Feasibility Of Therapeutic Drug Monitoring Research Articles

Evaluating the Clinical Impact and Feasibility of Therapeutic Drug Monitoring of Pazopanib in a Real-World Soft-Tissue Sarcoma Cohort.

Pazopanib is registered for metastatic renal cell carcinoma and soft-tissue sarcoma (STS). Its variable pharmacokinetic (PK) characteristics and narrow therapeutic range provide a strong rationale for therapeutic drug monitoring (TDM). Prior studies have defined target levels of drug exposure (≥20.5 mg/L) linked to prolonged progression-free survival (PFS), but the added value of using TDM remains unclear. This study investigates the effect of TDM of pazopanib in patients with STS on survival outcomes and dose-limiting toxicities (DLTs) and evaluates the feasibility of TDM-guided dosing. A TDM-guided cohort was compared to a non-TDM-guided cohort for PFS, overall survival (OS) and DLTs. PK samples were available from all patients, though not acted upon in the non-TDM-guided cohort. We evaluated the feasibility of TDM by comparing the proportion of underdosed patients in our TDM cohort with data from previous publications. A total of 122 STS patients were included in the TDM-guided cohort (n = 95) and non-TDM-guided cohort (n = 27). The average exposure in the overall population was 30.5 mg/L and was similar in both groups. Median PFS and OS did not differ between the TDM-guided cohort and non-TDM-guided cohort (respectively 5.5 vs 4.4 months, p = 0.3, and 12.6 vs 10.1 months, p = 0.8). Slightly more patients in the non-TDM-guided cohort experienced DLTs (54%) compared to the TDM-guided cohort (44%). The proportion of underdosed patients (13.3%) was halved compared to historical data (26.7%). TDM reduced the proportion of patients with subtherapeutic exposure levels by ~50%. Nonetheless, the added value of TDM for achieving target trough levels of ≥20.5 mg/L for pazopanib on survival outcomes could not be confirmed in STS patients.

Reliability and feasibility of home-based dried blood spot in therapeutic drug monitoring: a systematic review and meta-analysis.

Dried blood spot (DBS) is one of promising home sampling methods for therapeutic drug monitoring (TDM). However, the associated reliability and feasibility (including yield, adherence, and preference), which are criteria for the promotion of home-based DBS, remain unknown. This systematic review and meta-analysis aimed to evaluate the reliability and feasibility of TDM using DBS sampling. In this study, a combination of MeSH and free terms for (dried blood spot*[title/abstract])AND ("Drug Monitoring"[Mesh])AND(home OR venous)was surveyed using EMBASE, PubMed, Cochrane Library, and Web of Science upon gathering published. we registered this study protocol with the International Prospective Registry of Systematic Reviews (CRD42021247559). Approximately half (35/75) of the evaluations reported good agreement between DBS and plasma, and the results for drugs with poor agreement may be improved using a haematocrit-based physiological equation. The yield and adherence to home-based DBS exceeded 87%, and questionnaire-based preference for DBS was 77%. DBS may be a reliable and feasible home sampling method; however, it requires intricate design and evaluation before implementation.

Establishment and validation of a LC-MS/MS method for the determination of anlotinib in human plasma: Application to therapeutic drug monitoring.

Anlotinib is a novel small molecule multitarget tyrosine kinase inhibitor for the treatment of several cancers. We developed and validated a highly sensitive, rapid and stable high-performance liquid chromatography-mass spectrometrymethod for the determination of anlotinib in human plasma with anlotinib-d5 as a stable isotopically labeled internal standard (SIL-IS). To explore the feasibility of therapeutic drug monitoring in the treatment of tumors with anlotinib, human plasma samples were prepared by protein precipitation. The mobile phases comprised of (A) 5.0mm NH4 AC aqueous solution containing 0.1% formic acid and (B) 100% methanol containing 0.1% formic acid. A gradient mobile phase system was adopted for chromatographic separation using a BEH C18 (2.1 × 50 mm, 1.7μm) column. A positive ion pattern was chosen for quantification under multiple reaction monitoring mode. The ion pairs were detected at m/z 408.2→339.1 and m/z 413.4→344.3 for anlotinib and anlotinib-d5 (SIL-IS), respectively. The total run time was 5.0min. The calibration curve was found to be linear within a plasma concentration range of 2-400 ng·ml-1 . The precision and accuracy, matrix effect, extraction recovery and stability were all validated and met the requirements of international guidelines. The proposed methods were successfully applied to support therapeutic drug monitoring in breast and thyroid cancer patients receiving anlotinib for therapy. Clinical data showed that in the 12 mg dose group, the mean plasma concentrations of anlotinib in breast cancer patients and thyroid cancer patients were 87.1 and 118.8ng·ml-1 , respectively. The data demonstrate that the peak concentration of anlotinib may be related to the different tumor types in patients.

Feasibility of therapeutic drug monitoring of sorafenib in patients with liver or thyroid cancer

IntroductionSorafenib is a tyrosine-kinase inhibitor approved for the treatment of renal cell carcinoma, hepatocellular carcinoma, thyroid carcinoma, and desmoid fibromatosis. As high inter-individual variability exists in exposure, there is a scientific rationale to pursue therapeutic drug monitoring (TDM). We investigated the feasibility of TDM in patients on sorafenib and tried to identify sub-groups in whom pharmacokinetically (PK) guided-dosing might be of added value. MethodsWe included patients who started on sorafenib (between October 2017 and June 2020) at the recommended dose of 400 mg BID or with a step-up dosing schedule. Plasma trough levels (Ctrough) were measured at pre-specified time-points. Increasing the dose was advised if Ctrough was below the target of 3750 ng/mL and toxicity was manageable. ResultsA total of 150 samples from 36 patients were collected. Thirty patients (83 %) had a Ctrough below the prespecified target concentration at a certain time point during treatment. Toxicity from sorafenib hampered dosing according to target Ctrough in almost half of the patients. In 11 patients, dosing was adjusted based on Ctrough. In three patients, this resulted in an adequate Ctrough without additional toxicity four weeks after the dose increase. In the remaining eight patients, dose adjustment based on Ctrough did not result in a Ctrough above the target or caused excessive toxicity. ConclusionsTDM for sorafenib is not of added value in daily clinical practice. In most cases, toxicity restricts the possibility of dose escalations.

Feasibility of therapeutic drug monitoring of sunitinib and its implications on response and toxicity in patients with metastatic renal cell cancer.

Sunitinib is an oral tyrosine kinase inhibitor approved for the treatment of metastatic renal cell carcinoma (mRCC). High variability in pharmacokinetics coupled with a proven exposure-effect relationship makes sunitinib an ideal candidate for therapeutic drug monitoring (TDM). The feasibility of TDM of sunitinib in patients with mRCC was evaluated in this prospective observational study in a real-world scenario. Seventy patients with mRCC treated with sunitinib at a fixed dose of 50mg per day were enrolled in the study. Total trough plasma level (TTL) of sunitinib (sunitinib and its active metabolite, SU12662), was measured between days 14/15 of cycle 1. The discriminatory potential of TTL of sunitinib for the prediction of responders and occurrence of grade ≥ 3 toxicity was determined using receiver operating characteristic (ROC) curve. The median TTL of sunitinib was 76ng/mL. Forty six out of 70 patients were evaluable for response, whereas 60 out of 70 patients were evaluable for toxicity. Threshold concentrations obtained from ROC analysis showed that TTL of 60.75ng/mL and 82.3ng/mL was discriminatory for response and occurrence of grade ≥ 3 toxicity respectively. 31/34 (91.7%) patients having TTL ≥ 60.75ng/mL responded to treatment, while only 5/12 (41.6%) responded when TTL was < 60.75ng/mL (P = 0.001). On the other hand, the incidence of grade ≥ 3 toxicity was 9/24 (37.7%) in patients with TTL ≥ 82.3ng/mL compared to 4/36 (11.1%) in patients with TTL < 82.3ng/mL (P = 0.024). The TTL range of 60.75-82.3ng/mL was found to be optimal in terms of safety and efficacy. More than 50% of patients in our cohort attained TTL of sunitinib outside the optimal range, thus demonstrating the feasibility of TDM to improve safety and efficacy of sunitinib in mRCC.

Feasibility of Using Oral Fluid for Therapeutic Drug Monitoring of Antiepileptic Drugs.

Therapeutic drug monitoring (TDM) of antiepileptic drugs (AED) using blood is well established but limited by its invasiveness, accessibility, cost, interpretation errors, and related disturbances in protein binding. TDM using oral fluid (OF) could overcome these limitations. This paper provides a summary of the current evidence for using OF as a matrix to perform TDM of AEDs, as well as practical considerations. A literature search of MEDLINE, EMBASE, and the Cochrane Library was conducted on April 9, 2018 (and then updated on May 20, 2020) using all AEDs as keywords along with "oral fluid," "saliva," "salivary," "seizure," "epilepsy," "antiepileptic," and "anticonvulsant." A total of 18 relevant articles were found and included in this review. There is evidence to suggest that AED TDM using OF is feasible and that reference ranges can be calculated for the following drugs: carbamazepine, ethosuximide, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, primidone, topiramate, and valproic acid. For all other AEDs, there is either a lack of evidence on the feasibility of TDM using OF or the evidence indicates that TDM using OF is not feasible. Practical considerations should include the timing and method of OF collection (stimulated or unstimulated) due to their probable impact on the reliability of AED TDM. Using OF may improve the acceptability and accessibility and reduce the cost of AED TDM. Clinical implementation requires standardized collection protocols, more rigorously defined OF reference ranges, and further studies to determine the relevance to clinically important outcomes.

A fluorescence biosensor for therapeutic drug monitoring of vancomycin using in vivo microdialysis

Clinical vancomycin (Van) treatment is administered over a prolonged period to achieve a sustained therapeutic effect. Accurate, rapid, and continuous Van detection is an unmet medical monitoring need that can provide data-based guidance for doctors to adjust the dosage and treatment plan in real-world settings. In this study, we created a Van-specific, fluorescent biosensor that was combined with a microdialysis sampling technique to develop a rapid, simple, accurate, and sensitive detection method, which was validated for Van in vivo. A Van-specific probe was created by separately conjugating each of the two peptide chains of a dimeric derivative of the Van binding peptide L-Lys-D-Ala-D-Ala to a fluorescent dansyl chloride group. Subject-specific pharmacokinetics of Van was recorded in normal rabbits and rabbits with adenine-induced chronic renal failure (CRF), which indicated the feasibility of therapeutic drug monitoring in vivo. The area under the concentration–time curve (AUC0–last) was 10,715 min μg mL−1 (95% CI = 8,892 to 12,538) in the normal rabbits, and 14,822 and 19,025 min μg mL−1 in two selected CRF rabbits. Furthermore, using pharmacokinetic dosing of Van in a rabbit study, we designed the dosage and drug administration interval to achieve a sustained therapeutic effect. The normal rabbits received three Van doses, 20, 5, and 5 mg kg−1, administered at 0, 500, and 900 min, respectively. The CRF rabbits received two Van doses, 20 and 5 mg kg−1, administered at 0 and 600 min, respectively. Thus, we established an effective method for the continuous monitoring of Van. This method facilitates the detection of Van in clinical treatment and provides the scientific basis for an effective approach to monitor blood drug levels during the clinical treatment of various diseases.

Feasibility and safety of tailored dosing schedule for eculizumab based on therapeutic drug monitoring: Lessons from a prospective multicentric study.

Eculizumab is an anti-C5 monoclonal antibody approved for rare diseases including atypical haemolytic-uraemic syndrome. The maintenance phase dosing regimen is identical for all adult patients: 1200 mg every 2 weeks. Recent studies reported an overexposure in many patients when considering a target trough concentration range of 50-100 mg/L. The aim of the present work was to validate the feasibility of therapeutic drug monitoring of eculizumab in atypical haemolytic-uraemic syndrome patients. We performed a 2-step prospective multicentre study. In the first phase, we developed a pharmacokinetic population model using data from 40 patients and identified patients for whom a 1-week lengthening of interval between infusions would lead to a trough concentration above 100 mg/L. In the second phase, selected patients were allocated a 1-week extension and eculizumab trough concentrations were monitored. The model confirmed the previously reported influence of bodyweight on elimination clearance and predicted that 36 (90%) patients would be eligible for interval extension. In the second phase of the study, a 1-week lengthening of interval between infusions was performed in 15 patients whose trough concentration at the next visit was predicted with a Bayesian model to be above 100 mg/L. After interval extension, 10 patients (67%) presented measured trough concentrations over 100 mg/L. No biological or clinical recurrence of disease was observed, even in the 5 patients with concentrations below 100 mg/L in whom the initial dosing regimen was resumed. Safe eculizumab interval adjustment is feasible with a PK monitoring.

Urine colorimetry for levofloxacin pharmacokinetics and personalized dosing in people with drug-resistant tuberculosis.

Background:Levofloxacin is a preferred drug for multidrug-resistant (MDR)-tuberculosis (TB) with bactericidal activity that correlates with the pharmacokinetic exposures of serum peak concentration (Cmax) and total area under the concentration time curve (AUC0-24). Pharmacokinetic exposures can be measured to personalize dosing to reach targets, but this practice requires venepuncture, chromatographic or mass spectrometry equipment, and technical expertise. We sought to demonstrate the accuracy of using urine colorimetry as a more feasible estimation of levofloxacin exposure.Method:A colorimetric method using bromocresol green was tested on spiked urine samples with levofloxacin measured using a spectrophotometer. This method was tested in urine samples of healthy volunteers given one 750 mg dose of levofloxacin with urine collected at 0–4 h, 4–8 h, and 8–24 h intervals, and concomitant serum samples were collected and analyzed by high-performance liquid chromatography. Validation of this assay was done in a cohort of people living with human immunodeficiency virus (PLWH), initiating a levofloxacin containing MDR-TB regimen.Results:Urine colorimetry was reproducible in spiked samples and the calibration was curve linear for levofloxacin concentrations ranging from 7.8 μg/ml to 250 μg/ml, with r = 0.98. In healthy volunteers, correlation between urine absorbance values and serum AUC0-24 was highest in urine collected between 4 and 8 h (r = 0.91, P = 0.01), yet in PLWH, urine collected between 0 and 4 h had highest correlation (r = 0.66, P = 0.05). The area under the receiver operating characteristics curve was >0.8 in the derivation, as well as the validation cohort for the urine absorbance values identifying people with total serum exposure below target.Conclusion:Urine colorimetry was highly sensitive in predicting target serum concentrations. Colorimetric methods to determine levofloxacin in urine may improve the feasibility of therapeutic drug monitoring and personalized dose adjustment in TB endemic settings.

Intrapatient Variability in the Pharmacokinetics of Etanercept Maintenance Treatment

Etanercept has shown to mediate a favorable effect on immune-mediated inflammatory diseases (IMID), including plaque psoriasis. Therapeutic drug monitoring (TDM) of etanercept could improve clinical outcome and cost-effectiveness. A high intrapatient variability (IPV) of etanercept trough concentrations at standard dosing would reduce the feasibility of therapeutic drug monitoring. Studies have focused on the interpatient differences associated with the exposure to biologics. The aim of this study was to determine IPV of etanercept and correlate etanercept trough concentrations and IPV with treatment response. Repetitive serum samples of 29 psoriasis patients on standard etanercept maintenance treatment were collected. In these samples, etanercept trough concentrations were determined and IPV was assessed in relation to response to treatment. The median IPV of etanercept trough concentrations was 33.7% (Q1 = 21.3% and Q3 = 51.7%) ranging from 8% to 155%. All 6 nonresponders showed an IPV at or above the median value of 33.7%. The 6 nonresponders showed a higher IPV as compared to the 23 responders (53.9% versus 24.2%; P = 0.031). The mean etanercept trough concentration for each patient ranged from 0.7 to 6.8 mcg/mL, with a median trough concentration of 2.7 mcg/mL. Patients with an IPV above the median had lower mean etanercept trough concentrations compared to patients with an IPV below the median (1.96 mcg/mL, 95% CI, 1.7-2.4 versus 3.2 mcg/mL, 95% CI, 2.7-4.0; P = 0.001). The median IPV of etanercept trough concentrations in this study population was 33.7%. A higher IPV was correlated with lower etanercept trough concentrations and with nonresponsiveness. Prospective trials are required to demonstrate the value of adjusting the etanercept dose based on drug trough concentrations. The relatively high IPV observed in this study may complicate therapeutic drug monitoring.

Therapeutic Drug Monitoring in Interstitial Fluid: A Feasibility Study Using a Comprehensive Panel of Drugs

This study compared drug concentration-time profiles in interstitial fluid (ISF) and blood, using an established animal model and a comprehensive panel of drugs, to examine the feasibility of therapeutic drug monitoring (TDM) in ISF. An intravenous bolus of vancomycin, gentamicin, tacrolimus, cyclosporine, mycophenolate, valproic acid, phenobarbital, phenytoin, carboplatin, cisplatin, methotrexate, theophylline, or digoxin was administered into the ear vein (n = 4-6) of rabbits. Serial (0-72 h after dose) blood and ISF concentrations (collected via an ultrafiltration probe) were determined by validated analytical assays. Pharmacokinetic parameters were generated by noncompartmental analysis. Vancomycin, gentamicin, and carboplatin showed no significant difference in area under the curve (AUC) values in ISF and blood, respectively. Other AUCs were lower (mycophenolic acid, valproic acid, phenobarbital, cisplatin, methotrexate, theophylline, and digoxin) or not measurable (tacrolimus, cyclosporine, and phenytoin) in ISF with our extraction technique. Similar concentration-time profiles in the two matrices were evident for a selection of drugs tested. Using a comprehensive panel of drugs in a single experimental setting, we have identified agents that can be quantified in ISF. Our newly developed scoring algorithm can help determine the feasibility of conducting TDM in ISF.

Therapeutic Drug Monitoring of Antimycobacterial Drugs in Patients with Both Tuberculosis and Advanced Human Immunodeficiency Virus Infection

To determine the feasibility of therapeutic drug monitoring for adjusting low serum antimycobacterial concentrations in patients with both tuberculosis and advanced human immunodeficiency virus (HIV). Retrospective cohort study. De-identified dataset from a tuberculosis clinic. Twenty-one patients (median age 38 yrs, range 25-68 yrs) with advanced HIV infection (CD4(+) cell count < 100 cells/mm(3)) who received treatment for active tuberculosis between March 2002 and September 2007. We evaluated data based on the practices performed at the tuberculosis clinic. After the daily doses of isoniazid and rifamycins (rifampin or rifabutin) were ingested, serum concentrations were obtained at 2 hours for isoniazid and rifampin, at 3 hours for rifabutin, and, when possible, at 6 hours for all three drugs to detect delayed absorption. Antimycobacterial drug concentrations were compared with published reference levels, and dosages were adjusted to achieve desired concentrations. Costs of monitoring were recorded for all patients. Of the 21 patients, 18 (86%) had low serum concentrations of at least one drug 2 hours after ingestion: 2 (10%) had low isoniazid concentrations, 5 (24%) had low rifamycin concentrations, and 11 (52%) had low serum concentrations of both drugs. The median number of dosage adjustments to attain normal concentrations was 1 (range 0-4 adjustments). The median cost/patient for therapeutic drug monitoring was $619 (range $230-1948). The median final doses to achieve normal concentrations were isoniazid 600 mg/day (range 300-1500 mg/day), rifampin 1050 mg/day (range 600-1200 mg/day), and rifabutin 300 mg (range 150-450 mg) 3 times/week. No patient demonstrated any adverse effects attributed to these higher doses. Low serum concentrations of antituberculous drugs, which suggest malabsorption, are common among patients with advanced HIV who also have tuberculosis but can be overcome with higher doses. Therapeutic drug monitoring may be an effective tool to optimize therapy, but needs further study.

P26 The feasibility of therapeutic drug monitoring (TDM) for HIV protease inhibitors (PIs)

P26 The feasibility of therapeutic drug monitoring (TDM) for HIV protease inhibitors (PIs)