Therapeutic drug monitoring of voriconazole and posaconazole for invasive aspergillosis

Voriconazole and posaconazole are extended-spectrum triazoles recommended for treatment, prophylaxis and salvage therapy of Aspergillus diseases. Over the past decade many papers have emerged supporting the use of therapeutic drug monitoring (TDM) for azole antifungals. TDM is used to tailor the exposure of a specific drug to the individuals to optimize treatment response and minimize side effects. We reviewed the pharmacokinetics and pharmacodynamics (PK-PD) characteristics of voriconazole and posaconazole. We present the available evidence on target concentrations defining maximal efficacy and minimal toxicity. Finally we provide some practical recommendations how to best perform TDM in clinical practice.     

Level of evidence for therapeutic drug monitoring of taxanes

Taxanes are anticancer drugs on the market for more than 10 years that are thought to be interesting for therapeutic drug monitoring (TDM): high inter‐ and intra‐patient variability, relationship between exposure and efficacy and especially toxicity. Nevertheless, the paclitaxel and docetaxel characteristics result in different conclusions for these two molecules with respect to their TDM. For paclitaxel, the nonlinear pharmacokinetics makes that the parameter which seems the more reliable to toxicity or outcome is the time during which the plasma concentration exceeds 0.05 μm . Concentration controlled studies using Bayesian adaptation showed that the TDM of paclitaxel is feasible in routine. However, this target needs to be prospectively validated with new weekly schedules of administration, leading to a balance between ‘recommended’ and ‘potentially useful’. For docetaxel, the 3‐weekly administration, which is the more effective scheme, is also the more toxic. However, neutropenia can be individually modeled and efficiently predicted without using plasma drug concentrations. The docetaxel TDM using this docetaxel‐related neutropenia modeling however needs to be prospectively validated in routine. The level of evidence of TDM thus ‘needs to be assessed’.     

Level of evidence for therapeutic drug monitoring for etoposide after oral administration

Oral etoposide displays high intervariability and intravariability. Convincing relationships were observed between hematological toxicities and exposure of which total etoposide area under the curve seems the more relevant in routine practice. Linear pharmacokinetics, limited sampling strategies and reduction in variability during concentration‐controlled studies argue in favor of therapeutic drug monitoring. However, such reduction in variability should be confirmed after oral administration. For these reasons, such practice can be considered as ‘potentially useful’. Further studies using Bayesian approach are nevertheless needed to definitely state regarding the level of evidence therapeutic drug monitoring of oral etoposide.     

去甲万古霉素临床药代动力学及血药浓度监测

目的 :比较国产去甲万古霉素在老年人和年轻人中的体内过程 ,为制订去甲万古霉素在治疗老年人感染时的合理给药方案提供依据 ;建立快捷、实用的去甲万古霉素治疗药物监测 (TDM)方法。方法 :同期对照研究去甲万古霉素在 1 0名健康老年受试者 (老年组 )和 1 0名健康年轻受试者 (年轻组 )中的药代动力学。以微生物法和荧光偏振免疫法 (FPIA)测定血药浓度 ,以微生物法测定尿药浓度。结果 :老年组和年轻组静脉滴注去甲万古霉素 80 0mg后的体内过程均符合二室模型。与年轻组比较 ,老年组表观分布容积 (Vd)增大 ,总清除率 (CLt)及肾清除率 (CLr)降低 ,药时曲线下面积 (AUC)增加和消除半衰期(t1 /2 β)延长。以上各项药代参数在两组间差异均具非常显著性 (P <0 .0 1 ) ;两组血药峰浓度相近 (P >0 .0 5 )。去甲万古霉素给药后 1 2h内的累积尿排出率老年组较年轻组明显为低 ,分别为 (77.1 3± 8.95 ) %和 (83.82± 1 6 .80 ) % (P <0 .0 1 ) ,但给药后4 8h两组的累积尿排出率相近 ,分别为 (85 .38± 8.6 2 ) %和 (86 .1 2± 1 6 .85 ) % ,两组差异无显著性 (P >0 .0 5 )。以微生物法和FPIA同时测定去甲万古霉素血清标本。两种测定方法测得结果呈良好线性相关性。线性回归方程为Y =0 .75 34X - 0 .5 94 8(Y :微生物     

St. John's wort does not interfere with therapeutic drug monitoring of 12 commonly monitored drugs using immunoassays

St. John's wort, a popular herbal remedy for depression, is known to interact with many Western drugs because of the ability of its components to induce liver enzymes. Lower concentrations of various drugs due to increased clearance have been reported. Because immunoassays are commonly used in clinical laboratories for therapeutic drug monitoring, we studied the potential interference of St. John's wort with commonly monitored therapeutic drugs. Drug-free serum pools were supplemented with St. John's wort to achieve in vitro St. John's wort concentrations mimicking in vivo concentrations after both recommended use and overdose. Concentrations of digoxin, tricyclic antidepressants (TCAs), phenytoin, carbamazepine, theophylline, valproic acid, quinidine, phenobarbital, procainamide, and N-acetyl procainamide were measured in serum. Pooled serum specimens from patients who were taking a particular drug were also supplemented in vitro with concentrations of St. John's wort to investigate whether observed concentrations changed after supplementation with St. John's wort. The effect of St. John's wort on cyclosporine and tacrolimus (FK 506) was studied in whole blood. We found no significant interference from St. John's wort with any assay studied. Moreover, when drug-free serum was supplemented with very high concentrations of hypericin (2 microg/mL) and hyperforin (2 microg/mL) pure standard, we observed no apparent drug level with any immunoassay. The presence of both hypericin and hyperforin was also confirmed by thin layer chromatography (TLC) in both preparations of St. John's wort. We conclude that immunoassays may be used to measure levels of therapeutic drugs in patients who self-medicate with St. John's wort.     

Estimation of minimum whole-blood tacrolimus concentration for therapeutic drug monitoring with plasma prednisolone concentration: A retrospective cohort study in Japanese kidney transplant recipients

Background: In immunosuppressive therapy administered after organ transplantation, therapeutic drug monitoring (TDM) of tacrolimus must be performed frequently because of the large variation in its pharmacokinetic properties and a progressive decrease in dose requirements. An indicator for estimating the target minimum whole-blood tacrolimus concentration (C_{min TAC}) would be useful to minimize the number of blood samplings required for tacrolimus TDM.Objectives: The primary objective of this study was to investigate whether plasma prednisolone concentration, postoperative days (POD) and AUC 0 to 9 hours before transplantation (AUC_0-9int) are useful indicators of tacrolimus TDM. The secondary objective was to determine the usefulness of blood tacrolimus concentration as an indicator of the development of nontraumatic, glucocorticoid-induced necrosis of the femoral head, an adverse event that has been associated with the use of prednisolone in vivo.Methods: This open-label, nonrandomized, retrospective study was conducted at the Department of Transplantation and Regenerative Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan. Data from 43 male and 22 female patients (mean age, 38 years [range, 9-64 years]) who received a living-related kidney transplant from 2001 to 2004 were included. Multiple blood samplings were performed to determine AUC_0-9int, AUC 0 to 9 hours after drug administration and after transplantation (AUC_0-9), C_{min TAC}, C_max, and T_max after transplantation. The correlations between each parameter were determined. The correlation between POD and the changes in tacrolimus bioavailability was investigated using the indicator, defined as the tacrolimus dose required to maintain the target (10-15 ng/mL) C_{min TAC} (dose/C_10-15). Correlations between dose/C_10-15 and AUC_0-9int (3 AUC_0-9int groups, defined as follows: low, medium, and high [<93, ≧93−≤152, and ≧152 ng·h/mL, respectively]) were determined. Correlations between mean C_min values of prednisolone at a dose of 40 mg on PODs 4 to 11 (C_{min PSL40}) and C_{min TAC}, or AUC_0-9int were determined. A subanalysis was used to determine the relationship between dose/C_10-15 and the prevalence of nontraumatic, glucocorticoid-induced necrosis of the femoral head.Results: C_{min TAC} was found to be significantly correlated with AUC_0-9int (r=0.554; P<0.001) and C_{min PSL40} (r=0.336; P<0.001). In the low-AUC_0-9int group, dose/C_10-15 was higher than that of the other groups (P<0.001). AUC_0-9int was significantly correlated with C_{min PSL40} (r=0.445; P<0.001)). Dose/C_10-15 in the patient group that had necrosis of the femoral head was lower than that of the group without necrosis (n=6; P<0.01).Conclusions: The results of this small, retrospective study suggest that C_{min PSL40}, AUC_0-9int, and POD were significant predictors of C_{min TAC}. These parameters were found to be a useful indicator of tacrolimus TDM in these Japanese transplant recipients. Our results also suggest that dose/C_10-15 and AUC_0-9int might be useful indicators for estimating the risk for nontraumatic, steroid-induced necrosis of the femoral head. (Curr Ther Res Clin Exp. 2006;67: 103-117) Copyright © 2006 Excerpta Medica, Inc.     

Successful determination of imatinib re‐administration dosage by therapeutic drug monitoring in a case of chronic myeloid leukemia initiating dialysis for acute renal dysfunction

Fixed dose regimen is currently the standard administration method for TKI. However, this case report indicated that TDM may by a useful approach to individualized dosing of TKI for the treatment of CML when initiating dialysis.     

Therapeutic drug monitoring of imatinib in chronic myeloid leukemia: experience from 1216 patients at a centralized laboratory

This study set out to examine in a large real‐life cohort of patients with chronic myeloid leukemia (CML) the impact of imatinib threshold of 1000 ng/mL on molecular response, as suggested in a small subset of patients. Patient plasma samples were submitted from around France to a central facility, free of charge under the auspices of the European Treatment and Outcome Study (EUTOS) for CML. Submitting physicians were required to complete an ‘imatinib monitoring request form’, including details of why therapeutic drug monitoring (TDM) was requested, dose and duration of imatinib treatment, cytogenetic and molecular response, adverse events, and concurrent medications. Imatinib trough plasma concentration (C_min) was measured at the central facility. Among 1985 eligible plasma samples analyzed, from 1216 CML patients, imatinib C_min correlated positively with reported imatinib dose, but interpatient variability in C_min was high (60%). A logistic regression analysis revealed that treatment duration and imatinib C_min > 1000 ng/mL were significantly associated with major and complete molecular responses with odds ratios of 1.69 and 2.08, respectively. These data support in real‐life setting that imatinib C_min threshold of 1000 ng/mL is associated with major and complete molecular response and that TDM could play an important role in dose optimization.     

Predictability of individualized dosage regimens of carbamazepine and valproate mono- and combination therapy

What is known and Objective: Many investigators agree that appropriate rational utilization of therapeutic drug monitoring (TDM) with Bayesian feedback dosage adjustment facilitates epilepsy treatment with carbamazepine (CBZ) and/or valproate (VPA) by increasing the seizure control and safety, as well as by reducing treatment costs. In previous works we have developed and used in clinical practice population pharmacokinetic (PK) models of different dosage forms for VPA and post‐induction CBZ behaviour, as well as for combined therapy with CBZ plus another ‘old’ antiepileptic drug (AED). An important step of external validation is to evaluate how well a procedure of Bayesian individualizing AED dosage regimens based on a proposed population PK model and sparse TDM data ‘works’, and how helpful it is in real practical clinical settings. The aim of this study was to evaluate the predictability of individualized dosage regimens for monotherapy with CBZ in the post‐induction period or with VPA, as well as for CBZ and VPA given as combination therapy based on TDM data of epileptic patients and the earlier developed population models. Methods: Four groups of TDM data were analysed using the USC*PACK software for PK/PD analysis: 556 predictions for adult epileptic patients on CBZ monotherapy, 662 predictions for VPA monotherapy, 402 predictions of CBZ serum levels and 430 predictions of VPA serum levels for adult epileptic patients on CBZ+VPA combination therapy. Statistical characteristics of the prediction errors (PE) and weighted PE were used to estimate bias and precision of predictions. Intraindividual and interoccasional variability of predictions were also estimated. Results and Discussion: This study demonstrated that in most cases of CBZ and VPA monotherapy and combination therapy, predictions of future AED concentrations based on the earlier developed population PK models, TDM data and patient‐specific maximum a posteriori probability Bayesian posterior parameter values provided clinically acceptable estimates. Statistical analysis of the residuals demonstrated that the distributions of residual and weighted residual were close to the normal distribution (Kolmogorov–Smirnov test, P > 0·05) and their mean values did not differ statistically significant from zero (no statistically significant bias, P > 0·05) for all groups of predictions. The observed decreased quality of predictions of VPA concentrations during VPA+CBZ combination therapy, especially when CBZ dosages were changed, might well be explained by their PK interactions. For all groups, in linear regression analysis, the observed trend of decreasing of the prediction quality over various future prediction time horizons was considered statistically significant (P < 0·05). Prediction of serum levels further in future was less precise than those closer to the present for a 1·5‐ to 3·5‐year observation period. No bias in predictions was associated with the time horizons. What is new and Conclusion: Our validation results suggest good predictive performance of the population models developed earlier, and quite acceptable predictions of future AED serum levels for individualized dosage regimens of CBZ and VPA therapy in real clinical settings.     

Evaluation of once-daily dosing and target concentrations in therapeutic drug monitoring for arbekacin: A meta-analysis

IntroductionArbekacin is the first aminoglycoside antibacterial agent approved for treating methicillin-resistant Staphylococcus aureus infection in Japan. Although therapeutic drug monitoring (TDM) is recommended during arbekacin treatment, little evidence for the target exposure and once-daily dosing has been reported. This study aimed to clarify the target peak/trough concentrations and the effectiveness of once-daily dosing of arbekacin against nephrotoxicity or treatment failure via meta-analysis.MethodsA literature search was performed using MEDLINE, Cochrane Library, and Ichushi-Web.ResultsNine observational cohort studies met the inclusion criteria. A peak arbekacin concentration of ≥15–16 μg/mL did not exhibit a statistically significant lower risk of treatment failure (risk ratio [RR] = 0.61, 95% confidence interval [CI] = 0.30–1.24). A trough arbekacin concentration of <2 μg/mL resulted in a significantly lower risk of nephrotoxicity (RR = 0.30, 95% CI = 0.15–0.61). Once-daily dosing significantly reduced the risk of treatment failure (RR = 0.61, 95% CI = 0.39–0.97) but not nephrotoxicity (RR = 0.54, 95% CI = 0.16–1.75).ConclusionsOnce-daily dosing can improve the therapeutic efficacy of arbekacin, and a trough arbekacin concentration of <2 μg/mL can reduce the risk of nephrotoxicity. A peak arbekacin concentration of ≥15–16 μg/mL did not exhibit the significant lower risk of treatment failure. Additional clinical trials are required to confirm these findings.