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.

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.

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.

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.

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.

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 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).

Clinical pharmacokinetics of slow-acting antirheumatic drugs.

The pharmacokinetics of the slow acting antirheumatic drugs (SAARDs), hydroxychloroquine, chloroquine, penicillamine, the gold complexes and sulphasalazine, in humans have been studied. For all these drugs, both in controlled clinical trials and in empirical observations from rheumatological practice, delays of several months are reported before full clinical effects are achieved. Variability in response is also characteristic of these agents. Pharmacokinetic factors may partially explain these clinical observations. Delays in the achievement of steady-state concentrations or of concentrations likely to have a therapeutic benefit may occur because of slow drug accumulation. Variable concentrations may arise after standard administered doses because of interindividual pharmacokinetic variability. These factors are likely to contribute to the delay in response and the variable response, respectively. Pharmacokinetics of the antimalarials, hydroxychloroquine and chloroquine, are characterised by extensive tissue sequestration with reported volumes of distribution in the thousands of litres. Both drugs have reported elimination half-lives of greater than 1 month. A 2- to 3-fold range occurs in the fraction of an oral dose absorbed from a tablet formulation. Variable interindividual clearance is also reported. Hydroxychloroquine and chloroquine are administered as racemates. Enantioselective disposition of both compounds occurs, again with notable interindividual variability. Sulphasalazine is split in the large intestine into sulphapyridine, proposed to be the active compound in rheumatoid arthritis, and mesalazine (5-aminosalicylic acid). Sulphapyridine is metabolised partly by acetylation, the rate of which is under genetic control. A wide range of sulphapyridine steady-state concentrations are reported after standard doses of sulphasalazine. The gold complexes are administered either intramuscularly or in an oral form (auranofin). Gold is widely distributed in the body. Very long terminal elimination half-lives and slow accumulation rates are reported. Penicillamine is administered orally. Its bioavailability is variable and may decrease by as much as 70% in the presence of food, antacids and iron salts. Penicillamine forms disulphide bonds with many proteins in the blood and tissues, creating potential slow release reservoirs of the drug. Like the other SAARDs, gold complexes and penicillamine are found in a wide range of blood concentrations after administration in standard doses to different individuals. More research must be conducted into the concentration-effect relationships of the SAARDs before the pharmacokinetic characteristics of these drugs can be used effectively to optimise patient therapy.

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.

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.

Use of methotrexate in older patients. A risk-benefit assessment.

Methotrexate is eliminated almost entirely by the kidneys. The risk of methotrexate toxicity is therefore increased in patients with poor renal function, most likely as a result of drug accumulation. Declining renal function with age may thus be an important predictor of toxicity to methotrexate. Up to 60% of all patients who receive methotrexate for rheumatoid arthritis (RA) discontinue taking it because of adverse effects, most of which occur during the first year of therapy. Gastrointestinal complications are the most common adverse effects of methotrexate, but hepatotoxicity, haematological toxicity, pulmonary toxicity, lymphoproliferative disorders and exacerbation of rheumatic nodules have all been reported. Decreased renal function as a result of disease and/or aging appears to be an important determinant of hepatic, lymphoproli ferative and haematological toxicity. Concomitant use of low doses of folic acid has been recommended as an approach to limiting toxicity. Interactions between methotrexate and several nonsteroidal anti-inflammatory drugs have been reported, but they may not be clinically significant. However, caution is advised in the use of such combinations in patients with reduced renal function. More serious toxicities (e.g. pancytopenia) may result when other inhibitors of folate utilisation [e.g. cotrimoxazole (trimethoprim-sulfamethoxazole)] or inhibitors of renal tubular secretion (e.g. probenecid) are combined with methotrexate. Before starting low dose methotrexate therapy in patients with RA, a full blood count, liver function tests, renal function tests and chest radiography should be performed. Blood counts and liver function tests should be repeated at regular intervals. Therapeutic drug monitoring of methotrexate has also been suggested as a means of limiting toxicity. Patients with RA usually respond very favourably to low dose methotrexate therapy, and the probability of patients continuing their treatment beyond 5 years is greater than for other slow-acting antirheumatic drugs. Thus, given its sustained clinical utility and relatively predictable toxicity profile, low dose methotrexate is a useful addition to the therapy of RA.

Bioavailability of hydroxychloroquine tablets assessed with deconvolution techniques.

Four deconvolution methods (staircase, delta function, and least squares methods using single and sequential first-order input functions) were used to assess the absolute bioavailability of hydroxychloroquine tablets in nine healthy fasting volunteers. The volunteers received, in a random crossover design, a 155-mg oral tablet and a 155-mg iv infusion of racemic hydroxychloroquine. The mean fractions of the dose absorbed, calculated using the four deconvolution methods, were not statistically different (p = 0.70). The mean fraction absorbed (+/- SD) was 0.67 +/- 0.12, which was not significantly different from that reported previously in a conventional bioavailability study (p = 0.22). The mean absorption half-life was calculated to be 4.0 +/- 1.3 h. The mean lag time before absorption commenced was 0.57 +/- 0.30 h. The fraction of the dose absorbed ranged from 0.44 to 0.86. Low and/or variable bioavailability of hydroxychloroquine may be a cause of therapeutic failure in some patients. Validation of the deconvolution methods means that these techniques may now be used to assess the bioavailability of hydroxychloroquine in patients. An advantage of these methods is that samples need only be collected over the expected time period of absorption, rather than the whole time drug can be detected in the body, as is required in conventional area under the concentration-time curve ratio methods. Deconvolution studies may be completed in 2 weeks rather than the 10 months required for a conventional bioavailability study of hydroxychloroquine.

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.

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.

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.

Improved high-performance liquid chromatography determination of methotrexate and its major metabolite in plasma using a poly(styrene-divinylbenzene) column.

A sensitive high-performance liquid chromatographic assay has been developed for measuring plasma concentrations of methotrexate and its major metabolite, 7-hydroxymethotrexate. Methotrexate and metabolite were extracted from plasma using solid-phase extraction. An internal standard, aminopterin was used. Chromatographic separation was achieved using a 15-cm poly(styrene-divinylbenzene) (PRP-1) column. This column is more robust than a silica-based stationary phase. Post column, the eluent was irradiated with UV light, producing fluorescent photolytic degradation products of methotrexate and the metabolite. The excitation and emission wavelengths of fluorescence detection were at 350 and 435 nm, respectively. The mobile phase consisted of 0.1 M phosphate buffer (pH 6.5), with 6% N,N-dimethylformamide and 0.2% of 30% hydrogen peroxide. The absolute recoveries for methotrexate and 7-hydroxymethotrexate were greater than 86%. Precision, expressed as a coefficient of variation (n=6), was <10% at each of five methotrexate concentrations in the range 2.5-50 ng/ml. The limits of quantitation of methotrexate were 1 and 2.5 ng/ml for methotrexate and 7-hydroxymethotrexate, respectively (using 1 ml plasma). A robust HPLC method has been developed for the reproducible quantitation of methotrexate in plasma of patients taking a weekly dose of methotrexate for rheumatoid arthritis.

Pharmacokinetics of fluconazole in people with HIV infection: a population analysis.

1. The population pharmacokinetics of fluconazole have been investigated in 113 male subjects with HIV infection and AIDS. Plasma concentration-time data (between 1 and 17 observations per dose) were collected from individuals as part of a pharmacokinetic investigation (13 subjects) or during routine fluconazole therapy (100 subjects) for the treatment or prophylaxis of fungal infection. 2. A one-compartment pharmacokinetic model was used to describe the disposition of fluconazole after oral and intravenous infusion doses. Population pharmacokinetic parameters were generated using the NONMEM and P-PHARM computer programs. 3. The population estimates (calculated using NONMEM) of fluconazole clearance and volume of distribution were 0.78 l h-1 and 47.61, respectively. The intersubject variability for these parameters was 41% and 8%, respectively. The model-dependent estimate of the extent of absorption was 0.99 with an intersubject variability of 6%. Mean population estimates generated by NONMEM and P-PHARM were in close agreement. 4. Examination of the relationship between patient covariates and pharmacokinetic parameters indicated that intersubject variability in fluconazole clearance could in part be explained by the severity of disease (as indicated by CD4 + T-lymphocyte count) and renal function (indicated by estimated creatinine clearance). Other pharmacokinetic parameters were unaffected by these covariates. 5. Fluconazole clearance (estimated using NONMEM) in subjects with a CD4 + T-lymphocyte count less than and greater than 200 cells mm3 was 0.73 l h-1 (95% CI; 0.64-0.82 l h-1) and 0.99 l h-1 (95% CI; 0.86-1.12 l h-1), respectively. The regression model for fluconazole clearance that accounted for changes in renal function and disease severity was CL (l h-1) = 0.25 (33%) + 0.0057 (32%) x CLcr (in ml min-1) + 0.00068 (10%) x CD4 cell count (in cells mm-3) where intersubject variability (expressed as %CV) is shown in brackets. 6. Based on pharmacokinetic considerations a reduction in the dose of fluconazole would appear to be warranted in people with HIV infection who are seriously ill or who have compromised renal function. However, the emergence of resistance to fluconazole must also be considered when thinking of dosage adjustments.

Apparent dose-dependence of chloroquine pharmacokinetics due to limited assay sensitivity and short sampling times.

We have shown that apparent nonlinearities in the pharmacokinetics of chloroquine and wide variability in reported kinetic values are possibly artefacts of experimental design. We have used simulated data based on linear equations to demonstrate that chloroquine kinetics may appear to be dose-dependent if samples are collected over a short period or if they are assayed with a method of low sensitivity.

Effect of metabolic inhibitors on cyclosporine pharmacokinetics using a population approach.

Drugs known to inhibit the metabolism of cyclosporine are administered concomitantly to those who undergo cardiothoracic transplantation. The aim of this study was to examine in quantitative terms the relationship between cyclosporine oral dose rate and the trough concentration (Css(trough)) at steady state in patients who undergo cardiothoracic transplantation and are administered cyclosporine alone or in combination with drugs known to inhibit its metabolism. Dose and whole blood cyclosporine Css(trough) observations measured using the enzyme-multiplied immunoassay technique (EMIT) (396 observations) or the TDx assay (435 observations) were collected as part of routine blood concentration monitoring from 182 patients who underwent cardiothoracic transplantation. Data were analyzed using a linear mixed-effects modeling approach to examine the effect of metabolic inhibitors on dose-rate-Css(trough) ratio. The mean (and 95% confidence interval) dose-rate-Css(trough) ratio for cyclosporine generated from concentrations measured using EMIT was 94 (82.5-105.5) Lh(-1) for patients administered cyclosporine alone, 66.7 (58.1-75.3) Lh(-1) for patients administered concomitant diltiazem, 47.9 (15.4 -80.4) Lh(-1) for patients administered concomitant itraconazole, 21.7 (14.8-28.5) Lh(-1) for patients administered concomitant ketoconazole, and 14.9 (11.8-18.1) Lh(-1) for patients concomitantly administered diltiazem and ketoconazole. For patients administered concomitant cyclosporine, ketoconazole, and diltiazem, the dosage of cyclosporine, if it is administered alone, should be 20% to achieve the same blood concentrations. This will allow safer drug concentration targeting of cyclosporine after cardiothoracic transplantation.