scholarly journals Therapeutic Drug Monitoring of Busulfan in Patients Undergoing Hematopoietic Cell Transplantation: A Pilot Single-Center Study in Taiwan

2021 ◽  
Vol 14 (7) ◽  
pp. 613
Author(s):  
Rong-Long Chen ◽  
Li-Hua Fang ◽  
Xin-Yi Yang ◽  
Mohsin El Amrani ◽  
Esther Veronique Uijtendaal ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Dose Adjustment ◽  
Conditioning Regimen ◽  
Hematopoietic Cell ◽  
Therapeutic Drug ◽  
Single Center ◽  
Taiwanese Population ◽  
Single Center Study ◽  
Center Study

(1) Background: Busulfan has been used as a conditioning regimen in allogeneic hematopoietic cell stem transplantation (HSCT). Owing to a large inter-individual variation in pharmacokinetics, therapeutic drug monitoring (TDM)-guided busulfan dosing is necessary to reduce graft failure and relapse rate. As there exists no TDM of busulfan administration for HCT in Taiwan, we conducted a pilot study to assess the TDM-dosing of busulfan in the Taiwanese population; (2) Methods: Seven patients with HCT from The Koo Foundation Sun Yat-Sen Cancer Center, Taipei, Taiwan, received conditioning regimens consisting of intravenous busulfan and other chemotherapies. After the initial busulfan dose, blood samples were collected for busulfan TDM at 5 min, 1 h, 2 h, and 3 h. Busulfan was extracted and detected by performing stable-isotope dilution LC–MS/MS. Plasma busulfan concentration was quantified and used for dose adjustment. Potential adverse effects of busulfan, such as mucositis and hepatic veno-occlusive disease (VOD), were also evaluated; (3) Results: The LC–MS/MS method was validated with an analyte recovery of 88–99%, within-run and between-run precision of <15%, and linearity ranging from 10 to 10,000 ng/mL. Using TDM-guided busulfan dosing, dose adjustment was necessary and performed in six out of seven patients (86%) with successful engraftments in all patients (100%). Mild mucositis was observed, and VOD was diagnosed in only one patient; (4) Conclusions: This single-center study in Taiwan demonstrated the importance of busulfan TDM in increasing the success rate of HCT transplantation. It is also necessary to further investigate the optimal busulfan target value in the Taiwanese population in the future.

Generic Intravenous Busulfan in Hematopoietic Stem Cell Transplantation: Relevance of Therapeutic Drug Monitoring

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4322-4322 ◽  
Author(s):  
Ezhil Pavai Mohanan ◽  
Shareen Stella Backia Royan ◽  
John C Panetta ◽  
Fouzia Nambiathayil Abubacker ◽  
Anu Korula ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Dose Adjustment ◽  
Conditioning Regimen ◽  
Therapeutic Drug ◽  
Dose Increase ◽  
Median Dose ◽  
Historical Cohort ◽  
Hematopoietic Stem ◽  
Routine Therapeutic Drug Monitoring

Abstract Pharmacokinetic (PK)-targeted dose adjustment of oral Bu has been shown to minimize the toxicity and treatment related mortality following hematopoietic stem cell transplantation (HSCT). Intravenous busulfan (IV Bu) based myeloablative conditioning regimen has significantly reduced the inter-patient variability, ease of administration and reduced toxicities compared to oral Bu. However due to challenges in availability and cost of original formulation (Busulfex, Otsuka Pharmaceuticals) has resulted in the increased use of generic versions of the drug worldwide. Also, in many parts of the world, regulatory approval for generic drugs is obtained only with bioequivalence studies without a clinical trial or PK data. From June 2010 to December 2014, our center has used generic IV busulfan Bucelon™ (Celon Labs, Hyderabad, India) with routine therapeutic drug monitoring and dose adjustment. Since January 2015, Buslera™ (Biem Pharmaceuticals, Ankara, Turkey), a newer generic IV busulfan formulation, is being used in patients undergoing HSCT in our centre due to non-availability of Bucelon™. We prospectively analyzed the PK of IV Buslera™ and compared the systemic exposure and targeted dose adjustment pattern with our experience with Bucelon™. Eighteen patients underwent HSCT with IV Buslera™ based conditioning regimen between January and July 2015. Twelve patients received once daily Bu dose (Q24H; 40mg/m2/day x 4 days) and 6 received every 6 hour dosing (Q6H; 0.8mg/kg/dose x 4 days). In the historical cohort, 135 patients (30 Q6H and 105 Q24H) received Bucelon™ (Mohanan et al, Blood 2013; 122:3280). Demographics of the patients in both groups are depicted in the Table. Blood samples were collected at predetermined time points on day 1 and 3 & busulfan plasma concentrations analyzed using previously published method (Desire et al, 2013). Further doses of busulfan were adjusted to achieve target busulfan AUC (4500-5500 mmoles*min for Q24H and 900-1350 mmoles*min for Q6H). In patients receiving Q24H IV Buslera, the median busulfan AUC on day 1 was 6516 mMoles*min (3908-14064 mMoles*min). The Buslera dose was reduced in 8 patients (median dose reduction 13%; range: 7-18%), increased in one (9%) and 3 patients did not require any dose adjustment. In patients receiving Q6H IV Bu, the AUC on day 1 was 784 mMoles*min (446-960 mMoles*min). Five out of 6 patients required a moderate increase in dose (median dose increase 5%; range: 5-8%) and one did not require any dose adjustment. This data is strikingly different when compared to the historical cohort of patients receiving IV Bucelon™ where 60% patients receiving Q24h dose required dose increase, while with Buslera™ only 9% of patients needed dose increase (p<0.001) to achieve target AUC of busulfan. In general, we noticed that the median clearance of Buslera™ was significantly lower compared to Bucelon™ (Figure) Our study strongly suggests the need for routine therapeutic drug monitoring and targeted dose adjustment of busulfan, especially when different generic busulfan formulations are used. TDM with generic busulfan is even more relevant in markets where approval of generics is done only based on bioequivalence studies with PK data in an appropriate clinical setting and without a clinical trial. Disclosures No relevant conflicts of interest to declare.

Evaluation of Existing Limited Sampling Models for Therapeutic Drug Monitoring of Busulphan in Children and Adults Undergoing SCT.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1150-1150
Author(s):  
Zuzana Hassan ◽  
Marie Sandström ◽  
Moustapha Hassan
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Conditioning Regimen ◽  
Trapezoidal Rule ◽  
Therapeutic Window ◽  
Therapeutic Drug ◽  
High Dose ◽  
Time Interval ◽  
Suitable Model ◽  
Limited Sampling

Abstract Busulphan (Bu) is used in high dose conditioning regimen prior to stem cell transplantation. Bu has a narrow therapeutic window and over- and under-dosing may have a fatal outcome. Bu pharmacokinetics and pharmacodynamics were extensively studied and wide inter- and intra-individual variation was found. Several limited sampling models (LSM) have been developed for Bu administered orally to simplify therapeutic drug monitoring and consequently dose adjustment. The aim of this study was to evaluate the existing LSM in adults and children undergoing conditioning regimen before SCT. Seventy-four patients (62 adults and 12 children) with malignant and non-malignant diseases were analysed. Plasma was sampled at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5 and 6 hours after the first dose of Bu. Bu was determined using gas chromatography with electron capture detection. The area under the plasma concentration-time curve (AUC) for time interval 0 to 6 hours was determined using Winnonlin program and trapezoidal rule. Results were compared to the estimated AUCs using LSMs (Vassal 1992, Schuler 1994, Hassan 1996, Chatergoon 1997). The best correlation between the AUCs determined using trapezoidal rule and 3-points model by Schuler was found (R²=0.95 for all patients, R²=0.97 for children and R²=0.94 for adults). In children, a correlation between AUCs determined with trapezoidal rule and following LSMs was found: 2-points LSM by Schuler (R²=0.94), LSM by Hassan (R²=0.94), LSM by Vassal (R²=0.81) and 3 of 5 LSMs by Chatergoon (R²=0.85, 0.88 and 0.87, resp.). AUCs in children determined using Winnonlin showed good correlation with both Schuler’s models, model by Hassan and one of 4-points models by Chatergoon. However, the correlation between the AUCs determined using trapezoidal rule and Winnonlin was good in children (R²=0.98), but not in adults (R²=0.65). Thus, several limited sampling models are suitable for AUC estimation in children, while there is only one suitable model for adults. This conclusion is made with reservation that even the trapezoidal rule may underestimate the real AUC dependent on sampling density.

Posaconazole Prophylaxis in Patients Undergoing Chemotherapy for Acute Myeloid Leukemia: A Single Center Experience of Therapeutic Drug Monitoring.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2595-2595 ◽  
Author(s):  
Laura Pavan ◽  
Arianna Loregian ◽  
Angela Maria Quinto ◽  
Speranza Antonia Di Maggio ◽  
Silvana Pagni ◽  
...  
Keyword(s):  
Liquid Chromatography ◽  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Salvage Therapy ◽  
Plasma Concentrations ◽  
Response To Therapy ◽  
Therapeutic Drug ◽  
Single Center ◽  
Breakthrough Infection ◽  
Acute Myeloid

Abstract Abstract 2595 Background: Posaconazole is indicated for prophylaxis and salvage therapy of invasive fungal infections. Based on pharmacokinetic-pharmacodynamic data, a minimum serum concentration higher than 0.5 mg/L and 1.0 mg/L has been proposed for prophylaxis and therapy, respectively. While therapeutic drug monitoring (TDM) of plasma concentrations is widely accepted for triazole antifungal agents such as voriconazole, the utility of TDM for posaconazole is controversial due to debate over the relationship between posaconazole exposure in plasma and clinical response to therapy. In fact only few reports correlate posaconazole plasma concentrations (PPCs) with breakthrough infection. Methods: In this retrospective single center study we evaluated the correlation of PPCs with breakthrough invasive mould infections (IMIs) in 50 patients with acute myeloid leukaemia (AML) who underwent chemoterapy (induction or salvage therapy) between July 2009 and March 2012. To measure the posaconazole concentration in human plasma, we developed and validated a rapid and simple high-performance liquid chromatography method. The method involved a solid-phase extraction of posaconazole using Oasis HLB cartridges, a reversed-phase liquid chromatography on an XTerra RP18 column with a mobile phase consisting of acetonitrile/ammonium acetate and ultraviolet detection. Patient characteristics and microbiological data such galactomannan detection and TDM were collected retrospectively. A total of 454 PPCs were measured before and 4 hours after administration in 50 patients with AML receiving posaconazole prophylaxis at dose of 200 mg 3 times/day. When plasma levels were below 0.5 mg/L, the dose was increased to 200 mg 4 times/day. Results: Average levels below the target of 0.5 μg/mL were detected in 38 (76%) out of 50 cases; 5 out of 38 cases showed plasma concentrations <0.20 μg/mL. Six patients (12%) receiving PCZ prophylaxis met the criteria of breakthrough infection (5 possible and 1 probable). Noteworthy, none of these patients achieved a complete remission after chemotherapy. Prior to development of IMIs, PPCs were below the target in 4 out of 6 (66%) cases experiencing breakthrough infection (between 0.2 and 0.5 μg/mL). Interestingly, only one patient had galactomannan positivity in the bronchoalveolar lavage fluid whereas none of the cases had serum galactomannan. Furthermore, out of 13 patients with resistant disease who did not develop IMIs, 8 (62%) presented PCPs < 0.5 μg/mL. Conclusions: Our data demonstrate that low PPCs are common in patients receiving posaconazole prophylaxis during chemotherapy for AML. However, in spite of low PPCs, the rate of IMIs was low. This is possibly due to the good lung bioavailability of the drug, despite the presence of low drug serum levels. In addition, our data seems to confirm that refractory disease is a strong risk factor for the development of IMIs. Even in this high risk group, low PPCs did not correlate with high IMIs' incidence. A prospective evaluation of TDM of posaconazole is needed. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Population Pharmacokinetic Model Development of Tacrolimus in Pediatric and Young Adult Patients Undergoing Hematopoietic Cell Transplantation

2021 ◽  
Vol 12 ◽  
Author(s):  
Jordan T. Brooks ◽  
Ron J. Keizer ◽  
Janel R. Long-Boyle ◽  
Sandhya Kharbanda ◽  
Christopher C. Dvorak ◽  
...  
Keyword(s):  
Young Adult ◽  
Therapeutic Drug Monitoring ◽  
Continuous Infusion ◽  
Drug Monitoring ◽  
Model Building ◽  
Hematopoietic Cell ◽  
Adult Patients ◽  
Therapeutic Drug ◽  
Poppk Model ◽  
Best Fit

Background: With a notably narrow therapeutic window and wide intra- and interindividual pharmacokinetic (PK) variability, initial weight-based dosing along with routine therapeutic drug monitoring of tacrolimus are employed to optimize its clinical utilization. Both supratherapeutic and subtherapeutic tacrolimus concentrations can result in poor outcomes, thus tacrolimus PK variability is particularly important to consider in the pediatric population given the differences in absorption, distribution, metabolism, and excretion among children of various sizes and at different stages of development. The primary goals of the current study were to develop a population PK (PopPK) model for tacrolimus IV continuous infusion in the pediatric and young adult hematopoietic cell transplant (HCT) population and implement the PopPK model in a clinically available Bayesian forecasting tool.Methods: A retrospective chart review was conducted of 111 pediatric and young adult patients who received IV tacrolimus by continuous infusion early in the post-transplant period during HCT from February 2016 to July 2020 at our institution. PopPK model building was performed in NONMEM. The PopPK model building process included identifying structural and random effects models that best fit the data and then identifying which patient-specific covariates (if any) further improved model fit.Results: A total of 1,648 tacrolimus plasma steady-state trough concentrations were included in the PopPK modeling process. A 2-compartment structural model best fit the data. Allometrically-scaled weight was a covariate that improved estimation of both clearance and volume of distribution. Overall, model predictions only showed moderate bias, with minor under-prediction at lower concentrations and minor over-prediction at higher predicted concentrations. The model was implemented in a Bayesian dosing tool and made available at the point-of-care.Discussion: Novel therapeutic drug monitoring strategies for tacrolimus within the pediatric and young adult HCT population are necessary to reduce toxicity and improve efficacy in clinical practice. The model developed presents clinical utility in optimizing the use of tacrolimus by enabling model-guided, individualized dosing of IV, continuous tacrolimus via a Bayesian forecasting platform.

scholarly journals Advantages of Tailored Isotretinoin Treatment in Moderate to Severe Acne: Real-Life Data

2021 ◽  
Vol 12 ◽  
Author(s):  
Nevena Skroza ◽  
Ersilia Tolino ◽  
Veronica Balduzzi ◽  
Nicoletta Bernardini ◽  
Alessandra Mambrin ◽  
...  
Keyword(s):  
Dose Adjustment ◽  
Systemic Treatment ◽  
Real Life ◽  
Efficacy And Safety ◽  
Single Center ◽  
Severe Acne ◽  
Life Data ◽  
Real Life Data ◽  
Single Center Study ◽  
Center Study

This retrospective single-center study analyzes the efficacy and safety of isotretinoin for the treatment of moderate to severe acne in real-life clinical practice, particularly with regard to acne severity, isotretinoin cumulative dosage, and patients’ gender. The results suggest the opportunity of an early isotretinoin systemic treatment in patients affected by moderate acne and emphasize the importance of an appropriate dose adjustment in order to minimize adverse events.

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