance in healthcare: perspectives of general practitioners, complementary and alternative medicine practitioners and pharmacists in Australia.

Partnerships and concordance are desirable concepts for optimal healthcare. The concept of concordance is based on negotiation between equals in a therapeutic relationship, forming a therapeutic alliance between all partners. One field of healthcare in which concordant relationships may be particularly desirable is complementary and alternative medicine (CAM). CAM is increasingly used by consumers worldwide, and provider-patient relationships are important across the spectrum of CAM-to-conventional medicine; thus, it was considered useful to research CAM and concordance in parallel. The objective of this problem-detection study (PDS) was to investigate practitioners' (general practitioners', pharmacists' and CAM practitioners') views on their relationships and reaching concordant partnerships with consumers in the areas of both conventional medicine and CAM. Focus groups and semi-structured interviews guided the development of the PDS instrument. The questionnaire consisted of 36 items corresponding to seven thematic units deduced from the preliminary data. The differences in perceptions between the surveyed groups indicated that achieving concordance relies on mutual respect and communication and understanding of roles, responsibilities and limitations, and differences in opinion may be compromising the formation of partnerships. Potentially problematic issues identified by this research could be addressed by educational interventions and enhancement of communication between all parties involved, as information loses value when not shared, and may be prone to contradiction and confusion. Further research is warranted in order to facilitate positive changes in the health system.

Pharmaceutical company influences on medication prescribing and their potential impact on quality use of medicines.

BACKGROUND: Pharmaceuticals are big business, reporting strong market growth year after year. The 'gatekeepers' of this market are prescribers of medicines, who are the major target of pharmaceutical companies, utilizing direct and indirect influences. METHODS: This paper draws on previous research investigating pharmaceutical company prescribing influences to develop a qualitative model demonstrating the synergism between commercial influences on prescribing. The generic model was used to explore a realistic but hypothetical scenario to ascertain the applicability of the model. RESULTS AND DISCUSSION: A generic influence model was developed. The model was readily able to be adapted to reflect a realistic practice scenario. CONCLUSION: Prescriber awareness of the linkages between various seemingly separate marketing techniques could potentially improve medicines usage in an evidence-based practice paradigm.

Why is the use of clopidogrel increasing rapidly in Australia? An exploration of geographical location, age, sex and cardiac stenting rates as possible influences on clopidogrel use.

PURPOSE: To explore clopidogrel use within Australia, investigating geography, age, sex and cardiac stenting rates. METHODS: Data for clopidogrel supply (Pharmaceutical Benefits Scheme (PBS) and Repatriation Pharmaceutical Benefits Scheme (RPBS)) and cardiac stenting procedures (State Health Departments) were obtained for four different geographic regions (very remote/remote and major city in two Australian states). General linear modelling and correlation analyses were used to test for associations and chi2 analyses for proportions. RESULTS: Clopidogrel supply increased rapidly in Australia since introduction, from 1.2 to 9.0 Defined Daily Doses (DDD)/1000 population/day. Among concessional and veteran populations use was much higher. Analysis of geographical area data confirmed an association between clopidogrel supply rates and cardiac stenting rates (r = 0.8-0.9 Spearman's rho, p < 0.01). Sex, age and geographical location were associated with both rates when considered together and when considered independently. Further modelling indicated that between 30 and 73% of clopidogrel supply could be accounted for by people receiving cardiac stents. CONCLUSIONS: The supply of clopidogrel increases with age, male sex and living in a major city. These same demographic variables were important for cardiac stenting, an indication which is currently not approved for subsidy by the Australian government, but which modelling indicated could account for between one-third and three quarters of clopidogrel use. A review may be required to ensure subsidised indications reflect current evidence and cost-effective use.

Clinical pharmacology: opportunities for educating new practitioners--an Australian perspective.

There has been a transformation in the role of clinical pharmacologists in Australasia. The traditional approach was for medically qualified, college-accredited (postgraduate education), hospital-based clinical pharmacologists to confine themselves mainly to a local focus. Today many more opportunities exist for expanding the roles of health professionals who have the clinical pharmacology training. These professionals can influence national and international policy, practice, and education in their field. However, the new roles do require extra initiatives in providing educational input in clinical pharmacology to take care of future needs. Some of the potential gaps in the process are identified in this article.

Relationships of tacrolimus pharmacokinetic measures and adverse outcomes in stable adult liver transplant recipients.

BACKGROUND AND OBJECTIVES: Alternative measures to trough concentrations [non-trough concentrations and limited area under the concentration-time curve (AUC)] have been shown to better predict tacrolimus AUC. The aim of this study was to determine if these are also better predictors of adverse outcomes in long term liver transplant recipients. METHODS: The associations between tacrolimus trough concentrations (C(0)), non-trough concentrations (C(1), C(2), C(4), C(6/8)), and AUC(0-12) and the occurrence of hypertension, hyperkalaemia, hyperglycaemia and nephrotoxicity were assessed in 34 clinically stable liver transplant patients. RESULTS AND DISCUSSION: The most common adverse outcome was hypertension, prevalence of 36%. Hyperkalaemia and hyperglycaemia had a prevalence of 21% and 13%, respectively. A sequential population pharmacokinetic/pharmacodynamic approach was implemented. No significant association between predicted C(0), C(1), C(2), C(4), C(6/8) or AUC(0-12) and adverse effects could be found. Tacrolimus concentrations and AUC measures were in the same range in patients with and without adverse effects. CONCLUSIONS: Measures reported to provide benefit, preventing graft rejection and minimizing acute adverse effects in the early post-transplant period, were not able to predict adverse effects in stable adult liver recipients whose trough concentrations were maintained in the notional target range.

Relationships between sirolimus dosing, concentration and outcomes in renal transplant recipients.

AIM: To explore relationships between sirolimus dosing, concentration and clinical outcomes. METHODS: Data were collected from 25 kidney transplant recipients (14 M/11 F), median 278 days after transplantation. Outcomes of interest were white blood cell (WBC) count, platelet (PLT) count, and haematocrit (HCT). A naive pooled data analysis was performed with outcomes dichotomized (Mann-Whitney U-tests). RESULTS: Several patients experienced at least one episode when WBC (n = 9), PLT (n = 12), or HCT (n = 21) fell below the lower limits of the normal range. WBC and HCT were significantly lower (P < 0.05) when sirolimus dose was greater than 10 mg day(-1), and sirolimus concentration greater than 12 microg l(-1). No relationship was shown for PLT and dichotomized sirolimus dose or concentration. CONCLUSIONS: Given this relationship between sirolimus concentration and effect, linked population pharmacokinetic-pharmacodynamic modelling using data from more renal transplant recipients should now be used to quantify the time course of these relationships to optimize dosing and minimize risk of these adverse outcomes.

Motivations and perceived influences on rural and urban general practitioners when prescribing conventional non-steroidal anti-inflammatory drugs or COX-2 inhibitors.

BACKGROUND AND OBJECTIVE: Prescribers in rural and remote locations perceive that there are different influences on their prescribing compared with those experienced by urban prescribers. The aim of this study was to compare the motivations and perceived influences on general practitioners (GPs) when prescribing COX-2 inhibitors rather than conventional non-steroidal anti-inflammatory drugs (NSAIDs) between rural and urban-based GPs in Queensland, Australia. METHODS: A questionnaire was administered to two geographically distinct groups of GPs, one urban (n=67) and one rural (n=67), investigating the reasons that the GP would prescribe a COX-2 inhibitor rather than a conventional NSAID or vice versa and also focusing on patients requesting a prescription for a COX-2 inhibitor. RESULTS AND DISCUSSION: A 51% response rate (n=68) was achieved. The difference between the rural and the urban GPs was that the urban GPs were more likely to perceive that they were influenced to prescribe COX-2 inhibitors by their patients' knowledge of these new (at the time) drugs. GPs in both the rural and urban areas perceived the COX-2 selective inhibitors to be safer than conventional NSAIDs, and that there was little difference in terms of efficacy between the two drug classes. However, GPs from both of the study areas stated that conventional NSAIDs were preferred over COX-2 selective inhibitors, primarily due to their expense, if their patients were not at risk for developing a GI bleed. CONCLUSION: The motivations and perceived influences to prescribe a COX-2 inhibitor in rural and in urban areas of Queensland, Australia were very similar. Almost all surveyed GPs in rural and urban areas had patients request a prescription, or enquire about the COX-2 inhibitors. Urban GPs were more likely to feel pressured to prescribe a COX-2 inhibitor than their rural counterparts, agreeing with other research which found that patient pressure to prescribe appears to be greater in urban general practice.

Impact of mycophenolate mofetil loading on drug exposure in the early posttransplant period.

UNLABELLED: Achieving adequate therapeutic levels of immunosuppressive medications is important in rejection prevention. This study examined exposure to mycophenolic acid (MPA) in kidney transplant patients within the first 5 days posttransplantation. METHODS: This single-center, nonrandomized study of first solitary kidney allograft recipients receiving cyclosporine (n = 116) or tacrolimus (n = 50) included patients who received either 1 g or 1.5 g of mycophenolate mofetil twice daily starting postoperatively. Exposure to MPA was measured at days 3 and 5 posttransplant using published limited sampling time equations. RESULTS: There were no significant differences in exposure in the cyclosporine-treated patients receiving 3-g (n = 22) compared to 2-g (n = 94) daily doses (AUC([0-12]) 33.8 +/- 10.0 mg*h/L versus 30.1 +/- 9.7 mg*h/L, P = .20, respectively). About half the patients in both groups had AUC([0-12]) <30 mg*h/L on days 3 and 5 posttransplant. On the other hand, there was significantly greater exposure on day 3 in the tacrolimus-treated patients receiving 3 g (n = 21) compared to 2 g (n = 29) daily (AUC([0-12]) 43.1 +/- 9.0 mg*h/L versus 36.8 +/- 11.1 mg*h/L, P = .016, respectively). On day 3 one (4.8%) patient receiving 3 g had an AUC([0-12]) of <30 mg*h/L; whereas, eight (27.5%) receiving 2 g were below this level (P = .068). The AUC([0-12]) levels were not different on day 5. CONCLUSIONS: Loading with higher doses of mycophenolate mofetil results in greater exposure and a trend toward more patients in the therapeutic window within the first week for tacrolimus- but not for cyclosporine-treated patients.

Population pharmacokinetic analysis of mycophenolic acid in renal transplant recipients following oral administration of mycophenolate mofetil.

AIM: To develop a population pharmacokinetic model for mycophenolic acid in adult kidney transplant recipients, quantifying average population pharmacokinetic parameter values, and between- and within-subject variability and to evaluate the influence of covariates on the pharmacokinetic variability. METHODS: Pharmacokinetic data for mycophenolic acid and covariate information were previously available from 22 patients who underwent kidney transplantation at the Princess Alexandra Hospital. All patients received mycophenolate mofetil 1 g orally twice daily. A total of 557 concentration-time points were available. Data were analysed using the first-order method in NONMEM (version 5 level 1.1) using the G77 FORTRAN compiler. RESULTS: The best base model was a two-compartment model with a lag time (apparent oral clearance was 27 l h(-1), and apparent volume of the central compartment 98 l). There was visual evidence of complex absorption and time-dependent clearance processes, but they could not be successfully modelled in this study. Weight was investigated as a covariate, but no significant relationship was determined. CONCLUSIONS: The complexity in determining the pharmacokinetics of mycophenolic acid is currently underestimated. More complex pharmacokinetic models, though not supported by the limited data collected for this study, may prove useful in the future. The large between-subject and between-occasion variability and the possibility of nonlinear processes associated with the pharmacokinetics of mycophenolic acid raise questions about the value of the use of therapeutic monitoring and limited sampling strategies.

Prescription drug samples--does this marketing strategy counteract policies for quality use of medicines?

Prescription drug samples, as used by the pharmaceutical industry to market their products, are of current interest because of their influence on prescribing, and their potential impact on consumer safety. Very little research has been conducted into the use and misuse of prescription drug samples, and the influence of samples on health policies designed to improve the rational use of medicines. This is a topical issue in the prescription drug debate, with increasing costs and increasing concerns about optimizing use of medicines. This manuscript critically evaluates the research that has been conducted to date about prescription drug samples, discusses the issues raised in the context of traditional marketing theory, and suggests possible alternatives for the future.

Using a problem detection study (PDS) to identify and compare health care provider and consumer views of antihypertensive therapy.

The objectives of this study were to ascertain consumer knowledge and behaviour about hypertension and treatment and to compare these with health care providers' perceptions (of 'most' consumers). The design for the study was a problem detection study (PDS): focus groups and then survey. Focus groups and survey participants were convenience samples of consumers, doctors, nurses and pharmacists. The main outcome measures were agreement on a 5-point Likert scale with statements about consumers' knowledge and behaviour about high blood pressure and medication. The survey identified areas of consensus and disagreement between consumers and health providers. While general knowledge and concordance with antihypertensive therapy among consumers was good, consequences such as eye and kidney disease, interactions with herbal medicines, and how to deal with missing a dose were less well known. Side effects were a problem for over one-quarter of participants, and cost was a problem in continuing therapy. Half the consumers had not received sufficient written information. Providers overall disagreed that most consumers have an adequate understanding of the condition. They agreed that most consumers adhere to therapy and can manage medicines; and about their own profession's role in information provision and condition management. Consumers confirmed positive provider behaviour, suggesting opportunities for greater communication between providers about actions taken with their consumers. In conclusion, the PDS methodology was useful in identifying consumer opinions. Differences between consumer and provider responses were marked, with consumers generally rating their knowledge and behaviour above providers' ratings of 'most' consumers. There are clear gaps to be targeted to improve the outcomes of hypertension therapy.

Evaluating Australia's National Medicines Policy using geographical mapping.

BACKGROUND: There has been a proliferation of quality use of medicines activities in Australia since the 1990s. However, knowledge of the nature and extent of these activities was lacking. A mechanism was required to map the activities to enable their coordination. AIMS: To develop a geographical mapping facility as an evaluative tool to assist the planning and implementation of Australia's policy on the quality use of medicines. METHODS: A web-based database incorporating geographical mapping software was developed. Quality use of medicines projects implemented across the country was identified from project listings funded by the Quality Use of Medicines Evaluation Program, the National Health and Medical Research Council, Mental Health Strategy, Rural Health Support, Education and Training Program, the Healthy Seniors Initiative, the General Practice Evaluation Program and the Drug Utilisation Evaluation Network. In addition, projects were identified through direct mail to persons working in the field. RESULTS: The Quality Use of Medicines Mapping Project (QUMMP) was developed, providing a Web-based database that can be continuously updated. This database showed the distribution of quality use of medicines activities by: (i) geographical region, (ii) project type, (iii) target group, (iv) stakeholder involvement, (v) funding body and (vi) evaluation method. At September 2001, the database included 901 projects. Sixty-two per cent of projects had been conducted in Australian capital cities, where approximately 63% of the population reside. Distribution of projects varied between States. In Western Australia and Queensland, 36 and 73 projects had been conducted, respectively, representing approximately two projects per 100,000 people. By comparison, in South Australia and Tasmania approximately seven projects per 100,000 people were recorded, with six per 100,000 people in Victoria and three per 100,000 people in New South Wales. Rural and remote areas of the country had more limited project activity. CONCLUSIONS: The mapping of projects by geographical location enabled easy identification of high and low activity areas. Analysis of the types of projects undertaken in each region enabled identification of target groups that had not been involved or services that had not yet been developed. This served as a powerful tool for policy planning and implementation and will be used to support the continued implementation of Australia's policy on the quality use of medicines.

Opioid analgesic prescribing and use - an audit of analgesic prescribing by general practitioners and The Multidisciplinary Pain Centre at Royal Brisbane Hospital.

AIMS: This study evaluated the use of and need for opioids in patients attending the Multidisciplinary Pain Centre at the Royal Brisbane Hospital (RBH). METHODS: All consecutive in-patient admissions in 1998 were reviewed. A 10-point scoring system based on the World Health Organization (WHO) analgesic ladder was devised to facilitate comparison of analgesic prescribing on admission and at the time of discharge. A conversion table was used to standardize opioid analgesic doses to an oral morphine equivalent. RESULTS: Of the 370 patients reviewed, 233 (81%) were by their general practitioners. Records of 288 (78%) were available for full review and 270 (94%) of these had noncancer pain. On admission, 239 (83%) were taking an opioid analgesic, with 135 (47%) taking strong opioids (e.g. morphine, oxycodone, methadone). There was a significant decrease in the mean total daily oral morphine equivalent prescribed on discharge 36.9 mg (95% CI: 33.4, 40.4) compared with that on admission 88.7 mg (95% CI: 77.6, 99.8) (P < 0.001). There was a significant decrease (P < 0.05) in the proportion of patients taking a primary opioid on discharge 153 (58%) compared with admission 239 (83%), although the proportion of patients taking a strong opioid on discharge 150 (52%) compared with admission 135 (47%) was not significantly different (P > 0.05). The proportion of patients taking a laxative showed a significant increase on discharge 110 (73%) compared with admission 38 (28%) (P < 0.05). CONCLUSIONS: Our analgesic prescribing scoring system and opioid conversion table have the potential to be developed further as tools for assessing opioid analgesic prescribing. The significant decrease in total daily oral morphine equivalents signifies the value of prescribing in accordance with the WHO analgesic ladder, and the necessity of general practitioner education. The management of chronic pain is complex, and it requires interventions additional to pharmacological therapy. Evaluation by a multidisciplinary team, coupled with experience in and an understanding of analgesic prescribing and rehabilitation provides an effective basis for improving the management of patients with chronic pain.

Population pharmacokinetics of tacrolimus in children who receive cut-down or full liver transplants.

BACKGROUND: The aim of this study was to investigate the population pharmacokinetics of tacrolimus in pediatric liver transplant recipients and to identify factors that may explain pharmacokinetic variability. METHODS: Data were collected retrospectively from 35 children who received oral immunosuppressant therapy with tacrolimus. Maximum likelihood estimates were sought for the typical values of apparent clearance (CL/F) and apparent volume of distribution (V/F) with the program NONMEM. Factors screened for influence on the pharmacokinetic parameters were weight, age, gender, postoperative day, days since commencing tacrolimus therapy, transplant type (whole child liver or cut-down adult liver), liver function tests (bilirubin, alkaline phosphatase [ALP], aspartate aminotransferase [AST], gamma-glutamyl transferase [GGT], alanine aminotransferase [ALT]), creatinine clearance, hematocrit, corticosteroid dose, and concurrent therapy with metabolic inducers and inhibitors of tacrolimus. RESULTS: No clear correlation existed between tacrolimus dosage and blood concentrations (r2=0.003). Transplant type, age, and liver function test values were the most important factors (P<0.01) that influenced the pharmacokinetics of tacrolimus. CL/F estimates were greater in whole liver recipients, decreased with increasing patient age and AST values, and increased with increasing GGT values. Average parameter estimates were CL/F=5.75 L/h (cut-down liver), CL/F=44 L/h (whole liver), and V/F=617 L. Marked intersubject variability (CV%=110% to 297%) and residual variability (CV%=42%) was observed. CONCLUSIONS: Pharmacokinetic information obtained in this study may assist physicians in making individualized dosage decisions in regard to tacrolimus in pediatric liver transplant recipients. Children who received a whole child's liver appeared to retain "pediatric" clearance, whereas those who received a cut-down adult liver had "adult" clearances (on average 7-fold less).

Low tacrolimus concentrations and increased risk of early acute rejection in adult renal transplantation.

BACKGROUND: A retrospective analysis was performed on adult renal transplant recipients to evaluate the relationship between tacrolimus trough concentrations and the development of rejection in the first month after transplant. METHODS: A total of 349 concentrations from 29 patients, measured by enzyme-linked immunosorbent assay (ELISA), were recorded. Based on an increased serum creatinine, 12 patients were considered to have organ rejection. Rejection was confirmed by biopsy in five of these. The median trough concentration of tacrolimus over the first month of therapy, or until the time of first rejection was compared in rejecters vs non-rejecters. RESULTS: Median trough concentrations of tacrolimus were found to be lower in biopsy-proven rejecters vs non-rejecters (P=0.03) and all rejecters vs non-rejecters (P=0.04). The average median concentration (+/-SD) in the biopsy-proven rejecter group was 5.09+/-1.16 ng/ml, compared to 9.20+/-3.52 ng/ml in the non-rejecter group. After exclusion of an outlier, the average median concentration in all rejecters was 5.57+/-1.47 ng/ml, compared with 9.20+/-3.52 ng/ml in non-rejecters. A rejection rate of 55% was found for patients with a median trough concentration between 0 and 10 ng/ml. This compared with no observed rejection in patients with a median concentration between 10 and 15 ng/ml. CONCLUSION: A significant relationship exists between organ rejection and median tacrolimus trough concentrations in the first month post-transplant, with patients displaying low concentrations more likely to reject. In order to minimize rejection in the first month after renal transplantation, trough concentrations greater than 10 ng/ml must be achieved.

Simultaneous administration of a cocktail of markers to measure renal drug elimination pathways: absence of a pharmacokinetic interaction between fluconazole and sinistrin, p-aminohippuric acid and pindolol.

AIMS: Previous studies suggest that estimated creatinine clearance, the conventional measure of renal function, does not adequately reflect changes in renal drug handling in some patients, including the immunosuppressed. The aim of this study was to develop and validate a cocktail of markers, to be given in a single administration, capable of detecting alterations in the renal elimination pathways of glomerular filtration, tubular secretion and tubular reabsorption. METHODS: Healthy male subjects (n = 12) received intravenously infused 2500 mg sinistrin (glomerular filtration) and 440 mg p-aminohippuric acid (PAH; anion secretion), and orally administered 100 mg fluconazole (reabsorption) and 15 mg rac-pindolol (cation secretion). The potential interaction between these markers was investigated in a pharmacokinetic study where markers (M) or fluconazole (F) were administered alone or together (M + F). Validated analytical methods were used to measure plasma and urine concentrations in order to quantify the renal handling of each marker. Plasma protein binding of fluconazole was measured by ultrafiltration. All subjects had an estimated creatinine clearance within the normal range. The renal clearance of each marker (mean+/- s.d.) was calculated as the ratio of the amount excreted in urine and the area-under-the-concentration-time curve. Statistical comparisons were made using a paired t-test and 95% confidence intervals were reported. RESULTS: The renal clearances of sinistrin (M: 119 +/- 31 ml min(-1); M + F: 130 +/- 40 ml min(-1); P = 0.32), PAH (M: 469 +/- 145 ml min(-1); M + F: 467 +/- 146 ml min(-1); P = 0.95), R-pindolol (M: 204 +/- 41 ml min(-1); M + F: 190 +/- 41 ml min(-1); P = 0.39; n = 11), S-pindolol (M: 225 +/- 55 ml min(-1); M + F: 209 +/- 60 ml min(-1); P = 0.27; n = 11) and fluconazole (F: 14.9 +/- 3.8 ml min(-1); M + F: 13.6 +/- 3.4 ml min(-1); P = 0.16) were similar when the markers or fluconazole were administered alone (M or F) or as a cocktail (M + F). CONCLUSIONS: This study found no interaction between markers and fluconazole in healthy male subjects, suggesting that a single administration of this cocktail of markers of different renal processes can be used to simultaneously investigate pathways of renal drug elimination.

A retrospective analysis of mycophenolic acid and cyclosporin concentrations with acute rejection in renal transplant recipients.

OBJECTIVES: Although monitoring of cyclosporin (CsA) is standard clinical practice postrenal transplantation, mycophenolic acid (MPA) concentrations are not routinely measured. There is evidence that a relationship exists between MPA area under the concentration-time curve (AUC) and rejection. In this study, a retrospective analysis was undertaken of 27 adult renal transplant recipients. METHODS: Patients received CsA and MPA therapy and had a four-point MPA AUC investigation. The relationship between MPA AUC performed in the first week after transplantation, as well as median trough cyclosporin concentrations, and clinical outcomes in the first month posttransplant were evaluated. RESULTS: A total of 12 patients experienced biopsy proven rejection (44.4%) and 4 patients had gastrointestinal adverse events (14.8%). A statistically significant relationship was observed between the incidence of biopsy proven rejection and both MPA AUC (p = 0.02) and median trough CsA concentration (p = 0.008). No relationship between trough MPA concentration and rejection was observed (p = 0.21). Only 3 of 11 (27%) patients with an MPA AUC > 30 mg x h/L and a median trough CsA > 175 microg/L experienced acute rejection, compared with a 56% incidence of rejection for the remaining 16 patients. Patients who experienced adverse gastrointestinal events had significantly lower MPA AUC (p = 0.04), but median trough CsA concentrations were not significantly different (p = 0.24). Further, 3 of these 4 patients had rejection episodes. CONCLUSIONS: In addition to standard CsA monitoring, we propose further investigation of the use of a 4-point sampling strategy to predict MPA AUC in the first week posttransplant, which may facilitate optimization of mycophenolate mofetil dose at a time when patients are most vulnerable to acute rejection.