Evidence Of Therapeutic Drug Monitoring (TDM) In The Treatment Of Invasive Aspergillosis (IA) With Voriconazole (VCZ) In Cancer Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2977-2977
Author(s):  
Meinolf Karthaus ◽  
Thomas Lehrnbecher ◽  
Dieter Buchheidt
Keyword(s):  
Invasive Aspergillosis ◽  
Cancer Patients ◽  
Plasma Levels ◽  
Drug Exposure ◽  
Pediatric Population ◽  
Serum Levels ◽  
Therapeutic Drug ◽  
Evidence Based ◽  
Double Blind ◽  
Intervention Thresholds

Abstract Introduction Invasive aspergillosis is a life-threatening complication in hematological cancer patients (pts). VCZ is the established first-line standard treatment of IA. Failure of VCZ therapy in IA due to lack of efficacy or adverse events (AEs) occurs in 30-40% of treated pts. VCZ has a nonlinear pharmacokinetic profile and exhibits considerable variability of drug exposure. Therefore, TDM of VCZ may help to improve treatment results in pts with IA. While TDM is recommended by some authors, evidence-based data on the clinical use of TDM in pts treated with VCZ for IA are scarce. Our present analysis assessed published studies for evidence-based criteria guiding TDM of VCZ to improve efficacy and safety of IA therapy in cancer pts. Evidence-based guidance is needed to support decisions on the use of TDM in clinical routine VCZ therapy of IA. Patients and methods Literature searches of Medline, Cochrane database and conference abstracts were performed. We identified 25 clinical studies (comprising a total of 3822 pts, range 5 - 1091) reporting on the use of TDM for VCZ. For each study, strength of recommendation and quality of evidence was categorized according to criteria defined by Kish et al. (Clin Infect Dis 2001). Each trial was was assessed separately.for the categories efficacy, toxicity, timing of TDM and dose adjustment. The majority of trials included cancer pts. Two trials reported on a pediatric population (>0 - < 12 yrs of age), 21 trials reported on adults only, while the remaining 5 trials reported on children and adults. Evaluable TDM data were reported for 3313 pts, whereas 509 pts were not included for TDM for various reasons. VCZ plasma levels were determined by HPLC in 23 trials. A total of 8266 VCZ serum levels were reported. Of the 7 prospective studies, 1 randomized prospective, double-blind trial included pts treated with VCZ or fluconazole. The primary endpoint of a significant AE reduction by TDM of VCZ versus no TDM was not reached (CI), while efficacy was higher in pts managed with TDM (BI). The other studies were observational or retrospective cohort studies. 18 reports provided data on both intravenous and oral use of VCZ, 4 trials reported on intravenous VCZ and 3 on oral VCZ only. 13/25 trials were evaluable for evidence on TDM regarding efficacy, 10/25 for toxicity. High inter- and intra-study variability was observed for timepoints of VCZ measurement (day 1 to >day 210) and number of VCZ plasma levels (n = 2 to >40). Across the studies, VCZ levels >5-5.5 mg/L were found to be associated with toxicity (BII), while reaching minimum levels of >1-2 mg/L appeared to improve efficacy (BII). Timing (CIII), frequency (CIII) and intervention thresholds (CIII) of VCZ TDM remain an open question. Conclusion Although a substantial number of studies is published on TDM in VCZ therapy of IA, there is still no robust evidence for recommendations in clinical practice. VCZ levels >5-5.5 mg/L were reported to be associated with toxicity (BII), while minimum levels of >1-2 mg/L may improve efficacy (BII). However, timing (CIII) and frequency (CIII) of TDM als well as intervention thresholds (CIII) and dosage increments for adjustment of VCZ plasma levels need to be established in a multicenter randomized clinical trial to provide a scientifically adequate basis for guidance on TDM of VCZ for IA in cancer pts. Disclosures: Karthaus: Pfizer: Honoraria; MSD: Honoraria; Gilead: Honoraria; Astellas: Honoraria. Lehrnbecher:Gilead: Honoraria; MSD: Honoraria; Pfizer: Honoraria; Astellas: Honoraria. Buchheidt:Gilead: Honoraria; MSD: Honoraria; Astellas: Honoraria; Pfizer: Honoraria.

Therapeutic drug monitoring in the treatment of invasive aspergillosis with voriconazole in cancer patients—an evidence-based approach

2015 ◽  
Vol 94 (4) ◽  
pp. 547-556 ◽  
Author(s):  
Meinolf Karthaus ◽  
Thomas Lehrnbecher ◽  
Hans-Peter Lipp ◽  
Stefan Kluge ◽  
Dieter Buchheidt
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Invasive Aspergillosis ◽  
Cancer Patients ◽  
Drug Monitoring ◽  
Therapeutic Drug ◽  
Evidence Based

Importance of voriconazole therapeutic drug monitoring in pediatric cancer patients with invasive aspergillosis

2012 ◽  
Vol 60 (1) ◽  
pp. 82-87 ◽  
Author(s):  
Soo-Han Choi ◽  
Soo-Youn Lee ◽  
Ji-Young Hwang ◽  
Soo Hyun Lee ◽  
Keon Hee Yoo ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Invasive Aspergillosis ◽  
Cancer Patients ◽  
Pediatric Cancer ◽  
Drug Monitoring ◽  
Therapeutic Drug ◽  
Pediatric Cancer Patients

scholarly journals Exposure-Response Relationships for Isavuconazole in Patients with Invasive Aspergillosis and Other Filamentous Fungi

2017 ◽  
Vol 61 (12) ◽  
Author(s):  
Amit V. Desai ◽  
Laura L. Kovanda ◽  
William W. Hope ◽  
David Andes ◽  
Johan W. Mouton ◽  
...  
Keyword(s):  
Steady State ◽  
Invasive Aspergillosis ◽  
Filamentous Fungi ◽  
Aspartate Aminotransferase ◽  
Drug Exposure ◽  
Fungal Infections ◽  
Plasma Concentrations ◽  
Water Soluble ◽  
Therapeutic Drug ◽  
Exposure Response

ABSTRACT Isavuconazole, the active moiety of the water-soluble prodrug isavuconazonium sulfate, is a triazole antifungal agent for the treatment of invasive fungal infections. The purpose of this analysis was to characterize the isavuconazole exposure-response relationship for measures of efficacy and safety in patients with invasive aspergillosis and infections by other filamentous fungi from the SECURE clinical trial. Two hundred thirty-one patients who received the clinical dosing regimen and had exposure parameters were included in the analysis. The primary drug exposure parameters included were predicted trough steady-state plasma concentrations, predicted trough concentrations after 7 and 14 days of drug administration, and area under the curve estimated at steady state (AUCss). The exposure parameters were analyzed against efficacy endpoints that included all-cause mortality through day 42 in the intent-to-treat (ITT) and modified ITT populations, data review committee (DRC)-adjudicated overall response at end of treatment (EOT), and DRC-adjudicated clinical response at EOT. The safety endpoints analyzed were elevated or abnormal alanine aminotransferase, increased aspartate aminotransferase, and a combination of the two. The endpoints were analyzed using logistic regression models. No statistically significant relationship (P > 0.05) was found between isavuconazole exposure and either efficacy or safety endpoints. The lack of association between exposure and efficacy indicates that the isavuconazole exposures achieved by clinical dosing were appropriate for treating the infecting organisms in the SECURE study and that increases in alanine or aspartate aminotransferase were not related to increase in exposures. Without a clear relationship, there is no current clinical evidence for recommending routine therapeutic drug monitoring for isavuconazole.

scholarly journals Vincristine dosing, drug exposure and therapeutic drug monitoring in neonate and infant cancer patients

2021 ◽  
Author(s):  
Shelby Barnett ◽  
Farina Hellmann ◽  
Elizabeth Parke ◽  
Guy Makin ◽  
Deborah A. Tweddle ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Cancer Patients ◽  
Drug Monitoring ◽  
Drug Exposure ◽  
Therapeutic Drug

Position statement of the European Psychiatric Association (EPA) on the value of antidepressants in the treatment of unipolar depression

2012 ◽  
Vol 27 (2) ◽  
pp. 114-128 ◽  
Author(s):  
H.-J. Möller ◽  
I. Bitter ◽  
J. Bobes ◽  
K. Fountoulakis ◽  
C. Höschl ◽  
...  
Keyword(s):  
Drug Treatment ◽  
Clinical Decision Making ◽  
Psychiatric Treatment ◽  
Severe Depression ◽  
Position Statement ◽  
Therapeutic Drug ◽  
Number Needed To Treat ◽  
Evidence Based ◽  
Double Blind ◽  
The Right

AbstractThis position statement will address in an evidence-based approach some of the important issues and controversies of current drug treatment of depression such as the efficacy of antidepressants, their effect on suicidality and their place in a complex psychiatric treatment strategy including psychotherapy. The efficacy of antidepressants is clinically relevant. The highest effect size was demonstrated for severe depression. Based on responder rates and based on double-blind placebo-controlled studies, the number needed to treat (NNT) is 5–7 for acute treatment and four for maintenance treatment. Monotherapy with one drug is often not sufficient and has to be followed by other antidepressants or by comedication/augmentation therapy approaches. Generally, antidepressants reduce suicidality, but under special conditions like young age or personality disorder, they can also increase suicidality. However, under the conditions of good clinical practice, the risk–benefit relationship of treatment with antidepressants can be judged as favourable also in this respect. The capacity of psychiatrists to individualise and optimise treatment decisions in terms of ‘the right drug/treatment for the right patient’ is still restricted since currently there are no sufficient powerful clinical or biological predictors which could help to achieve this goal. There is hope that in future pharmacogenetics will contribute significantly to a personalised treatment. With regard to plasma concentration, therapeutic drug monitoring (TDM) is a useful tool to optimize plasma levels therapeutic outcome. The ideal that all steps of clinical decision-making can be based on the strict rules of evidence-based medicine is far away from reality. Clinical experience so far still has a great impact.

Axitinib for first-line metastatic renal cell carcinoma (mRCC): Overall efficacy and pharmacokinetic (PK) analyses from a randomized phase II study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4503-4503 ◽  
Author(s):  
Brian I. Rini ◽  
Viktor Grünwald ◽  
Mayer N. Fishman ◽  
Bohuslav Melichar ◽  
Takeshi Ueda ◽  
...  
Keyword(s):  
Phase Ii ◽  
Drug Exposure ◽  
Objective Response ◽  
Dose Titration ◽  
Therapeutic Drug ◽  
First Line ◽  
Antihypertensive Medications ◽  
Double Blind ◽  
Randomized Phase Ii ◽  
Optimal Drug

4503 Background: Axitinib is a potent, selective, second-generation inhibitor of vascular endothelial growth factor receptors with efficacy in mRCC. Due to PK and pharmacodynamic variability, some patients have sub-optimal drug exposures at the standard 5-mg twice daily (BID) dose. Prior analyses indicated higher drug exposure enhanced efficacy; thus, dose titration based on individual tolerability may optimize exposure and improve outcomes. A randomized phase II trial evaluated the efficacy and safety of axitinib dose titration from 5 mg BID to a maximum of 10 mg BID in first-line mRCC. Methods: Patients with treatment-naïve mRCC received axitinib 5 mg BID for a 4-week lead-in period (cycle 1). Then, patients with 2 consecutive weeks of blood pressure (BP) ≤150/90 mmHg, no axitinib-related toxicities >grade 2, no dose reductions, and ≤2 antihypertensive medications were randomized in a double-blind fashion to axitinib 5 mg BID + dose titration with either axitinib (arm A) or placebo (arm B); those ineligible for randomization continued with same dose (arm C). Primary endpoint is objective response rate (ORR). Serial 6-hr PK sampling and 24-hr ambulatory BP monitoring (ABPM) were performed on cycle 1 day 15 in a subset of patients. Results: In all, 203 patients were accrued; 112 randomized to arms A or B, and 91 in arm C. As of July 1, 2011, ORR (95% confidence interval [CI]) was 40.2% (31.0, 49.9) in A+B (blinded pooled analysis) and 56.0% (45.2, 66.4) in C. Median progression-free survival (mPFS) (95% CI) was 13.7 mo (9.2, not estimable [NE]) in A+B and 12.2 mo (8.6, 16.7) in C. Patients with drug exposure above therapeutic threshold (AUC24 ≥300 ng·h/mL; n=27) on cycle 1 day 15 had longer mPFS and higher ORR than those with sub-therapeutic exposure (n=25) (mPFS [95% CI]: 13.9 mo [12.2, NE] vs 8.3 mo [5.5, NE]; ORR: 59% vs 48%). Patients with mean increases of diastolic BP (ΔdBP) ≥15 mmHg (n=18) per ABPM had higher ORR than those with ΔdBP <15 mmHg (n=36) (61% vs 53%). Conclusions: Axitinib is effective in first-line treatment of mRCC, with high ORR and mPFS >1 yr. Preliminary results suggest therapeutic drug exposure and ΔdBP ≥15 mmHg on cycle 1 day 15 may be associated with better outcomes.

Position Statement of the European Psychiatric Association (EPA) on the Value of Antidepressants in the Treatment of Unipolar Depression

2011 ◽  
Vol 26 (S2) ◽  
pp. 2200-2200
Author(s):  
H.-J. Möller
Keyword(s):  
Drug Treatment ◽  
Clinical Decision Making ◽  
Psychiatric Treatment ◽  
Severe Depression ◽  
Position Statement ◽  
Therapeutic Drug ◽  
Number Needed To Treat ◽  
Evidence Based ◽  
Double Blind ◽  
The Right

This position statement will address in an evidence-based approach some of the important issues and controversies of current drug treatment of depression such as the efficacy of antidepressants, their effect on suicidality, their place in a complex psychiatric treatment strategy including psychotherapy.The efficacy of antidepressants is clinically relevant. The highest effect size was demonstrated for severe depression. Based on responder rates and based on double-blind placebo-controlled studies, the number needed to treat (NNT) is 5–7 for acute treatment and 4 for maintenance treatment. Monotherapy with one drug is often not sufficient but has to be followed by other antidepressants or by comedication/augmentation therapy approaches.Generally antidepressants reduce suicidality, but under special conditions like young age or personality disorder, they can also increase suicidality. However, under the conditions of good clinical practice, the risk-benefit relationship of treatment with antidepressants can be judged as favourable also in this respect.The capacity of psychiatrists to individualise and optimise treatment decisions in terms of ‘the right drug/treatment for the right patient’ is still restricted since currently there are no sufficient powerful clinical or biological predictors which could help to achieve this goal. There is hope that in future pharmacogenetics will contribute significantly to a personalised treatment. With regard to plasma concentration, therapeutic drug monitoring (TDM) is a useful tool to optimize plasma levels therapeutic outcome.The ideal that all steps of clinical decision making can be based on evidence-based medicine is far away from reality. Clinical experience still has a great impact.

The d-Enantiomer Form of Indobufen Totally Accounts for the Anti-Cyclooxygenase and Antiplatelet Activity Ex Vivo and for the Increase in Bleeding Time by Indobufen in Man

1992 ◽  
Vol 67 (02) ◽  
pp. 258-263 ◽  
Author(s):  
Raffaele De Caterina ◽  
Rosa Sicari ◽  
An Yan ◽  
Walter Bernini ◽  
Daniela Giannessi ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Platelet Aggregation ◽  
Plasma Levels ◽  
Bleeding Time ◽  
Ex Vivo ◽  
Random Sequence ◽  
Antiplatelet Agent ◽  
Antiplatelet Drug ◽  
Double Blind

SummaryIndobufen is an antiplatelet drug able to inhibit thromboxane production and cyclooxygenase-dependent platelet aggregation by a reversible inhibition of cyclooxygenase. Indobufen exists in two enantiomeric forms, of which only d-indobufen is active in vitro in inhibiting cyclooxygenase. In order to verify that also inhibition of platelet function is totally accounted for by d-indobufen, ten patients with proven coronary artery disease (8 male, 2 female, age, mean ± S.D., 58.7 ± 7.5 years) were given, in random sequence, both 100 mg d-indobufen and 200 mg dl-indobufen as single administrations in a double-blind crossover design study with a washout period between treatments of 72 h. In all patients thromboxane (TX) B2 generation after spontaneous clotting (at 0, 1, 2, 4, 6, 8, 12, 24 h), drug plasma levels (at the same times), platelet aggregation in response to ADP, adrenaline, arachidonic acid, collagen, PAF, and bleeding time (at 0, 2, 12 h) were evaluated after each treatment. Both treatments determined peak inhibition of TXB2 production at 2 h from administration, with no statistical difference between the two treatments (97 ±3% for both treatments). At 12 h inhibition was 87 ± 6% for d-indobufen and 88 ± 6% for dl-indobufen (p = NS). Inhibition of TXB2 production correlated significantly with plasma levels of the drugs. Maximum inhibitory effect on aggregation was seen in response to collagen 1.5 pg/ml (63 ± 44% for d-indobufen and 81 ± 22% for dl-indobufen) and arachidonic acid 0.5-2 mM (78 ± 34% for d-indobufen and 88 ± 24% for dl-indobufen) at 2 h after each administration. An effect of both treatments on platelet aggregation after 12 h was present only for adrenaline 2 μM (55 ± 41% for d-indobufen and 37 ± 54% for dl-indobufen), collagen 1.5 pg/ml (69 ± 30% for d-indobufen and 51 ± 61% for dl-indobufen), arachidonic acid 0.5-2 mM (56 ± 48% for d-indobufen and 35 ± 49% for dl-indobufen). The extent of inhibition of TX production and the extent of residual platelet aggregation were never significantly different between treatments. Bleeding time prolongation was similar in the two treatment groups without showing a pronounced and long lasting effect (from 7.0 ± 2.0 min to 10.0 ± 3.0 min at 2 h and 8.0 ± 2.0 min at 12 h for d-indobufen; from 6.0 ±1.0 min to 8.5 ± 2.0 min at 2 h and 8.0 ± 1.0 min at 12 h for dl-indobufen). These results demonstrate that the biological activity of dl-indobufen as an antiplatelet agent in vivo is totally accounted for by d-indobufen.

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