scholarly journals Fixed-dose combination and therapeutic drug monitoring in tuberculosis: friend or foe?

2016 ◽  
Vol 48 (4) ◽  
pp. 1230-1233 ◽  
Author(s):  
Marlanka A. Zuur ◽  
Onno W. Akkerman ◽  
Lina Davies Forsman ◽  
Yi Hu ◽  
Rongdong Zheng ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Fixed Dose Combination ◽  
Fixed Dose ◽  
Therapeutic Drug ◽  
Dose Combination

Concomitant intake of abiraterone and food to increase pharmacokinetic exposure: Real-life data from a therapeutic drug monitoring program.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3117-3117 ◽  
Author(s):  
Stefanie L. Groenland ◽  
Andre M. Bergman ◽  
Alwin Huitema ◽  
Neeltje Steeghs
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Monitoring Program ◽  
Real Life ◽  
Progression Free Survival ◽  
Abiraterone Acetate ◽  
Fixed Dose ◽  
Therapeutic Drug ◽  
Castration Resistant Prostate Cancer ◽  
Regular Treatment

3117 Background: Abiraterone acetate is registered for the treatment of metastatic castration resistant prostate cancer. Pharmacokinetic (PK) exposure has been linked to efficacy, since patients with Cmin ≥ 8.4 ng/mL have a significantly longer progression free survival compared to patients with a Cmin below this threshold (7.4 vs. 12.2 months, p = 0.044) (Carton, 2017). At the recommended fixed dose of 1000 mg QD administered in a modified fasting state, 35% of patients do not reach this efficacy threshold (Carton, 2017), providing a strong rationale for therapeutic drug monitoring (TDM). Since a clinically relevant food effect has been established, concomitant intake of abiraterone and food could offer a cost-neutral solution in case of low exposure (Chi, 2015). This study aims to evaluate whether PK-guided abiraterone dosing is feasible and results in an increased proportion of patients with concentrations above the target. Methods: Patients starting regular treatment with abiraterone were included. PK sampling occurred 4, 8 and 12 weeks after start of treatment, and every 12 weeks thereafter. Abiraterone concentrations were measured and Cmin was calculated. In case of Cmin < 8.4 ng/mL and acceptable toxicity, a PK-guided intervention was advised. As a first step, concomitant intake of abiraterone and a light meal or a snack was advised. Results: In total, 35 patients were included, of which 18 patients (51%) had at least one Cmin < 8.4 ng/mL. These patients were advised to take abiraterone concomitantly with food, after which Cmin increased significantly from 5.6 (47%) ng/mL [mean (CV%)] to 40.6 (110%) ng/mL (p = 0.006) without additional toxicities. This intervention led to adequate exposure in 15 patients (83%). Seventeen patients had all Cmin levels ≥ 8.4 ng/mL, in these patients mean Cmin was 31.5 (65%) ng/mL. Conclusions: TDM of abiraterone was applied in clinical practice and proved to be feasible. Concomitant intake with food resulted into a significant increase in Cmin and offers a cost-neutral opportunity to optimize treatment for patients with low PK exposure. Up to 100 patients will be included to evaluate the effect of PK-guided abiraterone dosing on treatment efficacy. Clinical trial information: NL6695.

Inadequate Therapeutic Response to a Recommended Antituberculosis Fixed-Dose Combination Regimen in an Overweight Patient with Mycobacterium bovis Infection

2013 ◽  
Vol 47 (1) ◽  
pp. e4-e4
Author(s):  
Célia Lloret-Linares ◽  
Stéphane Mouly ◽  
Dan-Tranh Hoang-Nguyen ◽  
John Evans ◽  
Laurent Raskine ◽  
...  
Keyword(s):  
Mycobacterium Bovis ◽  
Fixed Dose Combination ◽  
Fixed Dose ◽  
Therapeutic Drug ◽  
Combination Regimen ◽  
Overweight Patient ◽  
Tuberculosis Complex ◽  
Drug Concentrations ◽  
Dose Combination ◽  
Lymph Node Tuberculosis

OBJECTIVE To report a case of an overweight man with lymph node tuberculosis due to Mycobacterium bovis, a part of the Mycobacterium tuberculosis complex, treated with fixed-dose combination (FDC) chemotherapy. CASE REPORT Following guidelines, according to the patient's weight (92 kg), we prescribed the maximum recommended doses of isoniazid-rifampin-pyrazinamide FDC. It led initially to underdosing, with a poor clinical outcome, justifying increased doses and a complex regimen using separate drugs (isoniazid 600 mg, rifampin 1200 mg, and levofloxacin 1000 mg) to achieve therapeutic drug concentrations and clinical response. DISCUSSION Usually recommended doses of FDC chemotherapies may be inappropriate in overweight patients. We discuss here the different factors that may be involved in poor clinical outcomes, particularly the consequences of excess weight on drug metabolism: drug-drug interaction, FDC use, generic formulation use, intestinal malabsorption, and acetylation profile. CONCLUSIONS Therapeutic drug monitoring in overweight patients may be useful in the clinical setting to help clinicians individualize drug therapeutic regimens and optimize drug response, adherence, and safety.

Therapeutic drug monitoring of nivolumab in clinical practice: Preliminary experience.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14089-e14089
Author(s):  
Manuel Sureda ◽  
Ana Catalán-Latorre ◽  
Juan José Mata ◽  
Vanesa Escudero ◽  
Antonio Brugarolas
Keyword(s):  
Clinical Practice ◽  
Steady State ◽  
Therapeutic Drug Monitoring ◽  
Solid Tumors ◽  
Drug Monitoring ◽  
Cell Cancer ◽  
Plasma Concentrations ◽  
Fixed Dose ◽  
Therapeutic Drug ◽  
Multiple Tumor

e14089 Background: Fixed dose schemes, regardless of body weight, have been accepted by the regulatory agencies for the PD-1 targeting antibodies. Zaho X. and Ratain M. have elucidated that the mean steady state concentrations of nivolumab (N) at flat-doses of 240 mg Q2W or 480 mg Q4W were 57 µg/mL and 47 µg/mL, respectively. These levels are very similar to those observed at the dosage of 3 mg/kg Q2W. Considering the long half-life of N, its mechanism of action and the absence of correlation between exposure and response or toxicity at clinically tested doses, other schemes can be explored. Moreover, therapeutic drug monitoring (TDM) can contribute to individualize and optimize dosage. We determined serum N levels in patients with solid tumors. Methods: The PK profile of N was analyzed in 15 patients with solid tumors who received 3 mg/kg Q2W from May 2017 through January 2019. Eligible patients had non-small-cell lung cancer (n = 7), urothelial cancer (n = 1), gastric cancer (n = 1), breast cancer (n = 1), renal cell cancer (n = 1), colorectal cancer (n = 1), prostate cancer (n = 1), melanoma (n = 1) and sarcoma (n = 1). Free N serum concentrations were determined with a quantitative ELISA capable of detecting ≥ 0.3 µg/mL (Shikari Q-Nivo, Matriks Biotek, Ankara, Turkey). A total of 28 TDM were done after steady state (6th and 26th cycle). Results: For different reasons, 9 patients received N at 3, 4, 5, 6 or 7 week intervals once the steady state was reached. In these patients, a median reduction of 20.8% (6.7% - 43.0%) of the received doses was observed. Mean plasma concentrations of N observed after administration every 2 weeks was 73.5±32.5 µg/mL (n = 9). Once the steady state was reached, mean plasma concentrations at 3, 4, 5, 6 or 7 weeks, were 54.0±1.3 µg/mL (n = 2), 45.1±25.3 µg/mL (n = 7), 42.9±29.5 µg/mL (n = 5) and 24.4±11.7 µg/mL (n = 5), respectively. No statistically significant differences were observed in the serum levels of N between the dosing intervals of 3, 4 and 5 weeks and the standard regimen (Q2W) (p > 0.05). These data are similar to those described by Long G.V. et al. that compared N pharmacokinetic exposure for the 480 mg Q4W schedule simulated in 3817 patients across multiple tumor types with those for the 3 mg/kg Q2W and 240 mg Q2W schedules. Conclusions: The incorporation of the TDM of N in routine clinical practice could help to maintain a therapeutic drug plasma concentration with lower or less frequent doses, adding a financial benefit, without decreasing clinical efficacy. Further randomized trials to explore alternative dosing schemes of N, including personalization through TDM, are warranted

Therapeutic Drug Monitoring: Role for a Pharmacist in Multidisciplinary Antiretroviral Management

2005 ◽  
Vol 18 (4) ◽  
pp. 310-321
Author(s):  
Judianne C. Slish ◽  
Linda M. Catanzaro ◽  
Olanrewaju Okusanya ◽  
Lisa M. Demeter ◽  
Mary Albrecht ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Drug Exposure ◽  
Treatment Guidelines ◽  
Management Strategies ◽  
Additional Patient ◽  
Fixed Dose ◽  
Therapeutic Drug ◽  
Multiple Drug ◽  
Clinical Tool

The current treatment guidelines for HIV pharmacotherapy recommend combinations of antiretrovirals (ARVs) to achieve optimal suppression of HIV replication. However, the initiation and long-term management of ARV therapy in a patient is often complicated by variable medication adherence, complex medication use with multiple drug interactions, the occurrence of drug toxicity, and drug therapy for comorbid conditions that require additional patient education and laboratory monitoring. For these reasons, the inclusion of a well-trained pharmacist in multidisciplinary health system management strategies has been increasing. Furthermore, the use of fixed-dose ARVs is accompanied by considerable interpatient variation in pharmacokinetics yielding a range of drug exposures from any given ARV dose. One approach to overcoming this variable drug exposure is to use plasma concentration monitoring (eg, therapeutic drug monitoring [TDM]) as a clinical tool to adjust doses to achieve targeted concentration ranges, often in conjunction with HIV resistance tests. While data in support of TDM are emerging, the development of programs that include an HIV pharmaceutical care specialist and an adherence program with an integrated clinical pharmacology resource that can provide reliable TDM assays has been reported and provides the rationale for including pharmacists in the implementation of ARV TDM programs.

Therapeutic drug monitoring of pazopanib: Using cost-neutral PK-guided interventions to optimize exposure.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3598-3598
Author(s):  
Stefanie L. Groenland ◽  
Ruben A.G. van Eerden ◽  
Stijn L.W. Koolen ◽  
Dirk Jan A.R. Moes ◽  
Alex Imholz ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Standard Dose ◽  
Daily Practice ◽  
Fixed Dose ◽  
Therapeutic Drug ◽  
Fasting State ◽  
Reduced Dose ◽  
Drug Concentrations ◽  
Clinical Trial Information

3598 Background: Pazopanib is an approved treatment for renal cell carcinoma (RCC) and soft tissue sarcoma (STS). At the currently registered fixed dose of 800 mg QD, 20% of patients (pts) do not attain the efficacy threshold of Cmin ≥ 20.5 mg/L (Suttle et al, 2014), providing a strong rationale for therapeutic drug monitoring (i.e. individualizing the dose based on measured plasma drug concentrations). Previous studies provided cost-neutral alternatives to absolute dose increments to optimize exposure (i.e. splitting intake moments or concomitant intake with food (Groenland et al, 2020; Lubberman et al, 2019)). This study aimed to investigate the feasibility, tolerability and efficacy of TDM of pazopanib, using cost-neutral interventions. Methods: Patients starting treatment with pazopanib at the standard dose of 800 mg QD in modified fasting state were included in the prospective DPOG TDM study (www.trialregister.nl, NL6695). PK sampling occurred 4, 8 and 12 weeks after start of treatment, and every 12 weeks thereafter. Pazopanib concentrations were measured with LC-MS/MS and Cmin was calculated. In case of Cmin < 20.5 mg/L and acceptable toxicity, a dose intervention was recommended. As a first step, intake moments were split (i.e. 400 mg BID). Secondly, concomitant intake with food was recommended. Results: In total, 34 pts were included (19 STS, 15 RCC), of whom 158 PK samples were collected. Eleven pts (32%) were underdosed and had at least 1 PK sample below the target. In 24% of the pts a PK-guided intervention could be performed, which was successful in 6 pts (75%). Median Cmin increased from 15 mg/L to 32 mg/L (p = 0.027). Eventually, 3 pts went back to 800 mg QD due to toxicity, after which Cmin remained ≥ 20.5 mg/L in 2 pts. In pts with adequate exposure throughout the study, median Cmin was 32 mg/L (range 23 – 65 mg/L). In 3 pts, a PK-guided intervention could not be performed, due to progression (n = 1) or logistical issues (n = 2). Twelve pts (35%) received a dose reduction due to toxicity (lowest dose was 200 mg QAD), exposure remained adequate at this reduced dose in all pts. For STS pts, median PFS was 19.8 months in pts with Cmin < 20.5 mg/L who did need an intervention vs. 6.4 months in pts with all Cmin ≥ 20.5 mg/L (not significant). For RCC pts, this was 15.5 months vs. 7.4 months, respectively (not significant). Conclusions: This prospective study shows that PK-guided dose optimization of pazopanib using cost-neutral interventions is feasible in daily practice. A PK-guided intervention was performed in 24% of the patients, which was successful in 75% of these patients. Clinical trial information: NL6695 .

Diagnose und Monitoring bei chronisch-entzündlicher Darmerkrankung

2018 ◽  
Vol 75 (5) ◽  
pp. 316-328
Author(s):  
Christian Ansprenger ◽  
Emanuel Burri
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Morbus Crohn ◽  
Therapeutic Drug ◽  
Körperliche Untersuchung

Zusammenfassung. Die Diagnose und auch die Überwachung von chronisch entzündlichen Darmerkrankungen ruht auf mehreren Säulen: Anamnese, körperliche Untersuchung, Laborwerte (im Blut und Stuhl), Endoskopie, Histologie und Bildgebung. Die Diagnose kann nicht anhand eines einzelnen Befundes gestellt werden. In den letzten Jahren hat sich das Therapieziel weg von klinischen Endpunkten hin zu endoskopischen und sogar histologischen Endpunkten entwickelt. Für einige dieser neuen Therapieziele existiert allerdings noch keine allgemein gültige Definition. Regelmässige Endoskopien werden von Patienten schlecht toleriert, weshalb Surrogat-Marker wie Calprotectin untersucht wurden und eine gute Korrelation mit der mukosalen Entzündungsaktivität nachgewiesen werden konnte. Entsprechend zeigte sich bei Morbus Crohn eine Algorithmus-basierte Therapiesteuerung – unter anderem basierend auf Calprotectin – einer konventionellen Therapiesteuerung überlegen. Die Überwachung der medikamentösen Therapie («Therapeutic Drug Monitoring» [TDM]) ist ein zweites Standbein des Monitoring von chronisch entzündlichen Darmerkrankungen. Mit zunehmendem Einsatz vor allem der Biologika-Therapien wurden sowohl reaktives TDM (in Patienten mit klinischem Rezidiv) als auch proaktives TDM (in Patienten in Remission / stabiler Erkrankung) untersucht und haben (teilweise) Eingang in aktuelle Richtlinien gefunden. Zukünftige Studien werden die vorgeschlagenen Therapieziele besser definieren und den Nutzen der medikamentösen Therapieüberwachung auf den Krankheitsverlauf weiter untersuchen müssen.

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