Quantitative justification for target concentration intervention - parameter variability and predictive performance using population pharmacokinetic models for aminoglycosides

Aims [1] To quantify the random and predictable components of variability for aminoglycoside clearance and volume of distribution [2] To investigate models for predicting aminoglycoside clearance in patients with low serum creatinine concentrations [3] To evaluate the predictive performance of initial dosing strategies for achieving an aminoglycoside target concentration. Methods Aminoglycoside demographic, dosing and concentration data were collected from 697 adult patients (>=20 years old) as part of standard clinical care using a target concentration intervention approach for dose individualization. It was assumed that aminoglycoside clearance had a renal and a nonrenal component, with the renal component being linearly related to predicted creatinine clearance. Results A two compartment pharmacokinetic model best described the aminoglycoside data. The addition of weight, age, sex and serum creatinine as covariates reduced the random component of between subject variability (BSVR) in clearance (CL) from 94% to 36% of population parameter variability (PPV). The final pharmacokinetic parameter estimates for the model with the best predictive performance were: CL, 4.7 l h(-1) 70 kg(-1); intercompartmental clearance (CLic), 1 l h(-1) 70 kg(-1); volume of central compartment (V-1), 19.5 l 70 kg(-1); volume of peripheral compartment (V-2) 11.2 l 70 kg(-1). Conclusions Using a fixed dose of aminoglycoside will achieve 35% of typical patients within 80-125% of a required dose. Covariate guided predictions increase this up to 61%. However, because we have shown that random within subject variability (WSVR) in clearance is less than safe and effective variability (SEV), target concentration intervention can potentially achieve safe and effective doses in 90% of patients.

The effect of adsorption, filter material and point of dilution on antibiotic elimination by haemofiltration - An in vitro study of levofloxacin

We studied an in vitro model of continuous venous-venous haemofiltration (CVVH), into which levofloxacin 100 mg was infused, to determine levofloxacin adsorption and to determine the effect of filter material and point of dilution (pre- or post-filter) on sieving coefficient. Mean (standard deviation; S.D.) adsorption was 18.7 (5.3) mg for the polyamide filter and 40.2 (2.0) mg for the polyacrylonitrile (PAN) filter (P < 0.001). Post-dilution resulted in a minor, but statistically significant, decrease in sieving coefficient (pre-dilution 0.96 (S.D. 0.10), post-dilution 0.88 (S.D. 0.11) with the PAN filter. These data indicate that the variability in published values for levofloxacin sieving coefficient are not due to variation in point of dilution or membrane type (PAN or polyamide). Significant adsorption of levofloxacin onto PAN filters occurs. (C) 2004 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

CEDIA (R) sirolimus assay compared with HPLC-MS/MS and HPLC-UV in transplant recipient specimens

The role of the therapeutic drug monitoring laboratory in support of immunosuppressant drug therapy is well established, and the introduction of sirolimus (SRL) is a new direction in this field. The lack of an immunoassay for several years has restricted the availability of SRL assay services. The recent availability of a CEDIA (R) SRL assay has the potential to improve this situation. The present communication has compared the CEDIA (R) SRL method with 2 established chromatographic methods, HPLC-UV and HPLC-MS/MS. The CEDIA (R) method, run on a Hitachi 917 analyzer, showed acceptable validation criteria with within-assay precision of 9.1% and 3.3%, and bias of 17.1% and 5.8%, at SRL concentrations of 5.0 mu g/L and 20 mu g/L, respectively. The corresponding between-run precision values were 11.5% and 3.3% and bias of 7.1% and 2.9% at 5.0 mu g/L and 20 mu g/L, respectively, The lower limit of quantification was found to be 3.0 mu g/L. A series of 96 EDTA whole-blood samples predominantly from renal transplant recipients were assayed by the 3 methods for comparison. It was found that the CEDIA (R) method showed a Deming regression line of CEDIA = 1.20 X HPLC-MS/MS - 0.07 (r = 0.934, SEE = 1.47), with a mean bias of 20.4%. Serial blood samples from 8 patients included in this evaluation showed that the CEDIA (R) method reflected the clinical fluctuations in the chromatographic methods, albeit with the variable bias noted. The CEDIA (R) method on the H917 analyzer is therefore a useful adjunct to SRL dosage individualization in renal transplant recipients.

Hepatic pharmacokinetics of taurocholate in the normal and cholestatic rat liver

1 The disposition kinetics of [H-3] taurocholate ([H-3]TC) in perfused normal and cholestatic rat livers were studied using the multiple indicator dilution technique and several physiologically based pharmacokinetic models. 2 The serum biochemistry levels, the outflow profiles and biliary recovery of [H-3] TC were measured in three experimental groups: (i) control; (ii) 17α-ethynylestradiol (EE)-treated (low dose); and (iii) EE-treated (high dose) rats. EE treatment caused cholestasis in a dose-dependent manner. 3 A hepatobiliary TC transport model, which recognizes capillary mixing, active cellular uptake, and active efflux into bile and plasma described the disposition of [H-3]TC in the normal and cholestatic livers better than the other pharmacokinetic models. 4 An estimated five- and 18-fold decrease in biliary elimination rate constant, 1.7- and 2.7-fold increase in hepatocyte to plasma efflux rate constant, and 1.8- and 2.8-fold decrease in [H-3]TC biliary recovery ratio was found in moderate and severe cholestasis, respectively, relative to normal. 5 There were good correlations between the predicted and observed pharmacokinetic parameters of [H-3]TC based on liver pathophysiology (e.g. serum bilirubin level and biliary excretion of [H-3]TC). In conclusion, these results show that altered hepatic TC pharmacokinetics in cholestatic rat livers can be correlated with the relevant changes in liver pathophysiology in cholestasis.

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 mu g 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.

Population pharmacokinetics and association between A77 1726 plasma concentrations and disease activity measures following administration of leflunomide to people with rheumatoid arthritis

Aims To investigate the concentration-effect relationship and pharmacokinetics of leflunomide in patients with rheumatoid arthritis (RA). Methods Data were collected from 23 RA patients on leflunomide therapy (as sole disease modifying antirheumatic drug (DMARD)) for at least 3 months. Main measures were A77 1726 (active metabolite of leflunomide) plasma concentrations and disease activity measures including pain, duration/intensity of morning stiffness, and SF-36 survey. A population estimate was sought for apparent clearance (CL/F ) and volume of distribution was fixed (0.155 l kg(-1)). Factors screened for influence on CL/F were weight, age, gender and estimated creatinine clearance. Results Significantly higher A77 1726 concentrations were seen in patients with less swollen joints and with higher SF-36 mental summary scores than in those with measures indicating more active disease (P < 0.05); concentration-effect trends were seen with five other disease activity measures. Statistical analysis of all disease activity measures showed that mean A77 1726 concentrations in groups with greater control of disease activity were significantly higher than those in whom the measures indicated less desirable control (P < 0.05). There was large between subject variability in the dose-concentration relationship. A steady-state infusion model best described the pharmacokinetic data. Inclusion of age as a covariate decreased interindividual variability (P < 0.01), but this would not be clinically important in terms of dosage changes. Final parameter estimate (% CV interindividual variability) for CL/F was 0.0184 l h(-1) (50%) (95% CI 0.0146, 0.0222). Residual (unexplained) variability (% CV) was 8.5%. Conclusions This study of leflunomide in patients using the drug clinically indicated a concentration-effect relationship. From our data, a plasma A77 1726 concentration of 50 mg l(-1) is more likely to indicate someone with less active disease than is a concentration around 30 mg l(-1). The marked variability in pharmacokinetics suggests a place for individualized dosing of leflunomide in RA therapy.

Maternal valproate dosage and foetal malformations

Objective - To study the possible dose dependence of the foetal malformation rate after exposure to sodium valproate in pregnancy Methods - Analysis of records of all foetuses in the Australian Registry of Antiepileptic Drugs in Pregnancy exposed to valproate, to carbamazepine, lamotrigine or phenytoin in the absence of valproate, and to no antiepileptic drugs. Results - The foetal malformation rate was higher (P < 0.05) in the 110 foetuses exposed to valproate alone (17.1%), and in the 165 exposed to valproate, whether alone or together with the other antiepileptic drugs (15.2%), than in the 297 exposed to the other drugs without valproate (2.4%). It was also higher (P < 0.10) than in the 40 not exposed to antiepileptic drugs (2.5%). Unlike the situation for the other drugs, the malformation rate in those exposed to valproate increased with increasing maternal drug dosage (P < 0.05). The rate was not altered by simultaneous exposure to the other drugs. Valproate doses exceeding 1400 mg per day seemed to be associated with a more steeply increasing malformation rate than at lower doses and with a different pattern of foetal malformations. Conclusion - Foetal exposure to valproate during pregnancy is associated with particularly high, and dose-dependent risks of malformation compared with other antiepileptic drugs, and may possibly involve different teratogenetic mechanisms.

Quantifying the use of the statin antilipemic drugs: Comparisons and contrasts between Nova Scotia, Canada, and Queensland, Australia

Background: jurisdictions are developing public drug insurance systems to improve access to pharmaceuticals, cost-effective prescribing, and patient health and well-being. We compared 2 Jurisdictions with different pharmaceutical policies to determine prescribing patterns for 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (le, statins). Objective: The aim of this work was to investigate the feasibility of using available prescription admimstrative databases to compare the use of statins in Queensland, Australia, and in Nova Scotia, Canada. Methods: Data from the Nova Scotia Pharmacare Program and the Health Insurance Commission in Australia were used to obtain dispensing data. Utilization was compared for the 5-year period from 1997 through 2001, using the World Health Organization anatomic therapeutic chemical/defined daily dose (DDD) system. Results: In the year 2001, there were 177,000 beneficiaries in the public drug plan in Nova Scotia (62% aged &GE; 65 years old) and 960,000 concession beneficiaries (pensioners and social security recipients, 61% aged &GE; 65 years) in Queensland. These 2 groups were comparable. The overall utilization of statin medications increased steadily in both areas over the study period, from 50 to 205 DDD/1000 beneficiaries per day. Comparison of the 2 growth lines showed no statistically significant differences in overall statin use despite differences in brand availabilities and policies about prescribing. In the year 2001, atorvastatin was the most commonly prescribed statin in both areas, comprising 46% of statin use in Nova Scotia and 51% in Queensland. Mean doses of each statin prescribed were slightly above the DDDs. Expenditure on statins per 1000 beneficiaries and per DDD were similar in each jurisdiction, being slightly higher in Nova Scotia. Conclusions: Despite differences in pharmaceutical reimbursement systems, use of the statins was similar in Nova Scotia and Queensland. The feasibility of the methodology was demonstrated. Future studies, including comparisons of drug utilization for other classes of drugs for which drug policies may be divergent (eg, different pricing structures or prior authorization requirements), or for which less evidence for appropriate use is available, may be useful. © 2005 Excerpta Medica, Inc.